Research

Everyone knows medical research is about improving healthcare Recently I had some trouble with people one might call “pseudoscientists”. These individuals are often technically quite competent; they seem to know their craft and they produce seemingly good work. But there is something amiss. It took me a long time to find out what that might be. Now I think I have identified it — the pseudoscientist has entered the field of science for the wrong reason: to advance not medicine, but himself. This theme must have been on my mind the other night, when I had the most vivid dream. The dream took me to the “Annual Festival of Pseudoscience”, where a panel of the most distinguished pseudoscientists reached consensus on how to become a fellow pseudoscientist. Here are the 10 commandments of pseudoscience that they dictated to their audience. Ensure that passionate belief rather than reason is the force that drives you. In science, one tests (more accurately, falsifies) hypotheses. In pseudoscience you want to “prove” what you already “know”. Only the biased researcher can mislead the world effectively. Avoid scientific training. Pseudoscience needs enthusiastic amateurs who have picked up the rules of science while busy doing other things. The worst that could happen to pseudoscience is for properly trained career scientists to join its arena. Maintain your bias. Bias usually originates from interests that create financial, personal or emotional conflicts. Nurture those interests and never disclose these conflicts to anyone, particularly not when publishing. Use publicity to obtain funding. Research funds are becoming scarcer by the minute. Lack of funds can seriously delay your endeavours. If you find it difficult to compete, the time-tested approach is to make more noise than anyone else. Hire a PR firm, for instance. Once the daily papers regularly sing your praises, your pseudoscience will thrive. Do not lose sight of what you intend to prove. Some people say that good research can never be “negative” — even showing that therapy X is not effective would yield the positive result of enabling patients to choose something that does work. Make sure your goals are not obscured by such old-fashioned nonsense — your aim as a pseudoscientist is to assist your friends, the manufacturers or promoters of therapy X. Let your goals drive your data analysis. Even with safeguards in place, you might one day generate a result that does not fit your preconceived ideas (or those of your sponsors). Subanalyse and subanalyse until you have what you were fishing for — a significant result showing what you want. Suppress unwelcome results. If things should go disastrously wrong and even extensive data dredging does not yield the desired outcome, the professional pseudoscientist must resort to the last, desperate, but usually effective, measure. Make the unwelcome finding disappear — don’t ever publish anything that does not confirm your beliefs or that might upset your friends. Overinterpret. More often than not, you will create data that you and your sponsors like. Now you must ruthlessly overinterpret these findings to ensure that everyone knows about your work. Publish your results as often as you possibly can. Journal editors don’t like duplicate publications, so it would be foolish to tell them. Attack opposing scientists. There is always a danger that scientists will publish papers that upset pseudoscientists. In such cases, initiate a campaign of defamation against your opponent — this will decrease their credibility and increase yours, and all will be fine again. At this point, I woke up feeling sick and anxious. Where does the dream end and reality begin? Did I have a nightmare or a vision? And, horror of horrors, did I not recognise some of the faces of the panellists? But it must have been a nightmare! These 10 commandments are just a guide on “how not to conduct medical research”. Surely, medical research is not abused as a career springboard? This would result in chaos and lead us badly astray without a compass for orientation. Surely, any responsible researcher knows that medical research is about improving healthcare? If not, how could we continue with the progress medicine has made so far? Surely, medical research has not been taken over by pseudoscientists. Or has it?

Edzard Ernst MD, PhD, FRCP

Objective: To investigate whether 12 weeks of graded exercise with pacing would improve specific physiological, psychological and cognitive functions in people with chronic fatigue syndrome (CFS).Design: Randomised controlled trial.Setting: Human performance laboratory at the University of Western Australia.Participants: 61 patients aged between 16 and 74 years diagnosed with CFS.Interventions: Either graded exercise with pacing (32 patients) or relaxation/flexibility therapy (29 patients) performed twice a day over 12 weeks.Main outcome measures: Changes in any of the physiological, psychological or cognitive variables assessed.Results: Following the graded exercise intervention, scores were improved for resting systolic blood pressure (P = 0.018), work capacity (W·kg-1) (P = 0.019), net blood lactate production (P = 0.036), depression (P = 0.027) and performance on a modified Stroop Colour Word test (P = 0.029). Rating of perceived exertion scores, associated with an exercise test, was lower after graded exercise (P = 0.013). No such changes were observed in the relaxation/flexibility condition, which served as an attention-placebo control.Conclusions: Graded exercise was associated with improvements in physical work capacity, as well as in specific psychological and cognitive variables. Improvements may be associated with the abandonment of avoidance behaviours.

Karen E Wallman BSc(Hons), BEd, PhD · Alan R Morton DipPE, MSc, EdD · Carmel Goodman MD, MB BCh · Robert Grove PhD · Andrew M Guilfoyle PhD

Objective: To assess the accuracy and variability of clinicians’ estimates of pre-test probability for three common clinical scenarios.Design: Postal questionnaire survey conducted between April and October 2001 eliciting pre-test probability estimates from scenarios for risk of ischaemic heart disease (IHD), deep vein thrombosis (DVT), and stroke.Participants and setting: Physicians and general practitioners randomly drawn from College membership lists for New South Wales and north-west England.Main outcome measures: Agreement with the “correct” estimate (being within 10, 20, 30, or > 30 percentage points of the “correct” estimate derived from validated clinical-decision rules); variability in estimates (median and interquartile ranges of estimates); and association of demographic, practice, or educational factors with accuracy (using linear regression analysis).Results: 819 doctors participated: 310 GPs and 288 physicians in Australia, and 106 GPs and 115 physicians in the UK. Accuracy varied from about 55% of respondents being within 20% of the “correct” risk estimate for the IHD and stroke scenarios to 6.7% for the DVT scenario. Although median estimates varied between the UK and Australian participants, both were similar in accuracy and showed a similarly wide spread of estimates. No demographic, practice, or educational variables substantially predicted accuracy.Conclusions: Experienced clinicians, in response to the same clinical scenarios, gave a wide range of estimates for pre-test probability. The development and dissemination of clinical decision rules is needed to support decision making by practising clinicians.

John R Attia MD, PhD, FRCPC · David W Sibbritt PhD · Ben D Ewald BMed, MMedSci · Balakrishnan R Nair FRCP, FRACP · Neil S Paget MA, DipEd · Rod F Wellard MEd, PhD · Lesley Patterson · Richard F Heller MD, FRCP

Objective: To assess trends in selenium status in South Australians from 1977 to 2002.Design: Six cross-sectional surveys.Participants: 117 participants in 1977, 30 in 1979, 96 and 103 (separate surveys) in 1987, 200 in 1988, and 288 volunteer blood donors in 2002. A total of 834 healthy Australian adults (mean age, 42 years [range, 17–71 years]; 445 were male).Main outcome measures: Plasma and whole blood selenium concentrations.Results: The 2002 survey yielded a mean plasma selenium concentration of 103 μg/L (SE, 0.65), which reached the estimated nutritional adequacy level of 100 μg/L plasma selenium. Mean whole blood selenium declined 20% from the 1977 and 1979 surveys (mean whole blood selenium concentration, 153 μg/L) to the 1987, 1988 and 2002 surveys (mean whole blood selenium concentration, 122 μg/L). Plasma selenium was higher in men (P = 0.01), and increased with age in both men and women (P = 0.008).Conclusions: In healthy South Australian adults sampled from 1977 to 2002, whole blood and plasma selenium concentrations were above those reported for most other countries and in most previous Australian studies, notwithstanding an apparent decline in selenium status from the late 1970s to the late 1980s.

Graham H Lyons BAgricSc, MPH · James C R Stangoulis BAgricSc, PhD · Lyndon T Palmer BSc · Robin D Graham PhD, DAgricSc · Geoffrey J Judson BRurSc, PhD · Janine A Jones BCom/Eco, MStatSocAust

Objective: To examine whether proton-pump inhibitor (PPI) therapy influences the incidence and progression of dysplasia in patients with Barrett’s oesophagus.Design and setting: Review of prospective data on patients undergoing surveillance with regular endoscopy and biopsy at a private endoscopy centre in Canberra, ACT, between 1981 and 2001.Patients: 350 patients diagnosed with Barrett’s oesophagus.Interventions: PPI therapy was progressively introduced into clinical practice from late 1989. Once begun, PPI therapy was ongoing, with no attempt to reduce the dose.Main outcome measures: Relationship between development of dysplasia or adenocarcinoma and delay between diagnosis with Barrett’s oesophagus and starting PPI therapy was determined by Cox regression analyses, stratified by year of enrolment. Age, sex, presence of macroscopic markers (severe oesophagitis, nodularity, Barrett’s ulcer, stricture) and use of aspirin or non-steroidal anti-inflammatory drugs were considered as confounding factors in the regression analyses.Results: The 350 patients had 1422 surveillance endoscopies, with a median follow-up of 4.7 years. Patients who delayed using a PPI for 2 years or more after diagnosis with Barrett’s oesophagus had 5.6 times (95% CI, 2.0–15.7) the risk of developing low-grade dysplasia at any given time as those who used a PPI in the first year. Similar results were found for the risk of developing high-grade dysplasia or adenocarcinoma (hazard ratio, 20.9; 95% CI, 2.8–158).Conclusions: Use of ongoing PPI therapy appeared beneficial in the prevention of dysplasia and adenocarcinoma in patients with Barrett’s oesophagus. We suggest that all patients with this condition, even those with no oesophagitis or symptoms, should be encouraged to continue long term PPI therapy.

Lybus C Hillman MD, FRACP · Louise Chiragakis MA · Graham L Kaye FRACP · Anthony C Clarke FRCP, FRACP · Bruce Shadbolt PhD

Objective: To evaluate changes in quality of in-hospital care of patients with either acute coronary syndromes (ACS) or congestive heart failure (CHF) admitted to hospitals participating in a multisite quality improvement collaboration.Design: Before-and-after study of changes in quality indicators measured on representative patient samples between June 2001 and January 2003.Setting: Nine public hospitals in Queensland.Study populations: Consecutive or randomly selected patients admitted to study hospitals during the baseline period (June 2001 to January 2002; n = 807 for ACS, n = 357 for CHF) and post-intervention period (July 2002 to January 2003; n = 717 for ACS, n = 220 for CHF).Intervention: Provision of comparative baseline feedback at a facilitative workshop combined with hospital-specific quality-improvement interventions supported by on-site quality officers and a central program management group.Main outcome measure: Changes in process-of-care indicators between baseline and post-intervention periods.Results: Compared with baseline, more patients with ACS in the post-intervention period received therapeutic heparin regimens (84% v 72%; P < 0.001), angiotensin-converting enzyme inhibitors (64% v 56%; P = 0.02), lipid-lowering agents (72% v 62%; P < 0.001), early use of coronary angiography (52% v 39%; P < 0.001), in-hospital cardiac counselling (65% v 43%; P < 0.001), and referral to cardiac rehabilitation (15% v 5%; P < 0.001). The numbers of patients with CHF receiving β-blockers also increased (52% v 34%; P < 0.001), with fewer patients receiving deleterious agents (13% v 23%; P = 0.04). Same-cause 30-day readmission rate decreased from 7.2% to 2.4% (P = 0.02) in patients with CHF.Conclusion: Quality-improvement interventions conducted as multisite collaborations may improve in-hospital care of acute cardiac conditions within relatively short time frames.

for the CHI Cardiac Collaborative*

Objective: To estimate the effectiveness of a new high-performance Australian medical sheepskin (meeting Australian Standard 4480.1-1998) in preventing pressure ulcers in a general hospital population at low to moderate risk of these ulcers.Design: Open-label randomised controlled clinical trial.Setting: A large metropolitan teaching hospital in Melbourne, Victoria, in 2000.Participants: 441 patients aged over 18 years admitted between 12 June and 30 November 2000, with expected length of stay over 2 days and assessed as at low to moderate risk of developing pressure ulcers.Intervention: Patients were randomly allocated to receive a sheepskin mattress overlay for the duration of their hospital stay (218 patients) or usual treatment, as determined by ward staff (referent group, 223 patients).Main outcome measures: Incidence rate and cumulative incidence of pressure ulcers, assessed daily throughout hospital stay.Results: 58 patients developed pressure ulcers (sheepskin group, 21; referent group, 37). Cumulative incidence risk was 9.6% in the sheepskin group (95% CI, 6.1%–14.3%) versus 16.6% in the referent group (95% CI, 12.0%–22.1%). Patients in the sheepskin group developed new pressure ulcers at a rate less than half that of referent patients (rate ratio, 0.42; 95% CI, 0.26–0.67).Conclusions: The Australian Medical Sheepskin is effective in reducing the incidence of pressure ulcers in general hospital inpatients at low to moderate risk of these ulcers.

Damien J Jolley MSc(Epi), MSc · Robyn Wright RN, GradDipAppSci(SM) · Sunita McGowan RN, MAppSci · Mark B Hickey BAppSci(Hons) · Kenneth C Montgomery BSc, PhD · Don A Campbell MD, MMedSci(ClinEpi) · Rodney D Sinclair FACD

Objective: To assess obstetricians’ current antenatal screening practices for blood-borne viruses (hepatitis B, hepatitis C and HIV) and how they manage pregnant women infected with a blood-borne virus.Design and participants: National cross-sectional survey conducted between September 2002 and January 2003. All obstetricians (n = 767) registered with the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) were mailed a questionnaire assessing their antenatal screening practices and knowledge of management of women potentially infected with a blood-borne virus.Outcome measures: Concordance of clinical practice with RANZCOG recommendations and current evidence-based guidelines.Results: 523 obstetricians (68% response rate) completed the questionnaire. Fifty-one per cent of respondents said they would always offer HIV screening and 60% would always offer HCV screening. For HIV-infected women, 36% of obstetricians would always recommend elective caesarean section and 33% would always avoid rupture of membranes. Despite a lack of evidence, 34% of obstetricians advise patients that the risk of HBV transmission is increased with breastfeeding, and 47% give the same advice about HCV transmission.Conclusion: There is some discordance between the RANZCOG antenatal screening recommendations for HCV and HIV and current practice. Knowledge about the management of HIV-infected women could be improved, and more obstetricians need to be aware that current evidence suggests there is no increased risk of transmission of HBV or HCV with breastfeeding.

Michelle L Giles MB BS · Suzanne M Garland MB BS, FRCPA, FRANZCOG · Joseph J Sasadeusz MB BS, FRACP, PhD · Sonia R Grover MB BS, FRANZCOG · Margaret E Hellard MB BS, FRACP, PhD

Objective: To describe the patterns of use of cardiac rehabilitation in Victoria and to assess whether the survival benefits predicted in clinical trials have been realised in the community. Design: Cohort study based on data linkage. Participants: All patients admitted for acute myocardial infarction (AMI), coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) in Victoria in 1998 (n = 12 821). Interventions: Attendance at one of 66 participating outpatient cardiac rehabilitation centres in Victoria. Main outcome measures: Rates of attendance at rehabilitation based on key factors such as diagnosis, age, sex, and comorbidity. Five-year survival for attendees compared with non-attendees. Results: Rates of participation in rehabilitation were 15% for AMI, 37% for CABG, and 14% for PTCA. Rehabilitation attendance rates dropped sharply after 70 years of age. Attendees had a 35% improvement in 5-year survival (hazard ratio for death associated with rehabilitation attendance, 0.65 [95% CI, 0.56–0.75]). Conclusions: Attendance rates at cardiac rehabilitation are suboptimal, even though attendance confers a clinically significant difference in 5-year survival. The elderly, women, and those with comorbid conditions may benefit measurably from increased rates of attendance.

Vijaya Sundararajan MD, MPH, FACP · Stephen Begg MPH · Ric Marshall PhD · Stephen J Bunker PhD · Helen McBurney PhD

Objective: To determine the change in prevalence of asthma, eczema and allergic rhinitis in Australian schoolchildren between 1993 and 2002.Design: Questionnaire based survey, using the protocol of the International Study of Asthma and Allergy in Childhood.Setting: Metropolitan Melbourne primary schools within a 20 km radius of the GPO in 1993 and 2002.Subjects: All children in school years 1 and 2 (ages 6 and 7) attending a random sample of 84 schools in 1993 and 63 schools in 2002.Main outcome measures: Parent-reported symptoms of atopic disease; treatment for asthma; country of birth.Results: There was a 26% reduction in the 12-month period prevalence of reported wheeze, from 27.2% in 1993 to 20.0% in 2002. The magnitude of reduction was similar for boys (27%) and girls (25%). The 12-month period prevalence of reported eczema increased from 11.1% in 1993 to 17.2% in 2002, and rhinitis increased from 9.7% to 12.7%. There were reductions in the proportion of children attending an emergency department for asthma in the previous year (3.6% to 2.3%), the proportion admitted to hospital (1.7% to 1.1%) and the proportion taking asthma medication (18.5% to 13.4%). Of those who reported frequent wheeze, there was an increase in the proportion taking regular inhaled steroids (34.5% to 40.9%).Conclusion: There has been a significant reduction in the prevalence of reported asthma in Melbourne schoolchildren, whereas the prevalence of eczema and allergic rhinitis has continued to increase.

Colin F Robertson MD, FRACP · Mary F Roberts BAppSci · Johanna H Kappers BNursSci

Objectives: (i) To evaluate the benefits and adverse effects of a Diabetes Day Care Program (DDCP); and (ii) to compare outcomes in two cohorts diagnosed before and after implementing the DDCP (“pre-DDCP” and “post-DDCP”).Design: Outcomes from the pre-DDCP cohort were compared with those of the post-DDCP cohort.Setting: The study was conducted from March 2001 to October 2002 at the Children’s Hospital at Westmead.Participants: The pre-DDCP cohort comprised all children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n = 49). The post-DDCP cohort were those diagnosed from November 2000 to August 2001 (n = 61).Main outcome measures: Length of stay, adverse events, insulin requirement and glycohaemoglobin (HbA1c) level over the first year after diagnosis were ascertained from medical records. Questionnaires to measure parents’ knowledge of diabetes, emotional adjustment to diabetes, and responsibility for and conflict over specific diabetes management tasks were completed by parents at 6-monthly intervals.Results: Median length of hospital stay decreased from 5.14 days (range, 2–10) to 1.70 days (range, 0–10) (P < 0.001). There were no differences between the two cohorts in insulin requirement at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8–1.0]; post-DDCP: 0.8 U/kg [95% CI, 0.7–0.9]; P = 0.22), HbA1c level at 12 months (pre-DDCP: 8.4% [95% CI, 8.0%–8.9%]; post-DDCP: 8.2% [95% CI, 7.9%–8.5%]; P = 0.37) and adverse events over the first year after diagnosis. Both groups reported similar scores for the parental questionnaires.Conclusions: Ambulatory stabilisation of children with type 1 diabetes provides similar metabolic outcomes for the child, and comparable levels of diabetes knowledge and similar psychosocial outcomes for the family, to inpatient stabilisation programs.

Shubha Srinivasan MB BS, FRACP · Maria E Craig FRACP, PhD · Linda Beeney PhD · Rachel Hayes MND · Nuala Harkin RSCN, APN · Geoffrey R Ambler FRACP, MD · Kim C Donaghue FRACP, PhD · Christopher T Cowell MB, FRACP

Objective: To identify prescription drug-seeking behaviour patterns among young people who subsequently died of heroin-related overdose.Design: Linkage of Medicare and Pharmaceutical Benefits Scheme and Coroner’s Court records from Victoria.Subjects: Two hundred and two 15–24-year-olds who died of heroin-related overdose between 6 January 1994 and 6 October 1999.Main outcome measures: Patterns of use of medical services and prescription drugs listed on the Pharmaceutical Benefits Scheme in the years before death, and use of all drugs just before death.Results: Polydrug use was reported in 90% of toxicology reports, and prescription drugs were present in 80% of subjects. Subjects accessed medical services six times more frequently than the general population aged 14–24 years, and more than half of all prescribed drugs were those prone to misuse, such as benzodiazepines and opioid analgesics. A pattern of increasing drug-seeking behaviour in the years before death was identified, with doctor-visitation rates, number of different doctors seen and rates of prescriptions peaking in the year before death.Conclusions: An apparent increase in “doctor shopping” in the years before heroin-related death may reflect the increasing misuse of prescription drugs, but also an increasing need for help. Identification of a pattern of escalating doctor shopping could be an opportunity for intervention, and potentially, reduction in mortality.

Raymond F Martyres MB BS, MMed, FRACGP · Danielle Clode BA(Hons), DPhil(Oxon) · Jane M Burns BA(Hons), PhD

Objective: To determine changes in morbidity and management of disease in children in Australian general practice.Design and setting: A comparative study of general practice consultations in children under 15 years, using data from cross-sectional general practice surveys (1990–91 and 2000–01), and a descriptive comparison with a similar study from 1971.Main outcome measures: Relative rates of management (rate/100 general practice encounters) of the most common children’s problems and treatments.Results: Problems with significantly higher management rates in 2000–01 compared with 1990–91 included vaccination (11.1 v 7.6 per 100 encounters in 1990–91) and contact/allergic dermatitis (3.1 v 2.5). Those managed significantly less often in 2000–01 v 1990–91 included acute otitis media (7.7 v 9.4), asthma (5.4 v 8.8), tonsillitis (4.4 v 6.0), acute bronchitis (3.8 v 5.3) and gastroenteritis (1.7 v 2.7). Asthma management rates rose from 2.4% of all problems managed in 1971 to 7.2% in 1990–91, then fell in 2000–01 to 4.6%. More frequent rates of counselling and advice in 2000–01 (28.4% of encounters v 22.9% in 1990–91) were associated with a decrease in rates of prescribing and supply of medication (56.6% of encounters v 64.3% in 1990–91). Antibiotic prescribing declined significantly (from 33.8 per 100 encounters in 1990–91 to 25.2 in 2000–01), as did prescribing of respiratory medications (from 15.5 to 9.9 per 100 encounters), while prescribing of vaccines and systemic corticosteroids doubled (from 9.6 to 18.8 per 100 encounters, and from 0.6 to 1.2, respectively). (All comparisons between 1990–91 and 2000–01 are significant at P < 0.01.)Conclusions: These findings point to the emergence of a generation of Australian children who are generally well vaccinated and are less likely to present to GPs with “traditional” childhood illnesses.

Janice Charles BA, MSc(Med) · Ying Pan MCH · Helena Britt BA, PhD

Objective: To determine whether medical graduates who spent their intern year at a non-metropolitan hospital were more likely to practise outside metropolitan areas on completion of training than were interns in metropolitan hospitals.Design: Retrospective follow-up of doctors who held year-long internships at a non-metropolitan hospital and interns from metropolitan hospitals.Setting: Ballarat Base Hospital (BBH) (Rural, Remote and Metropolitan Area [RRMA] rural zone) and hospitals in Melbourne and Geelong (RRMA metropolitan zone).Participants: 57/63 (90%) Victorian medical graduates completing internships at BBH between 1989 and 1997 and 126/126 (100%) sex-matched metropolitan interns, chosen at random.Main outcome measures: Practice location in 2002.Results: More BBH interns were practising as GPs outside metropolitan areas (44%) than metropolitan interns (13%) (difference, 31%; 95% CI, 17%–45%). The proportion of interns in specialist practice outside metropolitan areas was small for both groups — zero and 3%, respectively (difference, − 3%; 95% CI, − 6% to 0). None of the specialist training posts held by interns were outside metropolitan areas. Of BBH interns entering general practice, 41% (95% CI, 24%–58%) did so in the local health region.Conclusions: Regional interns are a good source of non-metropolitan GPs, especially locally. Prospective studies to determine the precise influence of regional internships on eventual practice location, and whether more such posts would lead to more graduates entering non-metropolitan practice, would be worthwhile.

Hedley G Peach PhD, FFPH · Maxine Trembath · Bernie Fensling BSc, MB BS

Objectives: To determine the causes of sudden cardiac death in people aged 35 years or younger.Design and setting: A review of all autopsies performed between 1 January 1994 and 31 December 2002 at a major Sydney forensic medicine department serving an area with over 2 million people.Main outcome measures: Incidence of various types of cardiac disease causing sudden death in those aged ≤ 35 years; proportion of deaths in which no cause was found at autopsy.Results: There were 10 199 autopsies performed during the study period. Of these, 2986 (29.2%) deaths occurred in people aged ≤ 35 years; 193 were classified as sudden cardiac deaths. The cause of sudden death in this group was not established in 60 (31%), and was presumed to be due to primary arrhythmogenic disorders. Coronary artery disease occurred in 46 (24%), hypertrophic cardiomyopathy/unexplained left ventricular hypertrophy in 29 (15%), and myocarditis in 23 (12%).Conclusions: Unexplained deaths, presumed to result from sudden primary arrhythmogenic causes, occur in young Australians with structurally normal hearts. That underlying disease-causing genetic defects may be involved has clinical implications for family members.

Alessandra Doolan BMedSc · Christopher Semsarian MB BS, PhD, FRACP · Neil Langlois MB BChir, MD, FRCPA

Objective: To explore the reasons why individuals recurrently present with asthma to hospital emergency departments.Design: A predominantly qualitative study in which participants were interviewed in-depth about their asthma. Data on medication use, respiratory health and asthma knowledge were also collected, and asthma severity was determined from medical records.Setting: A tertiary teaching hospital and a suburban hospital emergency department (ED) from 1 March to 30 April 2000, and a rural hospital ED from 1 July to 31 August 2000.Participants: The participation rate was 32% of an initial 195 ED attendees (183 of whom were eligible) aged 18–70 years: 32 had presented to an ED for asthma care on more than one occasion over the preceding 12 months (reattendees), and 29 were non-reattendees.Results: Two-thirds (22/32) of reattendees had chronic severe asthma and presentation to ED was deemed appropriate for 18 of these, indicated by recurrent severe asthma attacks despite seeking prior medical intervention. Reasons for re-presentation identified in a third of all reattendees included poor asthma knowledge, and financial and other barriers to medication use.Conclusions: We identified potentially preventable issues in about a third of patients (most of whom had mild to moderate asthma) who recurrently presented to EDs for treatment. The remainder of the participants sought emergency asthma treatment appropriately after failing to respond to medical care, and this was frequently in accordance with their asthma management plans.

Dianne P Goeman MA, GradDipSoc · Francis C K Thien MD, FRACP · Jo A Douglass MD, FRACP · Rosalie A Aroni PhD · Michael J Abramson PhD, FRACP · Susan M Sawyer MD, FRACP · Kay Stewart PhD, BPharm(Hons)

Objectives: To describe the location of treatment, recruitment to clinical trials and outcomes for adolescents and young adults treated for cancer in Victoria.Design and setting: Retrospective review of all adolescents and young adults aged 10–24 years diagnosed with cancer between 1992 and 1996, identified from the Victorian Cancer Registry.Main outcome measures: Treatment regimen (clinical trial, treatment protocol or neither), compliance with treatment and 5-year survival.Results: Questionnaires were completed for 576 of 665 eligible adolescents and young adults (87% response rate). Recruitment into clinical trials decreased with increasing age. Adolescents aged 10–19 years were more likely to be recruited to a clinical trial if treated at a paediatric hospital. For all cancers, 5-year survival was similar across the age groups and was not influenced by the place of treatment. Only 1% of adolescents and young adults failed to complete planned therapy due to non-compliance.Conclusions: Despite a similar incidence of cancer to that in younger children, adolescents and young adults with cancer are poorly recruited into clinical trials in Victoria. Establishment of a cancer resource network in Victoria may provide information to both paediatric and adult oncologists about currently available clinical trials.

Anne E Mitchell MB ChB, FRACP · Deborah L Scarcella BSc, GradDip · Gemma L Rigutto BSc, GradDip · David M Ashley PhD, FRACP · Vicky J Thursfield BSc, GradDip · Graham G Giles MSc, PhD · Maree Sexton MB BS, FRANZCR

Objective: To determine how familiar human research ethics committees (HRECs) are with the principles of natural justice and whether they apply these principles.Design and setting: A postal survey conducted between April and September 2002 of the Chairs of all HRECs registered with the Australian Health Ethics Committee of the National Health and Medical Research Council (NHMRC) in 2001.Main outcome measures: HRECs’ reported familiarity with, and application of, three principles of natural justice: (1) the hearing rule, requiring a decision maker to allow a person affected by a decision to present his or her case; (2) the rule against bias, requiring a decision maker to be unbiased in the matter to be decided; and (3) the evidence rule, requiring that a decision be based on the evidence provided, and not irrelevant issues.Results: From 201 Chairs of HRECs Australia-wide, we received 110 completed questionnaires (55% response rate). About 33% of respondents were very familiar with the principles of natural justice, and 25% completely unfamiliar. Most respondents felt that natural justice should be, and usually is, applied by HRECs. In cases of possible positive bias of an HREC member towards a research proposal, 70% of respondents said they would exclude the member from decision making. In cases of possible negative bias, 43% said they would exclude the HREC member.Conclusion: The degree of familiarity with principles of natural justice varies widely among Chairs of HRECs. While many respondents felt that HRECs usually apply natural justice, responses to questions about bias suggest that HRECs do not always exclude members with possible bias, contrary to NHMRC guidelines.

Gabrielle L Van Essen CertNurs, MB BS, FANZCA · David A Story BMedSci(Hons), MB BS(Hons), FANZCA · Stephanie J Poustie BN, CritCareCert, MPH · Max M J Griffiths MBE, BA, BD · Cynthia L Marwood LLB, LLM

Objective: To establish the prevalence and predictors of skin screening by general practitioners in regional Queensland.Design: Questionnaire administered to participants by professional interviewers via telephone.Participants and setting: Participants were 3100 adults aged ≥ 30 years (66.9% overall response rate), selected from residents of 18 regional Queensland communities with populations of between 2000 and 10 000 (as recorded in the 1996 Australian census). Within the last 10 communities surveyed, an additional telephone survey of 727 participants evaluated mole density. The survey was conducted between January and October 1998.Main outcome measure: Prevalence of whole-body skin examinations by GPs.Results: 11% of participants reported a whole-body skin examination by a GP during the previous 12 months, and 20% during the previous 3 years. Men and women reported a similar prevalence of whole-body skin examinations. Factors associated with a significantly increased likelihood of having had a whole-body skin examination within the previous 3 years included a positive attitude towards skin screening, a personal history of non-melanoma skin cancer, a tendency to burn, and having more than four moles on the right upper arm.Conclusions: A substantial proportion of Queenslanders undergo skin screening. Those at highest risk for skin cancer are more likely to be screened.

Monika Janda PhD · Philippa H Youl MPH · Joanne F Aitken PhD · Mark Elwood MD · Ian T Ring FAFPHM · David W Firman MMath · John B Lowe DrPH

Objective: To identify doctor and patient characteristics associated with excision of benign versus malignant pigmented skin lesions.Design, setting and participants: Retrospective audit of data on 4741 pigmented skin lesions excised from November 1998 to February 2000 by 468 general practitioners (39% response rate) from 223 practices in Perth, WA. (The data used were from the baseline period of a randomised controlled trial of a diagnostic aid for pigmented skin lesions.)Main outcome measure: The number needed to treat (NNT), defined as the number of pigmented lesions needed to be excised to identify one melanoma, in relation to demographic characteristics of GPs and patients.Results: Relatively more benign lesions were excised per melanoma (NNT = 83) in the youngest patients (aged 10–19 years) compared with the oldest (aged ≥ 70) (NNT = 11) (P [trend] < 0.001), in females (NNT = 37) compared with males (NNT = 23) (P = 0.02), and in the most socioeconomically disadvantaged (NNT = 60) compared with the least disadvantaged group (NNT = 20) (P [trend] < 0.001). The most recently graduated GPs excised more benign lesions for each melanoma (NNT = 59) than the least recently graduated (NNT = 22) (P [trend] = 0.01).Conclusions: GPs could raise their threshold for excising pigmented lesions in patients who are young, female, or from areas of low socioeconomic status, or if the GPs themselves are recent graduates.

Dallas R English PhD · Chris Del Mar MD · Robert C Burton MD, PhD

Objective: To investigate the efficacy of continuous infusion of hydrocortisone with or without chlorpheniramine bolus against early adverse reactions to polyspecific antivenom.Design and setting: Prospective, double-blind, randomised, placebo-controlled trial at General Hospital, Anuradhapura, Sri Lanka.Subjects: 52 patients with snake envenoming were randomised to receive infusion of hydrocortisone (Group A), hydrocortisone with chlorpheniramine bolus (Group B) or placebo (Group C) during the administration of antivenom.Intervention: Hydrocortisone 1000 mg in 300 mL of normal saline infusion was started 5 min before and continued for 30 min after antivenom. Chlorpheniramine 10 mg intravenous bolus dose was given 5 min after commencement of antivenom.Main outcome measures: Occurrence and severity of adverse reactions to antivenom.Results: Adverse reactions were observed in 80% (12/15) of Group A, 52% (11/21) of Group B, and 81% (13/16) of Group C. Reactions were mild or moderate except in two patients. A significant reduction in the number of adverse reactions was seen in Group B compared with the placebo group (difference, 29 percentage points; 95% CI, 0.2 to 58 percentage points). There was no significant difference between Group A and the placebo group.Conclusion: Prophylaxis with a parallel hydrocortisone infusion alone is ineffective in reducing the occurrence of acute adverse reaction to antivenom serum, but combining it with chlorpheniramine seems efficacious.

Indika Bandara Gawarammana MB BS · S Abeysingha M Kularatne MB BS, MD, FRCP(UK) · Ranjith P V Kumarasiri MB BS, MSc, MD · Nimal Senanayake PhD, DSc, FRCP · Wasantha P Dissanayake MB BS, DCH, MD · H Ariyasena MB BS, MD, MRCP

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

Along with its new graduate-entry medical program, the University of Sydney has introduced the Combined Degree (Research) Program which allows students to graduate with an MB BS and PhD. The program includes 2–3 years of full-time research between Years 2 and 3 of the 4-year MB BS program. The program aims to produce clinician–scientists committed to continuing research that reflects their experience of clinical practice. Eight women and 23 men have enrolled since the program began in 1998, with the first cohort graduating in 2003. The students have been active in helping to develop the program and establishing a society and other student support networks.

Brian D Power BMedSc(Hons) · Andrew J White BMedSc(Hons), MB BS, PhD · Ann J Sefton AO, PhD, DSc

Objective:To describe the policy and practice relating to cardiopulmonary resuscitation (CPR) and defibrillation in cardiac arrest in Australian hospitals.Design:Cross-sectional postal survey conducted in December 2001, using a semi-structured, four-page questionnaire.Participants:Australian hospitals with more than 10 beds.Main outcome measures:Type of defibrillator; provision of CPR/defibrillation training for healthcare professionals; hospital policy as to who can use the defibrillator.Results:Of the 878 hospitals surveyed, 665 (76%) responded. All but one hospital indicated that CPR training was provided for nursing staff, with 12-monthly or more frequent updates; only 55% of hospitals (366) indicated that CPR training was provided for doctors. 21 of the 665 responding hospitals (3.2%) indicated that they did not have a defibrillator. 43% of hospitals had one or more defibrillators with shock advisory capacity (ie, automated external defibrillators [AEDs]). Of the 644 hospitals with defibrillators, 16% (101) indicated that registered nurses were not permitted to defibrillate; this included 9% of hospitals with AEDs.Conclusions:The importance of CPR in cardiac arrest has been accepted by Australian hospitals, but the overwhelming evidence that “time to defibrillation” is the single most important determinant of cardiac arrest outcome seems less accepted. All Australian hospitals should review their resuscitation policies and practices to reflect this fact, with defibrillation by nurses, who are usually first on the scene, providing the best opportunity to minimise time to defibrillation.

Judith C Finn PhD, RN · Ian G Jacobs PhD, RN