History and humanities

Reputation should be neither sought nor avoided. — Lao Zi It always surprises people, especially those with an Asian heritage, when I say that I have never been disadvantaged, in my schooling or my professional life, by being Chinese. I suspect that I am often not believed, but that is my experience. A: J S Y at home in Nanjing, aged 2 years B: Joshua Young Wai, uncle of J S Y, as a junior resident medical officer at Sydney Hospital, circa 1939 My parents met when my father visited Sydney as part of a Chinese government delegation. I was born in Nanjing in December 1934, and in my third year of life my family was disrupted by the Japanese invasion of Manchuria and then China, in those fateful years leading to the Second World War. I came to Australia with my mother and sister, while my father remained in China, serving as part of the Nationalist Government of Chiang Kai Shek. My mother had been born in Australia and was returning to the safety of her home. I came as a refugee — by a regular passenger ship, different to those used by more recent refugees. My maternal grandfather, Young Wai, had left southern China for the Victorian gold-fields in 1867. Shortly afterwards, he worked as a Presbyterian mission worker to the Chinese miners. He was later ordained into the Presbyterian Church and moved to Sydney to start the first Chinese Presbyterian Church (now located in Crown Street, Surry Hills). His eldest son, Joshua Young Wai, was the first Chinese graduate in medicine from the University of Sydney. It was in his household that I grew up. English was spoken at home; we ate Chinese food on weeknights, but at other times we had Australian food. Thus, my experiences may well have been very different to those of other Chinese people in Australia at that time. I guess that my early life may be seen as a privileged one for an Asian growing up in a country known for its “White Australia” immigration policy. I was clearly Chinese, but, at Summer Hill Primary School and then at Fort Street High School, I did not feel different. When I hear about other experiences from contemporaries, I feel grateful for the liberal attitudes and values of my teachers and schoolmates. I had an older sister, but I was the first-born son, and with that came a family obligation, not spoken but clearly understood by me. I cannot recall actively thinking about what I would do in later life, but I knew there was a family expectation, with my uncle being a general practitioner, that I would study medicine. I did what was expected of me, and that, I suppose, was a reflection of my Chinese sense of duty. Fifty years later, I have no regrets. I would still choose medicine, despite the interference of governments into medical practice and the burden of indemnity insurance. Paediatrics was a chance residency term allocation, but luck had me working for Arnold Tink, who helped make that clinical term a life-determining experience. Kids were fun; they were gutsy and brave and very honest. I cannot imagine any other specialty giving me the satisfaction and joy that looking after children and their families has provided over a working lifetime. Healing and harmonyIn the early 1970s, through the Royal Australasian College of Physicians and the Australian Department of External Affairs, I was given the opportunity (as Head of Medicine at Royal Alexandra Hospital for Children) to take part in a graduate teaching program in paediatrics in Singapore and Manila. I returned to both cities over the next 5 years. Being Chinese had not seemed to be a factor in my medical life. However, seeing sick Asian children being cared for in poorly equipped hospitals (albeit by excellent clinicians) made me feel guilty about the inequities of life; the fact that these children were Asian made me identify with them in a way I had not expected. I felt more Asian than I had ever felt before. Seeing the top-class facilities of Singapore today, and their standards of care, makes you realise that money and a government priority can make a difference. I think Singapore is the one country in the world that spends a lot on both defence and health. The move of the Children’s Hospital from Camperdown to Westmead in 1995 allowed the hospital to re-equip with the latest and best technology. Even more importantly, it allowed us to provide not just medical science, but a hospital designed to recognise the importance of light and colour. The gardens, entertainment systems and art programs, including an artist in residence, a music therapist and a drama therapist, were all designed to create a total healing environment for patients and their families and carers. It foreshadowed the awareness of fun and laughter in feeling better and getting better. Now that Singapore equals our technical standards of medical care, I am going back to help them recruit their own community into providing the humanity of care that characterises Westmead Kids. I will help promote fund raising for children’s charities and talk about making healthcare more truly caring. But Singapore is a very special case. In other parts of the world, especially in countries like Vietnam, Cambodia, Laos and the small countries of the South Pacific, the help we expect for our sick children is denied to so many. We in Australia can make a very meaningful contribution to our region through education. This is a relatively inexpensive means of aid with a long term yield of goodwill. I am delighted that so many of our colleagues are giving their services as teachers and mentors to healthcare workers in the more disadvantaged countries of the Asia–Pacific region. To me, the key to a peaceful, harmonious region is through education. Life events 1934 Born in Nanjing, China 1937 The Rape of Nanjing; come to Australia as a war refugee 1959 Graduate in medicine at University of Sydney 1960 Junior Resident, Royal Alexandra Hospital for Children 1967 Membership of Royal Australasian College of Physicians 1971 Head, Department of Medicine, Royal Alexandra Hospital 1978 Chief Executive, Royal Alexandra Hospital 1989 Member, Order of Australia 1995 Involved in planning move of Children’s Hospital to Westmead 1996 Sidney Sax Medal, Australian Health Care Association (for outstanding contribution to health services) Australian of the Year Deputy Chancellor, University of Western Sydney DLitt(honoris causa), University of Western Sydney MD(honoris causa), University of Sydney 1997 Retire from Children’s Hospital Trustee, Art Gallery of New South Wales 2000 Chancellor, University of New South Wales Chair, VisAsia Chair, Australia China Council, Department of Foreign Affairs Chair, Specialist Advisory Committee, NSW Commission for Children and Young People 2001 Companion, Order of Australia 2003 Weary Dunlop Medal, Asialink (for fostering Australia–Asia relationships) Art, culture and toleranceLike so many other medicos, my life has been busy with the hours that I have worked and the burdens of responsibility for my patients and then for my hospital. My solace and my escape have been found in music and the arts. I have actively sought ways of giving something back to these areas that have sustained my sanity and provided so much enjoyment. Having little artistic ability, I volunteered my organisational skills. Over the years, I have served on the National Board of Musica Viva, the Boards of Trustees of the Powerhouse Museum and the Penrith Regional Gallery, and I am currently Deputy President of the Art Gallery of New South Wales and Chairman of VisAsia. VisAsia is the arm of the gallery that promotes an understanding and appreciation of Asian art (www.visasia.com.au). A: J S Y in the orthopaedic ward of the Children’s Hospital at Westmead, 1996 B: J S Y, with staff, visiting Macau Hospital, 1999 I am an enthusiastic collector of ceramics and textiles, especially those of the Asia–Pacific region. I believe that art and culture provide a non-threatening way of introducing different cultures and values to people who may be unfamiliar with them. Understanding and accepting the differences in art and culture make it easier to be tolerant of other differences. Over the years, I have become aware that many young Asian people who live in Australia have little knowledge of, or indeed interest in, their own cultural heritage. I hope through VisAsia, and through the various student organisations in our tertiary education institutes, that these young people may learn something of this heritage and feel some pride in their own heritage as well as that of their new home in Australia. Being proud of your own family heritage helps in building self-esteem, especially when others may question or challenge differences that they see as being of lesser value. I believe the same holds true of young people of other cultural backgrounds, most topically at present, young people of Islamic heritage. Confucius wrote, “If you set an example by being correct, who would dare to remain incorrect?” Being part of your community and giving something back is very much in line with Confucian teachings — it is something that doctors traditionally did when medicine was judged a noble profession. But perhaps I am just becoming more Chinese as I get older.

John S Yu

Two generations of Santoros have served the Italian community of Melbourne for over 70 years My father, Soccorso Santoro, was born near Naples, Italy, in 1902. After graduation in medicine from the University of Genoa and internship at Alessandria, north of Genoa, he was called up for military service in the Battalion of Doctors and Pharmacists. On completing this service, he decided to travel around the world. As he spoke English well, and Italy was an ally of Britain in the 1914–1918 war, he took the sensible precaution of registering his Genoa medical degree in London, which allowed him to practise throughout the English-speaking world. Soccorso Santoro unveiling Dante, Melbourne, 1958 Soccorso Santoro (standing) at the official unveiling of a bust of Dante Alighieri (a gift of the Dante Alighieri Society to the City of Melbourne) in the Treasury Gardens. When Soccorso resigned as President of the Society after nearly 20 years, he received a gold medal “Società Dante Alighieri” for his long service and for promoting the Italian language. In June 1930, my father sailed to Australia on the Orient Line’s “Orama”. He arrived in Melbourne well equipped with the appropriate medical, surgical, obstetric and even dental instruments (his degree gave him the right to practise dentistry, although he never did). He started practice in the “Professional Chambers”, 110 Collins Street, Melbourne, in August 1930. In 1933, he married my mother, and in 1935 I was born. My father’s gross income in the previous year was £761 ($1522), and he stated in his 1935 tax return that as his “. . . practice consists of mainly Italians . . . scattered in all suburbs of Melbourne . . . , [his] average monthly mileage is 1200”. He noted that petrol was 1 shilling and seven pence (15 cents) per gallon (3.5 cents per litre)! My father’s practice was not easy. Most of his patients were working-class Italians, who would occasionally sit on the floor in the corridor outside his rooms, to the surprise of the specialists in three-piece suits and watch chains also practising in the building. My father spent a great deal of time translating for patients and accompanying them to specialists. This was an era of great respect for the family doctor, who was the confidant of many families. Migrants wanted someone who could understand them and their family ties. As their children mixed with local children, family strictness and unity broke down; many children refused to speak Italian and were desperate to be considered Australian. This rejection was upsetting to the older migrants, especially as they relied on the young to interpret. My father took me on home calls to the Italian families around Carlton. They would be roasting coffee or making spaghetti, ravioli, salamis or prosciutto, but all work would cease as the whole family became involved in prolonged conversation with my father about some medical problem. It was unusual for him to complete a home call in under an hour. My father was also involved in the Dante Alighieri Society, which promotes Italian culture and language, and was its president from 1931 to 1959. He was a delegate of the Italian Red Cross and responsible for financial donations, as well as the official doctor of the Italian Consul General in Melbourne and the Italian shipping lines. When war was declared in 1939, my father was interned in a camp at Tatura in Victoria. Through the efforts of my mother, an Australian citizen, he was released after 6 weeks, while other Italians remained for the duration of the war. The conditions were that he report to Kew police station three times a week, not travel more than 40 kilometres from Kew and not go near the beach on Port Philip Bay, as he might signal enemy shipping! He was allowed to continue practice in Collins Street, but no more than two other Italians were to be in his surgery or waiting room at the same time — as a meeting of four was defined as a conspiracy. Any other Italian patients were asked to “go for a walk around the block”. For the same reason, tennis could not be played at our home with other Italians. The prohibition on speaking foreign languages on the telephone restricted history-taking before home visits. Our home was searched for subversive literature, but the complete library of the Dante Alighieri Society, hidden under the house, was not found. Nevertheless, our family was treated with great courtesy by the authorities, and, the few times I visited my father at Tatura camp, I remember Australian soldiers giving me oranges and playing with me. In 1948, my father made his first trip back to Italy (a 96-hour plane flight) to see his family. Back in Australia, he continued to work tirelessly to promote the Italian community. For instance, he mobilised Italian clubs to donate to St Vincent’s Hospital’s building program in 1953 and presented 200 books by Italian authors to Melbourne Public Library in 1956. In 1960, the Italian language was accepted as a subject at the University of Melbourne, and an annual “Dr Santoro Prize” is given to the best student in first-year Italian. In 1960, my father received the honour of “Cavaliere Ufficiale” (Officer of the Order of Merit of the Republic) from the Italian government. In 1961, on a trip to Genoa, he suffered a heart attack and was admitted to the same hospital in which he had studied medicine. In the preceding months, he had contacted many of the 1926 graduates from the Genoa medical school to arrange a 35-year reunion. It was not to be. He died on 10 July 1961, aged 59, having practised in Collins Street for 31 years. Soccorso Santoro 1902 Born Serino Italy 1926 Graduates in Medicine from the University of Genoa, Italy 1927–28 Internship at Alessandria, north of Genoa 1928–29 Military service 1930 Registers as medical practitioner, London, and sails from Naples to Australia 1931–61 General practice, Collins Street, Melbourne 1933 Marries Vida Clancy (a nurse who trained at St Vincent’s Hospital), at St Ignatius Church, Richmond 1935 Attends British Medical Association 103rd Annual General Meeting and 1st Australian Congress (Melbourne); first Italian member of the BMA in Victoria (his copy of the Book of Melbourne Australia 1935, a review of contemporary medical practice written for this conference, is still in my possession) 1940 Interned as an enemy alien at Tatura, Victoria, for 6 weeks 1956 Official doctor for the Squadra Olimpica Italiana, in Melbourne for the 16th Olympic Games 1960 Cavaliere Ufficiale, Republic of Italy 1961 Dies Genoa, Italy, aged 59 years George Santoro 1935 Born Melbourne 1962 Graduate in Medicine from the University of Melbourne 1965–2001 Solo general practice in Richmond, Victoria 1970–2001 Nominated Medical Officer for Italian government, assessing Italian pensions and past work-injury claims 1976–99 Treasurer and President of the Medical Benevolent Association of Victoria 1977 Cavaliere, Order of Solidarity of Republic of Italy 1983 President, Victorian branch of the Australian Medical Association 1983–present Director, Medical Defence Association of Victoria 1984 Cavaliere Ufficiale, Republic of Italy 1983–96 Inaugural President, Italian Medical Society 1986–94 Federal Council, Australian Medical Association 1988–89 Chairman, Lord Mayor’s Fund for Metropolitan Hospitals and Charities 1989–97 Board Member and Chairman, St Carlo Complex for Italian Aged 1990 Member, Order of Australia 1994 Commendattore Order of Merit, Republic of Italy 1994–present Director and Treasurer, Melbourne Division of General Practice 1994–99 Board Member, Faculty of Medicine, University of Melbourne 1996 Current Member of Order of Australia Council (Governor General’s committee for Australian honours) The year after my father died, I graduated in medicine from the University of Melbourne. Internship at Queen Victoria Hospital and locums in a few Italian and Australian practices led me to practise in the inner, (at that time) industrial, suburb of Richmond, where many Italians lived and worked. There was no alternative to solo practice, as few general practitioners spoke Italian, and a non-Italian-speaking partner could not have shared the workload equally. I was on call 24 hours a day to a large group of patients, as my father had been. In this situation, deputising services were a godsend, and, in 1970, I helped develop a service which still operates today. In caring for the Italian community, not only is the capacity to communicate in Italian important, but so is the cultural understanding of illness. “Fire of St Anthony” explains the excruciating pruritis of shingles nicely, while an inability to weed or tend a vegetable garden suggests the shortness of breath of cardiac failure. I enjoyed my numerous home visits, which gave enormous insight into patient care. Taking a detailed medical history often revealed past medical misunderstandings, which had led to inappropriate medications and unhelpful stereotypes, such as “Mediterranean backache” and “Mediterranean gut ache”. I found it best to involve the patient and family and their opinions of the illness, its cause and treatment. Compliance with treatment is increased if combined with traditional management; dietary restriction is relished, as this supports the sick person being the centre of family attention. In my career, I have also found time for community service as office bearer of the Victorian branch of the Australian Medical Association and the Medical Benevolent Association. I also formed the Italian, Greek and Chinese medical societies and was the inaugural president of the Italian Medical Society for 14 years. Many ethnic doctors feel isolated from their Australian peers because of the unusual demands of their ethnic patients. I have a particular interest, as chairman of the board of a home for Italian aged, in the special accommodation needs of ageing migrants. I was very proud to be honoured by both the Italian and Australian governments for my contribution to the health and welfare of the Italian community. Recently, I have been involved with Dr Tony Mariani, current president of the Italian Medical Society, in producing a 300-page book on preventive medicine, in English and Italian, to assist migrants in lifestyle choices. With continuing migration to Australia, there is still much to be done toward compassionate primary medical care. My family’s contribution gives me great pride.

George R Santoro AM, MB BS, FAMA

During the 20th century Australians have benefited immensely from improvements in their general health and life expectancy. Our average life span has increased by 25 years, and even in the century’s dying decade we managed to gain another two years!1 As with many success stories, there have been numerous contributors, but there is no doubt that basic medical research has played a prominent part. Indeed, the interplay between basic research and advances in medicine is succinctly captured by the phrase “from bench to bedside” or by the term “translational highway”2 — an autobahn for taking basic research advances and transferring these into clinical practice. The powerhouses of basic research in Australia are our universities and research institutes. Their financial underpinnings are the competitive grants provided by both government and non-government organisations. In 2002, for example, the National Health and Medical Research Council’s expenditure on health research and development was $276 million. Of this, the universities received $190 million (69%) and the medical research institutes received $74 million (27%).3 Since 1995, the Christmas issue of the Journal has regularly featured Australian medical research institutes, beginning with portraits of the Walter and Eliza Hall Institute in Melbourne and the John Curtin Institute of Medical Research in Canberra, and featuring most recently the Menzies Centre for Population Health Research in Hobart in 2001 (now the Menzies Research Institute). This year, we sought to explore a different avenue. In 1998, the then Minister for Health, Dr Michael Wooldridge, empowered a prominent committee chaired by Peter Wills, then Chairman of the Garvan Institute of Medical Research, Sydney, to review health and medical research in Australia and report on strategies for these efforts in the first decade of the 21st century. In its final report,4 the committee identified a number of issues including: the need to sustain and expand an effective health and medical research sector underpinned by innovative and high impact basic research; a greater need for research that contributes directly to the health of the people and the healthcare system; and the need for links between research and industry to capitalise on the potential commercialisation of research findings.4 In short, the report recommended an increased emphasis on “bench-to-bedside” research, focused on the health and economic wellbeing of the nation. To gain some perspective on the vitality of this research in Australian medical research institutes, we recently conducted a poll of institute directors (see Box). Their responses are given on the following pages. What inferences can we draw from this snapshot? Survey of Medical Research Institutes in Australia The directors of Australian medical research institutes were contacted in September 2003 and asked : “Most Australian medical research institutes have been operative for more than 25 years and the theme we wish to pursue is . . . what has come out of [name of your institute] that has been translated into population health or clinical practice; ie, what has made it from ‘bench to bedside’? We want you to restrict these to two major impacts.” Twenty-eight research institutes were approached and we accepted 22 submissions (Australian Capital Territory, 1; New South Wales, 5; Northern Territory, 1; Queensland, 2; South Australia, 1; Tasmania, 1; Victoria, 9; and Western Australia, 2). Firstly, it is apparent that “bench-to-bedside” research is alive and well in Australian medical research institutes, and is wide-ranging in its scope. It includes public health advances relevant to South-East Asian and Australian Indigenous communities, clinical advances in areas such as assisted reproduction and cancer, and improved treatments for chronic disorders, such as diabetes or visual impairment in older people. Secondly, this research is achieved by teamwork between clinician–scientists and scientists working together in a collegial spirit. Thirdly, and most importantly, it takes time. Finally, it is apparent that our research institutes are increasingly forging closer links with industry. However, there is one overriding message — that success in basic research cannot be solely developed from imposed priorities and schemes. Research is driven by human imagination, inquisitiveness, insight and a generous sprinkling of serendipity. For, as observed by the Nobel laureate Albert Szent-Gyorgi, “. . . research means going out into the unknown with the hope of finding something new to bring home. If you know in advance what you are going to do or even to find there, then it is not research at all: then it is only a kind of honorable occupation.”5 In short, basic research has two defining features: uncertainty and surprise.6 As long as these twin principles are treasured in our medical research institutes, meaningful “bench-to-bedside” research will continue to advance the practice of medicine. Australian Capital TerritoryEradication of smallpoxIn 1988 Frank Fenner of the John Curtin School, along with Donald A Henderson of the Johns Hopkins University School of Hygiene and Public Health and Isao Arita, Director of the Kumamoto National Hospital, Japan, were awarded the Japan Prize for Preventive Medicine in recognition of their international team effort in eliminating smallpox from the world. This feat is one of the greatest accomplishments of modern medical science. Fenner’s work at the John Curtin School on pox viruses (ectromelia, myxoma and vaccinia) through the 1950s, 60s and 70s had uniquely qualified him to lead the WHO smallpox eradication team which announced to the World Health Assembly in 1980 that the disease had been eradicated worldwide. Doherty and Zinkernagel with their Nobel prize medals. Discovery of MHC restriction In the early-to-mid 1970s, Peter Doherty and Rolf Zinkernagel, working on the response of mice to viruses discovered a major property of the immune system — major histocompatibility (MHC) restriction. In order for T lymphocytes to destroy cells infected by foreign invasion, their receptors must simultaneously recognise on the cell’s surface a complex of foreign antigen and a self molecule, one of the MHC antigens. Their discovery revolutionised our understanding of how the immune system works and won Doherty and Zinkernagel the 1996 Nobel Prize for Physiology or Medicine. MHC restriction has many clinical implications for organ transplantation and for the treatment of diseases involving the immune system. Peter Jeffrey, Public Affairs Manager, JCSMR Western AustraliaFolate supplementationPerhaps the longest established and best known research from the Institute that has had an enduring impact on health is the case–control study of neural tube defects conducted in Western Australia in the early 1980s by Carol Bower and Fiona Stanley.7 This showed that maternal dietary and supplemental folate intake around the time of conception protected against neural tube defects in the offspring. Further international studies showed that 70% of neural tube defects could be prevented by folate intake. Based on these findings, the Institute, in collaboration with the WA Health Department, embarked on a health promotion project in 1992, the first in Australia and one of the first in the world. There was an increase to 30% of women taking folic acid supplements periconceptionally, and a 29% fall in neural tube defects in WA. FunhalerA more recent contribution from the Institute addresses a major problem for children with asthma, who typically show poor adherence to prescribed frequency and technique of inhaled medication. The Funhaler (Visiomed Group Ltd, Australia), invented by the Institute’s Paul Watt, is a small volume spacer device incorporating an incentive toy module. A pilot study showed that the Funhaler reduced problems in giving children asthma medication, improved child and parental adherence to the medication regimen and created a more positive attitude towards treatment.8 A recent grant from the US National Institutes of Health (US$700 000) supports further study of the device, which is due to be launched throughout Australia by the end of 2003. Fiona Stanley, Director, TICHR AlphaCor artificial corneaStarting in 1990, polymer chemistry research by Traian Chirila and Celia Hicks resulted in the world’s first soft artificial cornea, now marketed by the WA company, Argus Biomedical Pty Ltd. Hundreds of novel polymers were formulated and tested for physical characteristics, including optical clarity, tensile strength and elasticity as well as biocompatibility in tissue culture and after implantation in animals. Novel chemical methods were developed to create a porous outer rim into which human cells would grow and establish a firm bond. This porous outer rim was co-polymerised with the same polymer materials under differential conditions to create an optically clear centre via an interpenetrating network. Human trials of the novel artificial cornea started in 19979 and CE-Mark European approval was followed in 2002 by FDA approval in the United States. Laser-induced surgery and central retinal vein blockageIn the early 1990s, Ian McAllister, Ian Constable and Dao-Yi Yu began developing a method to bypass the outflow from blocked retinal venous circulation, which commonly causes rapid loss of vision in older people with hypertension. After experiments in animals, Ian McAllister realised that a very powerful laser was required to break the structural barrier (called Bruch’s membrane) between the retinal and overlying choroidal circulation. In addition, rupture of the obstructed retinal vein was required to create an anastomosis between the two circulations and this was best achieved with a Yag cutting laser.10 Further experiments and observations identified a group of patients with incomplete central retinal vein occlusion for trials. Case–control studies showed that a successful shunt could be achieved in about two-thirds of the target population, and that visual acuity markedly improved as a result. This procedure has been taken up in a number of centres around the world. A randomised controlled clinical trial is under way in four Australian locations. Ian J Constable, Director, Lions Eye Institute VictoriaMobilising myelopoiesisBasic research at WEHI and LICR has had a profound impact on cancer treatment. Don Metcalf’s tenacious research at WEHI over three decades transformed understanding of blood cell production and haemopoietic diseases. He and his colleagues, including Nic Nicola (WEHI) and Tony Burgess (then at WEHI, later at LICR), purified two of the hormones involved in white blood cell production. Known as colony-stimulating factors (CSFs), these hormones (GM-CSF and G-CSF) accelerate white blood cell regeneration in patients undergoing chemotherapy or radiotherapy and have helped treat over 3.5 million patients worldwide.11 During the first clinical trials of CSFs at the Royal Melbourne Hospital (directed by George Morstyn, LICR), Uli Duhrsen (WEHI) and the team made the unexpected observation that CSFs mobilise blood stem cells into the bloodstream, a discovery which led to bone marrow transplantation being replaced by blood stem cell therapy.12 The CSFs are now finding new applications in in-vitro fertilisation and treatment of Crohn’s disease. Suppressing autoimmunityIan R Mackay, Head of the Clinical Research Unit at WEHI, formally defined the concept and key features of autoimmune diseases in a book co-authored by Frank Macfarlane Burnet in 1963.13 Despite considerable scepticism about the concept, Mackay pioneered the treatment of autoimmune (lupoid) hepatitis with the immunosuppressive drugs, azathioprine and prednisolone. This approach continues to be the gold-standard for immunosuppression and has saved the lives of countless patients with autoimmune hepatitis and other autoimmune diseases. Suzanne Cory, Director, WEHI Antony W Burgess, Director, LICR Concepts and conceptionAlan Trounson, together with Carl Wood and his colleagues from Monash University Department of Obstetrics and Gynaecology, pioneered studies of in-vitro fertilisation and other reproductive technologies for the management of human infertility. Building on the work of Edwards and Steptoe in the UK, they integrated ovarian stimulation into the routine IVF protocol,14 providing multiple oocytes for fertilisation. When combined with the capacity to freeze embryos these technologies contributed to improved IVF success rates.15 The Monash group also developed the conditions necessary for oocyte donation to become a routine procedure and extended the capacity for IVF to women without ovaries.16 The ability to biopsy a blastomere from an embryo17 and determine its genetic status18 has enabled preimplantation genetic diagnosis to be successfully performed for fertile couples with a history of genetically based disease. Y Chromosomal defectsIn 40% of infertile men the cause of the spermatogenic defect is unknown, but the observation of small Y chromosomes in some of these men suggests a genetic cause. Scientists from the Institute, together with colleagues at Charles Drew University Los Angeles, further defined the deleted regions of the Y chromosome causing azoospermia or severely reduced sperm counts.19 These observations, together with others, showed that some Y chromosome deletions did not completely prevent sperm production, raising the possibility of using intracytoplasmic sperm injection (ICSI). The Institute’s scientists, together with colleagues at Monash IVF, demonstrated transmission of Y chromosome deletions from father to son by the use of ICSI.20 They also developed a routine clinical test to screen men with sperm counts less than 5 million/mL, enabling genetic counselling for couples where the man has a Y chromosomal deletion. Current estimates indicate that 3%–8% of men with idiopathic infertility have a Y chromosomal disorder. David M de Kretser, Director, MIRD Murray Esler and Gavin Lambert performing noradrenaline spillover measurements to quantify sympathetic nervous system activity in a patient during head-up tilting. Noradrenaline in heart failureIn the 1980s scientists led by Murray Esler developed a unique radiotracer technique for neurochemical quantification of sympathetic nervous system activity and measurement of the spillover of the sympathetic neurotransmitter, noradrenaline, from individual organs. With this advance they were able to isolate neurophysiological mechanisms in heart failure. At that time the accepted view was that the failing heart was functionally and anatomically sympathetically denervated and β-adrenergic blocking drugs were said to be contraindicated. An innovative series of research projects at the Baker showed that in many patients with heart failure the sympathetic nerves of the heart were, in reality, stimulated at an exceedingly high level.24 A prospective study of patients with severe heart failure showed that the cardiac sympathetic tone was the strongest predictor of death.25 This research provided the pathophysiological evidence for the use of β-adrenergic blocking drugs in cardiac failure. The renin–angiotensin system (RAS) in diabetesOver the last 15 years it has become apparent that blockade of the RAS plays a central role in diabetic nephropathy, the leading cause of endstage renal disease in the developed world. Basic research, including that of Mark Cooper’s group, showed that, despite RAS suppression, intervention with angiotensin-converting enzyme inhibitors or angiotension II antagonists could reduce the functional and structural manifestations of diabetic nephropathy.26-30 Over the last decade the underlying molecular and cellular pathways whereby angiotensin II promotes renal injury have been unravelled and may provide new targets for further renoprotection. This basic research was the impetus for three landmark studies exploring blockade of the RAS in type 2 diabetic patients with incipient and overt renal disease. More recently, research has linked the RAS to other diabetic complications involving the retina, heart and vascular system. Multicentre clinical trials are now investigating the benefits of interrupting the RAS for diabetic complications at these extrarenal sites. Garry Jennings, Director, BHRI Linking research with health outcomesOver the past 15 years the Institute’s major achievements have involved the development of appropriate and sustainable technologies to prevent or control infectious diseases in resource-poor regions. Immunisation programsIn the early 1990s the Institute pioneered the introduction of routine hepatitis B immunisation in Lombok, Indonesia, and demonstrated the feasibility of implementing universal hepatitis B vaccination without damaging other vaccine programs. This was the first demonstration of the usefulness of hepatitis B vaccination in a developing country’s immunisation program,21 and contributed to the models used now by Global Alliance for Vaccines and Immunization and the Gates Foundation to support universal hepatitis B immunisation in the world’s 70 poorest countries. Harm reductionSince 1989 the Institute has championed the application of harm-reduction approaches to mitigate the impact of HIV and hepatitis C infection, and has played a major role in driving the acceptance and implementation of these approaches, especially in South-East Asia.22 Cheap sustainable diagnosticsThe Institute has led the development of cheap and sustainable CD4 cell assays23 to support the widespread implementation of antiretroviral drug therapy to treat HIV infection in developing nations. It has also developed, and is now commercialising, new technologies for the diagnosis of hepatitis E and hepatitis A infections. Steven L Wesselingh, Director, Burnet Institute Cellular therapiesThe stem cell biology program at Peter Mac, a major node of the National Stem Cell Centre, is studying fundamental properties of stem cells in adult tissues and using their unique biological properties in novel cellular therapies. The stem cell facility at Peter Mac has good manufacturing process (GMP) accreditation and is licensed by the Therapeutic Goods Administration. It has been used for stem cell therapy in several patient groups, including Australia’s first clinical trial with ex-vivo expanded haematopoietic stem and progenitor cells for breast cancer patients after repetitive high-dose chemotherapy. A significant reduction in neutropenia and platelet transfusion requirements was demonstrated in these patients. The Peter Mac propagated mesenchymal stem cells (MSC) to treat a non-union fracture of the ulna. This pioneering proof-of-principle procedure was the first use of prospectively isolated autologous MSC in a clinical setting. Characterising cancerIn about 5% of cancer patients, extensive clinical workup fails to reveal the primary carcinoma. Researchers at Peter Mac are using microarray-based gene expression profiling, a method of molecular diagnostics that may assist in diagnosing and treating this kind of cancer. Metastatic tumours have been shown to maintain gene expression patterns that are consistent with tissue of origin. Clinically plausible prediction of the origin of the metastatic tumour has been made in numerous cases of carcinoma of unknown primary, suggesting that the test will facilitate clinical management. David Bowtell, Director of Research Division, PMCI In-situ gene expression In the 1980s, researchers John Coghlan, Jennifer Penschow, Geoffrey Tregear and Hugh Niall developed the technique of hybridisation histochemistry using oligonucleotides for detection of in-situ gene expression in tissues.31,32 The Institute holds patents on this technique, which is now widely used for the diagnosis of viral and infectious diseases and in research. Fortifying bone with ForteoA peptide comprising part of human parathyroid hormone (PTH[1-34]) was recently approved by the US Federal Drug Administration for the treatment of osteoporosis. Marketed by Eli Lilly & Co as Forteo, or teriparatide, it is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. Hugh Niall and Geoffrey Tregear played a pivotal role in the discovery and development of PTH(1-34). Working initially at the Massachusetts General Hospital, Boston, and then at the Howard Florey Institute in the 1970s, they were the first in the world to isolate and sequence parathyroid hormone.33 They subsequently synthesised parathyroid hormone fragments and established that the amino terminal 1–34 region of the sequence had full biological activity.34 Forteo is the peptide originally designed and synthesised by Tregear. Frederick A O Mendelsohn, Director, HFI InhibinA major focus of the Institute has been reproductive endocrinology, particularly the relationship between the hypothalamus, anterior pituitary and the gonads. The most significant outcome of this research was the first isolation, purification and characterisation of a new gonadal hormone, inhibin. Inhibin acts as a feedback signal regulating the secretion of follicle stimulating hormone (FSH) by the pituitary. This achievement was the result of collaboration between scientists as Prince Henry's, Monash University, St Vincent's Institute of Medical Research and La Trobe University. The major impact on clinical practice came with the finding that concentrations of inhibin were markedly elevated in the serum of patients with ovarian granulosa cell tumours or mucinous epithelial cancers.35-36 The marker commonly used for ovarian cancer diagnosis and monitoring, CA125, is not especially helpful in these two types of ovarian tumour. Work at the Institute has shown that combining inhibin and CA125 measurement can diagnose 95% of ovarian cancers.37-39 Inhibin measurement is now standard practice in following up patients with ovarian granulosa cell tumours. Research on inhibin has also clarified the mechanisms involved in the hormonal changes in women as they approach the menopause, and has indirectly led to the realisation that measurements of FSH and oestrogen are of little value in the assessment of perimenopausal women. Henry G Burger, Emeritus Director, PHIMR Automating amino-acid sequencesSt Vincent’s Institute has a long heritage of studying protein structure and function. The founding director, Pehr Edman (1957–1972), discovered how to sequence the order of amino acids within proteins and ways to automate this process.40 Protein sequencing enabled characterisation of proteins for diagnostic (eg, radioimmunoassay) and therapeutic use, as well as the unravelling of protein mutations in genetic diseases such as phenylketonuria and thalassaemia. Salmon calcitonin, for example, was sequenced using the Beckman commercial version of Edman’s automated sequencer by Hugh Niall (who had been a student of Edman) and then synthesised by Sandoz (now Novartis) for widespread therapeutic use in Paget’s disease. Obtaining amino acid sequence using Edman’s technology has been a necessary step in cloning many recombinant molecules used as drugs, such as growth hormone, tissue plasminogen activator and erythropoietin. Calcium and cancerJack Martin and his team discovered parathyroid hormone-related protein (PTHrP), a hormone secreted by cancers that causes the syndrome known as humoral hypercalcaemia of malignancy41 and contributes to bone metastasis. This discovery established a molecular explanation for this common clinical syndrome, and led to its accurate diagnosis by radioimmunoassay and immunohistochemistry for PTHrP. A humanised monoclonal antibody against PTHrP is now in Phase III clinical trials, having been developed by Chugai as a result of proof of principle supplied by this Institute’s research. Protein kinases as drug targetsBruce Kemp has made pivotal discoveries about the structure and function of protein kinases, particularly the amino-acid sequences used by kinases to interact with their substrates. Most recently these have been applied to adenosine monophosphate-activated protein kinase (AMPK), which Kemp and colleagues purified and sequenced.42 This is an enzyme involved in fuel metabolism that is activated by drugs that increase insulin sensitivity, including metformin and the glitazones.43 The Institute’s intellectual property in this area has been licensed to Mercury Therapeutics and Aventis, who are searching for new drugs that activate AMPK. The pharmaceutical industry has the protein kinases as one of its three top targets for drug development. Thomas W H Kay, Director, SVIMR TasmaniaSIDSBy the 1980s sudden infant death syndrome (SIDS) had become the commonest cause of death in postneonatal infants in Australia and some other developed countries. However, little was known about its causes or prevention. As early as 1944, it had been proposed that placing a baby prone (on the abdomen) might increase risk.44 Despite the gradual accumulation of retrospective evidence from case–control studies of an association between prone position and SIDS,45,46 concerns about recall bias (particularly at a time when many hospitals advised prone sleeping) limited the acceptance of sleeping position as a cause. Prospective data were needed. The Menzies team reported the first prospective evidence, obtained from the Tasmanian infant cohort, in the Lancet in 1991,47 confirming a higher risk for infants sleeping in the prone position. This research work led to a rapid policy response. A national meeting in July 1991 provided a new recommendation that healthy infants should not sleep prone. SIDSAustralia incorporated the finding into health education advice to new parents. In Australia the number of SIDS deaths declined from 507 in 1990 to 101 in 2001 (rate, 1.93 to 0.41) — a fall of about 80%.48,49 Similar successful campaigns occurred internationally. Subsequent research at the Menzies Institute has continued to inform international policy and contributed to a continued decline in SIDS deaths.50 Terence Dwyer, Director, MRI South AustraliaCause and prevention of discitis after discographyFor more than 50 years discography has been used to confirm a diagnosis of internal disc disruption and the presence of normal discs adjacent to the level of an intended spinal fusion. Discitis following discography is a serious complication and, although the presence of infection is occasionally confirmed, numerous authors have suggested that it is caused by a chemical or aseptic process. Fraser, Osti and Vernon-Roberts showed that the injection of a single Staphylococcus epidermidis into an intervertebral disc in a sheep was sufficient to produce radiographic, macroscopic and histological discitis, but that organisms could not be isolated from the lesion after 6 weeks.51 They found also that in 7 patients with discitis no bacteria were isolated from the 3 biopsied 6 weeks after discography but bacteria were isolated in 3 of the 4 biopsied within 6 weeks. These findings indicated that discitis after discography is initiated by needle-tip infection, but the causative bacteria are rapidly eliminated after the inflammatory destruction of the plate of bone separating the avascular disc from the richly vascular bone marrow of the vertebral body. Changing from a single needle lacking a stilette to stiletted needles and a two-needle technique reduced the incidence of discitis from 2.7% to 0.7%. Combining the two-needle technique with a single prophylactic dose of broad spectrum antibiotic effectively prevented discitis in a follow-up study. Barrie Vernon-Roberts, Director, Institute of Medical and Veterinary Science QueenslandThe Institute for Molecular Bioscience was formed in 2000 by the amalgamation of the Centre for Molecular and Cellular Biology (which focused on mammalian cell and developmental biology) and the Centre for Drug Design and Development (which focused on pharmaceutical development), both at the University of Queensland. Inflammation and painIn the past 6 years researchers at the IMB have discovered three candidate molecules to treat rheumatoid arthritis, chronic pain and neuropathic pain. The first orally active small molecule C5a-receptor antagonist (an anti-inflammatory drug which blocks an important component of the complement system) was designed and developed by David Fairlie and Steve Taylor and has progressed to Phase II clinical trials for rheumatoid arthritis patients.52 The molecule was licensed to the spin-off company Promics to undertake full development. Model of the inflammatory protein C5a and a small molecule C5a receptor antagonist. Antagonist (yellow) mimics a key turn conformation (red) in human C5a (white). A molecule, CVID (a conotoxin from Conus catus, a fish-eating marine cone snail on the Great Barrier Reef), which blocks N-type voltage-gated calcium channels, was discovered by Paul Alewood and Richard Lewis.53 The molecule, which has the potential to alleviate neuropathic pain, was licensed to AMRAD and Phase I/II clinical trials have been successfully completed in cancer patients with pain refractive to morphine treatment. Another molecule from cone snails, MrIA (a conotoxin from Conus marmoreus), was discovered by the Lewis and Alewood team.54 It is a potent blocker in vitro and in vivo of the reuptake of noradrenaline by the noradrenaline transporter and has shown excellent efficacy in preventing chronic pain in rats. It is now under pre-clinical development by the spin-off company Xenome. John J S Mattick, Director, IMB Controlling dengue in VietnamBrian Kay, head of mosquito control at QIMR, realised that the copepod predator of young mosquito larvae, Mesocyclops, had enormous potential for dengue fever control in Asia. Mesocyclops inhabit freshwater ponds and lagoons, but, from surveys in Vietnam, were also found in water storage containers (eg, concrete tanks, jars, wells).55 Brian Kay inspecting water storage tanks in central Vietnam. In 1989, Kay began working with Vu Sinh Nam from the National Institute of Hygiene and Epidemiology, Hanoi, to develop community-driven programs for dengue vector control, using new sampling technologies, key container prioritisation and Mesocyclops. Nine years later they reported the first eradication of Aedes aegypti without insecticide, in the 400 households of Phan Boi.56 By 2002 the program had expanded to 6 communes (11 675 households) in 3 other provinces.57 At the project’s completion, local leaders committed themselves to maintaining and expanding dengue control, supported by the national dengue budget. To date 40 of 46 communes (93 111 households and 386 544 people) are free of Ae. aegypti, and all 46 have no further reports of dengue and dengue haemorrhagic fever. Vaccine to prevent rheumatic feverMichael Good, Michael Batzloff, Colleen Olive and Sri Sriprakash have been developing a vaccine to prevent group A streptococcus (GAS, Streptococcus pyogenes) infection and its associated diseases such as rheumatic fever. GAS is a serious problem in developing countries58 and in Indigenous communities of developed countries including Australia.59 The vaccine is based on a conformational peptide antigen from the conserved region of the M-protein.60 In preclinical studies the peptide was immunogenic in inbred mice. In outbred mice, the peptide was conjugated to the carrier protein, diphtheria toxoid, and formulated with the human-compatible adjuvant alum. Mice immunised with this formulation had significantly enhanced survival following challenge with several GAS serotypes.61 We have used our peptide in combination with several experimental intranasal adjuvants in outbred mice to induce a local mucosal immunoglobulin-A response capable of significantly reducing GAS colonisation of the throat following intranasal GAS challenge. We are now planning to commence the “Good Manufacturing Process” production of our peptide-conjugate/alum formulation for Phase I human clinical trials. Michael F Good, Director, QIMR Brian Kay, Director, Australian Centre for International and Tropical Health and Nutrition Northern TerritoryScabies and skin health: Scabies and complicating streptococcal pyoderma are major causes of morbidity in Indigenous communities in central and northern Australia. The templates for communities to develop their own skin-health programs have resulted from a mix of clinical, public health and laboratory initiatives leading to evidence-based best practice. The first molecular genetics studies ever undertaken on scabies mites were specifically directed at determining whether current dog and human scabies infections are separate epidemics.62 This research enabled the focus of programs to be on prevention and treatment of scabies in children — rather than targeting the dogs. Community-based healthy skin programs have resulted in large decreases in both scabies and streptococcal pyoderma, and current initiatives are directed at sustaining the programs.63,64 Reversing Indigenous renal failureAboriginal people in many remote parts of Australia are experiencing an epidemic of diabetes, cardiovascular disease and end-stage renal disease. The introduction of a systematic pharmacotherapy program over several years on the Tiwi Islands (NT) addressing albuminuria, hypertension, dyslipidaemia and diabetes was associated with a marked fall in rates of renal failure and natural death, reversing a consistent historical trend for both to increase. Rates of the combined endpoints of renal failure and natural death per 100 person-years were 2.9 for the treatment group and 4.8 for the control group.65 Current challenges are how to resource and sustain such activities within the day-to-day clinic activities. Improving dietary quality in remote Aboriginal communities: Poor nutrition in remote Aboriginal communities is linked to high rates of obesity, diabetes and cardiovascular disease. Two well evaluated community-based intervention programs to improve the quality of diets through improved quality of foods in the communities’ local stores have been accompanied by a marked reduction in risk markers for vascular disease across the adult populations. The focus of the Minjilang Nutrition Program66 and the Looma Healthy Lifestyle Program67 has been to reduce the high consumption of sugar and fat, and to increase consumption of fresh fruit and vegetables. Kerin O’Dea, Director Menzies School of Health Research New South WalesDeveloping microsurgeryEarl Owen returned to Australia in 1967 from postgraduate studies in the UK where he had been involved in developing surgical techniques for whole-organ transplantations. An appointment to the Children’s Medical Research Institute from 1967–1970 as the James Fairfax Surgical Research Fellow provided him with the opportunity and resources to develop his expanding interests in the field of microsurgery. This had evolved from his appreciation of the importance of surgical repair of blood vessels and nerves in transplant survival.68 He designed or modified a range of instruments and magnifying devices which facilitated these procedures. His enthusiasm and skill in promoting the advantages of microsurgical techniques led to their rapid widespread adoption in Australia and internationally, particularly in the disciplines of plastic and reconstructive surgery. Gene therapyIn 1995 the Institute and the Children’s Hospital Westmead created a Gene Therapy Research Unit, based on a longstanding interest within the Institute in the use of retroviral gene vectors in biomedical research. Directed by Dr Ian Alexander, the unit has established a gene-vector production unit which is unique in Australia. In March 2002 in conjunction with the Hospital Necker in Paris, this unit and the Immunology Department of the Hospital treated a child with X-linked severe combined immunodeficiency by transducing the infant’s haemopoetic stem cells with a normal copy of the mutant gamma-c subunit of the interleukin receptors.69 This has resulted in a successful reconstitution of the T cell compartment and the patient remains free of infection 18 months later. While gene therapy is far from being routine clinical practice, there is no doubt that it will play a major role in future therapy of a range of diseases from single gene defects to cancer. Peter B Rowe, Director, CMRI l-Arginine and vascular adhesionResearch by Mark Adams, David Celermajer and Wendy Jessup, in a collaboration between the Institute and the Department of Cardiology at Royal Prince Alfred Hospital, found that l-arginine reduces human monocyte adhesion to vascular endothelium and endothelial expression of cell adhesion molecules.70 Subsequent clinical studies showed that oral l-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease.71 This research has translated into the clinical use of oral l-arginine as a treatment in patients with intractable angina. A surrogate marker for advanced atherosclerosisLen Kritharides and co-investigators are developing non-invasive tests for the presence of vascular disease. Using samples obtained from patients undergoing bypass surgery and coronary angiography, they found that coronary arteries release a number of molecules into the blood stream. One of these is haptoglobin, a protein not normally measured in patients with atherosclerosis,72 but which is present at elevated levels in the circulation in patients with advanced coronary disease. This non-invasive test has the potential to identify the presence of vulnerable atherosclerotic plaques before their rupture. Philip J Barter, Director, Heart Research Institute Diabetes and obesityIn 1973 a small team led by Les Lazarus at the Garvan developed the low-dose intravenous insulin infusion method to treat a major complication of diabetes, ketoacidosis.73 This has saved the lives of innumerable Australians and has been taken up around the world. Over the past 20 years, the diabetes research team, including Ted Kraegen, Lesley Campbell and Don Chisholm, has made major contributions to our understanding of the impact of lifestyle on type 2 diabetes. They were one of the first groups to show that exercise training improves whole-body insulin sensitivity.74 They were also one of the first to unravel the impact of dietary lipids on insulin sensitivity75,76 and to show that fat deposition in specific regions plays a key role in the development of insulin resistance.77 These findings have made major contributions to the management of this extremely complex and common human disease. Breast cancerGarvan scientists led by Professor Rob Sutherland carried out an extensive series of studies which helped elucidate the mode of action of the breast cancer drug, tamoxifen.78 Garvan scientists pioneered research demonstrating the role of the cell cycle regulatory protein cyclin D1 in development and progression of breast cancer.79 Recently, this research was judged by the international ISI Essential Science Indicators as one of the top 20 advances (and most cited papers) in breast cancer in the past decade. Further work has confirmed this molecule as an adverse prognostic marker and therapeutic target in breast cancer. John Shine, Executive Director, GIMR Established 3 years ago, the ANZAC Research Institute is one of Australia’s youngest medical research institutes, located on the campus of Concord Hospital and affiliated with the University of Sydney. Its primary research focus is on ageing. Hepatic pseudocapillarisation and cardiovascular diseaseDavid Le Couteur’s observations that ageing is accompanied by obliteration of endothelial pores that allow the liver to metabolise circulating macromolecules80 has led him to a novel approach to examining the liver and postprandial hyperlipidaemia as pivotal elements linking ageing and cardiovascular disease. Genetics of neurodegenerationGarth Nicholson’s discovery of the gene for hereditary sensory neuropathy81 provides an elegant and unique neurogenetic model for classical sensory neuropathies of leprosy and diabetes which both feature painless damage to joints and extremities. Hormonal male contraceptionRecently published work by David Handelsman first proved the efficacy of a hormonal male contraceptive using a prototype combination depot.82 This proof of principle has been adopted by a collaboration between two major multinational pharmaceutical companies, Organon and Schering, to develop a marketable product. David J Handelsman, Director, ARI New antiviral strategies for herpesThe herpes virus periodically reactivates from dormancy and is transported down sensory nerves to skin causing genital lesions. WMI virologists including Tony Cunningham, Russell Diefenbach and Monica Miranda first showed that the virus is transported down these nerves as two components, the inner core and outer (glyco) proteins, subsequently assembling at the nerve terminus. Transport along microtubules (the “railway tracks” of the nerve) was found to be mediated by the interaction of a virus core protein (US11) with a cellular protein, kinesin.83,84 The exact regions of the interaction were mapped and patented as a drug target. A collaboration with Pharmacia is now seeking small molecule inhibitors of this interaction as a new drug strategy for herpes. First success in herpes simplex vaccinesThe first success in vaccine development for genital herpes by GlaxoSmithKline (GSK) has just been reported. This development was partly guided by, and depended upon, key discoveries by WMI scientists, Tony Cunningham and Zorka Mikloska, who showed that the immune control of herpes lesions was mediated by an early influx of CD4 and later CD8 lymphocytes. Both cell populations secrete interferon gamma, which controls viral transmission from nerve to skin and viral mechanisms for evading immune control. The key viral stimulant for CD4 lymphocytes was glycoprotein D (gD).85 The GSK vaccine incorporated gD and an adjuvant to stimulate these mechanisms. This proved 75% successful.86 Refined advice for those at genetic risk of melanomaCancer researchers at WMI, led by Richard Kefford and Graham Mann, have been unravelling melanoma susceptibility genes. They confirmed that the major melanoma gene, CDKN2A (“p16”), is located on chromosome 9p, and went on to perform the largest analysis of mutations in this gene in 132 Australian families.87 WMI researcher Helen Rizos and her team have established the importance of p14ARF, an alternate product of the CDKN2A gene, in the genesis of melanoma, and have recently described a number of highly novel functions of this molecule in regulating the cell cycle at several key points.88,89 Collaborative research between WMI and Nicholas Hayward of the Queensland Institute of Medical Research, together with the members of the international Melanoma Genetics Consortium, has enabled this genetic information to be translated into clinical guidelines for managing those at high risk of developing melanoma, including the use of genetic testing.90,91 Anthony Cunningham, Director, WMI

Martin B Van Der Weyden

Big clinical breakthroughs begin with basic science The 2003 Nobel Prize in Medicine or Physiology was awarded to a chemist, Paul Lauterbur (US), and a physicist, Peter Mansfield (UK), for their discoveries concerning magnetic resonance imaging,1 while the Nobel Prize in Chemistry was awarded to two medical graduates: Peter Agre (US) for the discovery of water channels and Roderick MacKinnon (US) for structural and mechanistic studies of ion channels.1 The prizes were awarded for seminal discoveries that have had major impacts on medicine and biology. The fascinating story of these discoveries illustrates the value of pursuing basic science research and how breakthroughs at a fundamental level can lead to revolutionary advances in medical care. The Nobel Prize in MedicineBackground to magnetic resonance imagingMany atomic nuclei possess the property of spin. When placed in a magnetic field they wobble (precess) on their axis, like a spinning top near the end of its twirl. The precession frequency is directly proportional to the strength of the magnetic field in which the nuclei are immersed, and lies in the frequency range of radio waves. When radio waves at the same frequency as the nuclear precession are applied to a sample, resonance energy transfer takes place and the nuclei become “excited”. Hence, radio waves can be used to detect (observe) atomic nuclei based on their characteristic absorption frequency. This discovery by the groups of Bloch and Purcell in the US led to their award of the Nobel Prize in Physics in 1952. Nuclear magnetic resonance (NMR) is extraordinarily useful in biology and medicine for two reasons. Firstly, because the nuclear spins are observed with radio waves, biological samples can be studied in a non-invasive and non-destructive way. Radio wave photons have about 1/1011 of the energy of x-ray photons, so they produce no radiation damage to biological samples. Secondly, the absorption frequency is precisely determined by the local magnetic field of the nucleus in an atom in a molecule. Since it is possible to measure changes in this field to better than 0.01 parts per million, chemical compounds are able to be identified even in complex mixtures. The incredible precision with which one can determine the frequency of nuclear resonance, and hence the local magnetic field experienced by a nucleus, means that we can (for example) distinguish a hydrogen atom in a methyl group of an alanine side chain in a protein from one in a methyl group of valine in the same protein. The Nobel Prize for Chemistry was awarded to Richard Ernst (1991) and Kurt Wüthrich (2002) for the development of techniques to use NMR to determine protein structure. Remarkably, this is possible within living cells; so metabolism can be followed in real time in a totally non-invasive way. Both of these features make NMR ideal for medical imaging. The discovery of magnetic resonance imagingIn the early 1970s, Paul Lauterbur (at the State University of New York at Stony Brook, US) surmised that if one could vary the magnetic field across a sample in a defined way then it should be possible, by measuring the frequency at which a given ensemble of nuclei were precessing, to determine the exact location of the ensemble in the sample. Lauterbur’s first images were of a “phantom sample” of two tubes of water located within a larger tube of heavy water (ie, water in which the hydrogen atoms are replaced with deuterium atoms).2 Heavy water is chemically almost identical to water and to the eye is indistinguishable. But deuterium nuclei are very different from hydrogen nuclei, so they give no signal when radio waves at the frequency absorbed by hydrogen are applied. By applying a graded magnetic field across the entire sample, Lauterbur reconstructed an accurate cross-sectional image of the two water-filled tubes (Box 1a). At the time this seemed a rather esoteric experiment, but it was a wonderful model to use for the human body, which is essentially a series of water-filled tubes (eg, arteries) and containers (eg, organs) located within a larger water-filled tube (ie, the body walls). Lauterbur’s water-filled tubes were geometrically simple, making it relatively easy to solve the mathematics required to reconstruct the images from the radiofrequency output. Although Peter Mansfield (at the University of Nottingham, UK) was working on a different physical system, it was he who was responsible for sorting out the complicated mathematics required to derive images rapidly from NMR spectrometers, thereby making magnetic resonance imaging a feasible clinical application. He also developed the technique of very fast gradient variations (so called echo-planar scanning) that enabled very rapid imaging.3 The journey from the first images of tubes of water to the installation of the first magnetic resonance imaging (MRI) scanner in a hospital required a huge amount of research and development both in the private and public sector, but it only took about 10 years. This involved mathematicians, physicists, engineers, computer scientists, biomedical scientists and medical practitioners in one of the best modern examples of “translational research”. It is estimated that in 2002 about 60 million MRI examinations were performed throughout the world. MRI has had a major impact on many aspects of clinical practice; probably most notably in neurology (Box 1b). The Nobel Prize in ChemistryBackground to water and ion transport in the bodyAll cells, from bacteria to plants and animals, are surrounded by a lipid membrane that forms a barrier between the inside of the cell (where most of the important events such as gene transcription and metabolism take place) and the extracellular environment. The maintenance of a stable intracellular environment is crucial for cell survival. The first barrier of defence is the lipid membrane, which is largely impermeable to water and water soluble substances, such as ions. Equally important, though, is the ability of cells to interact with the outside world; to respond to stresses imposed from the outside and to communicate with other cells. This is achieved by having proteins embedded in the lipid membrane that can selectively allow the passage of water or ions into or out of the cell. Discovery of aquaporinsWe now know that channels that permit the selective flow of water across cell membranes (aquaporins) are present in almost all cells, but they were only definitively identified 15 years ago. Why did it take so long for them to be discovered? In a sense it was because they are so difficult to measure and because they are so common. Often the easiest way to identify something is to compare two similar objects (in this case, cells) and then determine what it is that is different between them. This of course was not possible for water channels, as almost all cells have them. In the late 1980s, Peter Agre, while working on the rhesus blood group antigens at Johns Hopkins University, US, serendipitously discovered a new membrane protein that he called CHIP28 (channel integral membrane protein of molecular weight 28k). At the time he had no idea what it did.4 Previously and independently, Gheorghe Benga and his group in Romania5 had shown that the water transport inhibitor p-chloromercuribenzoate is selectively bound to a protein in red blood cell membranes. Subsequent studies showed that this was a glycosylated form of CHIP28. After extensive analysis of the CHIP28 protein Agre’s group recognised that it must form a channel in the red blood cell membrane. The crucial experiment they performed was to over-express the new protein in another cell type (the Xenopus oocyte); they found that the cells became much more permeable to water.6 Since then, Agre and colleagues have shown that there is a whole family of genetically related aquaporins in almost every cell type,7 with some also permeable to glycerol and urea. In addition to all fluid transporting epithelia, one obvious place where water channels serve a crucial function is in the kidney, where they permit the reabsorption of hundreds of litres of water that pass through the renal glomeruli each day.7 Discovering the channels was one thing, but how do they work? How can these channels allow the passage of water at a very high rate but not allow the passage of hydrated protons (ie, hydronium ions, H3O+)? This question was answered by Agre in collaboration with Fujiyoshi’s group in Kyoto and Engel’s group in Basel when they solved the structure of aquaporin-1 using electron microscopy (Box 2, a,b).8 Structural basis of ion selectivity in potassium channelsIn contrast to water channels, those that selectively allow the transmembrane flux of ions, such as sodium, potassium or calcium, were first implied in a functional assay and theoretical simulation over 60 years ago, and genes encoding for ion channels were first cloned over 20 years ago.9 We now know that there are hundreds of different ion channels in human cells. Despite extensive analysis of ion channel function, one of the most intriguing conundrums has been how these proteins allow the selective passage of one type of ion at very high rates, while preventing the passage of all others. In the mid 1990s, after electrophysiological measurements combined with molecular biological manipulations of ion channel proteins initially made in Christopher Miller’s laboratory and later in his own laboratory at Harvard University, Roderick MacKinnon realised that the only way to answer this question was to determine the structure of an ion channel using x-ray crystallography. Determining the structure of membrane proteins is extraordinarily difficult, and many people suspected it would not be possible for an ion channel. However, in 1998, MacKinnon and his team (having moved to Rockefeller University) succeeded in crystallising the bacterial potassium channel, KcsA;10 and, just as they had hoped, the structure provided the answer to the riddle of how potassium channels permit the selective passage of potassium ions at a high rate (Box 2, c,d). Furthermore, the combination of x-ray crystallography, electrical measurements and mathematical simulations enabled them to make fundamental predictions about how the channels select ions and open and close to regulate their passage.11 The selectivity of ion channels and the exquisite control of their opening and closing is central to the role they play, for example, in neurotransmission and controlling the heart beat. Indeed, recently it has been shown that even subtle mutations in the genes that encode ion-channel proteins are a potent cause of diseases including epilepsy and cardiac arrhythmias.12 The meaning of the PrizeThe stories behind the discoveries that lead to the award of a Nobel Prize are always fascinating, while the act of singling out individuals among many who have contributed to a field of research is frequently controversial. However, this should not distract from the real message behind the Nobel Prizes in Medicine or Physiology and Chemistry, which is that pursuing basic science research has enormous practical value. Discoveries made regarding the fundamental properties of molecules, whether by physicists, chemists or biologists, can and do lead to major advances in medical care. Particularly at a time when researchers in Australia are under pressure to pursue applied research at the expense of basic science, this year’s Nobel Prizes provide a potent reminder of the importance of fundamental research. 1: Magnetic resonance imaging a) Lauterbur’s first published image of a section of a water phantom. Left: model of the phantom. Right: the reconstructed magnetic resonance image (reproduced from reference 2). b) Modern magnetic resonance sagittal section of a human head. 2: Ion channels a) Ribbon diagram showing structure of aquaporin-1 (water channel). b) Model illustrating mechanisms of water permeation in a water channel. The positive charge on the wall of the channel repels hydronium ions, thereby excluding them from crossing the transmembrane region (from reference 8, reproduced with permission of Nature Publishing Group). c) Structure of the KcsA potassium channel. The channel is a tetramer, but only two subunits are shown, illustrating the cavity and the narrow selectivity filter region formed by the pore helices, labelled ‘P’ (from reference 11, reproduced with permission of Nature Publishing Group). d) Model illustrating K+ permeation. The orientation of the pore helices is such as to produce an electronegative well in the cavity, which attracts K+ ions. The narrow selectivity filter region is just the right diameter to accommodate dehydrated K+ ions. K+ permeation occurs in single file. As one K+ ion enters the selectivity filter it repels the K+ ion ahead of it (from reference 10, reproduced with permission of the American Academy for the Advancement of Science).

Jamie I Vandenberg MB BS, PhD · Philip W Kuchel MB BS, PhD

Shall quips and sentences and these paper bullets of the brain awe a man from the career of his humour? — Shakespeare, Much Ado About Nothing (II.iii.260) In 1993, when interviewing me for the archives of the Royal College of Physicians, Dr Max Blythe suggested that I write my autobiography. Never reluctant to take pen to paper, I put this suggestion to my family. Their answer was unequivocal — “No, Dad, no. Nothing exciting has ever happened to you. You’ve led a charmed life”. However, as a person who even enjoys filling in questionnaires, I found it hard to resist the invitation of the Editor of the Journal to reminisce about my decision to undertake a medical career, the mentors who guided me and the influences in my chosen pathway to become a clinical investigator. Why medicine?I wanted to be a doctor from the age of 12 years; why, I am not sure. I had no medical forebears but admired an uncle by marriage, Justin Markell, a physician at St Vincent’s Hospital and a keen skier. As a boy I read everything medical I could lay hands on — “The Citadel”, “Viewless Winds”, “The Story of San Michele” and “The Healing Knife” come to mind — and many other books about the history and challenges of the medical life. I found their messages stirring and thought that this was the life for me. I have never regretted my decision. As a medical student I was fortunate in my introduction to clinical work at the Royal Prince Alfred Hospital (RPAH). Frank Mills, debonair and charming, was a kind and understanding tutor in surgery. Keith Harrison, our tutor in medicine, was a first class clinician, caring and courteous. The senior physicians included dedicated teachers such as Archy Collins, C G McDonald, Tom Greenaway and Bill Morrow, all of whom were later knighted, and Professor Lambie, who improved our history taking and physical examination with the rigour of the Scottish discipline he imposed. Cotter Harvey ran the only specialist medical unit in RPAH, the Thoracic Unit, which was of world standard. The pathway to researchAfter graduation I knew that I wanted to undertake research work. My uncle, Justin Markell, exclaimed “Why would you want to do research? You don’t have any deformity or handicap. You could go into practice.” I approached Hugh Ward, Professor of Bacteriology, to discuss my aspirations. When Sir Howard Florey visited Sydney, Professor Ward introduced Henry Harris, another recent graduate, and me to him as possible candidates for a research career. Florey advised us to work in the Physiology Department of Melbourne University and then to do the honours course in physiology at Oxford. Henry Harris followed this advice, and eventually succeeded Florey as Director of the Sir William Dunn Institute in Oxford. I did fly to Melbourne, but was not excited by the work in progress. It was not until I met Peter Bishop, newly returned from London and setting up the Brain Research Unit in the Department of Surgery, University of Sydney, that I focused my research ambitions on neurophysiology. Peter was an enthusiast and transmitted that enthusiasm to others. I have written elsewhere about his influence on the development of neurology in Australia.1 It is necessary not only to make a discovery but to repeat the findings at intervals to prevent the results from sinking into oblivion and to deter others from going through the same motions. While in Peter’s laboratory I kept in touch clinically by seeing patients at the Northcott Neurological Centre, Cammeray, under the guidance of George Selby. George was a superb clinician and teacher who patiently imparted his art, which stood me in good stead when I departed for the then customary 2 years of postgraduate training in London. Marking timeOn returning from Queen Square (now The National Hospital for Neurology and Neurosurgery) in 1956, I looked for an appointment combining clinical work with research. There were none. I was appointed Superintendent of the Northcott Neurological Centre and an Honorary Assistant Physician to the Sydney Hospital. I was one of a group of young specialist physicians who were astounded when informed that we could not conduct a clinic in our own speciality but had to rotate throughout all the clinics so that we could work in our own speciality clinic for 6 months every three years or so. We naturally rebelled against this mad manifestation of entrenched antagonism to specialisation until it was conceded that we could all work for a half day each week in our speciality, provided that we ran a general medical clinic on another half day and took fourth year students on physical examination 2 other half days in the week. As all hospital work was honorary this left three days a week to earn an income. Having completed training in neurology, I had thought that I might reasonably be asked to lecture in this discipline. I gave a series of lectures in physiology at Sydney University but the task allocated to me at Sydney Hospital was to give lectures to nurses on hygiene. The neurological topics were covered by the senior general physicians. When the opportunity arose for Sydney Hospital to be rebuilt on the Prince of Wales site at Randwick, the main teaching hospital of the new University of New South Wales Medical School, my spirits rose. They were dashed when the honorary staff voted by a small margin in favour of the status quo. I decided to jump ship. Sir Kenneth (“Bob”) Noad, senior physician at Sydney Hospital, kindly wrote to Dr Raymond Adams in Boston on my behalf and supported my application for a Lilley Travelling Fellowship. Dr Adams was the Bullard Professor of Neuropathology and Chief of the Neurology Service at the Massachusetts General Hospital. I was accepted to start there in August 1960. There were 2 events worth recording in my four years as an “Honorary” before going to Boston. Bob Noad had looked after four members of a family with epilepsy that he passed on to my care. They had myoclonic jerks and falling attacks with cerebellar signs, known then as the Ramsay Hunt syndrome (a form of familial myoclonic epilepsy). Bob Noad and I reported the family in Brain.2 This experience aroused my interest in myoclonus, which I was later able to investigate in Boston. The second was the suggestion by George Selby that we analyse the case histories of patients with migraine headache. The resulting article3 was published in 1960 and is still quoted today. That work started me on the headache road. My wife Judy and I arrived in Boston with our daughter Fiona in September 1960. While I was working in the centrally heated comfort of the Massachusetts General Hospital, Judy trudged through the snow of a cold New England winter, dragging one reluctant daughter and pregnant with another. While in Boston I followed up my interest in myoclonus, working and publishing with Ray Adams on a group of patients with myoclonus after hypoxia, and on the cause of myoclonic falling attacks (Box 1).4 I completed another interesting project with Dr Robert Schwab, who ran the Parkinson’s disease clinic at the Massachusetts General Hospital, on the relationship between action and resting tremors and cogwheel rigidity.5 Neurological grand rounds were held in the Ether Dome, where ether was first used as a general anaesthetic in 1846 (Box 2). Foremost among the clinicians were Raymond Adams, Miller Fisher and Maurice Victor. From Boston, I applied for the position of Chairman of Neurology at the Prince Henry and Prince of Wales Hospitals, which were to become the teaching hospitals of the Medical School of the University of New South Wales. To my great joy I was appointed. There are many legacies of the year in Boston — a lasting friendship with Raymond Adams, one of the great neurologists of the twentieth century, continuing contact with my colleagues in training at the Massachusetts General who went on to chair most of the major neurology departments in the US, honorary membership of the American Neurological Association, being a foundation member of the editorial board of Annals of Neurology and becoming the proud father of our second daughter, Sarah. Re-entryThe task of creating a teaching hospital out of a rundown infectious disease hospital (Prince Henry) and a collection of wooden huts dating back to the First World War (Prince of Wales) was challenging. The great merit of Prince Henry was that it was a very happy hospital, superbly situated between the Pacific Ocean and Botany Bay with its own golf course. I set up a modest laboratory in a disused ward where our work on the neurophysiology of movement disorders began. In investigating reflex actions we discovered that it was the vibration wave set up by percussion which was the essential trigger for tendon jerks, and this led to the discovery of the tonic vibration reflex, which had important clinical implications, and which led to collaboration with Karl-Erik Hagbarth in Sweden, who had recently discovered the same phenomenon. Studies on the mechanism of spasticity and the control of movement were carried out with David Burke, David Gillies, Colin Andrews, Carlo Tassinari (visiting from Marseilles) and Peter Ashby (from Toronto). I have summarised the early motor studies and their clinical implications in the Wartenberg Address that I gave to the American Academy of Neurology in 19806 and in my book on clinical neurophysiology in which I collaborated with Jim McLeod.7 I wish that the findings were more widely known to guide clinical neurologists today. It is necessary not only to make a discovery, but to repeat the findings at intervals to prevent the results from sinking into oblivion and to deter others from going through the same motions. David Burke and Simon Gandevia later joined Ian McCloskey in founding the Prince of Wales Institute of Medical Research. The motor program, which started in a disused ward and moved to a basement under the EEG Department and then to an abandoned operating theatre at Prince Henry Hospital, now resides in handsome villas on the Prince of Wales site at Randwick. Headaches and serotoninMy interest in headache was reignited by observations made in 1959 and 1961 by Federigo Sicuteri in Florence and by a group at the Montefiore Hospital in New York in 1960. It appeared a paradox that a serotonin antagonist, methysergide, could prevent attacks of migraine and yet an infusion of serotonin itself could ease the headache. We had the good fortune to have a biochemist at Prince Henry Hospital, Herta Hinterberger, who was an expert amine chemist, to teach Don Curran (our first Research Fellow), and then Michael Anthony (our second), the mysteries of estimating serotonin (5-hydroxytryptamine, 5-HT) in blood. We found that serotonin was discharged from blood platelets at the onset of migraine headache. An intravenous infusion of serotonin would constrict cranial blood vessels and relieve the headache (Box 3).8 These and other of our observations on blood vessels in migraine came to the attention of Dr Patrick Humphrey in the Glaxo laboratories in England. He set out to find an analogue of serotonin that had its beneficial effects without its side effects of chest tightness and lightheadedness. At the time of our early studies, there were only 2 receptors known for serotonin. Now there are at least seven main groups with many subdivisions. Patrick Humphrey came up with a substance that was active at the B and D subtypes of the serotonin1 receptor and named this sumatriptan. This and the other triptans developed later have proved to be highly effective agents in cutting short or preventing the development of migraine headache. It is gratifying that our observations qualify us to be godfathers to the triptans. Our initial concentration on the vascular aspects of migraine was carried on by Ewan Mylecharane, pharmacologist, with Paul Spira, John Duckworth, Michael Welch (from the UK and US) and Jusef Misbach (from Indonesia) who quantified the effects on the monkey cranial circulation of various vasoactive agents and their antagonists with a potential use in migraine. Geoff Lambert took over the pharmacological reins in 1978 as the emphasis in migraine research moved to determining the cerebral mechanisms that could underlie vascular changes and be of significance in the genesis of migraine. Some of the headache research team are shown in Box 4. Peter Goadsby and Richard Piper joined the team as BSc(Med) students in the early 1980s, followed by Rick Adams and Sandrino Zagami as Higher Degree candidates. A series of papers established the way in which the cerebral circulation of cat and monkey could be controlled by brainstem structures,9 thus filling a gap in the hypothesis of migraine mechanisms.10 Peter Goadsby continued research as a PhD and MD candidate investigating the pathophysiology of migraine, including a collaborative study of peptide neurotransmitters with Lars Edvinsson of Lund, thus forming our second Swedish connection. Peter later accepted an invitation from the Wellcome Foundation to set up a research department at the National Hospital, Queen Square, London. He joined me as a co-author for the sixth edition of my headache book,11 which outlines the research that has led to the current hypothesis of the mechanism of migraine. We have participated in many therapeutic trials including the triptans. Two early publications are worth mentioning. Don Curran and I conducted a double-blind controlled trial of amitriptyline for chronic tension headache in 1964,12 which has been accepted as a main line of treatment since then. Michael Anthony and I13 reported in 1969 on a successful open label trial of phenelzine for migraine patients resistant to other treatment which opened the door for the use of monoamine oxidase inhibitors when all else had failed. Odd neurological syndromesIn parallel with the research programs, our clinical work grew apace. We had close relationships with our neurosurgical colleagues under the leadership of Alex Gonski. Among the routine case load unusual problems appeared from time to time.14 We studied patients with phaeochromocytoma15 to define the headache and “funny turns” of this disorder, as well as benign sex headache, “neck–tongue syndrome”, visual hallucinations and paroxysmal dystonia.16 The arrival of Dr Peter Drummond, an experimental psychologist, brought a new dimension to our group’s studies of the autonomic nerve system. He worked out the part that the sympathetic nervous system played in facial flushing and the mechanism of the unilateral flushing in harlequin syndrome17,18 and clarified the nature of autonomic deficits in migraine and cluster headache. There are always new diagnostic and therapeutic challenges arising from our patients’ histories. Recent examples are the red ear syndrome19 and the “blip” syndrome.20 EpilogueSurely neurologists must have one of the most exacting and exciting occupations in the world. I have been fortunate in being able to set up the first Academic Department of Neurology in Australia and being appointed a Professor of Neurology rather than Professor of Medicine. The struggle to have neurology regarded as a discipline separate from general medicine has been long, hard and eventually rewarding. I want to emphasise that the research described here is very much the result of a team effort, and I regret that I have not had enough space to record all of it or to mention here all those that have been involved. I am indebted to my wife Judy for so many things, not least for her tolerance of my deskbound habits. I have been shielded from the uglier side of paperwork and helped over the years by three wonderful secretaries — the late Margaret Kendall, Patricia Miller and Carol Flecknoe. New techniques of studying cerebral function and dysfunction are granting us deeper insight year by year. I have no wish to be young again, but would not object to a 20 per cent discount so that I could observe further into the future. I am cheered by the fact that bright eyes and brighter minds are carrying on the exploration of the unknown. 1: Myoclonus In 1960, the cause of myoclonic falling attacks was not understood. Our investigations established that it was not the violence of the myoclonic jerking that caused the fall, but the following period of silence in all muscle groups. (a) Myoclonic jerk and falling attack. (b) Sharp and slow wave seen in an electroencephalogram (upper trace) and myoclonic jerk followed by a silent period in an electromyogram (lower trace). Reproduced with permission from Brain.4 2: The Ether Dome of the Massachusetts General Hospital. Dr Miller Fisher on my right and Professor Raymond Adams on my left during a lecture visit in 1989. 3: Serotonin and migraine Our investigations of migraine in the 1960s clarified the role of serotonin and paved the way for others to find serotonin analogues that would be safe and effective in treating and preventing migraine. (a) Levels of platelet serotonin in a migrainous patient. The injection of reserpine releases serotonin from body stores. Platelets discharge serotonin at the onset of a migraine headache, whether spontaneous or induced. Both spontaneous and induced headaches were relieved by intravenous infusion of serotonin. Reproduced with the permission of the Editor of Archives of Neurology. (b) The vasoconstrictor effect of intracarotid serotonin on the superficial temporal artery pulsation. The upper trace in each pair shows respiratory function, the lower, arterial pulsation. Reproduced with the permission of Karger Publishers (New York, Basel). 4: Members of the headache research team, 1987, in front of the Clinical Sciences Building, Prince Henry Hospital. From left to right: (front row) Professor Michael Anthony, Professor James Lance, Mr. Mark Hellier (Technical Officer), Mr. Basil Daher (Biochemist); (middle row) Mrs Patricia Miller, Mrs Francine Skane (Secretaries), Mr Paul Charalambous (Histology Technician); (back row) Dr Geoff Lambert (Pharmacologist), Dr Peter Goadsby, Dr Alessandro Zagami (Research Fellows), Mr John Duckworth (Technical Officer).

James W Lance MD, FRCP, FRACP

In the pregnant pause between when the conductor bows to the audience, and then turns, raising his baton, to face more than 100 musicians with their instruments poised, it can feel as if time has stopped. The anticipation of a whole concert of magical music to follow, the culmination of much concentrated work, gives way to relief mixed with excitement as the sound that follows is full and impressive. The surprise is that this talented troupe are all doctors. Where else would you find such a large group of doctors from all fields of medicine coming together every year from all corners of Australia, to focus intensely on the same thing for 3 days — not only playing for free, but actually paying to be there? These doctors have more than medicine in common — they share a love of music. The combination of music and medicine is nothing new. There are prominent examples dating back many centuries. Thomas Campion (1567–1620), English poet and musician, studied both law and medicine and worked as a doctor in London from 1606.1 The French composer Hector Berlioz (1803–1869) was originally educated in medicine,1 while Russian composer Alexander Borodin (1833–1887) studied medicine and helped found a medical school for women in 1872.1 Musicologist Albert Schweitzer (1875–1965) studied medicine in Strasbourg and worked as a medical missionary, returning regularly to Europe to give organ recitals to fund his hospital in Africa.1 Fritz Kreisler (1875–1962), violinist and composer, withdrew from music briefly to study medicine and to work as a medical officer in the Austrian army before returning to music fully in 1899.1 Flautist Jean-Pierre Rampal (1922–2000) left medical school to pursue his musical career,1 and conductor Zubin Mehta (1936- ) was another to abandon his medical studies, when he left India to pursue his musical studies.1 The Australian Doctors’ Orchestra under the baton of Keith Crellin in Perth, 2003. How we startedThe concept of combining medical and musical talents countrywide was the dream of Australian plastic surgeon and violinist Miklós Pohl, who was intrigued by the disproportionate number of doctors playing at the chamber music camps he attended. He saw the formation of a doctors’ orchestra as an exciting prospect, and his idea was welcomed with great enthusiasm by other musically talented medicos. Much planning preceded the first concert of the Australian Doctors’ Orchestra (ADO) in Melbourne in 1993. This concert featured Melbourne general practitioner, William Kimber, who received a standing ovation for his performance of Beethoven’s Piano Concerto No. 3 in C minor. Since the resounding success of our first concert, we have featured professional musicians as soloists in our annual concerts. They enjoy working with us, and are taken aback at our dedication, energy and enthusiasm. It makes a difference when you are choosing to play music, simply for fun. We have attracted a variety of renowned and notable artists, who are keen to fit us in between their commitments worldwide. We have been particularly fortunate to have British-born and trained Christopher Martin as conductor and artistic director. He recently retired after 20 years as senior lecturer in strings and conducting at the University of Melbourne. He works wonders to achieve cohesion from such a large and diverse group of doctors, drawing out the best possible performance in a very short time. He also chooses our music, and always seems to get it right — it is quite a feat to satisfy so many concerned and compulsive medicos! Our challenge is to satisfy him. We have often sympathised with him, especially at first rehearsals, as he tears his hair out, throws his baton down, and shakes his head as he gets over his initial concern that his choice of music might have been too ambitious. Somehow, he is always smiling at the end of each performance, and he keeps coming back for more. We have also had the privilege of working with Nicolette Fraillon (currently conductor of the Australian Ballet Orchestra) in 2002, and Keith Crellin (artistic director of the Adelaide Youth Orchestra) in 2003. Each conductor brings something of herself or himself to the orchestra, broadening our experience. Tony Prochazka, Cosmetic Surgeon, Sydney, NSW. Principal Cello. “I made a conscious decision 10 years ago not to pursue music as a career. I don’t regret that decision, but occasionally feel wistful about what might have been. Playing music forces you to make artistic decisions all the time. I’m certain that my artistic experience from music guides me in the aesthetic judgements I am required to make on behalf of my patients.” David Backstrom, Visiting Medical Officer, Royal Brisbane and Women’s Hospital, Qld. First Violin. “The most memorable musical moment in my life was probably the very first rehearsal piece of ADO in Melbourne 1993 — Mozart’s Il Seraglio overture. I was a founding member of the ADO. When asked about the oldest member, I think I was the only one willing (or silly enough) to volunteer my age!” James Lie, Rural General Practitioner, Albany, WA. First Violin. “All this music has a positive impact, even though I’m very busy. It makes me happier. My wife and son also play musical instruments. We do lots of after hours musical things as a couple or as a family. My patients also love my participation in music. They are always asking when and where I will be performing again.” Anita Green, General Practitioner, Darwin, NT. Principal Horn. “I work part-time to fit in music and family commitments. My most memorable musical moment was playing Sculthorpe’s Kakadu at Nourlangie Rock at sunset, and my favourite piece of music is Shostakovich’s 5th symphony; it has brilliant horn parts and laughs at authority — a strong Australian trait.” How it worksEach year, we meet for three days of rehearsals which culminate in our annual concert. The venue for our rehearsal period and concert alternated between Melbourne and Sydney for 5 years, after which we went to Adelaide, followed by Hobart, Brisbane, and, this year, Perth. Melbourne will be our host city in 2004, followed by Canberra in 2005. There are now over 500 doctors and medical students on the database, which has gradually grown as more and more people become aware of ADO, mainly by word of mouth. Invitations are sent to all, but only just over 100 participate each year. Our record was 170 players in Sydney in 2002, when we celebrated our 10th anniversary. It was a welcome achievement to have as many as 125 players in Perth this year. A hard core of players makes up about half of the orchestra; other players come and go. A few keen veterans have played in every one of the 11 years of our existence. About 3–4 months before the annual concert, we are sent the music scores as well as a practice compact disc. This recording helps us familiarise ourselves with the music, and allows us to play along in orchestral rehearsal at whatever times suit our schedules. When we meet, we have tremendous fun during the rehearsals, especially on first playing together something that we have only practised with the recording. However, the fun can be mixed with some initial doubt and trepidation, when facing unforeseen challenges just 2 days before the performance. It all gains momentum as we rehearse all day Friday, Saturday and the morning of Sunday, in preparation for the concert on Sunday afternoon. We soak in the uplifting spirit as the time of our concert looms closer. The sense of achievement is great, and it takes us a while to come down after such an adrenalin rush. Every performance has been recorded and videoed, so that players can keep a memento of their experience. In 2003, we also produced a CD of our performance. The orchestra donates all profits from its performances to a different medical charity each year. Apart from sacrificing time away from their work, all players pay a subscription fee, and meet all of their own costs, including those for travel and accommodation. Any sacrifices on our part are well compensated for by the sheer thrill of being part of such magic. A local organising committee in the host city works closely with the chosen medical charity to add corporate sponsorship to these funds wherever possible. This means that most of the door takings are passed on to the nominated charity. Many multi-talented doctors also take the opportunity to showcase their other skills, so that we don’t have to employ anyone else to organise the orchestra. The ADO was incorporated in 1998, and is coordinated with the assistance of a large team of doctors on national and local committees. Apart from a president and vice-president, treasurer and secretary, we also have librarians, a website manager (www.ado.net.au), database manager, publicity officer, video producer, photographer, stage manager, program editor, entertainment and social event organisers, and a master of ceremonies, in addition to many other willing helpers. Phillip Antippa, Cardiothoracic Surgeon, Royal Melbourne Hospital, Vic. Principal Viola. “Music is an integral part of my professional life. I never operate without music, be it classical or other. My favourite composer is Shostakovich and certainly my most memorable moment was playing his 11th Symphony at National Music Camp in 1985.” Rowan Thomas, Anaesthetist, St Vincent's Hospital Melbourne, Vic. First Violin and Concertmaster. “Playing music helps me relax. My association with professional musicians reminds me of a few fundamental truths — the best car to own is one that gets you from A to B, and if you can eat and are warm, there is not too much to worry about.” Cathy Fraser, General Practitioner–Psychotherapist, Sydney, NSW. Flautist, Leader of the Woodwinds. “The need to practise means something else has to go, and that usually can't be work, so it can mean less time eating, exercising or even sleeping! My favourite piece is Samuel Barber’s Adagio for Strings because it moves me more than any other piece of music.” Ti-wan Ng, Paediatrician, Perth. Double Bass player. First time player in 2003. “Music provides an escape from medicine and the chance to create something beautiful. Medicine is not intrinsically very creative. My most memorable musical moment was a night in Florence, listening to a recital in a small church which was raising funds for restoration work.”

Catherine Fraser MB ChB, FACPsychMed, MGPPsych

The pros and cons of anonymity For a small proportion of the patients who attend an emergency department, no name can be elicited. Of the 51 628 attendances at the Royal Perth Hospital Emergency Department in the 2001–02 financial year, 84 (0.163%) were made by 78 patients who were recorded as having no name. I hypothesised that unknown people would have a worse outcome (in particular, a higher death rate) than those with a name. I present here a descriptive analysis of a study I conducted to test my hypothesis. Of the 78 unknown patients who attended the emergency department, 56 (72%) were male (mean age, 32.9 years; range, 2–76 years; median, 31 years). Subsequently, patient names were able to be assigned to 36 (43%) of the 84 attendances. There were six deaths (7.1%) in the 84 attendances without a name, compared with 840 deaths (1.6%) in the 51 544 attendances with a name. This represents an odds ratio for death in the unknown group of 4.6 (95% CI, 2.0–10.7). (This figure, calculated by Woolf’s method, is based on the number of attendances. An alternative approach is to use the number of patients. Preliminary data for the latter also indicate a statistically significant result.) Of the six unknown patients who died, five were male (mean age, 38.3 years; range, 25–52 years). Four of the deaths were a result of trauma, and two were from medical causes. Of the six deaths in the unknown group, five occurred in the subgroup who were subsequently identified (effect size, 11.5%; 95% CI, 6.9%–16.1%). Review of these findings has led me to consider a prospective trial wherein patients attending the emergency department without a name would be randomly allocated to either receive a name or remain nameless. As the data clearly suggest that having a name is protective, an ethics committee will need to consider whether a permanent name change by deed poll is required to maintain this protective effect. On the other hand, the protective effect of having a name appears to be a “one off” benefit, as patients who are subsequently identified are more likely to die. I recommend that hospitals adopt the evidence-based approach of ensuring that patients remain unknown throughout their hospital stay in order to improve their outcome. Further study is required to determine whether the lives of these patients will be in danger once they resume their identity.

Daniel M Fatovich MB BS, FACEM

Quotes from MJA contributors in 2003 Ever since the Medical Journal of Australia was first published in 1914, the library-like atmosphere that usually pervades our premises (reflecting the quiet industry within) is occasionally shattered by an exclamatory outburst. Such fractures of the usual peace and quiet can be perpetrated by any of our editorial staff, and can signify joy, indignation, solid agreement, pure amazement or other sundry emotions. Outbursts usually occur on reading a submission to the Journal — be it a manuscript, a peer reviewer’s report or other form of correspondence. The general effect is to make the working day all the more enjoyable! This year, the Journal’s new, modern open-plan office has facilitated a sharing of these moments. Here, we share with you a selection from our discerning collection of putative, causative agents in the hope that you, too, will gain some measure of sonorous pleasure in the reading of them. The quotes are real life and presented in raw form, although we could not curb our habit of arranging (and rearranging) material being considered for publication in the Journal. Further, in deference to our journalistic colleagues, we have chosen not to reveal our sources. Some of you may recognise that a few of these excerpts are already in the public domain. In acknowledgement of the good sense of the penultimate quote, and our admiration for all statisticians, we leave any analysis of these data to the experts. Lastly, we wish to thank all of you for your contribution to the Journal. You are all esteemed by us, whether you be an author, reviewer or reader. What’s in a title?“Adverse event reporting in clinical trials: regulatory tail wags the research ethics committee dog, distracting the latter from more useful activity” Gender issues“Most women live in an environment that is also populated by men.” “Seven of the nine patients who developed neurological sequelae were female and the rest of them were male.” All in a day’s work“My apologies for the delay in getting this [economist’s review] back to you but it really is about time that you guys worked out a cure for the common cold.” “I am not sleeping until I get a draft revision to you. I have not heard from my co-authors as yet. I will keep you posted. Time: 3.30 am.” Making a statement . . .“Cardiac arrest is more successfully treated in Chicago or Heathrow airport, or an American Airlines or Qantas jet, or in a Boston post office, than in the vestibules, corridors or general wards of Australia’s premier hospitals.” “Declaring war and prescribing drugs are decisions dependent on information. If that information is incomplete or inaccurate there can be calamitous consequences.” “The Academic Clinician is well recognised to be a breed on the verge of extinction internationally, and this sort of program is the last great hope for ensuring its survival.” ArbitrationOn occasion, the Journal’s editorial committee asks a reviewer to help us out when an author and responder are at odds . . . the exercise generally proves fruitful! “In both of his letters, the author uses analyses which aren’t correct. In fact, his second letter misses the [critic’s] point entirely, since he repeats his error. The responder [critic] adopts the correct method. The story may be recast this way: Author: 1 + a = apple. Responder: The correct method is to compare like with like. If you compare dissimilar things, you get a third, uninterpretable thing; 1 + 1 = 2. Author: Don’t look at me. When I contacted my source, I was given the information I got. Oh, and by the way, I also found that 1 + b = orange. I will venture to say that arguments made on the basis of faulty statistics are themselves faulty. I would suggest that the author seeks professional statistical assistance to clarify his analysis.” End-note“The conclusions end on a note that is remote from the key of the paper (to use a musical analogy)”.

Ann T Gregory MB BS, GradDipPopHealth

a female practitioner with young children working part-time in the country faces many challenges. One particular morning I was looking forward to a 7 am paediatric journal club meeting to be held by teleconference. There are only six a year, and they are sponsored by the Royal Australasian College of Physicians and chaired by Michael Williams from Mackay in Queensland. They are well organised, well presented and packed with information. The night before the meeting I was feeling very positive about it. Why? I’d remembered the date and time of the meeting for a start, the pre-reading material had arrived and I’d read through it, the kids seemed to understand the pre-telephone meeting talk and I had a cloth nappy folded up ready on our home-office desk next to the phone. Everyone knows telephone meetings require minimal background noise — a remote possibility in a dedicated room in a hospital, but impossible in a “reality” home like ours, with polished floorboards and young children. So I always try to remember a folded up (clean) nappy to put over the mouthpiece of the telephone in an attempt to keep our family decibels out of the meeting. Coincidently, that night I’d also had a phone call asking if I would speak on the radio about a local charity that had donated items of equipment to the hospital. At 6.50 am things were still going well. All the kids were up, had eaten breakfast and were toileted (thus decreasing the possibility of any, “Mummy, I’m hungry” or “Mummy, I need a wee” requests over the next hour). I’d even washed the dishes (it doesn’t take long to learn that Weetbix left on plates quickly turns to cement). The children and I had another pre-telephone meeting talk — they were reminded that, for the next hour, all they had to do was be “quiet friends.” When I dialled the teleconference number, a polished adult voice told me to enter the account number and pin number. My husband had been away for five days so it was great to hear another adult voice, even if it did turn out to be a prerecorded message! I entered the numbers and was told I would be switched through to the conference. Several minutes of soft classical music passed but still no conference. I hung up and dialled again. This time, I was in luck. The meeting was informative and the kids were good, so I was really enjoying the education. Suddenly, during discussion of a paper reviewing meningococcal meningitis, there was a terrible din outside. Our three kelpie working dogs had found a kangaroo on the front verandah. Why, at the time of a medical telephone journal club meeting? There had never been a kangaroo on the verandah before. Of course nature took over and the dogs chased the kangaroo. Very soon they were all caught up with kids’ bikes, toy jumbo trucks and the wheelbarrow in the carport. The dogs barked at the kangaroo and the children yelled at the dogs. I doubted that the folded nappy could contain the noise and was about to hang up, when thankfully the kangaroo disappeared. There were no more hiccups. Immediately after the conference I returned the nappy to the cupboard and headed for the toilet — to find no toilet paper —explaining one of the “quiet friends” activities! As I collected more paper, the phone rang. It was the radio station. They needed to pre-record their interview now. It really wasn’t the ideal time. I hadn’t thanked the children for their efforts during the phone meeting; I hadn’t warned them that for this particular phone call I needed “silent friends;” I hadn’t received the faxes giving me the complete background information; and I still had the toilet roll in my hand — but I agreed to proceed. The interview started well, but before long world war house broke out. The four children, who now sounded like 44 children, were sick of being “friends” and needed my attention. I asked the interviewer to stop the tape while I settled the warriors. I was under a bit of pressure. There was no button on our phone to give the caller soft classical music, and I’d put the folded nappy away, so I tried gentle cajoling, explicit body language and my best “cross mum” frown. (Isn’t it a relief we have telephones in our homes and not videoconferencing?) I tried to explain that I was on the radio, but they are country children. Puzzled, the eldest spoke up, “Mum you’re not at the rodeo, you’re on the phone.” Finally they settled and the interview was continued. When it was all done, still feeling a little hassled, I apologised again to the interviewer for the children fighting. “Oh, no problem,” she replied, “It’ll be great on the regional news!” and hung up.

Susan M Gorton

Doctors are often criticised for failing to communicate adequately with their patients and for using medical jargon. But what about “patient speak” — those words that are nearly what we thought we meant? This collection of medical mispronunciations has been carefully recorded in a notebook (yes, one from a pharmaceutical company) kept in the top drawer of a suburban general practitioner's desk, and edited over dinner by the medical members of the family: we share them with you for the festive season. The obituary gland seems a sad place to start. Moving down the ophagus tube, past the broccoli, a fundoapplication may help. You may recognise the psychiatric nerve, but what about the haricot veins? The introverted uterus is a little shy, but the crucial ligaments are obviously important. Platinums and playtex are everywhere. (Pituitary gland, oesophagus, bronchi, fundoplication, sciatic nerve, varicose veins, retroverted uterus, cruciate ligaments, platelets.) Having sorted out the anatomy, the various ailments are next. There are many inflations in the vocabulary. Does the human Pavarotti virus affect the vocal chords? What organs are involved with a hippopotamus or a helicopter? (Inflammations, human papillomavirus, hypothalamus, helicobacter.) For the surgeons, we need help with the biblical hernias and erupted spleen. It may be a little more difficult to decide which specialist to refer a fractured zygote, a utopic pregnancy, bunyips, painful anodes and the occasional Arnold Curarie. (Umbilical hernias, ruptured spleen, fractured zygoma, ectopic pregnancy, bunions, nodes, Arnold Chiari malformation.) We could probably send the pigsty, cellutosis, cradle crop, scarytosis, and ectopic eczema to the dermatologists (if they are not at a conference in Barcelona or Melanesia), but who treats septic ulcers? (Stye, cellulitis, cradle cap, solar keratosis, atopic eczema, basal cell carcinoma, melanoma, peptic ulcers.) The respiratory physicians, with their stereophone can move from sleep apathy to bronchial ecstasy, but should postnatal drips and reproductive coughs go to them or the obstetricians? Even more confusing are Alka Seltzer's disease, tetanus and tendonitis, which are not what they seem. The physicians could investigate grout, osteoferocious and facetious anaemia and handle a myocardial infraction. And for the lawyers — is needless dysplastic syndrome considered as incompetence or a minuscule tear? (Stethoscope, sleep apnoea, bronchiectasis, postnasal drip, productive cough, Alzheimer's disease, tinnitus, gout, osteoporosis, pernicious anaemia, myocardial infarction, dysplastic naevus, incontinence, meniscal tear.) Then there are the things that doctors do to patients which make one wonder about informed consent. If you seduced the patient into pornography what would you expect? A tubal litigation may follow, or perhaps swifter justice with a lumbar punch. Monograms and egg, lettuce and fried tomatoes are common investigations, but who wants the Geiger counter or MI5? If the patient asked for the locum, or, worse still, for the results of their own autopsy, how would you respond? They may be better going to the physioterrorist, or just to the choir practice. (Induced, colostomy, tubal ligation, lumbar puncture, mammogram, E/LFT's, glucometer, MRI, local anaesthetic, biopsy, physiotherapist, chiropractor.) But the best mispronunciations of all are the muddled medications. The metropolis tablets are real blocker beaters, and others prefer the condominium lifestyle, but on a bad day it may be necessary to retreat to Nimbin for a bit of peace and quiet. We could go there in the Valiant, filling up with Caltex on the way, but hopefully avoiding an argument when the map reading leads us astray. (Metoprolol, beta blockers, Coumadin, Nemdyn ointment, Valium, Caltrate, Augmentin.) The medical profession has all sorts of alternative remedies, for Anzacs and aristocrats and perhaps even the odd pessowary. These include marzipan, genetic tablets and those well-known urinal tablets, and Laminex, but there is less demand for the repulsive tablets. (Zantac, Aristocort, pessary, temazepam, generic, Ural, Lasix, Prepulsid.) In our spare time we could join the local music scene with a microphone, or go on a picnic with the transistor patch and the Mortein, taking Ventolin noodles and Caviar tablets for lunch. Or we could take up walking and ease the aches and pains afterwards with Catacomb ointment, Denturub or Aquarius cream. At the opposite ends of the spectrum are the libido and the celibacy tablets. Taken along with some clandestine erotics, who knows what galactic splendour may result? (Micropore, Transiderm patch, morphine, Ventolin nebules, Karvea, Kenacomb, Dencorub, aqueous cream, placebo, Celebrex, Canesten, Aurorix, Largactil, Plendil.) On that note, now that you are completely confused by trying to be bilingual, get out the Kleenex, sit back and hope it all goes into remittance. (Nitrolingual, Keflex, remission.)

Catherine E Yelland FRACP · Stephen D Yelland FRACGP

A 51-year-old man presented with non-healing ulceration at the site of a tattoo on his right leg. Some 8 years previously, in celebration of the victory of his favourite team, Carlton, in the Australian Football League Grand Final, he and a friend both had a picture of a stylised Carlton footballer tattooed on one of their legs. The tattooist did not have a navy blue pigment (the team’s colour) to tint the jersey, but improvised with another source of pigment. The patient reported that about a year before presentation he had developed painful ulceration at the site of the tattoo. The ulcer had progressed and showed no signs of healing. Curiously, the ulceration had occurred at precisely the time when the club was undergoing a dramatic deterioration in its fortunes, as scandal and poor on-field performances saw the team fall to the bottom of the AFL ladder. My patient was just one of the many Carlton supporters who had become very disillusioned. At presentation, there was a granulating ulcer within the tattoo that corresponded to the navy blue areas of the figure (Box), with mild surrounding inflammation. After discussion with the patient, it was decided to excise the ulcer and perform a skin graft. The graft suffered partial loss, associated with a Pseudomonas infection. The wound eventually healed, although at 1 year follow-up the patient complained of occasional itch and mild swelling in the graft. Histology of the excised ulcer showed a dense lymphocytic infiltrate and multinucleated giant cells forming occasional granulomas, consistent with an immune response to the pigment. Black and yellow pigment was seen throughout the dermis and in histiocytes. DiscussionA delayed immune response to tattoo pigments is well described. Generally this takes the form of a granulomatous reaction with swelling and irritation in the affected areas. Ulceration is unusual. A delayed immune response can occur after laser treatment, or may be the first manifestation of systemic sarcoidosis. It can also begin spontaneously several years after having a tattoo, as happened in this case. But an immune rejection of a club’s colours by a disillusioned football supporter has not previously been contemplated as a cause of tattoo rejection.

Anthony J Penington MB BS, FRACS

To the Editor: Random-digit dialling is commonly used to select samples in telephone surveys. It has been used as a method of selecting survey samples for a diverse range of topics ranging from chronic pain to lesbian health issues.1,2 However, the method has come under criticism in recent years, primarily on the basis that a large number of residents are systematically excluded from the sample. We have recently completed a study where we compared random- versus fixed-digit dialling in telephone surveys. Our protocol was as follows: “random-digit” dialling — a randomisation protocol was developed to identify the digit (ie, finger) to be used in dialling for each attempted telephone contact; “fixed-digit” dialling — the same digit (ie, the index finger of the right hand) was used in all contact attempts. We found that, in both fixed- and random-digit dialling, we were repeatedly contacting the same individual. Thus, we believe that neither method is optimal in controlling for sample bias in telephone surveys. We recommend that, in future, researchers pay more attention to methods for selecting telephone numbers than to methods for selecting a finger to dial with.

Stuart C Howell BA (Hons) · Guy D Eslick MMedSci (Clin Epi)

Carrots sprouted unplanted in my garden, presumably from compost, but instead of long, symmetrical, uniconical down-growths, they spread laterally through the barely penetrable virgin clay to produce nutritious but commercially incorrect deformities — some anthropomorphic. Potential cannibalistic nightmares inhibited my appetite, and the “hand of fate” spent two months desiccating on the laundry windowsill before it was returned to the compost.

Lloyd K Morgan

When a 46-year-old man presented with chest pain, the key to the diagnosis was in his ECG tracing — the one on his thoracic CT scan, that is!

Andrew Bonura BSc(med) MBBS

Among the many “freebies” given to doctors by drug companies, I find “post-it” notes particularly handy. I stick ’em on my desk, in my diary, on my computer, on the fridge, on the dashboard . . . everywhere. Life is much more organised for their existence. And they are such innocuous little darlings . . . or are they? During the past year, I was informed that a young sportswoman hospitalised with severe septic arthritis of the right knee, but otherwise healthy, had been inadvertently prescribed a “novel antipsychotic”. The apparent reason for the error was that the surgical resident, weary at the end of a long shift, had transcribed on to the drug chart the names of the patient’s antibiotics (jotted down on a “post-it”) plus the name of the antipsychotic (advertised by the pharmaceutical company at the top of the “post-it”). It could have been messy. The hospital’s Risk Management Unit, in damage control, was back-pedalling fast. After all, these new antipsychotics, although better tolerated than the older variety, are not devoid of side effects — some potentially nasty. What happened to the patient? Fortunately, no adverse events occurred. Still hopping? — yes. Hopping mad? — thankfully no, and perhaps less likely to be with an antipsychotic “on board”.

Garry J Walter PhD, FRANZCP

In the O. R. I’m cold as hell wearing blue cotton apparel. At least the patient’s wrapped up well by a Bair Hugger and drapes; tucked away from the Antarctic duct spilling an icy stream of air at target range — you can guess where: upon me, huddled in the chair placed with ignorance or intent beneath its thin-lipped, hissing vent. My hands are numb, and nose runny, though the surgeons’ lamp is sunny; his voice sweet as red-gum honey. Insulated by gloves and gown he wants the temperature turned down. “Too hot in here!” I must delete whatever words seem indiscreet: these guys keep me on easy street. It’s even easier to see nobody has considered me. What’s also tough is, currently, professional indemnity costs rising like a tsunami. There is no excess fat to burn. Insurance takes half what I earn. Yet, for a while, I must persist. Another day, another list; another reason to exist since this is all that I can do: my “recherche du temps perdu”.

Philip J Armstrong FANZCA

I arrived in a dusty hot town to start a locum, and was greeted effusively by the resident dog, an enormous part-Alsatian. We became instant friends, but I realised, as he scattered the waiting-room patients the next morning, that this dog was not friends with everyone. He used his Houdini talents to escape and accompany me everywhere, and caused consternation when I entered the High Dependency Unit of the local hospital. He got into the hospital by hurling himself at the front glass doors. When I went for my evening walks, he amused himself by attacking the hubcaps of passing cars. His reputation was legendary — he had attacked every citizen of the small town, and regularly bailed up elderly ladies in their backyard dunnies. Pedestrians all carried stout sticks, and small children wore rubber boots if they wished to play in the park. Dr X, his owner, had been approached by the police, the dog-catcher, a deputation of citizens, even by the Mayor, but he had declared to everyone that if his dog came to harm, he would leave town — and that was that! I walked through the park one hot dry evening, trying to pretend that the dog had nothing to do with me. He did his usual thing — ran up to a small boy and bit him on the calf of his rubber boot. The boy gave a small scream, and went on playing. An elderly man rose from one of the seats, his stick held in front of him. The dog snarled obligingly. “That dog of yours . . .” he started. “Oh no, not my dog!” I protested. “That dog just shows you what is wrong with health services in country New South Wales. We have got to put up with that dog in order to keep our doctor in the town. If the doctor goes, the hospital goes, the chemist goes, and we are left with nothing. NOTHING!” The dog gave a hideous yellow grin. He had quite a sense of humour. I had already noticed his proclivity to break into the consulting room when a Pap smear was in progress. “Yeah” said the receptionist the next day. “Dr X will leave town if they try to poison his dog again. They shouldn’ta thrown them 1080 baits over the back fence.” I was soon gone and, I suppose, forgotten, but a drug rep told me that about a year later the dog had died under mysterious circumstances. Dr X had removed himself and his family instantly to the Eastern Suburbs of Sydney. This story has a happy ending. I travelled through the town recently. They have a new doctor. The council has built a new surgery and residence for him, and the old surgery is now a town museum, well frequented, with rooms out the back for the visiting drug and alcohol and women’s health nurses. The Country Women’s Association converted the waiting room to a mothers and babies restroom. The new doctor doesn’t speak much English, but everyone is very happy. The hospital is running and the aged-care hostel is packed. The little children can once more run around in thongs. And last but not least, old ladies can sit in their dunnies, confident of a happy outcome!

Robyn L Pogmore MB BS

This patient was sighted hanging around in the x-ray department. He was unable to give a history, so total body x-rays were performed. Although he seemed to be holding up well, he was advised against travelling by plane at any time in the near future.

Name Withheld

Human fetal tissue is a scarce resource that has been used in Australia for biomedical research since 1980. From 1994 to 2002, it has been used for research by 19 biomedical researchers at 12 separate Australian institutions (four universities, six major teaching hospitals and two research institutes). With an average of 265 samples distributed annually, researchers have conducted experiments in biomedical research with the approval of their Human Ethics Committees, and published 74 manuscripts in peer reviewed journals over the past decade. The tissue is obtained from therapeutic termination of pregnancies at 8–20 weeks’, but mostly 14–18 weeks’, gestation. The average number of fetuses obtained over the past 10 years was 108 per annum. Our understanding of the pathogenesis of human diseases such as diabetes, multiple sclerosis, retinopathy of prematurity and osteoporosis has been advanced because of such experiments, and better drug treatment of disorders such as osteoarthritis has been made possible with the use of human fetal tissue. The benefits of human fetal tissue research need greater recognition.

Bernard E Tuch FRACP, PhD · Hayley Scott BScAg · Muhammad T Tabiin PhD · Liping P Wang MSc · Patricia J Armati PhD

John Henry Winter Birrell, a general practitioner and former police surgeon, died on 25 March 2003 of myelodysplasia. He will be remembered especially for his tireless and ultimately successful campaigning to reduce road accident deaths by introducing Breathalyzer testing of drivers and compulsory wearing of seatbelts. John was born in Melbourne on 29 December 1924. As a student at Melbourne Grammar School, he excelled academically and on the football field. In 1942, he began studying medicine at the University of Melbourne and completed his first year with ease. Then, in defiance of his father’s wishes, John joined an army unit in Cowra. He was soon found and returned to university, but failing his second year enabled him to rejoin the army. He was posted to Papua New Guinea, where he joined the Medical Corps. He resumed his studies in 1944 and won the forensic medicine prize in his final year. Between 1952 and 1956, John was a lecturer in pathology at the University of Melbourne and a senior lecturer at Monash University. After working as Assistant Coroner’s Pathologist at the Melbourne City Morgue (1955–1957), he was selected to be Police Surgeon, a position he held for the next 20 years. One of his early duties was to do blood alcohol estimates of road crash victims. On call 24 hours a day at his home in Blackburn, his exposure to the carnage on Melbourne roads soon aroused his anger. He was horrified at the increasing number and severity of fatalities and injuries he witnessed. Joining the Traffic Injury Committee of the National Health and Medical Research Council in 1960, John’s influence was soon obvious when the committee recommended that seatbelts be fitted and worn in vehicles. He worked tirelessly with the media on seatbelt promotion, influenced politicians and parliamentary road safety committees, and educated schools and community groups about road safety issues. Several of his articles on seatbelts and the dangers of driving after drinking alcohol were published in the Journal in the 1960s.1,2 In the words of Basil Hetzel (Foundation Professor of Social and Preventive Medicine at Monash University), delivering the Boyer Lecture in 1971, “John Birrell became the public face on the issue of blood alcohol and road safety . . . the major force in arousing public awareness of the problem”. In 1966 it became an offence to drive with a blood alcohol level exceeding 0.05%. The mandatory wearing of fitted seatbelts by drivers and front-seat passengers became law in Victoria in January 1971 and was introduced in all states and territories by the end of the same year. It was in Victoria that “booze buses” (mobile breath-testing units) were first introduced (in 1990). In 1974, without the financial support of government or other alcohol and safety bodies, John made a successful bid to have the 7th International Conference on Alcohol, Drugs and Traffic Safety held in Melbourne in 1977. The event was an outstanding success, attracting extensive media coverage and raising community awareness about road safety issues. Another issue about which John felt very strongly was child abuse. He was the Patron of Australians Against Child Abuse. In 1977, John went into private practice in Foster (VIC), where he remained for 5 years. He then moved to Point Lonsdale, where, until a few years ago, he worked at the Community Health Centre in nearby Queenscliff. John is survived by his wife Jackie and sons John, Mike and Simon. Donald Gibb

Donald Gibb

John Winter Ashton, an anaesthetist, died suddenly and unexpectedly on 29 November 2002 of a pulmonary embolism. His death was preceded by a short illness, which necessitated his retirement from practice. John was born in October 1931 in Melbourne. He was educated at Melbourne Grammar School, where he distinguished himself as a formidable “back pocket player” in the 1948–49 Australian Rules football premiership 1st XVIII. Influenced by his father, a surgeon, and mother, a nurse, he studied medicine at the University of Melbourne, graduating in 1955. After internship at Prince Henry’s Hospital, Melbourne, and a short stint in general practice, John commenced anaesthetic training in Albany, New York, in 1958. He later worked at the Croydon group of hospitals in England, and obtained his Fellowship of the Royal College of Surgeons’ Faculty of Anaesthetics from the Royal Postgraduate Medical School, Hammersmith, England, in 1963. John returned to Melbourne later that year to commence public and private anaesthetic practice. He was elected a Fellow of the Royal Australasian College of Surgeons’ Faculty of Anaesthetics in 1969. He was strongly linked to the anaesthetic department at Prince Henry’s Hospital and the Monash Medical Centre and heavily involved in the development of the Chair of Anaesthesia at Monash University. In the early 1970s, John’s determination to improve the status of anaesthetists led to his long association with the Australian Society of Anaesthetists (ASA). In 1982, he became Chairman of the Victorian Section of the ASA and in 1988 he was elected President of the ASA’s national body. John personified all that was best in the practice of medicine in general and anaesthesia in particular. He had the ability to establish instant rapport with everyone he met. His relaxed and warm manner concealed high technical skill and made it easy for him to teach others and provide reassurance to patients and surgeons alike. He was particularly known for his kindness and concern for those under his care. He was interested in many sports, but tennis, which he played with great skill and patience, was probably his major love. At least two members of Kooyong Tennis Club owe their lives to John’s resourcefulness when they collapsed on court. He was also a keen advocate of conservation issues and was never happier than on his property in the Dandenongs. John is survived by his third wife, Barbara; sons Gerard, Julian and Nigel; and stepsons, Craig, Sean and Stuart.

Rowan Blogg · Les R King · Bill P Lewis · Herb C Newman · Graham A Syme

Ethics and evidence-based medicine. Fallibility and responsibility in clinical science. Kenneth W Goodman. Cambridge: Cambridge University Press, 2003 (xii + 168 pp). ISBN 0 521 79653 9. Goodman explores the links between scientific knowledge, clinical practice and ethics in this well-written and enthusiastic book. The main argument of the book is that practitioners are constantly faced with clinical decisions characterised by uncertainty — decisions with serious implications for patients. This uncertainty about the right course of action can be reduced through the use of evidence, making it morally blameworthy not to use evidence. For Goodman, an uninformed practitioner is a negligent practitioner, whose patients are “no longer seeing a physician, but visiting a museum”. A series of well-informed chapters engage with some of the major criticisms of evidence-based medicine (EBM). Issues such as flawed research, redundant publishing, publication bias, and the shortcomings of research synthesis are tackled squarely. Despite these problems, argues Goodman, the use of research is well founded both conceptually and practically, creating the imperative to improve the quality of research production and synthesis rather than abandon EBM. The only weakness in his reasoning is the lack of evidence that using EBM leads to better patient outcomes, or discussion of how this might be demonstrated. The author’s expertise in philosophy and computing are evident in the discussion of ethical issues raised by internet use in research, for data collection and for recruiting. As well as a chapter on clinical EBM and guidelines, the relationship between policy and evidence is explored through three case studies, providing concrete examples of the promises and problems of evidence-based public health. Overall, this is a thoughtful and sympathetic exploration of the moral imperative to use EBM. The detailed analyses are supplemented with practical suggestions, making the book of interest to academics and practitioners alike. This is a valuable early contribution on the ethics of EBM; no doubt further contributions will engage with some of the wider ethical issues that were beyond the scope of this text. Wendy A RogersNHMRC Research Fellow Flinders University, Adelaide, SA

Wendy A Rogers

Geoffrey Henry Moore was born on 26 August 1913 at Waverley, in Sydney. He grew up in humble circumstances in Riverstone, near Windsor, and attended Parramatta High School. He went on to become a highly regarded surgeon, well known and well respected for his clinical judgement. After graduating in medicine from the University of Sydney in 1935, Geoff did his residency at Royal Prince Alfred Hospital and Prince Henry Hospital. It was here that he met Gladys Duncan, whom he later married. He obtained a Fellowship of the Royal College of Surgeons (Edinburgh) in 1939, then spent two years at Harrow Road County Hospital in London during the Blitz. Geoff was destined to make a number of “lucky escapes” in life. When he decided to return to Australia, his development of chickenpox — thought at the time to be smallpox — prevented his embarkation on a ship that was subsequently sunk in the Atlantic. When, in 1941, he finally arrived in Australia on another ship, he attempted to enlist for service in Singapore, but was “manpowered” to Townsville instead. His replacement was interned in Changi prison for the duration of World War II. Geoff was directed to Townsville General Hospital (the largest state hospital outside Brisbane) as superintendent. He was faced with the enormous task of reorganising and re-establishing medical services, which were in disarray and decline. Apart from the decrepit facilities, discipline had broken down in a background of US occupation, imminent Japanese invasion and plans for evacuation of personnel west to Charters Towers. Geoff took on a horrendous workload, managing hospital inpatient and outpatient services, reorganising and re-establishing hospital administration, and improving medical and nursing training standards. He remained at Townsville General Hospital until 1949, when he resigned to enter private surgical practice. However, he continued as a visiting gynaecologist and representative of the Queensland Radium Institute to the hospital until forced retirement in 1976. Thereafter, he continued as honorary consultant gynaecologist until 1986 and as surgical assistant to younger surgeons until 1994. He obtained Fellowships of the Royal Australasian College of Surgeons (1969) and the Royal Australian College of Obstetricians and Gynaecologists (1979), and was awarded a Medal of the Order of Australia in 1986 for services to medicine. In his younger years Geoff was a keen tennis player and horseman. A quiet man, he was an avid reader with a large library of books, particularly history books. He enjoyed gardening, and had a special interest in native plants of North Queensland. He died on 14 December 2002 from a secondary malignancy. He is survived by his wife Gladys, two sons (both doctors) and a daughter (ex-nurse). Graeme G D Moore

Graeme G D Moore

Stephen C Due Editor, AMPI, Geelong Hospital Library PO Box 281, Geelong, VIC dueATbarwonhealth.org.au Readers interested in medical history may like to know about the Australian Medical Pioneers Index (AMPI), which is the first major Australian medical history website, and the first published encyclopaedia of Australian medical biography. AMPI aims to provide basic personal and professional information on every doctor resident in Australia, or professionally connected with Australia, up to the year 1875. This includes medical officers on immigrant and convict ships, doctors who practised in Australia, and doctors who pursued other occupations here. Over 3000 pioneer doctors are listed. In addition to biographical data, the website provides interesting material on the medical profession in colonial times, including a picture gallery containing rare images of pioneer medical life (Box). There is also a section on sources of information about early doctors. The original compiler of AMPI was Dr David Richards (1937–1998) of Nottingham, England, whose card file was computerised at the Geelong Hospital Library. The website was developed in conjunction with the State Library of Victoria as a community service. Anyone with additional data about a particular doctor is encouraged to contribute to the project. Colonial medical transport. Dr S R Robinson adopted this modern mode of transport when most of his colleagues still kept horses and buggies. (Geelong Heritage Centre — reproduced with permission.)

Stephen C Due

The 1973 inquiry into the "Expansion of Medical Education in Australia" resulted in the appointment of nine professors of "Community Practice". We (the foundation professors) have been leaders in a reform movement within medical schools and general practice and have had to fight hard for the right and resources to do the job for which we were appointed. Our most significant accomplishment has been to broaden the orientation of medical education beyond hospitals and laboratories to the community and those in the community who are underserved. Although small in numbers, our discipline fights above its weight and is essential for medical school accreditation by the Australian Medical Council.

Max Kamien MD, FRACGP