Volume 176 Issue 1

The special healthcare needs of young people have long been recognised, but, before 1990, much of Australian adolescent medical practice was confined to small inpatient units in the major city paediatric hospitals. Other facets of adolescent healthcare — primary care, sexual and reproductive health, student health and mental health — operated independently. This was in stark contrast to North America, where the specialty of adolescent medicine had taken the lead in adolescent healthcare for three decades. Centres for Adolescent Health. Much has now changed. The establishment of Centres for Adolescent Health in Melbourne, Sydney and Auckland has signalled a broader role for adolescent medicine. Shifting disease patterns lie behind these developments. Cancer, cardiovascular disease and neuropsychiatric disorders have become health priorities in an ageing population, highlighting the need for preventive and early interventions in younger people. Adolescent disease patterns have also shifted. Infectious diseases, both blood-borne (hepatitis C, HIV) and sexually transmitted (HIV, herpes, chlamydia), pose new threats. Drug dependence, eating disorders and depression have become common. Longer survival in young people with chronic illnesses and disabilities (eg, spina bifida, cystic fibrosis) has introduced complicating psychosocial and behavioural problems. In response to these trends, adolescent medicine has embraced preventive models of care, incorporating new clinical skills and building working relationships across the spectrum of health and welfare practice. The role of specialist adolescent units has been questioned, but the number of young people admitted to hospital in the United Kingdom justifies regional adolescent inpatient units.1 In Australia, their popularity with young people (and clinical staff) and their families is a strong endorsement.2 Prevention and early intervention. The care of adolescents with chronic physical illness extends beyond the acute problems (that trigger inpatient admission) to previously undiagnosed morbidities with longer-term health implications. It is now usual to screen for psychosocial and behavioural problems affecting adherence with therapeutic regimens and, in the case of tobacco and substance misuse, possibly causing early complications. Advances in other fields of medical practice have extended the scope for prevention, with simple immunological screens for hepatitis B and C, and HIV, and vaccination for hepatitis B. So too has the introduction of clinical tools such as HEADSS, a psychosocial screen covering an adolescent's Home life, Education, recreational Activities, Drugs, Sexuality and Suicide risk/depression.3 Prevention, early diagnosis and intervention have come to dominate the care of marginalised groups, such as young offenders and homeless youth, in whom risks for blood-borne and sexually transmitted infectious diseases, substance dependence and major psychiatric disorders are very high. An emphasis on prevention and early intervention is also important in the common health problems of teenagers — depression, substance dependence, eating disorders and obesity. The greatest barrier to effective early intervention is engagement with young patients. General practitioners are the healthcare providers most commonly accessed, but most consultations are for acne, respiratory and musculoskeletal problems rather than the major causes of disease burden in this age group. Practitioner lack of confidence, skills and training in dealing with adolescent mental health and behavioural problems explains some of the unmet need. To enhance competencies in adolescent healthcare, practitioners need well-designed training based on an understanding of adolescent development, a full risk assessment, sound communication skills and a respect for confidentiality.4 With greater Medicare card ownership and the availability of longer GP consultations, adolescent access to healthcare, perhaps in the form of a "wellness" visit, would improve substantially.5 Diagnosis and intervention. New diagnostic concepts have also changed clinical practice and revealed previously under-recognised problems, such as adolescent depression and attention deficit hyperactivity disorder (ADHD) persisting beyond puberty. Prodromal and subsyndromal forms of less common disorders, such as schizophrenia and anorexia nervosa, have also been recognised. Interventions (pharmacological, educational and psychotherapeutic) used in other age groups have been adapted and shown to be efficacious in adolescents. Cognitive-behavioural treatments of depression and eating disorders, motivational interviewing for adolescent substance misuse, and pharmacotherapy for ADHD, depression or prodromal psychosis, have all shown promise in influencing short-term outcomes and even preventing the onset of fully-fledged disorders. Conclusion. Australian adolescent medicine practice has moved from being a narrow specialty to a flourishing generality, dealing with common health problems and providing a point of convergence for disciplines such as paediatrics, primary care, psychiatry, and internal medicine. The potential for an integrative approach, emphasising prevention and early intervention, is clear, but is currently constrained by a disconnection in health policies for mental health, acute care, substance misuse and services for high risk groups. The need for a coherent adolescent and youth health policy across government has never been greater.

George C Patton · Lena A Sanci · Susan M Sawyer

The role of aged care in the practice of medicine is becoming more prominent with the increase in the proportion and absolute numbers of older people in our population. This is associated with an increase in diseases of advanced age — the neurodegenerative diseases, vascular diseases, and musculoskeletal disorders. Over the past five years significant advances have occurred in the management of these diseases and in the organisation of clinical services for older people. Prevention. Research in the high-prevalence problem areas of dementia and falls has shown that at least one in every 20 people in our population aged 65 years and older will suffer from dementia, with a large burden of care being placed on family members and community and health services. There is preliminary evidence that anti-inflammatory drugs and vitamin E may be protective against Alzheimer's disease, but the preventive role of folic acid (reducing homocysteine levels) and oestrogen is still under investigation.1 Falls and osteoporotic fractures are common: about 30% of older people fall at least once a year; between 4% and 5% of these falls result in fractures. Exercise, particularly balance, lower-limb strength training and walking, reduces the risk of both falling and sustaining a fall-related injury.2 Hip protectors (pads or shields which absorb, or divert to surrounding tissues, the energy of a fall onto the greater trochanter) have been shown to be effective in reducing hip fractures in older people who live in residential-care facilities.3 Compliance with their use has been variable, and their use in community settings still needs to be evaluated. The Commonwealth Government's Enhanced Primary Care Initiative, introduced in late 1999, includes an annual health assessment by general practitioners for people aged 75 years and over. While the impact of this initiative is yet to be evaluated, the aim is to prevent illness and improve health by providing patients with a written report and recommendations on staying healthy. Influenza vaccination, another important preventive measure, is encouraged as part of this assessment. This initiative also incorporates the National Falls Prevention for Older People strategy by encouraging GPs to identify and promote best practice in prevention and treatment of falls. Intervention. Recent advances in aged care have occurred in medication availability and service delivery. The cholinesterase inhibitors are the first medications to provide modest symptomatic improvement in cognition, function and behavioural symptoms for people with mild to moderate Alzheimer's disease.1 Their use requires a specialist diagnosis and evidence of improvement. As yet, there is no evidence that they alter progression of the disease. However, vitamin E (1000 IU twice daily) has been shown to delay clinical deterioration in established Alzheimer's disease. For older patients with documented osteoporosis, the bisphosphonates are recommended as a first-line treatment; in these patients they reduce vertebral fractures by about 50%. Raloxifene, a selective oestrogen-receptor modulator, modestly increases bone density and reduces the risk of vertebral fractures. The newer classes of antidepressants, including the specific serotonin reuptake inhibitors and the serotonin and noradrenaline reuptake inhibitors, have improved the management of depression. While their efficacy is similar to that of the tricyclic antidepressants, their improved side-effect profile means better tolerance, particularly in older people at risk of anticholinergic side effects. The management of stroke has been improved by the introduction of stroke units, which provide comprehensive, interdisciplinary care from the day of admission, often until discharge. Patients admitted to these units show a decrease in mortality, morbidity and disability compared with those receiving standard care.4 The treatment effect appears to be due to the combination of management strategies rather than any one particular intervention. Another improvement in service delivery for older people is the development of the Acute Care of the Elderly Unit (ACE Unit). Older people who are hospitalised often undergo a decline in physical function and these units aim to prevent or ameliorate this decline. The wards are designed with the acutely ill older patient in mind (good lighting, high–low beds, bedside chairs, rails, appropriate floor covering, ensuite bathrooms), with care provided both by the admitting general physician and the consulting geriatrician, and nursing and allied health staff (particularly physiotherapists and occupational therapists) trained in gerontology. The focus of care of the acutely ill older person is not only on the acute illness, but also on the patient's functional state. Randomised trials of these hospital units have shown improved functional outcomes and a reduction in nursing home placement in the intervention group.5 Conclusion. With a rapidly ageing population in Australia, it is important to continue these improvements in aged-care medicine. We need to balance the benefits and harms of new treatments in older patients in whom several disease processes may be operating, and we must evaluate the changes in aged-care service systems.

Susan E Kurrle MB BS, DipGerMed

Despite a scientific history spanning barely five decades, the field of alcohol and drugs is now a legitimate medical subspecialty. The conceptual base is developing, evidence-based approaches are being used, and more effective interventions are now available.1 With the first adoption of a scientific perspective came the development of more rigorous diagnosis and several robust screening questionnaires, which have proved valuable in research but are not yet widely used in clinical practice. Progress has been made in improving detection rates and in providing interventions for at-risk patients. Now, the Royal Australasian College of Physicians is establishing a Chapter of Addiction Medicine, reflecting the growing scientific base of the alcohol and drug field and paving the way for future expansion. Interventions. In the past decade or two, new and more effective drug treatments have been developed, and the pharmaceutical industry now sees alcohol and drug dependence as a new area for research and development. For alcohol dependence, acamprosate has been shown to promote abstinence or assist in reducing alcohol consumption in a substantial proportion of alcohol-dependent patients.2 Naltrexone, an opioid antagonist, may achieve similar results, but the evidence is less impressive than for acamprosate, and naltrexone's action of blocking opioid analgesics precludes pain management with morphine or other opioids. Brief cognitive-behavioural interventions have been used to help "problem drinkers" reduce their drinking to safer levels before their drinking has health, social or financial complications. For smokers, improved forms of nicotine replacement, nicotine replacement without prescription, and the combination of nicotine replacement with bupropion,3 have made smoking cessation more effective. As reduced smoking prevalence owes more to improved smoking cessation rates than to reduced smoking initiation, these are important developments. Smoking prevalence remains unacceptably high in some vulnerable populations, including Indigenous Australians, prison inmates, and people with alcohol and drug or mental health problems. For heroin dependence, buprenorphine, a partial opioid agonist released in Australia in 2001, is the second effective pharmacological treatment, methadone being the first.4 Naltrexone was introduced in 1997 amid extravagant claims for its effectiveness, but these have not been confirmed, strengthening the arguments for a more evidence-based approach. Perhaps the most important recent advance for people with illicit drug dependence has been the belated recognition that health and social interventions are less costly, more effective and less inclined to result in collateral damage than criminal justice interventions. Increasingly, drug treatment is being combined with criminal justice interventions, although methadone treatment, which was introduced officially in Australia in 1970, was not used in prisons in Australia until 1986. Buprenorpine is also very effective for ambulatory heroin detoxification, although obstacles must first be overcome before it can be made readily available from general practices. Management of selected amphetamine-dependent patients with prescribed dexamphetamine has shown encouraging results overseas, and there has been a successful Australian feasibility trial.5 Prevention. Following the decline in per-capita alcohol consumption over the past 20 years, alcohol-related mortality fell substantially during the 1990s. Alcohol-related brain damage declined after the introduction of thiamine-fortified flour in 1991. Tobacco-related deaths have fallen considerably among men and levelled off in women, reflecting the steady decline in smoking prevalence and per-capita tobacco consumption in recent decades. Antismoking campaigns have played a small part in this decline, with other factors including increased prices, reduced advertising, and restrictions on smoking in public places. Outcomes for prevention of illicit drug use have been extremely disappointing. Drug overdose deaths increased from six in 1964 to 958 in 1999, before dropping sharply in 2001 as a result of a "heroin drought". The control of HIV infection among and from injecting drug users in Australia is a major public health achievement, with successful early and comprehensive programs encompassing explicit and peer-based education, needle syringe programs, methadone treatment and community development. Rapid implementation of these programs was facilitated by the adoption of harm minimisation as Australia's official national drug policy in 1985. Remaining challenges. The alcohol and drug field still struggles to be emancipated from moral and politically inspired constraints. Although there are now better outcomes from the intake of legal drugs, they are still responsible for 97% of drug-related mortality. Moreover, alcohol and tobacco account for half of the 20 years' lower life expectancy of Indigenous Australians. Primary and secondary prevention for alcohol and tobacco needs to be more widely available from general practices. General practice is also an appropriate setting for shared-care management of heroin-dependent patients with methadone or buprenorphine. Improved outcomes for illicit drugs await a political decision to accept that health and social interventions are more effective than law enforcement.

Alex D Wodak

The specialty of anaesthesia has seen rapid development of its scientific and clinical basis and equally rapid changes in clinical practice, often driven by the quality and efficiency pressures of modern healthcare delivery. Prevention. Australia has been a world leader in establishing confidential audits of anaesthetic-related deaths, and, more recently, audits of critical incidents.1 Australian anaesthesia is among the safest in the world. The potential to further improve the quality and efficiency of patient care by increased anaesthetic involvement in pre- and postoperative care is increasingly recognised. Patient-controlled analgesia and prolonged epidural analgesia have become routinely available in most hospitals.2 The range of techniques and drugs used is increasing rapidly as we develop a better understanding of the physiology of pain. This has enabled many elderly or "sick" patients to have major surgery, and for other patients to have a much shorter postoperative hospital stay. The crossover from acute to chronic pain is being clinically recognised earlier, and early interventions to treat neuropathic postoperative pain are more common. Most elective surgery patients now arrive in hospital only shortly before their operation. This requires comprehensive preadmission patient assessment, intraprofessional communication and teamwork. Perioperative services, including preadmission clinics staffed by anaesthetists and specialised nurses, are becoming widespread. This has improved patient outcomes, reduced length of stay3 and led to enormous cost savings for the health system generally. Diagnosis. Continuous intraoperative monitoring of many patient variables has become routine and has been shown to improve patient outcomes. The technological development of anaesthetic monitors and "machines" is continuing. Continuous monitoring of the heart by transoesophageal echocardiography is becoming widespread in cardiac surgery. As a low-morbidity procedure providing unparalleled diagnostic information, it promises to become widespread in "sick" patients having non-cardiac surgery. There is some controversy about the use of monitoring aimed at identifying intraoperative awareness. The phenomenon of awareness under general anaesthesia is well recognised, although patients' fear of this may be disproportionate to its actual incidence. New devices (BIS monitoring) that use processed electroencephalographic data to (possibly) detect awareness in individual patients are being evaluated.4 In the United States, media discussion of the problem of awareness, and the possible "prevention" of this by monitoring, has verged on product promotion. Interventions. The widespread adoption of the laryngeal mask has revolutionised airway management. Based on this experience, the appropriate use of the laryngeal mask and endotracheal intubation outside the operating theatre needs to be reviewed. A number of new (and old) drugs are changing anaesthetic practice. Sevoflurane, an inhalational anaesthetic with short action and acceptable smell, has largely displaced halothane, particularly in children. A newer inhalational agent, desflurane, which has even shorter recovery but an unpleasant smell, will probably become widely used for relaxant anaesthesia. Remifentanil, an opioid with a remarkably short duration of action, also promises to change intraoperative anaesthesia, in particular by enabling extremely rapid recovery from deep general anaesthesia. The "setrons" (serotonin 5-HT3 receptor antagonists) have improved the management of perioperative nausea and vomiting. There is renewed interest in ketamine (an NMDA [N-methyl-d-aspartate] antagonist), particularly for pain prevention and management. New analgesics include injectable non-steroidal anti-inflammatory drugs (eg, ketorolac) and tramadol, an opioid which possesses novel non-opiate properties. Combined general and epidural anaesthesia is becoming widespread for major surgery, particularly as the epidural can readily be used for prolonged postoperative analgesia. Cardiac anaesthesia is changing from the traditional approach based on postoperative overnight ventilation to a variety of "fast-track" techniques, including the use of high thoracic epidurals and short-acting drugs. Recent studies identifying the benefits of perioperative β-blockade to prevent myocardial ischaemia for as long as six months postoperatively are increasing the use of this intervention. The adverse effects of inadvertent mild hypothermia are now better recognised, and techniques such as warming of intraoperative fluids and forced-air patient warming are becoming standard. Anaesthetists are now widely involved in intensive/critical care, pain medicine, and preoperative preparation. Complex imaging or therapeutic procedures (such as magnetic resonance imaging, brachytherapy, and endoscopy) mean that anaesthetists are increasingly required outside the operating theatre. There is also a broad need for hospital-based doctors who have procedural skills together with knowledge of acute medicine and perioperative care.5 These demands and pressures mean that the role of anaesthetists (or "hospitalists") may change considerably in the next decade.

Ross K Kerridge

An Australian study, published in 1998, described histological features of breast cancers occurring in young women with germline mutations in two specific genes.1 In 2000, a multicentre US group conducting molecular analysis of a series of diffuse large B-cell lymphomas reported that, within this group of morphologically indistinguishable tumours, two distinct types of lymphoma could be identified by gene-expression profiles, and that these two types had significantly different prognoses.2 Figure: A tissue array containing 109 samples of a specific cancer type, courtesy of Associate Professor Deon Venter, University of Melbourne. These two studies have important implications for the future of diagnostic medicine and anatomical pathology, although the message is different in each case. In the first study,1 Armes and colleagues identified morphological features associated with specific genetic alterations in a group of cancers, combining morphological interpretation and pattern recognition with knowledge of mutations at specific points of the chromosomes in the cancer cells. By examining thin tissue sections stained with vegetable dyes, a pathologist can not only name these cancers, grade them and provide staging information, but can now also suggest likely molecular and genetic events occurring in the tumour cells and assess the likelihood that cancer risk was inherited from the patient's parents and will be passed on to her children. In the second study,2 Alizadeh and colleagues used molecular techniques to identify biological differences between tumours that histopathologists were unable to distinguish microscopically. These techniques allowed a deeper understanding of the biology of the cancer than was possible by morphological examination alone, with significant prognostic implications for patients. So, what will be the impact of molecular biology on diagnostic tissue pathology? Skill in identifying the gross and microscopic features of diseases will remain important in the next few decades. The management of cancer demands more than simply a diagnosis, and much of the information provided by traditional histopathology (eg, margins of surgical excision and data for staging) will still be required. Moreover, much routine diagnostic histopathology and cytopathology involves diagnosis of non-neoplastic conditions — in the foreseeable future, this is likely to be performed most efficiently by individuals trained to recognise these conditions by microscopy. Nevertheless, there is no argument about whether molecular techniques will become important in diagnostic medicine — they already have. Array technology already allows profiles of gene expression to be developed for any specific tumour (see Figure),3 with the prospect in the next few years of therapy directed at specific molecular targets in an individual's tumour. Expertise in morphological interpretation will remain necessary for the utilisation of such techniques (eg, in both the studies described,1,2 morphological recognition of the cancers was vital before molecular analysis could be undertaken). Some histo- and cytopathologists are likely to incorporate molecular techniques into their repertoire, while others will focus on their expertise in morphology and leave molecular technology to non-pathologists, being content to provide diagnoses and tissue for other studies. The findings of Armes and colleagues were the result of merging the skills of morphological diagnosis and molecular biology within a small group; the analysis by Alizadeh and colleagues involved two distinct steps — morphological diagnosis then molecular analysis — that could have been carried out by different people at different times and places. Molecular biology will continue to alter our concepts of disease, and pathologists will have to adapt to providing new information required by clinicians for prognosis and therapy. In large centres, both public and private, pathologists will be expected to contribute tissue and information for clinical trials, which may require a willingness to be flexible in styles and protocols for handling and reporting specimens. At the same time, pathologists will retain their custodial responsibilities for tissue, and will be required to decide on the appropriate allocation of tissue for immediate diagnostic purposes, for clinical trials, and for other research projects. Many of the most obvious changes to histopathology and cytopathology relate to molecular biology, but debates and decisions in tissue pathology will not only be about advances in biotechnology. Although the attention of government and the media has moved on from the autopsy, the future of hospital autopsies is by no means clear, and pathologists will need to clarify their own commitment to the autopsy, possibly in the face of diminishing support from clinicians and hospital administrators. Medical teaching in Australia is undergoing a revolution, and the allocation of time and resources to pathology teaching has suffered considerably in many of the new integrated curricula. The consequences of this remain to be seen. The spectacular advances in molecular technology are costly, requiring sophisticated laboratories and highly trained people. One of the many challenges in healthcare in the future will be to minimise inequities in access to diagnostic information necessary for appropriate management, not just between richer and poorer nations but within each nation, including Australia.

Duncan P MacGregor MBBS, PhD, FRCPA

The most important developments in cardiology and cardiac surgery in recent years have come from the implementation of ideas and techniques that have taken many years to bring to fruition. Prevention. Recognition that drugs may have multiple effects is a major advance. Statins reduce the incidence of recurrent vascular events because they decrease plasma lipid levels, and also because they reduce the likelihood of plaque rupture and subsequent thrombotic arterial occlusion. Angiotensin-converting enzyme (ACE) inhibitors control blood pressure, but also lower the risk of subsequent death, myocardial infarction and stroke,1 perhaps because they reduce adverse cardiac remodelling and modify vasomotor function. While we recognise the importance of risk factors such as obesity and lack of fitness, patient compliance, smoking and low rates of treatment of hypertension and dyslipidaemias remain major problems. Diagnosis. Echocardiography continues to improve technically, and, for most patients, is the definitive investigation of cardiac morphology and function. Small portable machines that can be used as an extension of physical examination may revolutionise practice. Magnetic resonance imaging rivals echocardiography for examining the heart and great vessels, and can evaluate myocardial perfusion and viability. However, its inaccessibility and expense mean it will not displace echocardiography for most patients. Electron beam computed tomography (CT) can show coronary artery calcification, but its value in screening for disease is not yet clear. Contrast studies with multislice spiral CT show details of coronary artery morphology and may replace angiography for some purposes. Despite much research into the genetic basis of cardiovascular diseases, knowledge and technology are not yet sufficiently developed for this to be clinically useful. Intervention. The use of serum markers of myocardial damage (eg, troponin) has redefined the spectrum of acute coronary syndromes2 and improved identification of high-risk patients, for whom early angiography and revascularisation by angioplasty (with platelet glycoprotein IIb/IIIa inhibitors) or surgery is warranted. The best way to limit damage and reduce mortality in patients with myocardial infarction is to restore flow in the infarct-related artery as soon as possible. When it can be done promptly enough, angioplasty is safer and more effective than lysis.3 Issues of prehospital delay, diagnosis by paramedics before admission and the availability of interventional services need to be addressed. Thrombolysis, perhaps initiated in ambulances on the way to hospital, still offers the best outcome for most patients. It is difficult to compare angioplasty with surgery for treating chronic angina because of continuous modifications and improvements in both fields. While angioplasty is now usually combined with stenting, surgeons now prefer arterial conduits to saphenous vein grafts because of their superior long-term patency, and have developed techniques such as grafting the beating heart without cardiopulmonary bypass, limited-access surgery and even robotic surgery to reduce morbidity. In patients with multivessel disease who might be helped by either technique, angioplasty with stent deployment is as successful and safe as surgery,4 but more often requires further interventions because of restenosis. The use of stents which elute an immunosuppressive drug (eg, sirolimus) may reduce this risk, but surgery will still be necessary for chronically occluded vessels, for most lesions of the left main trunk, and probably for multivessel disease in patients with diabetes. Chronic heart failure is becoming more prevalent. There is excellent evidence for the value of ACE inhibitors, ß-blockers and spironolactone. A small number of patients will still undergo transplantation, but ventricular-assist devices (implanted pumps) may offer definitive treatment rather than simply a bridge to transplantation. Treatment of arrhythmias has changed. The perceived usefulness of antiarrhythmic drugs (apart from ß-blockers) for suppressing ventricular tachyarrhythmias has declined. Class 1 agents such as quinidine are now rarely used as they may be pro-arrhythmic. Radiofrequency ablation can cure most recurrent supraventricular arrhythmias, but the best approach to managing atrial fibrillation remains unclear. Complex implanted devices can pace for bradycardia, suppress ventricular tachycardia and terminate ventricular fibrillation,5 but cost limits their widespread use. The best hope for reducing mortality from out-of-hospital cardiac arrests may be to provide automatic defibrillators in public places. Conclusion. The benefits of developments in imaging, percutaneous coronary intervention and surgical innovation are limited by poor compliance (particularly in modifying risk factors). Ultimately, society must decide how much we can afford to spend on such expensive developments as magnetic resonance imaging or implantable defibrillators.

J H Nicholas Bett MB BS, FRACP · Malcolm J West · R Bruce Garlick

Clinical pharmacology is the clinical application of the action of drugs on the body, and involves understanding how the body handles and modifies drugs, and their side effects and interactions. Significant advances have occurred in the development of new drugs, and the genetics of drug actions, metabolism and transporters. Pharmacogenomics and new drug development. Pharmacogenomics1,2 is the use of molecular biology techniques (eg, microarray chips, expressed-sequence tags and proteomics) to identify and study genes relevant to drug therapy. Thousands of potential new targets for drug therapy have been described. Combinatorial and computational chemistry and high-throughput screening allow the synthesis and evaluation of large numbers of compounds. These strategies have resulted in new antiangiogenic (SU5416) and antileukaemic (ST1571, or glivec) drugs for cancer. Increasing sophistication of in-vitro testing may lead to virtual studies and reduce the requirement for animal and human investigations. Pharmacogenetics and drug response. Pharmacogenetics, a subsection of pharmacogenomics, studies the genetic basis for differences in individual responses to drugs. Common alterations to gene structure are single-base changes in the genome (single-nucleotide polymorphisms). Examples include the lack of response of some people to certain drugs (eg, salbutamol) due to genetic variation in the β2-adrenergic receptor;2 polymorphisms in both the cholesteryl ester transfer protein and stromelysin-1 affecting the efficacy of pravastatin in coronary atherosclerosis; and the cardioprotective effect of ACE inhibitors being greater in whites than African-Americans.2 Pretreatment genetic screening of patients will eventually enable this knowledge to be applied in clinical practice. Pharmacogenetics and drug metabolism. The genetics of the absorption, distribution, metabolism and elimination of drugs may also result in interindividual differences in treatment responses.1,2 Functionally significant polymorphisms have been detected in the genes for cytochrome P450 (oxidising) enzymes (eg, CYP2D6, CYP2C9), and many genotypes have been identified for ultrarapid, extensive, and poor metabolisers,3 with individuals with these genotypes requiring extremely high, average or low doses, respectively, of many drugs to achieve useful effects. Thus, extensive metabolisers for CYP2C19 need larger doses of protein-pump inhibitors (eg, omeprazole) to treat peptic ulcer and, conversely, poor metabolisers for CYP2D6 suffer from perhexilene toxicity caused by high blood levels even at low doses. Some analgesics (eg, codeine, tramadol) require activation by CYP2D6; poor metabolisers may not obtain any pain relief, but may suffer respiratory side effects. Drug transporters. Drug transporters are proteins that mediate the efflux of drugs from cells and tissues. They are widely expressed in normal tissues and also limit the uptake of foreign molecules (including drugs) across the blood–brain barrier and the gastrointestinal mucosa. They may contribute to the poor oral bioavailability of some drugs. Interest in transporters followed the observation that overexpression of P-glycoprotein (PGP) in cancer cells imparted resistance to many anticancer agents (multidrug resistance). Inhibition of PGP by drugs (eg, verapamil) increases the retention of cytotoxic agents in cancer cells. Genetically engineered mice that no longer express PGP develop neurotoxicity when given drugs that normally do not cross the blood–brain barrier (eg, vinca alkaloids, ivermectin). Some opiates are substrates for PGP and differences in analgesic response to these drugs may relate to PGP. Drug interactions. Our understanding of drug interactions has increased by identifying the drugs metabolised by CYP450 enzymes4 and/or excreted by PGP. Inducers and inhibitors of both these systems affect target drugs. CYP3A4 inhibitors (eg, ketoconazole, erythromycin) increase blood levels of drugs such as terfenidine, astemizole or cisapride and can provoke life-threatening arrhythmias. Coadministration of inhibitors with some "statins" increases the risk of rhabdomyolysis. Many inhibitors and inducers of CYP3A4 act similarly on PGP. PGP pumps drugs (eg, digoxin) into the gut lumen, thereby reducing its bioavailability.5 Consequently, blood levels of digoxin are increased when PGP is inhibited (eg, by macrolide antibiotics) or decreased when PGP is induced (eg, by rifampicin or St John's wort). The future. Rationally synthesised drugs and knowledge of molecular factors determining drug actions, toxicity and interactions may enable "individualised therapy", but will not remove the need for good clinical judgement. Glossary Microarray chips: Miniaturised assay systems enabling evaluation of structure and simultaneous expression of thousands of genes. Expressed-sequence tags: Short sequences of cDNA from specific tissues that can be "mined" for genetic polymorphisms and novel proteins. Combinatorial chemistry: Simultaneous synthesis of chemical compounds with multiple permutations of substituents. High-throughput screening: High speed robotic, often miniaturised, testing of new compounds against purified receptors, enzymes and cellular systems.

Gillian M Shenfield DM, FRACP · David G Le Couteur PhD, FRACP · Laurent P Rivory PhD

Dermatology, although a small specialty, has made great leaps forward in prevention, diagnosis and treatment in the past five years. Prevention. Skin cancer is the number one malignancy in Australia, and we lead the world in skin cancer control programs, which have now been running for over two decades. However, it is only within the past five years that we have been able to record a turnaround — not only in melanoma deaths but also in the incidence of both melanoma and basal cell carcinoma — in Australians young enough to have been influenced by these programs. Intervention. Major changes are coming in the treatment of some non-melanoma skin cancers. Topical imiquimod cream is the first of a new generation of immune modulators, which results in local cutaneous induction of interferon α and interleukin 12. Cure rates of almost 90% for superficial basal cell carcinomas have been recorded after six weeks of daily application.1 This topical treatment applied by the patient also shows promise for nodular basal cell carcinoma, solar keratosis and Bowen's disease (squamous cell carcinoma in situ). Research into the biology of ultraviolet (UV) radiation causing skin cancer has enhanced our awareness of its potential in treatment of skin disease. New techniques, such as photodynamic therapy, are being developed to treat many epithelial tumours, including those of the skin. The cosmetic results can be equal to or better than other treatment modalities.2 The role of photodynamic therapy in the treatment of solar keratoses, basal cell carcinoma, in-situ and invasive squamous cell carcinoma, cutaneous T cell lymphoma, and Kaposi's sarcoma is being delineated. Narrowband UVB therapy has largely superseded PUVA and broadband UVB in the management of psoriasis and atopic dermatitis. Narrowband UVB has the advantage of being safe in pregnancy and childhood, and is thought to have a lower risk of inducing the development of cutaneous malignancies. It has also been used in the prophylactic management of photosensitive conditions such as polymorphic light eruption, actinic prurigo, solar urticaria and cutaneous porphyria. The horizons of laser therapy continue to expand. Vascular lasers are being used to treat lesions ranging from spider telangiectases through poikiloderma of Civatte (the common sunlight-related pigmentation on the neck in women) to port wine stains. Short-pulse lasers are now the preferred method of treatment for tattoo removal. Disorders of cutaneous pigmentation, such as naevus of Ota, solar lentigines, café au lait macules, freckles, melasma and postinflammatory pigmentation, have been successfully treated with Q-switched ruby, Nd: YAG and alexandrite lasers. Laser-assisted epilation is not considered a permanent method of hair removal, but some patients achieve a long term reduction in hair density after a single treatment. Immunomodulatory drugs are increasingly used in dermatology for life-threatening diseases such as pemphigus vulgaris (100% mortality without treatment), pyoderma gangrenosum and vasculitis, as well as for patients with severe and intractable inflammatory diseases with an immunological component, such as psoriasis and atopic dermatitis. Mycophenolate mofetil and tacrolimus are now well established in the treatment of refractory immunobullous diseases, and newer agents such as rapomycin, infliximab and leflunomide all show promise, with enhanced efficacy and side effect profiles compared with conventional systemic therapies such as prednisolone, azathioprine and cyclosporin.3 Diagnosis. Genetic identification of dermatological diseases inherited as single-gene disorders has led to greater understanding of their mechanism, improved diagnosis (including antenatal testing) and classification, as well as genetic counselling.4 Some examples include porphyria, epidermolysis bullosa, Darier's and Hailey–Hailey diseases, xeroderma pigmentosum, and a variety of familial multiple tumour syndromes, such as neurofibromatosis and Gardner's, Gorlin's (multiple basal cell naevus) and Cowden's (multiple haematomas) syndromes. As our understanding of virology has increased, we have been finding more cutaneous diseases that appear to be caused by a viral infection. Examples include pityriasis rosea, a common disease in young people, and also Kaposi's sarcoma, both now being attributed to infection with human herpesviruses 7 and 8, respectively. Educating future generations. An atlas of common skin diseases has been published which is based on epidemiology studies looking at the frequency, morbidity and treatment in Australia of conditions such as acne, eczema, tinea, warts, and nappy rash.5 No other country has been able to map out in detail the frequency and morbidity of these conditions. As a result, education programs similar to those used for skin cancer control are being developed in Victoria and introduced into all schools and the Maternal and Child Health network. This is another world first for public health in Australia, a country which has an international reputation for this approach to disease control.

Robin Marks MB BS, MPH, FRACP, FACD · Peter A Foley MB BS, BMedSc, MD, FACD · Rodney D Sinclair MB BS, FACD

Emergency Medicine (EM) was recognised as a principal specialty in Australia in 1993, and the development of EM has had a profound effect on the way healthcare is delivered in Australia. Most major Australian hospitals now have 6–12 full-time emergency physicians. The Australian Medical Workforce Advisory Committee has estimated that more than twice the current number of EM physicians will be needed by 2007.1 Within five years from now, major emergency departments (EDs) will have 16-hour, 7-day cover (some will have 24-hour cover). Subspecialisation will occur in toxicology, retrieval, disaster medicine, paediatric emergency medicine and hyperbaric medicine, and academic EM will grow rapidly. Prevention. The many presentations in EM provide fertile ground for surveillance in injury prevention and other areas. Data collected and computerised at the time of attendance provide great opportunities for monitoring of disasters and epidemics and for disease identification and surveillance. Some EDs are undertaking disease prevention programs, giving telephone advice and conducting quality assurance programs related to ambulatory care that should have a major impact on disease presentation and prevention. Training. Improvements in training and experience for emergency physicians and the reduced reliance on junior medical staff in EDs have significantly improved early diagnosis and reduced initial adverse events and times to critical therapies. Most routine ED laboratory tests and some imaging (eg, using ultrasound and portable computed tomography) will soon be performed at the bedside, although there are issues surrounding cost and reliability. Interventions. Little has changed in cardiopulmonary resuscitation over the past 30 years. High-dose adrenaline has been found to have no advantage over the standard dose, and there is some doubt about whether adrenaline is useful at all. Time to defibrillation remains the key to advanced life support for cardiac arrest. Easy-to-use automatic external defibrillators, which will eventually be accessible to the wider community, will improve survival after out-of-hospital cardiac arrests. EM physicians have developed great expertise in managing poisoning and envenomation, and five toxicology admitting services have been established nationally. This has reduced the frequency of the need for decontamination and antidote administration and reduced admission rates and length of stay, without increasing morbidity or mortality. Doctors managing an acute poisoning anywhere in Australia can rapidly get expert advice by calling Poisons Information Centres (on 131126), at which medical consultant support is largely provided by emergency physician toxicologists. Modifications to hospital and ED systems in recent years have enabled earlier intervention.2 For acute coronary syndromes, the early administration in the ED of aspirin, β-blockers, thrombolytic agents and platelet glycoprotein IIb/IIIa antagonists is improving outcomes. Glyceryl trinitrate and angiotensin-converting enzyme inhibitors improve outcomes in pulmonary oedema. The use of low molecular weight heparins has enabled most patients with venous thromboembolism to be managed at home with daily injections and has reduced mortality in patients with unstable angina. Non-invasive ventilation for respiratory conditions such as asthma and chronic airways limitation can prevent endotracheal intubation, reduce length of stay and reduce mortality. The most significant advance in EM has been formalisation and application of triage. The Australasian Triage Scale (ATS) is now used in all Australasian EDs, usually as part of a real-time patient tracking and reporting system. It has become the cornerstone of departmental clinical management, casemix measurement and interdepartmental workload comparisons, and has been applied in incentive bonus payment schemes in New South Wales and Victoria.3 The ATS is widely used as the basis of ED audit and quality improvement.4 It enables comparisons of very large patient populations, and has extraordinary research potential. System changes in EDs have led to integration of specialised teams for reception of emergency patients, and research and training in team dynamics in several areas, especially trauma. The development of clinical pathways (for asthma, chronic airways limitation and abdominal pain), chest pain units and nurse-based analgesia have reduced time to essential treatment, ED length of stay and unnecessary tests. Specialised observation medicine units run by EDs have had a significant impact on hospital lengths of stay for many illnesses.5 The ED is also a critical focus for developing out-of-hospital programs, integrating components of acute hospital care such as intravenous therapy, nursing support, specialist consultations and physiotherapy. Continuing improvements in EM are likely over the next five years.

George A Jelinek MD, FACEM · Lindsay M Murray MB BS, FACEM · Peter A Cameron MD, FACEM

During the past decade there have been significant advances in the prevention, diagnosis and management of endocrine disease. Here I concentrate on two disorders with significant disease burden — diabetes and obesity. Prevention. Preventing diabetes mellitus is a key goal in endocrinology. For type 1 diabetes, immunomodulation using nicotinamide and pre-emptive insulin therapy is being evaluated in high risk individuals (based on family history, autoimmune markers and metabolic profile).1 For type 2 diabetes, the key strategy is the primary prevention of obesity.1,2 Major trials in the 1990s have shown a continuous relationship between macro- and microvascular disease and hyperglycaemia, hypertension and dyslipidaemia. Current data indicate that remarkable improvements at the population level would be gained by achieving targets of glycohaemoglobin (HbA1c) < 7%, blood pressure < 130/80 mmHg, and low-density lipoprotein cholesterol < 2.6 mmol/L, using available therapies (HMGCoA reductase inhibitors, ACE inhibitors, and angiotensin 2 receptor antagonists).1 However, this knowledge is incompletely applied in practice and an important advance will be treating all patients with diabetes to established targets. Diagnosis. Refinements in existing techniques, such as immunoassay and medical imaging, have allowed previously complex diagnostic algorithms (eg, assessment of thyroid status) to be performed cheaply and with a high degree of precision. Many monogenic endocrine disorders, including the multiple endocrine neoplasia syndromes, are now also identifiable by presymptomatic gene testing. With contemporary advances in molecular biology and bioinformatics, the search for susceptibility genes for diabetes, obesity and other polygenic diseases is also progressing rapidly. Somatostatin-receptor (SR) imaging using radionuclide-labelled ligands allows localisation, staging and treatment planning in patients with SR-positive neuroendocrine tumours. An intraoperative γ-probe to localise labelled tissues (eg, with Tc-sestamibi) can also help localise occult tumour in patients with endocrine neoplasms. Interventions. Effective interventions for established obesity include bariatric and gastric bypass surgery. Laparoscopic gastric banding has the advantage that it requires minimal access and is adjustable.2 The pharmacological options for established obesity are currently limited. New drugs include the appetite suppressant sibutramine (a selective inhibitor of serotonin and noradrenaline reuptake) and orlistat (an intestinal lipase inhibitor). Individually, these agents achieve a 5%–15% weight reduction. Pharmacological agents that either suppress appetite or increase basal energy expenditure are likely to be developed over the next five years. Central factors (neuropeptide Y, melanocortins) and adipocyte hormones (leptin) are potential pharmacological targets. Drugs which increase thermogenesis (β3-adrenergic-receptor agonists and mitochondrial uncoupling proteins) are also being evaluated.2 The thiazolidinediones are a new class of insulin-sensitising agents for treating type 2 diabetes. Non-sulfonylurea insulin secretagogues, such as the glinide class (eg, repaglinide), improve meal-related insulin release, but minimise the risk of hypoglycaemia. An increasing array of insulin analogues (created by amino acid rearrangement in the insulin molecule) are available: rapid-acting agents (lispro and aspart insulin), and long-acting analogues (insulin glargine). New ways of delivering insulin and monitoring glucose are also available or under trial. Inhaled (aerosolised) insulin is showing promise in clinical trials, although problems remain with delivery efficiency and thus cost. Mechanical pumps for continuous ambulatory subcutaneous insulin infusion are used increasingly,1 offering improved glycaemic control for those willing to frequently monitor blood glucose level. Several technologies for continuous glucose sensing are also being developed, such as transcutaneous optical glucose sensing. Pancreatic transplantation for treating type 1 diabetes has long been available in Australia. Limited donor availability and a better outcome have restricted this treatment to patients requiring renal transplantation. An alternative, islet-cell transplantation using modified low-dose immunosuppressive regimens, is showing early promise in clinical trials.1 Developments in minimal-access endocrine surgery include laparoscopic adrenalectomy for benign adenoma (shorter hospital stay and lower morbidity), and minimal-access parathyroidectomy. The options for medical management of primary hyperparathyroidism are also expanding, with the identification of calcium-receptor agonists (calcimimetic drugs) which down-regulate parathyroid hormone secretion and normalise serum calcium level. Conclusion. While diagnostic and therapeutic modalities currently under development offer much promise for managing patients with endocrine disorders, significant improvements in health could also be achieved by fully applying current knowledge, technology and existing pharmaceuticals.

John R Burgess MD, FRACP

Forensic pathology is the application of the principles and practice of pathology to the needs of the courts, or, more broadly, the law. The administration of justice. Arguably the single biggest global advance in the administration of justice in the past 60 years has been the advent of international criminal tribunals. This has meant that gross abuses of human rights and related offences, committed in times of war or insurrection, can no longer be perpetrated with impunity. The tribunals need evidence, some of which has been provided by Australian forensic practitioners in places such as Bosnia, Kosovo and East Timor (although, in the last case, no such tribunal exists). The aim of forensic pathology in these circumstances (often involving multiple deaths) is to identify the deceased, to establish the cause of death and to help reconstruct the circumstances surrounding the death. The likely development of a standing International Criminal Court, possibly within the next two years, will increase the potential for contributions by Australia's forensic community in this important area. Domestically, DNA typing has provided the courts with valuable evidence in helping to convict those guilty of rape, assault and murder. The exclusion of suspected offenders is a less well appreciated but vital application of this methodology — in several cases overseas it has been used to identify wrong convictions. DNA typing has also led to important advances in identifying decomposed or skeletal remains and grossly traumatised remains in mass disasters. Healthcare delivery. Forensic pathology is also influencing healthcare delivery, with forensic and other medical specialists beginning to interact more closely. Tissues from complex cases of sudden and unexpected death are being submitted for cytogenetic and molecular biology studies, resulting in far more accurate diagnoses of rare conditions.1 There have been moves to institute national and international protocols to standardise the investigation of infant and childhood injuries and deaths. The use of such "gold standards" has been shown to improve diagnostic accuracy,2 identifying deaths incorrectly attributed to sudden infant death syndrome (SIDS). Future epidemiological studies, such as those that resulted in dramatic falls in the rates of SIDS during the nineties, will only be useful if diagnostic precision is maintained. Intervention and prevention. A recent innovation has been the setting up of the National Coroners' Information System at Monash University to store information about deaths reported to Australian coroners. The information will be available to coroners, forensic pathologists, researchers and others with an interest in preventable injury and death. "Tissue issues." The retention and use of organs and tissues removed at autopsy has been a matter of substantial publicity over the past 12–18 months. Formal inquiries were carried out in New South Wales and South Australia. The Australian Health Ethics Committee has provided advice on the handling of stored tissue, and the Australian Health Ministers' Advisory Council is currently developing national guidelines for the future conduct of autopsies. Repositioning the autopsy. The autopsy needs to be repositioned, not simply subjected to greater regulation. The information provided to pathologists before coronial autopsies (which constitute 80%–90% of autopsies in Australia) is generally poor. This is a global phenomenon, as it is unreasonable to expect police officers to provide what, in many cases, is a medical history. Much of this information resides with families. The complexity of the processes surrounding autopsy, and the necessity or desirability of retaining organs and tissues, is such that a proper understanding of them will only reside in pathology departments. Many, if not most, autopsies yield information of intense interest, or of healthcare relevance, to the families of the deceased. Increasingly, pathology services are recognising a duty to take more responsibility for informing families when autopsy has unexpectedly revealed a condition with a hereditary component (eg, prolonged QT interval, hypertrophic obstructive cardiomyopathy3 or haemochromatosis). For these reasons, pathology services need to consider the establishment of a relationship, like the normal therapeutic relationship between doctor and patient, with the family of the deceased. Such a relationship would clarify and facilitate the processes and necessary communications surrounding autopsy. But this will not be achieved within current resources.

Stephen Cordner FRCPA, FRCPath · Roger W Byard MD, FRCPC, FRCPath

Progress in new diagnostic tools and therapeutic strategies has been rapid in gastroenterology and hepatology, and pending advances include the use of magnification endoscopy with dye spraying to detect early cancers, and endoscopic sewing procedures for reflux oesophagitis. Prevention. Genetic tests have recently been developed for the hereditary colon cancer syndromes (< 3% of all colon cancers). This major advance helps to identify at-risk family members, so that premalignant lesions and early cancers can be removed, and those who are not carrying the gene can be reassured. Accuracy in both familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) approaches 100%, as long as the index case is positive for the mutation tested. The rate of carriage of an easily identifiable mutation is about 80% in FAP, but presently substantially less in HNPCC.1 Pilot testing of population screening for common (sporadic) colorectal cancer is about to begin in Australia. More specific immunochemical tests for occult gastrointestinal bleeding are now available. Diagnosis. First described in 1991, magnetic resonance cholangiopancreatography (MRCP) continues to evolve. It produces diagnostic-quality images of normal and diseased biliary ducts, is non-invasive, and does not require contrast media or ionising radiation. MRCP is gradually replacing invasive techniques, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography, for purely diagnostic imaging, leaving these procedures for interventional or problem cases. MRCP is indicated for detecting biliary stenosis and level of obstruction, and depicting the biliary tree on both sides of the stricture. It is also useful in identifying cases of choledocholithiasis likely to benefit from ERCP calculus removal. Avoiding intubation of the biliary tree decreases the risk of bacterial colonisation in cases of biliary stricture (including primary sclerosing cholangitis [PSC]) and choledocholithiasis. MRCP is not particularly good for detecting ampullary calculi, or assessing chronic pancreatitis or the very early changes of PSC. Availability is the main limiting factor to its widespread use.2 Intervention. Localised hepatocellular carcinoma (HCC) in patients with non-cirrhotic livers is best managed by surgical resection. Liver transplantation has been associated with excellent long term survival in highly selected cases of cirrhosis, but is limited in Australia by a small donor pool. Effective local control of small HCCs has been achieved with percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA). The main determinant of outcome is the size of the tumour. PEI, under ultrasound or computed tomography guidance, is simple, inexpensive and safe in patients with advanced cirrhosis. It is suitable for HCCs less than 3 cm in size, with fewer than three nodules, but multiple treatments may be required. There is minimal discomfort, so it can be performed as an outpatient procedure. RFA involves placing the needle electrode percutaneously with laparoscopic control or ultrasound guidance under local anaesthesia. However, heavy sedation or anaesthesia may be required as significant pain may occur. Both PEI and RFA have very low complication rates, and treatment can be repeated for recurrence or new lesions. Long-term survival rates have been reported at over 70% (three years) and over 40% (five years), but unfortunately no randomised controlled trials have been performed.3 The management of chronic hepatitis B infection has changed recently with approval of lamivudine, a nucleoside analogue and potent inhibitor of viral DNA replication. Sustained viral inhibition is seen within four weeks in over 95% of cases, with 15%–20% becoming e-antigen negative at 12 months. There is also evidence that liver fibrosis and inflammation decrease during therapy, even without seroconversion. A high proportion of patients with hepatitis B e-antigen seroconversion (73%) have a sustained virological remission for up to 19 months (median). As with other therapies, loss of surface antigen is relatively uncommon. The development of a drug-resistant mutant form of the virus (YMDD) emerges with prolonged therapy (about 50% at three years), and can be associated with significant flares of hepatitis.4 Infliximab, a cytokine-directed biological therapy, represents a significant advance in the understanding of Crohn's disease. This chimeric monoclonal antibody blocks tumour necrosis factor α (ΤΝF-α), a key cytokine in bowel inflammation. Therapy results in rapid reduction in the signs and symptoms of Crohn's disease in two-thirds of cases, with a decrease in bowel inflammation, and improved mucosal healing and quality of life. Three infusions are given for fistulous disease and rapid closure occurs usually within two weeks, with a median benefit exceeding three months. Serious adverse events are infrequent and have been successfully managed with medications. However, the cost of this therapy currently restricts widespread use. Allergic reactions are also a serious consideration, but may be addressed in the future with modified molecules already in trial.5

Amanda J Nicoll PhD, FRACP · Ian J Kronborg FRACP · Neville D Yeomans MD, FRACP

Gastrointestinal surgery continues to be informed by advances in basic science, technology and by the changing expectations of consumers. Prevention. The high rate of adhesions found after abdominal surgery supports the need to tackle this problem.1 Options currently being canvassed include simple technical modifications (eg, using powderless gloves), agents that minimise adherence of mesothelial surfaces, and a range of physical barriers that can separate these surfaces. The emergence of Level 1 evidence that mortality can be reduced by screening for colorectal cancer has led to increasing calls for screening programs;2 mooted pilot programs within Australia may herald their future widespread introduction. Prophylactic colectomy is well established for rare inherited colorectal cancer syndromes. Advances in molecular biology are extending this concept to patients with other inherited predispositions to cancer, with potential for broader application within the gastrointestinal tract (eg, gastric cancer).3 Diagnosis. Technological advances have allowed laparoscopy to spearhead advances in diagnosis and treatment. Leaps in imaging techniques (such as video capsules which can be swallowed by the patient, virtual endoscopy, enteroscopy) are enhancing the array of diagnostic tools. The intraoperative use of ultrasound has allowed more accurate staging of cancers and has facilitated hepatic resections. The use of transrectal imaging (ultrasonography, helical computed tomography and magnetic resonance imaging) has similarly assisted decision making and treatment for patients with complex anorectal diseases such as fistulas, abscesses and cancer. Molecular analyses of body fluids (including faeces) may have an increasing role to play in screening and surveillance. Intervention. Laparoscopic surgical management of disorders of the entire gastrointestinal and hepato-pancreatico-biliary tracts is thought to represent a significant advance by many. These and other technology-based advances are tempered by the aphorism that "technology moves faster than knowledge, which, in turn, moves faster than wisdom".4 The removal of rectal cancers by transanal endoscopic microsurgery (TEM) is becoming increasingly common outside Europe, where the procedure was initiated. Further evidence on cancer recurrence and survival when TEM is employed is awaited. A growing evidence base has bolstered adjuvant chemotherapy and radiotherapy treatments,2 and the preoperative use of adjuvant therapy for patients with rectal cancer will allow for down-staging of tumours, giving patients a more favourable prognosis. This may increase further the number of patients amenable to TEM. A similar acronym (TME) represents total mesorectal excision (excision of the perirectal tissue contained within the endopelvic visceral fascia and extending the length of the rectum) when resecting a rectal cancer. Proposed by some with messianic zeal (as reflected by the term "holy plane", which is a guide to the resection), it has been increasingly adopted, despite still-debated benefits in terms of survival and the prevention of local recurrence. Robotic surgery understandably receives much publicity. Surgery from a remote location is unlikely to be adopted widely in the next five years. However, telemonitoring (observation of performance), the use of computers for measuring and guiding dexterity enhancement and for simulating virtual environments are already occurring in multiple skills laboratory training centres.5 A less glamorous (but more painful) surgical topic is the management of patients with an anal fissure. Novel non-surgical interventions (such as the use of glyceryl trinitrate and botulinum toxin) have been described to avoid lateral sphincterotomy, which may cause postoperative incontinence. Quality and communication. Underpinning these advances is the need for surgeons to maintain their competence and to practise according to best evidence, as facilitated by the establishment of the Australian Safety and Efficacy Register for New Interventional Procedures – Surgical <http://www.surgeons.org/asernip-s/publications2.htm>. Doctors must now assiduously inform patients and relatives of benefits and risks of operations. This implies a detailed knowledge of outcomes, as gleaned from clinical-audit and peer-review processes using personal and comparative data. An example of how to collate these data can be found at http://www.pamuk.co.uk. Finally, advances should not be seen in terms of technology alone; knowing what to do and how to do it must be complemented by knowing how to explain what should be done and when and in whom to do it. The two websites cited above are important to facilitate this process.

Allan D Spigelman MB BS, MD, FRACS, FRCS · Daniel R McGrath MB BCh, BAO, MRCS · Richard D Levy MB BCH, DCHSA, FCSSA, FRCS(Edinburgh) FRCS(Glasgow)

Increasing subspecialisation, driven by new knowledge, experience and technology, challenges the relevance of a broad discipline like general internal medicine. However, these same influences are also responsible for the worldwide renaissance of generalism in clinical practice.1 With an ageing population, an increasing prevalence of chronic disease, rising costs of healthcare, greater consumer expectations, and more awareness of the risks and errors of clinical practice, our society needs general internal medicine to provide integrated, cost-effective and high quality specialist medical care. This need is even greater for people with complex, multisystem problems, who account for most acute hospital admissions. Here, we outline the fields pioneered by generalists and now common to many clinical disciplines. Evidence-based medicine (EBM). The EBM movement encourages consistent and judicious integration of best available research evidence with clinical expertise and patient values in making clinical decisions.2 EBM has spawned whole new fields of study of the design, conduct and reporting of clinical trials, and the searching, appraisal, synthesis and dissemination of published research. Quality improvement. Within the past decade, the magnitude of clinical error and suboptimal care has become apparent.3 This has created new disciplines of health service research and quality improvement. These aim to study and enhance the appropriateness, effectiveness, safety and efficiency of healthcare delivery. Concepts such as peer-review, physician profiling, performance indicators, clinical audit, and practice guidelines are now accepted as credible tools for promoting a "systems-based" approach to improving care. Outcomes management. Since publication of Ellwood's sentinel paper in 1994,4 the "outcomes movement" has focused attention on scientific methods for determining the impact of modern medicine on patients' quality of life and functional status, as well as on adverse events and survival. Although many benefits have accrued from advances in high-technology, specialised medicine, more could be achieved if common chronic diseases were managed optimally within a continuum of care which spans hospital and ambulatory practice, and integrates acute care with health maintenance. Physicians in general internal medicine, with their broad knowledge and experience, are in an ideal position to lead disease-management initiatives, especially in communities away from major urban centres. Interdisciplinary care. Healthcare teams have become the dominant units of care delivery. They comprise a diversity of professionals, including specialists, but have one inherent weakness: fragmentation of care among "too many chiefs". For patients with multiple problems who are vulnerable to the effects of polypharmacy and overly invasive interventions, the coordinating and temporising role of a general physician to prioritise goals of management and appreciate patients' needs and preferences is mandatory for providing compassionate, cost-effective care. The establishment in many hospitals of acute medical assessment and intervention units run by general physicians, and appointment of those with procedural skills and subspecialty interests, are examples of this integrative approach to care. In primary care, more general physicians are needed to meet general practitioners' demand for specialists who can provide "whole-patient" care. Links with other disciplines. With advances in surgical and anaesthetic techniques, more older patients with multiple comorbidities are undergoing elective and emergency surgery. General physicians play prominent roles in preoperative assessment and perioperative management. Many general physicians have contributed to advances in clinical pharmacology, emergency and intensive care medicine, palliative medicine, geriatrics, occupational health, rehabilitation and obstetric medicine. Other contributions to care. Because of their skills in diagnosis and management of common medical conditions, general physicians undertake much of the undergraduate and postgraduate teaching in teaching hospitals. Most directors and visiting consultants of medical departments of community public hospitals (> 150 beds) are general physicians. Many possess procedural skills (echocardiography and endoscopy) otherwise unavailable to patients in many parts of regional Australia. The future. The broader interests, skills and vision of physicians in general internal medicine complement the necessarily deeper, focused expertise of subspecialists. In the future, such physicians will be forging new alliances with patients, general practitioners, geriatricians, subspecialists, healthcare funders and policy makers in researching, delivering and teaching better practice. Newer models of specialist care, such as "hospitalism", regional disease management programs, hospital-in-the-home programs, multidisciplinary care teams and outreach services, will have the active participation of general physicians.5 The discipline of general internal medicine will continue to play its part in assisting specialist medical care to meet the challenges of the 21st century.

Ian A Scott · Peter B Greenberg

General practitioners remain the linchpin of frontline medical care, and continue to aim for comprehensive, coordinated care for their patients. Recent advances in general practice have focused on equipping GPs to better provide such care. Both international and within-country comparisons show that healthcare systems based on primary care produce better overall health outcomes than systems based on specialists.1 Prevention and population health. General practice stands at the interface between specialised medical care and population care. Two factors facilitate GPs' achieving population health goals. The personal relationship between GPs and their patients is basic, but greater use of government-funded incentives that encourage quality primary care is a recent development. As an example, the National Childhood Immunisation Program, which supported and provided financial incentives for GPs, achieved higher childhood vaccination rates. The more recent Enhanced Primary Care Package provides Medicare rebates for health assessments of the elderly, and care planning and case conferencing for those with chronic illnesses and a need for multidisciplinary care. However, this initiative still requires careful evaluation to determine its efficacy. The "lifestyle diseases" of the modern world, such as obesity, dyslipidaemia and diabetes, require early detection by GPs and long-term control. There is now greater awareness that changing diet and exercise patterns may be more effective than drug therapy2 in treating cardiovascular risk factors. Consultation time is limited, but, in the supportive context of a GP's personal approach, even low-intensity messages can be effective.3 To balance risk and benefit requires combining all factors, as emphasised by the New Zealand risk charts,4 rather than treating each one in isolation. Divisions of General Practice. The advent of the Divisions has helped develop a collective local identity for general practice, and provided crucial support for GPs in developing the skills they need for preventive care and healthcare improvement at the community level. The Divisions are also the conduit for forging relationships between GPs, hospitals and community health services, and for testing new models of collaboration. Continuing care. Depression will become the commonest cause of chronic morbidity, but there will never be enough specialised mental health professionals. National campaigns have emphasised GPs' central role in caring for patients with mental illness, and the need for further improvement of their skills in recognising and treating psychiatric conditions. There is growing recognition that there are now more people with chronic illness, disability or special needs who require continuing care. Various shared-care and partnership programs between GPs and hospitals have proved effective (eg, for antenatal care and diabetes). Evidence-based medicine. Recent emphasis on evidence-based medicine poses many challenges in general practice. Extrapolating specialist and hospital-based evidence into community settings is not always possible. In the information age, GPs have to develop the critical skills necessary for evaluating the evidence for and against available screening tools or new interventions, and be able to interpret the evidence appropriately for their patients (who may also be up to date with new developments). On the other hand, practising with an evidence base now enhances confidence in our treatment decisions, such as in reducing antibiotic prescribing for common respiratory tract infections.5 Computerisation. The widespread use of computers in Australian general practice has changed the way many practices function. Electronic medical records, and interlinking of prescribing, test ordering, evidence-based management protocols, patient recall and follow-up programs and patient education are now possible. However, there is still a need for more user-friendly decision-support systems. Quality improvement. Vocational registration and practice accreditation have encouraged continuous quality improvement. Although these programs are research-based, continuing evaluation is needed to determine which aspects need further development and which provide the most worthwhile change for the effort applied. The future. It will always be difficult to resolve the conflict between all that could be done to enhance health, and what can be achieved by general practitioners. By its nature, general practice is dependent on healthcare policy to provide adequate resources for support programs, education, organisation and information. To promote efficient practice, greater investment is needed in vocational and continuing education, in strategic development, research training, and especially in building research capacity.

James A Dickinson PhD, FRACGP

One of the most significant medical developments in the past five years has been the completion of the Human Genome Project (HGP). The first draft of the human DNA sequence is now available. The discovery of new genes for a range of human genetic disorders, as well as genes for normal traits, will have far-reaching effects on diagnosis, treatment and prevention.1 Genetic (DNA) diagnosis. Diagnostic DNA tests are now available for a limited number of genetic disorders. In Australia, these tests are usually accessed through clinical genetics services (listed along with available tests on the website of the Human Genetics Society of Australasia2). Emerging technologies, such as gene chips, have the potential to allow analysis of large numbers of genes, as well as thousands of mutations in each of these genes. Thus, the scope for DNA testing will expand. Developments in nanotechnology will lead to miniaturisation of DNA testing, allowing doctors to obtain genetic information at the point-of-care in a way comparable to a "dipstick" urine test. This individualisation of medical practice will be particularly valuable in determining drug doses, and identifying those at risk of drug side effects.3 As the HGP will continue to generate large volumes of data, more sophisticated bioinformatic approaches will be essential. In addition, the increasing complexity of counselling issues related to genetic disorders will require doctors and patients to develop new ways of interacting in terms of how doctors provide information. Computer-based resources will be needed to meet the demand for more knowledge, which may be complex in nature for both doctors and patients. There will be increasing reliance on a team approach for managing genetic diseases. The increased opportunities for DNA analysis are also generating disquiet, because of the implications for privacy and confidentiality, and the potential for discrimination in employment and insurance. Continuing professional and community education is crucial to ensure that DNA testing proceeds appropriately. A challenge will be population DNA screening, which should be undertaken only after evidence-based research shows a clear cost–benefit analysis. Immediate debate is needed on the place of population screening for the mutations responsible for haemochromatosis and cystic fibrosis. Genetic interventions. Somatic-cell gene therapy (the insertion of DNA or RNA into the somatic cells of humans) was first undertaken in 1990 to treat adenosine deaminase deficiency, a rare genetic disorder. Today, the scope for gene therapy has broadened, and it is being developed as an alternative treatment for cancer and HIV infection. Despite many clinical trials, it has taken a decade for gene therapy to succeed. In 2000, the first report emerged showing potential cures in X1 severe combined immunodeficiency disorder, a rare genetic defect that is usually fatal within the first two years of life. Five children have been treated, with four being able to return home and lead normal lives.4 Promising results are now coming from gene therapy for haemophilia. Disease prevention. DNA analysis can also be used for predictive (also called presymptomatic) testing for adult-onset disorders, such as Huntington's disease, genetic forms of colon and breast cancer and, more recently, haemochromatosis. Predictive testing allows DNA mutations to be identified before signs and symptoms develop. In genetic disorders with specific therapies (eg, haemochromatosis), this provides the opportunity to treat early and so prevent complications. The above disorders involve single gene defects or inheritance patterns that are easily defined. Increasingly, predictive testing will be directed at more common but complex disorders with multifactorial inheritance (ie, disorders that result from the interaction of genetic and environmental factors5). For example, Alzheimer's disease occurs in both genetic and sporadic forms. The DNA marker ApoE4 is strongly associated with early-onset disease. However, although this marker is a risk factor, the pathway by which it increases risk is not yet defined. Further understanding of the pathogenesis of Alzheimer's disease, which will become possible once genetic abnormalities in this condition are fully understood, will allow proactive steps to prevent disease onset or progression (eg, removing or avoiding environmental toxins, and specific therapies directed towards DNA-based abnormalities).

Ronald J A Trent PhD, FRACP, FRCPA

With our increased understanding of the molecular mechanisms of haematological disorders, it has become possible to target therapy precisely to the underlying defect. Targeted therapy can increase safety and potency, while causing fewer side effects than standard treatment. "Smart" drugs and gene therapy have recently shown great promise in a wide range of malignant haematological and coagulation disorders. Figure: Cytogenetic analysis showing ABL probe (red) on chromosome 9, BCR probe (green) on chromosome 22, and both probes on the Philadelphia chromosome, indicating the abnormal hybrid BCR-ABL gene. Chronic myeloid leukaemia.1 Since the Philadelphia chromosome was recognised over 40 years ago, the genetic changes that lead to chronic myeloid leukaemia (CML) have been progressively unravelled. A reciprocal translocation between chromosomes 9 and 22 creates a unique hybrid gene, BCR-ABL, which encodes a protein with tyrosine kinase activity. The abnormal gene is found in almost all patients with CML and can be detected routinely on cytogenetic analysis using fluorescent markers (Figure). The BCR-ABL protein confers on its host cell extended life span, disregard for marrow inhibitory signals and inevitable progression to a more malignant phenotype, clinically recognised as blast crisis. Imatinib is a specifically designed, highly targeted drug that blocks BCR-ABL tyrosine kinase action. At well tolerated oral doses, it eliminates the abnormal Philadelphia clone and dramatically normalises blood counts in almost all chronic-phase patients, as well as in most of those with advanced disease (accelerated phase and blast crisis). Remissions appear durable, although long term data are unavailable. While imatinib is not yet believed to cure CML, it could become initial therapy for all patients, including those who would otherwise have proceeded immediately to allogeneic stem-cell transplantation. Gene therapy in haemophilia.2 Much is already known about the genetic abnormalities, laboratory measurement and clinical course of haemophilia. This condition is an excellent model to demonstrate the feasibility of human gene transfer, as large clinical benefits can follow even small improvements in the level of clotting factors (eg, from less than 1% to 5% of factor VIII or IX). Factor VIII or IX genes have been successfully transferred in at least 29 people with haemophilia, using either skin, blood, muscle or liver cells transformed by various carrier vectors. All studies have demonstrated some clinical efficacy, with sustained improvement in factor level over a period, and reductions in bleeding symptoms and use of clotting-factor concentrate. However, concerns remain about the potential of the technique to alter the individual's genetic code, leading to cancer and transmission of changed genes to the next generation. "Magic bullet" therapy in non-Hodgkin's lymphoma.3 The CD20 antigen is a specific protein expressed in virtually all malignant B-cell lymphomas, but not non-lymphoid cells, normal early B lymphocytes or plasma cells. This antigen is the target for the monoclonal antibody rituximab, which has shown great clinical benefit in patients with non-Hodgkin's lymphoma. Around half of patients with relapsed or refractory low-grade, non-Hodgkin's lymphoma have a response to rituximab, which can last for over a year (median, 12 months). Because of its specificity, rituximab has side effects that are milder than and differ from those of other forms of chemotherapy. The main, but uncommon, problem is infusion-related fever, chills or wheeze. When rituximab is used in conjunction with standard chemotherapy as initial treatment for lymphoma, it improves response with virtually no added toxicity. Further benefit is seen in patients with refractory lymphoma, when radioactively tagged anti-CD20 antibody can be used to deliver targeted local radiation treatment. New anticoagulants.4,5 Anticoagulants have been designed that are more specific than standard and low molecular weight heparin. Most focus has been on factor X and thrombin, but there are new anticoagulants for almost every coagulant factor. Three direct thrombin inhibitors (hirudin, bivalirudin, and argatroban) are approved for clinical use in the United States. Four other anticoagulants (activated protein C, tissue factor pathway inhibitor, synthetic pentasaccharide, and the oral thrombin inhibitor H376/95) are undergoing or have completed phase III evaluation studies. Each drug must show a positive benefit-to-risk profile, and particularly cost effectiveness, in the face of the marginal therapeutic advantage over established agents. The new drugs are likely to avoid the serious non-anticoagulant side effects of heparin, such as thrombocytopenia, and perhaps osteoporosis. With the trend for reduced hospital stay and evidence suggesting that the risk of venous thrombosis remains high for several months after orthopaedic surgery, oral agents are likely candidates for improving care. The oral thrombin inhibitor H376/95 is arousing most interest, as it produces predictable anticoagulant response without laboratory monitoring. It is currently being evaluated in phase III trials as a possible substitute for warfarin in venous disease and atrial fibrillation. The early completion of the Human Genome Project and advances in biotechnology will inevitably increase the number of new therapies specifically designed for the individual patient and disease.

Ross I Baker FRACP, FRCPA · Alison M Street FRACP, FRCPA · Kerry M Taylor FRACP, FRCPA

Informatics aims to fix the "pathologies" in the information systems used to deliver healthcare. If physiology literally means "the logic of life", and pathology is "the logic of disease", then health informatics is the logic of healthcare.1 It is the rational study of how we think about patients and how treatments are defined, selected and evolved. The tools of informatics are likely to be clinical guidelines, formal medical languages, information systems, or communication systems like the Internet. Our understanding of information system pathologies in healthcare has advanced rapidly over the past decade, with the advent of evidence-based medicine and the focus on error reduction and improvement in the quality and safety of care. Computer-based prescribing. The most common cause of adverse clinical events is medication error, which accounts for about 19% of adverse events, and the commonest prescribing errors can be redressed by better information about medications or the patients receiving them.2 About 70% of Australian GPs now prescribe electronically, and it may soon be indefensible to prescribe without computer support. Computer support reduces serious prescribing errors by 55%, and overall prescribing errors by about 83%.2 Errors are reduced through automated checks for dosage, drug–drug interactions, and appropriateness of indication. Although the benefit of computer prescribing increases when it is integrated into an electronic patient record system, lack of such record systems is no reason to delay introducing electronic prescribing. The past two years have seen increased activity at a national level in developing standard electronic health records, notably through the Health Connect program <http://www.healthconnect.gov.au/>, but progress towards standard electronic record formats remains slow. Alerting systems. Alerting systems deliver urgent warnings to clinicians. For example, clinicians can be alerted by health authorities about civil defence matters with health implications, such as bioterrorist attacks, outbreaks of infectious diseases, or medication alerts. Alphanumeric pagers, text-enabled mobile phones, and wireless palmtop computers are all able to receive such messages, allowing clinicians to react rapidly to new information independent of their physical location. Increasingly, such technology is being used to support national emergency "cascade" systems that attempt to contact all clinicians quickly. Many clinical decisions require revision as new evidence arrives. Computer-generated alerts can also be used to inform clinicians about new information. Alerts may notify clinicians of errors in medication orders, new laboratory results, or changes in the status of patients attached to monitoring equipment. Simple alerts can be generated automatically (eg, by laboratory computer systems) or be sent as emails that get redirected into the alerting system (eg, when a hospital pharmacist detects a medication abnormality during routine patient review). Computer-generated messages can substantially improve clinical care. When physicians were alerted via email to increases in serum creatinine levels in patients receiving nephrotoxic medications, medications were adjusted or discontinued an average of 21.6 hours earlier than when no email alerts were delivered.3 When clinicians were paged about "panic" laboratory results, the time to therapy decreased by 11% and the mean time to resolution of an abnormality was 29% shorter.4 Continuing medical education. Continuing medical education (CME) can also benefit from new technologies. Traditional didactic measures such as lectures do not substantially change clinical performance or improve clinical care.5 In contrast, interactive educational activities, structured around actual problems in the clinical workplace, are more successful.5 Furthermore, clinical science produces information at a rate that far exceeds the capacity of clinicians to read or absorb it. Because keeping up-to-date as a separate activity is no longer feasible and learning works best in the clinical workplace, most future CME will involve using online information technology to answer immediate clinical questions. Thus, CME changes from periodic knowledge updates to a "just in time" model in which clinicians check the medical knowledge base, potentially at every clinical encounter. At present, online evidence delivery systems are in their infancy. Systems designed to support the information needs of clinicians have been in development for some years, and should be a routine component of clinical practice before the end of the decade. Current online evidence systems rely on the clinician to be an expert in searching for and identifying appropriate information. Future systems will be able to intelligently seek out the most appropriate information, and present it in a form most suited to the clinical context. In summary, practising clinicians are likely to see informatics interventions play a larger role in their clinical workplace over the next several years, often in novel and unexpected ways.

Enrico W Coiera MB BS, PhD, FACMI

Throughout the world until the mid-1990s, HIV infection was invariably fatal, with a median survival of one to two years after diagnosis of AIDS. Symptomatic HIV disease and AIDS imposed significant burdens on healthcare budgets, in addition to the often immeasurable societal costs. Now, for some, the availability of more effective antiretroviral therapies has transformed the HIV/AIDS epidemic. Mortality and AIDS diagnoses have fallen precipitously since widespread introduction of these treatments.1,2 Evidence to date suggests that the effectiveness of antiretroviral therapy has persisted.3 Mother-to-child HIV transmission can be effectively controlled, so that in the developed world paediatric HIV infection is rare. In developed countries, antiretroviral therapy is one of the most cost-effective interventions for treatment of a chronic disease.4 These unequivocal improvements are largely unprecedented for an infectious disease only 20 years old. However, HIV/AIDS continues to represent a significant global public health crisis. The United States identified HIV/AIDS as a threat to national security, and a special session of the United Nations General Assembly was convened in 2001 to address the epidemic. In the past five years, a clear paradox has emerged. On the one hand is the challenge of sustaining the improved longevity and quality of life for people who have access to effective treatments and care. On the other is the challenge of securing equivalent outcomes in the estimated 95% of HIV-infected people who live in countries that cannot afford antiretroviral therapy. For these 34 million or so people, HIV infection remains a death sentence. HIV/AIDS in developed countries. Combination antiretroviral therapy is not curative. The intent of treatment is to reduce the rate of virus replication, thus forestalling further damage to the immune system and, in most people, facilitating recovery and reducing the risk of life-threatening opportunistic infections or neoplasia. However, effective drug regimens are complex, and adherence is difficult. Ongoing virus replication increases the risk of selecting viruses that are resistant to treatment. As all 15 currently available antiretroviral drugs inhibit only one of two enzymes (HIV reverse transcriptase or protease), the selection of viruses resistant to one drug often carries the additional penalty of cross-resistance to other drugs. This limits the options available for future treatment. Each antiretroviral therapy has well described acute and chronic toxicities. More recently, clinical observations from Australian researchers implicate these agents in development of a syndrome termed lipodystrophy.5 Characteristically, patients present with abnormalities in body fat; many have insulin resistance, and some develop type 2 diabetes mellitus. The increased risk of cardiovascular disease arising from the glycaemic abnormalities may be compounded by hyperlipidaemia of an atherogenic profile. As all HIV-infected patients will need lifelong treatment with antiretroviral agents, these newly described toxicities could be a significant impediment to continued successful clinical outcomes. There is an urgent need for new therapies that inhibit HIV replication at new sites (such as HIV integrase and virus–cell fusion), that do not select for cross-resistance to other antiretrovirals, and that are not associated with metabolic toxicities. The potential role of immunotherapies (eg, interleukin 2 and therapeutic vaccines) warrants continued investigation, as they may be unaffected by cross-resistance to antiretrovirals and may have less long term toxicity. HIV/AIDS in developing countries. The scale of the HIV/AIDS problem in the developing world is alarming. Life expectancy in some countries will be reduced, in the absence of HIV treatment, by as much as 50%. This effectively negates all gains achieved through public health programs in these countries over recent decades. Addressing the inequities of healthcare around the world will take more than biomedical solutions — not only do drugs need to be made available more cheaply, but healthcare professionals need training, education, support and resources. In addition, treatment must be seen in the context of a comprehensive prevention and care framework. We need to revisit how medical research might contribute to resolving this enormous crisis. As part of such an approach, evaluations are being planned of simplified methods for clinical monitoring of HIV disease, deferred treatment strategies and abbreviated therapy regimens. We can be optimistic that research will deliver at least a partially effective prophylactic vaccine, but even optimistic estimates suggest this will take seven to 10 years. Every day about 15 000 people are infected with HIV, of whom 95% are in developing countries. In the seven to 10 years that a vaccine may take to develop, some 35 million people will be facing a reduced lifespan unless there is substantial change in their access to proven treatments. For the remaining 5% of HIV-infected individuals, the challenge is to develop new treatments.

Sean Emery BSc(Hons), PhD · David A Cooper MD, DSc, FRACP, FRCPA, FRCP

Allergy falls squarely into the class of common disorders caused by interaction between a genetic predisposition and an environmental stimulus. Genetic approaches are revolutionising the treatment of many primary immunodeficiencies, which are caused by single gene defects, but are unlikely to be of therapeutic value in the short term for multifactorial allergic disorders such as asthma, rhinitis and eczema. Nevertheless, advances have been made in our understanding and management of these disorders, which together are among the five most common conditions for which people consult their general practitioners. Prevention. It is unclear why the incidence of atopic diseases, particularly asthma, is rising so sharply in First World countries. Atopic diseases are associated with the persistence beyond infancy of a strong interleukin-4 (IL-4) dominant response by T cells that favour IgE synthesis and inflammation (TH2, or type 2 helper T cells). The "hygiene hypothesis" attributes this persistence to changes in infant diets (such as sterile water), early and increased use of antibiotics within the first year of life with consequent changes in gut bacterial flora, and reduced incidence of bacterial infections because of cleaner homes, smaller families and use of cleaner and more supervised childcare. The data support the view that a less affluent or rural lifestyle is protective.1 Mechanistically, the hypothesis postulates that a "clean lifestyle" is associated with decreased stimulation of the innate immune system because of less exposure to immunostimulatory DNA sequences (CpG motifs) ubiquitous in environmental bacteria. Vaccine adjuvants and DNA vaccines are under investigation that include these bacterial CpG motifs and drive an immune interferon (IFN-γ) dominant cytokine response by type 1 helper T cells (TH1), thereby inhibiting the allergic phenotype. These approaches and other forms of novel allergen-specific immunotherapy may play a preventive role in the future. Diagnosis. Diagnosis of allergy is now more precise, with better standardisation of allergen extracts and increasing use of monoclonal antibodies prepared from recombinant allergen proteins. Commercial diagnostic kits using recombinant antigens should become available within the next five years, particularly for conditions such as latex allergy, for which current tests have low diagnostic sensitivity and specificity.2 The causative mutations have been identified for most of the catastrophic sex-linked and autosomal primary immunodeficiencies, such as adenosine deaminase deficiency and severe combined immunodeficiencies, and prenatal diagnosis of these conditions is now available. Intervention. Some primary immunological disorders resulting from single gene defects can be corrected by gene therapy, largely because the treatment (which would be hazardous if attempted in vivo) can be undertaken ex vivo on cells from the patient's marrow or blood.3 This therapy is available in specialist centres only. Pharmacotherapy for atopic disorders has advanced over the past five years.4 Long-acting β-agonists for symptom control have been extremely effective additions to the treatment regimens for moderate and severe asthma, and exercise-induced asthma. The leukotriene-receptor antagonists are the first new class of asthma drugs for 25 years. Although their role in asthma is still not fully defined, they may be valuable in other allergic and immunological disorders, such as rhinitis, nasal polyposis and urticaria. Once-daily topical corticosteroid preparations are now available for use in rhinitis, asthma and eczema, providing increased topical potency, low systemic bioavailability and improved compliance. Allergic inflammatory processes involve multiple cytokines, decreasing the usefulness of antagonists to single cytokines, such as IL-4 and IL-5, or the anti-Th2 cytokine IL-12. IL-10 therapies were initially unsuccessful, but increasing evidence suggests this cytokine is important in effective immunotherapy, possibly by inducing antigen-specific tolerance (anergy) and by promoting a switch from IgE to IgG4 synthesis. Strategies focusing on IL-10 are likely to increase over the next five years. More recently, a monoclonal antibody directed against IgE has been developed for human use. This agent has potential for treating patients with multiple sensitivities, who benefit little from conventional allergen-specific immunotherapy. Clinical trials demonstrate that it attenuates both early and late asthmatic responses after allergen challenge. However, it is likely to be expensive. Anti-IgE treatments may play an adjunctive role in enhancing safety during rapid updosing of allergen immunotherapy. Allergen-specific immunotherapy may modify the natural course of allergic disorders, or even prevent their occurrence, and is attracting a resurgence of interest, particularly for bee-venom, pollen, cat and latex allergy. Research on vaccines containing the allergenic sites that react with T cells, but not IgE-binding sites (to minimise anaphylactic side effects), should result in new specific immunotherapy products within the next five years.5 Nevertheless, the strong environmental influence in atopic disorders suggests that public health intervention strategies are needed in addition to pharmacotherapy. The real advances of the next decade should come from creative combinations of molecular biology, immunology, pharmacology, genomics and proteomics, and allow us to manage allergic and immunological disorders more effectively and safely.

Robyn E O'Hehir FRACP, PhD, FRCP

Recent years have seen the continuing emergence of new infectious diseases and the re-emergence of old ones. However, there have also been major advances in diagnosis and treatment of infectious diseases, as well as in our understanding of their pathogenesis. Future control of these diseases will require attention to the behavioural, environmental and healthcare factors that drive microbial evolution. For example, the "epidemic" of injecting drug use promotes HIV spread; Legionnaires' disease is "opportunistic" on air-conditioning and water-treatment systems; and immunosuppressive therapies and medical instruments that are difficult to sterilise (eg, endoscopes and phaco-emulsification handpieces) create opportunities for new infections. HIV and hepatitis C. HIV epidemics are emerging in Papua New Guinea and South-East Asia. Australia successfully combated the first wave of HIV infection in the late 1980s and is in a position to support control programs in these areas. The most important development in HIV control is the concept that treatment is an essential component of prevention, promulgated at the recent United Nations General Assembly Special Session on HIV/AIDS.1 In Australia, where antiretroviral resistance is now common, the emerging approach to management is immunotherapy (boosting the immune response with agents such as interleukin 2 and vaccines). Hepatitis C virus has been revealed as more common than expected in Australia, with over 200 000 people estimated to be infected.2 It rarely presents as an acute symptomatic infection, but emerges insidiously with symptoms of chronic fatigue, and in some people progresses to cirrhosis and (rarely) hepatocellular carcinoma. Progression to chronic liver disease appears more likely if infection is acquired through transfusion or at an older age.3 For infection acquired through injecting drug use, rate of progression to cirrhosis is 5%–10% after 20 years. Endoscopy is a recognised route of transmission that requires attention. Creutzfeldt–Jakob disease. The emergence of variant Creutzfeldt–Jakob disease (vCJD) has prompted changes to transfusion services in Australia and review of food and therapeutic products and infection control measures. In routine medical practice, there is a need to identify people at risk of CJD before neurosurgery, ophthalmic surgery and diagnostic procedures that contact infected tissue, and to implement measures to contain healthcare-associated transmission of classic CJD. However, the necessary standards of infection control are neither widely agreed nor practised. As no cases of vCJD have yet been reported in Australia, the cost–benefit of implementing infection control measures for vCJD is uncertain and is currently being actively considered by the Special Expert Committee on Transmissible Spongiform Encephalopathies of the National Health and Medical Research Council. Emergence of vCJD in Australia will dramatically alter infection control practices, not least because vCJD manifests in a wider range of tissues than classic CJD (eg, in the tonsils). Infection control procedures will be needed for procedures involving lymphatic tissues as well as brain. Vaccines. Haemophilus influenzae type b (Hib) vaccine has substantially eradicated Haemophilus meningitis and pneumonia from the Australian community, and the new conjugated pneumococcal vaccines have similar potential to prevent invasive pneumococcal disease. A raft of other new vaccines are in advanced stages of development, including vaccines that stimulate cell-mediated responses against many viruses, Chlamydia spp. and even cancers. Vaccines for varicella are currently marketed, and clinical trials are under way on vaccines for herpes simplex virus, human papilloma virus, HIV, malaria and tuberculosis. Key factors in vaccine use are access, funding and long term safety. The role of routine vaccination for pneumococcus, varicella virus and meningococcus in Australia has yet to be debated, but these vaccines will have impacts on routine practice. Antiviral agents. There are now effective antiviral agents for the herpes viruses, HIV, hepatitis B and C viruses and influenza virus. The range of antiviral compounds is expanding, and their role in treatment and prevention is a current challenge for clinical research. Diagnostic methods. Molecular diagnostic methods are now established for infectious diseases and are being tailored for easy use in standard laboratories, and even as point-of-care kits for the consulting room. A prion diagnostic kit should be available within two years. Concepts in pathogenesis. Infection is now recognised to have a role in conditions as diverse as cancer of the cervix (human papilloma virus), preterm birth (bacterial vaginosis) and cerebral palsy (chorio-amnionitis). In contemplating the future, the bad news is that infectious diseases evolve continuously and will continue to present in new guises. The good news is that molecular biology has provided new tools for diagnosis and control. However, advances have mostly comprised new strategies to control emerging disease agents. The challenge is to modify the environmental, social and behavioural factors that promote the emergence of new infections.

Peter J McDonald AM

Although evidence-based intensive care medicine is gradually developing, progress in clinical trials has been hampered by the small number of patients, broad range of diagnostic categories, and lack of diagnostic criteria and illness severity measures. Prevention. Preventing critical illness has become a focus of intensive care practice. As cardiac or respiratory arrest in hospital wards carries substantial mortality, it is essential that deterioration of a patient's condition be recognised as early as possible. In a detailed observational study conducted in three Australian acute-care hospitals,1 at least 50% of patients who had an arrest were found to have had recognisable deterioration prior to the arrest. Ideally, it should be mandatory for nursing staff to call an emergency team if, during routine observations, they notice deterioration in a patient. Where such a system exists, the number of ward-based in-hospital cardiac arrests has fallen by 80%, with a 32% fall in all-cause mortality. Diagnosis. Standardising and defining the illnesses encountered in the intensive care unit (ICU) has allowed the creation of "illness severity scores", which combine information on pre-existing illness, diagnosis and physiological derangement to predict outcome. Actual outcome is compared with predicted outcome to produce a "standardised mortality rate". Recently, widespread application of these methods has improved reliability and comparability of clinical studies. Intervention. Systematic study of standard ICU therapies is relatively new. Debate over simple questions, such as what tidal volume should be used for ventilator settings, has raged for many years. The Australasian method uses a tidal volume of 7 mL/kg (to prevent barotrauma), while the US method uses a tidal volume of 10–15 mL/kg (to prevent atelectesis). In the Acute Respiratory Distress Syndrome (ARDS) study,2 in which 861 ventilated patients with ARDS were randomly allocated to receive low-volume ventilation or standard-volume ventilation, mortality was lower in the low-volume group (31% v 39.8%; P = 0.0007). A study by the Australian and New Zealand Intensive Care Society Clinical Trials Group (CTG) of the role of dopamine in preventing acute renal failure is another striking example of a known "proven" therapy finally meeting scientific rigour and failing.3 Red-cell transfusion has been a cornerstone of critical-care practice for many years. Routine transfusions were given to maintain the haemoglobin concentration at 100 g/L, with the aim of maximising flow and oxygen-carrying capacity. In 1999, the Canadian Critical Care Trials Group reported on the first randomised controlled trial of blood transfusion in ICU,4 which compared a conservative blood transfusion strategy (Hb 70–90 g/L) with a liberal transfusion strategy (Hb 90–110 g/L). Fewer patients in the conservative group died than in the liberal group (18.7% v 23.3%; P = 0.11). The rate of red blood cell transfusion was 2.6 units per patient in the conservative group versus 5.6 units per patient in the liberal group. The potential for saving a valuable resource, blood, without worsening outcome is large. Reducing the amount of blood transfused would also lower the risk of transfusion-related infections. Are the results of trials changing practice? To evaluate the Australian response to the transfusion study,4 the CTG surveyed transfusion practice in Australia in 2000. The national results of the survey are not yet available, but in our own unit there was compliance with the conservative transfusion protocol in all cases except one, in which transfusion was demanded by the surgical consultant preoperatively. After a Cochrane study showed that the use of intravenous albumin for resuscitation was associated with a higher death rate, the use of albumin in the United Kingdom and Europe fell by 20%. In Australia, the CTG has begun a trial to allocate 7000 patients randomly to treatment with either colloid (albumin) or crystalloid fluids for resuscitation. There is a need for definitive studies rather than meta-analysis, especially in the diverse ICU patient population. The elucidation of the inflammatory cascade and pro-coagulant pathways in septic shock (a leading cause of death in ICU) has led to new therapies using naturally occurring anti-inflammatory and anticoagulant proteins synthesised in vitro. Although antiendotoxin antibody studies have been disappointing, activated protein C, which has anticoagulant and anti-inflammatory properties, appears promising. Protein C is activated by thrombin coupled to thrombomodulin. Thrombomodulin is down-regulated in sepsis by inflammatory cytokines. A low plasma level of activated protein C is a marker of sepsis and is associated with death from sepsis. In a study of 1690 patients performed in 164 centres in 11 countries, infused activated protein C was shown to decrease the mortality due to sepsis.5 Furthermore, activated protein C is showing promise for treatment of meningococcal septicaemia. Basic research into understanding the inflammatory system and its inter-relation with the coagulation pathway in sepsis may pay clinical dividends in treating septic shock. The past decade has seen ICU evolve from an experience-based to an increasingly scientifically based practice. Continued advances should see further improvements in patient survival rates.

Anthony J Bell MD FRACP · Andrew J Turner FRACP

Our knowledge of the biology of cancer has increased exponentially in the past 30 years. Although application of this knowledge to patient care has been modest, some important improvements in healthcare delivery are available now or expected in the near future. Prevention. The prevention of cancer through dietary or drug interventions is a critical but largely unmet challenge. Recent clinical trials have shown that drugs such as the non-steroidal anti-inflammatory agent sulindac can reduce the size and number of adenomas in individuals with familial adenomatous polyposis.1 Tamoxifen and the newer selective oestrogen- receptor modulators have similar benefits in breast cancer.1 Yet, cancer chemoprevention is in its infancy, and issues regarding dosage and long-term treatment risk are unresolved. Finally, control of Helicobacter pylori infection may lead to lower rates of gastric cancer. Diagnosis. Advances in cancer knowledge and genomics allow predictions of familial predisposition to several tumours, including breast, ovarian and colon cancer. The accurate diagnosis of familial cancer involves input from various medical practitioners, and increasingly involves recognition by pathologists of distinctive cancer phenotypes, such as breast cancer with BRCA1 mutations or colorectal cancers seen in hereditary non-polyposis colorectal cancer. The identification of germline mutations that cause colorectal or breast/ovarian cancer is both labour- and time-intensive. However, identification of these mutations facilitates screening of family members and the targeting of strategies for prevention or early detection of cancer, and allows reassurance of unaffected individuals within a cancer-prone family. Intervention. Incremental advances in treatment modalities, including cytotoxics, hormonal agents and anti-emetics, have yielded modest improvements during the past five years. Sadly, of the more than 480 cancer therapeutics currently in clinical development,2 few novel cancer treatments will reach the oncology clinic, and even fewer will have significant effects on cancer care. For decades, we have been promised drugs that will target cancer cells without damaging normal cells, be they "magic bullets" based on monoclonal antibodies, or, more recently, "silver bullets" — small molecules that target genetic events central to carcinogenesis. In the past year, the clinical utility of some of these new therapies has been realised. Two genetically engineered antibodies, trastuzumab and rituximab, are now available for treating breast cancer and non-Hodgkin's lymphoma, respectively. Their effectiveness results from targeting molecules important for tumour growth rather than from immune-mediated cell killing. Trastuzumab targets the erbB-2 (HER-2/neu) receptor, which is overexpressed in about 20% of breast cancers, and antibody binding culminates in cell-cycle arrest.3 Trastuzumab is well tolerated, although it must be administered regularly to control tumour growth. One study has shown that the combination of trastuzumab and paclitaxel modestly improves the survival of women with advanced breast cancer. However, trastuzumab cannot be used safely with all chemotherapy, as illustrated by the high incidence of cardiac dysfunction (27% of patients) when the drug was combined with anthracyclines. The "silver bullets" target fundamental genetic changes in tumour cells. One example is ST1571, a small molecule that inhibits the tyrosine kinase activity of the BCR-ABL fusion protein.4 This oral drug shows great promise for treating chronic myeloid leukaemia, reversing the haematological and cytogenetic features of the disease.5 It may also be effective against gastrointestinal stromal tumours owing to its activity against the tyrosine kinase KIT. This is particularly encouraging, as these tumours rarely respond to chemotherapy and radiotherapy. As drugs can now be tailored to specific molecular targets, there is a demand for complex molecular assessments of each tumour. For example, suitability for trastuzumab therapy is predicated on accurate identification of erbB-2 overexpression. This requires specialised, expensive techniques such as immunostaining and FISH analysis. This trend is likely to continue. Up to 200 new anticancer drugs will be launched by 2005. These drugs will increasingly utilise our knowledge of the molecular basis of cancer. It is hoped that many of these drugs will act against malignancies of the lung and colorectum, for which there remains a large unmet clinical need.2

Robyn L Ward MB BS, PhD · Nicholas J Hawkins MB BS, PhD

Several recent developments in the basic and applied sciences have been incorporated into neurological and neurosurgical practice. Diagnosis. New magnetic resonance imaging (MRI) and molecular technologies have facilitated neurological diagnoses. Diffusion-weighted MRI (DWI) is the most sensitive imaging technique for acute brain lesions (eg, infarction), and distinguishes acute from chronic lesions. Coupling DWI with perfusion-weighted MRI (PWI) promises to identify which ischaemic stroke patients benefit from thrombolysis. Magnetic resonance spectroscopy, which detects metabolites (eg, lactate, choline) and N-acetyl-aspartate (NAA), can distinguish tumours (high in choline) from infarcts (low NAA and normal or low choline levels). Functional MRI (fMRI), which combines anatomical with physiological imaging, allows preoperative planning for resecting lesions in functionally important brain regions. Anatomical imaging by MRI, combined with functional imaging by ictal single- photon-emission computed tomography (SPECT) and interictal positron-emission tomography (PET), aids video-electroencephalogram monitoring and clinical assessment in localising seizure foci. The chromosomal position of many genes which, when mutated, cause neurological disorders is now known. In some (eg, Huntington's disease, muscular dystrophy, childhood-onset generalised primary dystonia), the genes, their disease-causing mutations, and gene products have been characterised. This has facilitated the development of new diagnostic techniques, implementation of predictive testing and genetic counselling services, and promise of novel approaches to treatment and prevention.1 Treatment. For patients with chronic tension-type headaches, the combination of antidepressant medication and stress management therapy is more effective than monotherapy.2 Among the newer specific acute migraine therapies, the triptans are of comparable efficacy, but differ in their onset and duration of action and adverse effect profile. Sodium valproate is an effective prophylactic for migraine. Ischaemic stroke patients benefit from 300 mg aspirin immediately or intravenous thrombolysis within three hours of onset. Anticoagulation with heparins causes 20 more deaths per 1000 patients treated (mainly intracranial haemorrhage) than aspirin, despite preventing 10 more symptomatic deep venous thromboses per 1000 patients treated. Stroke care by a multidisciplinary team in a stroke unit maximises survival free of handicap. The treatment of focal spasticity and dystonias has been revolutionised by botulinum toxin injections into affected muscle groups. The benefit lasts about 3–5 months, after which the injections can be repeated. In early Parkinson's disease, dopamine agonist monotherapy controls symptoms in a third of patients for up to five years, with fewer motor complications than with levodopa therapy. For other patients, levodopa remains the most effective symptomatic treatment. In patients with motor fluctuations due to "wearing off" of pharmacotherapy, "on" time may be increased by 10%–25% with slow-release levodopa, dopamine agonists, and catechol-o-methlytransferase inhibitors. Amantadine is an effective form of chemical pallidotomy for dopa-induced dyskinesia. In some patients, neurosurgical interventions may alleviate drug-resistant tremor and control parkinsonian symptoms. Frameless stereotaxy enables neurosurgeons to navigate and operate safely in high-risk areas of the brain. Neuroendoscopy is used in the ventricular system (eg, to remove dislodged shunt tubes, intraventricular blood, and colloid cysts, and to treat obstructive hydrocephalus by ventriculostomy) and assist trans-sphenoidal pituitary surgery. Prevention. For patients with a history of transient ischaemic attack or stroke of any type (and no contraindication to blood-pressure-lowering therapy), gradually introducing antihypertensive medication, to slowly lower blood pressure by at least 9/4 mmHg, reduces the risk of recurrent serious vascular events by at least a quarter.3 Interventional neuroradiology offers potential strategies for stroke prevention with techniques such as coiling of intracranial aneurysms and carotid angioplasty and stenting for patients with symptomatic severe carotid stenosis.4 Several newer anti-epileptic drugs (lamotrigine, topiramate, vigabatrin, gabapentin, tiagabine) have been approved as "add-on" agents in patients who have seizures despite conventional first-line treatment. For patients with temporal lobe epilepsy refractory to anti-epileptic medication, surgical resection of a part of the temporal lobe improves the proportion of patients seizure-free at one year from 8% to 58% (P < 0.001), and improves quality of life.5 For patients with multiple sclerosis who have at least two disabling relapses every two years, interferon betas reduce the relapse rate by a third, and may delay the progression of disability. Glatiramer acetate and mitoxantrone, a new immunomodulatory drug, also reduce relapses and possibly delay the progression of disability.

Graeme J Hankey MB BS, MD, FRCP, FRCPEdin, FRACP

Through improvements in radiopharmaceuticals and instrumentation, nuclear medicine continues to develop and refine in-vivo approaches for diagnosis (including staging and prognosis) and treatment of disease. Diagnosis. Positron-emission tomography (PET) using the glucose analogue 18F-fluorodeoxyglucose exploits the higher rate of glycolysis in malignant tumours relative to most normal tissues. PET is cost-effective, and is more sensitive than anatomical imaging for diagnosis, staging or restaging of patients with cancers of the lung, breast, colon, head and neck, oesophagus, lymphoma and melanoma.1 Nevertheless, optimal targeting of therapy requires careful correlation of the metabolic data derived from PET with the anatomical detail provided by CT or MRI, ideally by "fusing" the datasets from these modalities. The illustration shows a "fused" PET-CT image. In Australia, the Commonwealth Government will expand its present funding of two PET facilities to six in 2002, which will improve patient access to this technology. Myocardial perfusion imaging (MPI) using thallium-201 chloride or technetium-99m-labelled agents (sestamibi, tetrofosmin) has been validated for diagnosis of coronary artery disease (CAD) and detecting viable myocardium after myocardial infarction. More recently, its prognostic value for known or suspected CAD has been established: MPI provides incremental predictive value for overall cardiac mortality and major cardiac events over clinical evaluation, exercise testing or coronary angiography. A normal scan indicates a probability of less than 1% for death or non-fatal infarction within 12 months; this benign prognosis applies equally to patients at high risk of CAD who are to undergo non-coronary surgery. Assessment of regional and global left ventricular function is now possible, so MPI can be used to assess regional myocardial perfusion at rest and exercise, and simultaneously quantify left ventricular performance. A novel application of MPI is evaluation of patients presenting with chest pain and indeterminate ECG results. A normal MPI examination rules out myocardial infarction or significant ischaemia, and permits safe discharge of the patient for later outpatient evaluation.2 The most important prognostic indicator for breast carcinoma is axillary lymph node involvement at the time of surgery. This is conventionally ascertained by axillary clearance, which is associated with significant morbidity. Assuming that lymphatic dissemination from breast cancers is predictable, the sentinel lymph node (SLN) represents the first draining lymph node encountered by tumour cells. If the SLN can be shown to be free of metastatic disease, no further axillary exploration should be necessary. Lymphoscintigraphy following the peritumoral injection of Tc-99m-labelled microcolloid — coupled with the intraoperative use of a radiosensitive probe and (non-radioactive) isosulfan blue dye — can accurately identify the SLN in patients with apparently localised breast cancer.3 Tc-99m sestamibi imaging, particularly when coupled with high-resolution ultrasound, can accurately localise parathyroid adenomas in over 90% of patients. Confident preoperative localisation allows minimally invasive parathyroid surgery, which can be combined with the intraoperative use of a radiosensitive probe and rapid parathyroid hormone assays to shorten operating time, hospital stay, and convalescence. Intervention. Several β-emitting radiopharmaceuticals selectively localise in skeletal metastases and reduce pain, presumably by irradiating the metastatic lesions. Strontium-89 (for metastatic prostate carcinoma) and samarium-153 lexidronam (for prostate or breast cancer) reduce pain in up to 80% of patients and have excellent safety profiles. Preliminary evidence in patients with advanced androgen-independent prostate carcinoma suggests that 89Sr added to doxorubicin chemotherapy improves overall survival.4 Monoclonal antibodies directed against the CD-20 antigen expressed on B lymphocytes have been conjugated with β-emitting radionuclides to treat non-Hodgkin's lymphoma. Two such antibodies (iodine-131-labelled tositumomab and yttrium-90-labelled ibritumomab) have entered phase III trials. In 52 patients with relapsed B-cell lymphoma treated with 131I-tositumomab, chemotherapy and stem-cell transplantation, progression-free survival was 68% at two years.5 Many neuroendocrine tumours express cell-surface somatostatin receptors and can be detected with γ-emitting somatostatin analogues. A new class of somatostatin analogues labelled with 90Y allows targeting of somatostatin-receptor-positive tumours with high radiation doses. In patients with refractory progressive disease, response rates of up to 80% have been reported with minimal toxicity. As our understanding of disease increases, nuclear medicine will find new targets and roles, such as individual drug dosimetry, prediction of likely response to therapy, and early documentation of responses to therapy.

Frederick A Khafagi FRACP · S Patrick Butler MD, FRACP

The continuing rise in the mean age for childbearing has a widespread impact on the practice of obstetrics. It has been accompanied by an escalation in the rate of caesarean section to around 25% in many tertiary centres and into the 35%–45% range in private practice. The reasons are complex, but advancing maternal age, patient request and obstetric litigation are all factors. Increasing maternal age has brought with it increased exposure to and awareness of the risks of fetal abnormalities. As a "screening test", maternal age alone performs poorly. At best, its sensitivity for detection of Down syndrome is only 30%, with a false positive rate of 5%–14%. Invasive procedures (chorionic villus sampling and amniocentesis) carry a risk to the pregnancy that is often unacceptable, especially for women who have used assisted reproductive techniques. There has been a rapid evolution of non-invasive screening methods. Biochemical screening of maternal serum in the second trimester (involving alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotropin [hCG]; the triple test), coupled with maternal age, has been shown to increase the sensitivity to 60% while maintaining the false positive rate at 5%. Technical advances have increased the application of ultrasonography. It can be used to examine the nuchal fold, which has been found to increase the risk of Down syndrome 10-fold when thickened to more than 6 mm in the second trimester. Large studies at 11–14 weeks' gestation have shown that "nuchal translucency" measurements, in combination with maternal age, increase sensitivity to 75%–80%.1 Combining this with first-trimester biochemical markers (free b subunit of hCG in serum, and pregnancy-associated plasma protein, PAPP-A) may increase the sensitivity to 90%. The latest report of the absence of nasal bone in the first trimester in fetuses with Down syndrome indicates that combination screening could improve the sensitivity to beyond 95% while maintaining a false positive rate of 5%.2 If these projections are substantiated in larger studies, Down syndrome screening will shift to the first trimester, with obvious benefit for the mother. The past decade has seen a veritable explosion in our understanding of fetal physiology and pathology. The concomitant development of ultrasound technology has enabled identification of a higher proportion of fetuses with structural abnormalities. Such diagnoses have made possible early correction of the developmental abnormalities. The most successful fetal therapy is the treatment of severe anaemia from Rhesus isoimmunisation by intrauterine fetal transfusions. Survival rates of over 90% have been achieved. With routine administration of anti-D immunoglobulin, and the consequent fall in the incidence of alloimmunisation, training and maintenance of skill and expertise will be a major challenge. Maternal drug therapies are widely used. They include folate for preventing neural tube defects; digoxin, with or without flecainide, for fetal tachyarrhythmias; corticosteroids for both fetal lung maturation and congenital adrenal hyperplasia; and immunoglobulin for fetal alloimmune thrombocytopenia. Direct invasive fetal procedures have also been tried over the last decade. Shunts have been inserted in fetuses with bladder-outlet obstruction, idiopathic pleural effusion, and congenital cystic adenomatous malformation of the lung. Open fetal surgery, such as for congenital fetal diaphragmatic hernia and fetal sacrococcygeal teratoma, is rapidly giving way to less invasive endoscopic approaches. With increasing maternal age and the widespread use of assisted reproductive technology comes a rise in multiple pregnancies, with the associated impact of prematurity and the specific complication of twin-to-twin transfusion syndrome, which affects 10%–15% of monochorionic twins. In severe cases, mortality is over 90%. Aggressive amnioreduction can result in survivals of about 60%, but up to 20% of the survivors have long term handicaps. Fetoscopic laser coagulation of the communicating vessels has improved the survival rate to 75%–80%, and reduced the long-term handicap rate to 5%.3,4 The principal changes in gynaecological therapy have come from the introduction of effective alternatives to major invasive surgery. The place of endoscopic surgery for treating ectopic pregnancy, investigation of pelvic disorders and removal of benign adnexal masses is established, but the true costs versus benefits of advanced laparascopic procedures, such as for hysterectomy, require further evaluation. The development of improved medical alternatives for treating menstrual disorders, including both oral and direct intrauterine delivery systems, have markedly reduced the number of major operations. Similarly, non-surgical therapies in other spheres of gynaecology, such as urogynaecology, are being developed and evaluated.5 Complementing these changes has been the active participation in the Cochrane Collaboration by women's health professionals, so that the specialty is no longer the holder of Archie Cochrane's "wooden spoon".

Fung Yee Chan · Jeremy J N Oats DM, FRANZCOG

The major advance in ophthalmology in the past five years has been the findings from two recent epidemiological studies that have indicated the priorities for clinical and public health practice and basic science research in ophthalmology in Australia.1,2 These studies have shown that the prevalence of vision impairment increases threefold with each decade after the age of 40, with almost one in three people over the age of 80 having impaired vision. Prevention. There are five major causes of vision loss: under-corrected refractive error, age-related macular degeneration (AMD), cataract, glaucoma, and diabetic retinopathy.1,2 Of the 400 000 Australians with impaired vision, half have refractive error that is correctable. Almost all of the 9% with cataract will have excellent outcomes from surgery, and a further 8% have preventable vision loss due to glaucoma or diabetic retinopathy. With the ageing of the population, the number of cataract operations (currently about 125 000 a year) will need to double over the next 20 years. By the age of 90, most people will develop cataract and half will have already had cataract surgery. Another key finding of the two Australian studies was that cigarette smoking and ultraviolet-B exposure bring on cataract earlier, but lifetime exposure seems critical. These studies have also reported the impact of vision loss on quality of life. Even relatively minor vision impairment (< 6/12 vision) increases social isolation and doubles the dependency on community services, increases morbidity (with a twofold increase in falls and a threefold increase in depression), and doubles mortality rate. It is critical for healthy ageing that people with impaired vision be referred to vision-related rehabilitation services to reduce the impact of vision loss. Currently, less than one person in three with vision loss has used these services. Within the past few years, simple visual acuity tests have been developed to detect most treatable or correctable vision loss, particularly from refractive error, cataract and AMD. Vision screening targeted at older people (65 years and over) through primary healthcare is both simple and effective. Diagnosis. Although almost one in 10 people will develop glaucoma by the age of 80,3 only half of those with the disease are currently diagnosed. The measurement of intraocular pressure has been shown to be ineffective in detecting glaucoma. Current trials are investigating new screening technologies (frequency-doubling technology and confocal scanning laser tomography) and protocols for community use to detect early signs of damage to the retinal nerve fibre layer. The target group for screening is people with a family history of glaucoma and those over 50 years. Diabetes, associated with a 25-fold greater risk of vision loss, is a rapidly increasing problem. Although tight control of diabetes, blood pressure and blood lipid levels will reduce the development of diabetic retinopathy, the critical issue is its early detection (by screening at least every two years) and timely laser treatment.4 New, non-mydriatic fundus cameras used by non-specialised staff are an effective alternative to dilated ophthalmoscopy. They offer a great advantage in some situations, especially in rural and Indigenous communities. Intervention. Cataract surgery is now extraordinarily successful. The next major development will be an accommodating intraocular lens that will remove the need for reading-glasses after surgery — this is probably 5–10 years away. Ultimately, two in three people will develop AMD and one in four will lose vision. However, a third of AMD incidence is attributable to cigarette smoking.5 Only a few people with AMD benefit from current laser therapy. However, newly developed photodynamic therapy (PDT) can reduce or delay vision loss in selected cases. PDT involves the use of a diode laser with an intravenous light-sensitive dye (verteporfin). The laser photocoagulation of choroidal neovascularisation can reduce the risk of progression of vision loss from AMD. Treatment often has to be repeated three or four times a year and long-term benefits are still unclear. A large randomised controlled trial we completed this year showed that vitamin E supplementation did not protect against either AMD or cataract. The recently completed Age-related Eye Disease Study found that dietary supplements containing high-dose combinations of antioxidants and minerals (vitamins C, E, beta-carotene and zinc) reduced the risk of advanced AMD and vision loss (see <http: //www.nei.nih.gov/amd>). The development of glaucoma, cataract and AMD has been found to have a genetic basis. Genes related to presence and severity of glaucoma have been identified, but candidate genes for AMD are still to be found. It seems unlikely that gene therapy will prevent eye disease in the short term. As the famous baseball player Yogi Berra said, "predictions are always hard, especially when they are about the future". Even though the bionic ear is highly successful, a successful bionic eye is unlikely to be seen in the next 10 years or more.

Hugh R Taylor AC, MD, FRACO · Jill E Keeffe PhD

Joint arthroplasty is arguably the most successful operation in modern times. Orthopaedics of the future, however, will focus on new strategies for contemporary problems that integrate advancing technology and basic science with surgery. Figure: (a) MRI scan of a popliteal tumour gives excellent contrast to help plan surgical margins. (b) Increased metabolic activity on functional scanning (arrows) reflects either a high-grade tumour or a poor response to adjuvant therapy. (c) In future, growth factors may be used to enhance bone formation around prostheses (arrows) to increase their biological fixation and longevity. Diagnosis. Orthopaedics relies heavily on accurate anatomical imaging. Developments in soft-tissue contrast using magnetic resonance imaging (MRI) and the ability to demonstrate inflammation, hypervascularity and accurate anatomy has enhanced non-invasive diagnosis of such conditions as meniscal tears, labral tears in the hip, and occult fractures. MRI has been particularly valuable in assessing resectability of primary bone and soft-tissue malignancies when planning surgical margins and assessing the appropriateness of amputation or limb preservation. Future diagnostic modalities will combine anatomical with functional imaging, such as positron emission tomography, to improve the assessment of bone and soft-tissue lesions. Molecular biology and cytogenetics play increasing roles in the diagnosis of orthopaedic conditions, of which a substantial number have a genetic basis (eg, Marfan's syndrome, osteopetrosis and osteogenesis imperfecta). Identifying subcellular anomalies also clarifies aetiological mechanisms and helps to plan strategies for treatment and genetic counselling. Many sarcomas also display characteristic cytogenetic abnormalities1 with prognostic and tumorigenic significance. Future genetic studies of musculoskeletal tumours are likely to define subsets of patients who are good and poor responders to therapy, as well as identifying the genes responsible in many syndromes, dysplasias and cancers.2 Treatment. Delayed healing and non-union of fractures are responsible for protracted disability and pain. A variety of growth factors, such as the bone morphogenetic proteins (BMPs),3 are now known to be important in stimulating bone formation. Synthetic growth factors for treating problem fractures can now be mass produced using recombinant-DNA technology. Future strategies are likely to include coating prostheses with factors that stimulate bone formation to enhance the biological fixation of these devices. This would be particularly relevant for joint arthroplasty in young patients, for whom aseptic loosening of cementless prostheses is the commonest reason for revision surgery. Recently, factors that stimulate and inhibit osteoclast formation and function have been identified. Regulation of these factors by genetic manipulation or introduction of synthetic analogues may have important applications in treating conditions that have a genetic basis. Explantation of tissue, its manipulation and subsequent reimplantation into the body is a novel method for treating acquired musculoskeletal defects. Some articular cartilage defects can be treated by harvesting the patient's own articular cartilage cells, culturing them in vitro and then reimplanting them into the articular defects during surgery to obliterate the defect. Future strategies may include cloning explanted cells with genes that enhance their growth and production of cartilage matrix before reimplantation. Guided engineering of other tissues, such as muscle, ligaments and bone, is likely to extend the armamentarium of reconstructive surgeons for patients with post-traumatic or resection defects.4 Despite intensive chemotherapy, 30% of patients with osteosarcoma succumb to metastatic disease. The targets for future treatment are likely to be identified from studies of the metastatic cascade. For example, proteolysis is known to be important in tumour progression, and the expression of the urokinase plasminogen activator system during the growth of osteosarcoma has been identified.5 By genetically manipulating the expression of components of the urokinase plasminogen system in an animal model of osteosarcoma we have significantly inhibited the behaviour of osteosarcoma, paving the way for developing non-toxic strategies for treating this tumour. Prevention. In contrast to the advances in diagnosis, progress in improving prevention through genetic information has been slow. Conditions for which this has been successful include X-linked hypophosphataemic rickets and osteogenesis imperfecta. With over 40 000 joint replacements performed each year in Australia and a failure rate of 1% per year, techniques to reduce the failure rate from misalignment of the prosthesis are likely to have a major impact on clinical outcome and resource utilisation. Computer-assisted, image-guided surgery will improve the accuracy of surgical technique in the future, and may be extended to facilitate minimally invasive surgery. Important features of orthopaedics in the future will be multidisciplinary collaboration and reliance on high technology. The markedly increased safety in anaesthesia will allow more and bigger surgical procedures to be performed on an ageing population.

Peter FM Choong MD, FRACS, FAOrthA

Today, the specialty of otolaryngology/head and neck surgery encompasses a broad sweep of both medical and surgical diseases, with an emphasis on early diagnosis with the help of the telescope and the microscope. Major advances have been made in otoneurosurgery, rhinology, microlaryngeal and laser surgery, head and neck cancer surgery and paediatric otolaryngology. Figure: Digital photograph of a squamous cell carcinoma of the left vocal cord. Otology. All patients with asymmetric ear symptoms must first have audiometric assessment then a gadolinium-enhanced T1-weighted magnetic resonance imaging scan, which is sufficiently reliable to detect acoustic neuroma. The translabyrinthine (or sometimes middle cranial fossa) approach to acoustic neuromas and other tumours and cysts in the posterior cranial fossa allows preservation of facial nerve function in more than 95% of patients. Recently, skull-base surgeons have found an application for endoscopy of the cerebellopontine angle and have pioneered new approaches to the petroclival region. The investigation of dizziness, vertigo and imbalance is based on fundamental biological research and the findings from painstaking gross, microscopic and electronmicroscopic studies of the sensorineural elements of the cochlear and vestibular systems. The importance of a rehabilitation regimen and the benefit of vestibular manoeuvres for labyrinthine balance disorders have finally been recognised. Vestibular nerve section has been virtually replaced by controlled injection of gentamicin into the middle ear. With better understanding of inner-ear pathology, refined assessment of cochlear function, improved implantable devices and structured rehabilitation programs, cochlear implantation has become a routine operation. More predictable outcomes have widened the indications for younger children and for some individuals with marginal benefit from their hearing aid. Rhinology. In functional endoscopic sinus surgery (FESS) there is currently a more conservative attitude than previously, especially for paediatric patients. Because the ethmoid is such a complex structure, comprehensive computed tomography (CT) imaging is vital. In conjunction with CT scans, computer-controlled image guidance systems are now used in some centres for FESS operations and for transnasal hypophysectomy. This demanding "keyhole" surgery, performed with rigid telescopes and purpose-designed, slender instruments, requires a sound knowledge of the physiology of the mucociliary mechanism and the anatomy of the nasal cavities and paranasal sinuses. The surgeon must be familiar with the intricate anatomy and many individual variations of the ethmoid air cell system, whose delicate bony structures and lining mucosa require dexterous operative skills. The radical external operations of the past have mostly been replaced by these endoscopic techniques, which follow normal anatomical routes and aim to establish near-normal ventilation and drainage. Laryngology. Clinical interest in voice problems has been stimulated as research reveals a better understanding of laryngeal physiology in relation to the mass, elasticity, age-related contractility changes,1 viscoelastic qualities and vibration characteristics of the vocal cords. Our understanding will be enhanced by current investigations into the innervation of the larynx by central motor fibres from brainstem nuclei; cortical, subcortical and brainstem regulation; the relevance of small- and large-diameter axons; and nerve myelination. The field of neurolaryngology includes investigation of unilateral and bilateral vocal cord paralysis, paradoxical vocal cord movement and voice disorders in other neurological diseases such as multiple sclerosis and Parkinson's disease. Spasmodic dysphonia, previously untreatable, is now managed by botulinum toxin injections into the vocal folds. For diagnostic evaluation and treatment, the voice specialist and the speech pathologist use videostroboscopy, laryngeal electromyography, voice recording, objective acoustic analysis and aerodynamic assessment methods. Telescopes and special-purpose instruments (such as lasers and laryngeal microdebriders) have led to exciting advances in surgical intervention. The voice can now be restored or improved after endoscopic microsurgery or laser surgery for benign, premalignant or early malignant lesions. Head and neck surgery. Squamous cell carcinoma affects many thousands of people globally each year, yet currently available treatment with surgery, radiotherapy and chemotherapy is less than satisfactory. The five-year survival rate has shown little improvement over the past 20 years. For the future, we look forward to advances in molecular medicine and gene therapy that may improve the management of head and neck cancer, allowing preservation of function and higher cure rates. Novel molecular markers, such as the p53 gene, angiogenesis-related markers, cyclin D1 and epidermal growth factor receptor, are under intense study for their clinical implications.2 Australian otolaryngology/head and neck surgery maintains world-best standards in every respect. For young surgeons it is a popular and attractive specialty that promises an exciting and stimulating future.

Bruce NP Benjamin OBE, DLO, FRACS, FAAP

In the arena of child health, there is no better example of efficacious and cost-effective prevention than vaccination. The World Health Organization Global Polio Eradication Initiative has resulted in a 99% decline in polio cases since 1988, half in the past two years.1 Australia has contributed by the surveillance, since 1995, of acute flaccid paralysis (AFP), under the auspices of the Australian Paediatric Surveillance Unit, and in October 2001 the Western Pacific Region, including Australia, was certified polio free.2 Haemophilus influenzae type B vaccination has dramatically reduced the incidence of meningitis in the past 10 years, and the introduction of multivalent-protein conjugate pneumococcal vaccines that are immunogenic in young children will further reduce meningitis as well as other overwhelming sepsis. Rotavirus vaccines are on phase II clinical trials, with tremendous potential to save lives in developing countries, as well as reduce morbidity in developed countries. In paediatric surgery, sophisticated new diagnostic and assessment techniques are guiding progress in acute and chronic conditions. In severe intractable epilepsy, electrode implantation and intraoperative electrocorticography, somatosensory evoked potentials and cortical stimulation allow precise localisation of seizure foci and mapping of brain function, then accurate surgical resection. Outcomes include dramatic reduction or cessation of seizures and improved behaviour. Children with spastic cerebral palsy are at high risk for secondary hip dislocation, leading to severe pain and loss of mobility. In the past, late diagnosis has meant that by the time surgery was performed the child had often been wheelchair-bound for years, with scoliosis and other musculoskeletal deformities making anaesthesia, surgery and postoperative care very difficult and potentially dangerous. Electronic gait laboratories can now be used to diagnose early signs of hip dislocation in high-risk patients, leading to preventive surgery and thus avoiding reconstructive surgery or complex salvage surgery.3 Thus, such use of the gait laboratory has the capacity to improve the general health and quality of life in children who are disadvantaged by severe physical disability. Over the past 10 years there have been dramatic findings in the neurobiological, behavioural and social sciences, leading to new understanding of the highly interactive influences of genetics and the environment on brain development and behavioural maturation in early childhood.4 There are critical periods of development when the brain is primed to respond to particular stimulation. If these sensitive periods are missed, brain structure and function is altered, sometimes with long term consequences. This concept of "use it or lose it" has long been recognised in absent language development in profoundly deaf children, or "cortical blindness" in children with uncorrected congenital cataracts. Now there is evidence for similar critical periods in early childhood for development of emotional control and self-regulation.5 There is evidence that the midlife "epidemics" of cardiovascular disease, obesity and diabetes have their origins in fetal, perinatal and early-childhood nutrition and hormonal patterning. The socioeconomic gradient of health is apparent from the very early years. Governments around the world are using such evidence to drive a multisectoral or whole-of-government approach to early childhood, linking health, education and social services to provide a more optimal environment for the healthy development of children within their families. In Australia we have strong primary care health networks, almost universal access to education from the age of about four years, and complex systems of child care, family support and other social services. We have an opportunity to build on this infrastructure as we focus priorities on children and families. Child health professionals have a particular responsibility to use evidence-based advocacy, whether in their clinics, their community or their country, for appropriate linking of all services that promote healthy development of children. The future direction for research which will make a measurable difference to children's health lies in prevention and public health — including immunisation, gene therapies, prevention of obesity, promotion of literacy, and support for families and communities in the care of the young child.

Jillian R Sewell MB BS, FRACP

The past five years in palliative medicine have involved a period of review and rapid progress in research and service provision. The development of sound evidence to refine longstanding practice is the hallmark of research programs. Pain management. In pain, useful laboratory models now support observations that have been difficult to confirm. Significant nervous system changes in receptors/neurotransmitters and in anatomy are now known to occur in response to uncontrolled pain. Studies of the complex interactions of opioid receptors, N-methyl-d-aspartate receptors, and substance P and its receptors are broadening our knowledge of what happens in chronic pain. In animal models, there is evidence of nerve growth in response to chronic pain. These results indicate a need to control pain aggressively before irreversible changes in the central nervous system occur. The time scale for such changes in humans is still not clear. Morphine receptors multiply in response to uncontrolled pain. Their migration to the perisynaptic region of the nerve is necessary for them to modulate pain transmission, and is impaired in states of direct nerve damage. The concept that chronic pain is disease of the CNS, not simply nerves firing because of noxious stimuli, is important and clinically relevant.1 Palliative medicine has been dominated by the concept of new ways of using old medications. Research and validation of medications for use subcutaneously and in the syringe driver has been of medicolegal significance, as many common practices were outside recommended administration guidelines. The common combinations of medications in syringe-driver infusions had been based on anecdotal observations; recent research has validated some combinations, and provided some surprises for clinicians.2 The development of long-acting preparations of common opioids has revolutionised clinical care. New delivery systems for opioids have led to slow-release (8–12 hours) and sustained-release (12–24 hours) oral morphine preparations. Transdermal delivery of fentanyl every three days is now widespread. The plethora of opioid preparations and formulations has assisted in individualising treatment of pain for patients with life-limiting illnesses. The ease of use of new formulations has assisted the trend from inpatient to community-based care, with benefits to patients and their carers. Service provision. Palliative service provision has received closer evaluation, and overview data are now available to demonstrate the benefits of coordinated interdisciplinary palliative care. Important issues in service delivery include better coordination of services (rather than simply adding new services), greater access to out-of-hours support, and the specialised knowledge of someone who can advise because they do it all day, every day. Improved patient outcomes include increased time at home, fewer inpatient bed-days, better patient and carer satisfaction, and a greater likelihood of people dying where they want to.3 The complexity of supporting patients with widely differing diagnoses on a journey with a common end remains the challenge in palliative care. There is a growing emphasis on non-malignant diseases —end-stage organ failure, AIDS and neurodegenerative diseases. The focus of what is important to patients, recently bereaved families, physicians and other healthcare professionals is being researched. Issues that come to the fore include symptom management, achieving a sense of completion, decisions about treatment preferences, and treatment of the "whole person". For patients, other strong themes include being mentally aware, having funeral arrangements in place, not being a burden, helping others, and coming to peace with God.4 Research. Studying palliative-care populations poses ethical dilemmas, but such studies do improve care. One study of signal-averaged EEGs for patients who have entered unconsciousness at the end of life5 showed the response of unconscious patients to stimuli such as familiar voices, the lightening of consciousness just before death in most patients, and the importance of continued use of analgesics in people with a history of pain. In patients sedated with benzodiazepines, the level of unconsciousness was no deeper than in patients not sedated. As far as direct therapeutic advances are concerned, there have been few advances for the most common symptom, fatigue. Study is also required into cachexia syndromes and restlessness associated with the terminal state. These are areas where a great deal of work is needed if we are to make a sustained difference to people whose bodies are closing down. Future advances in the mechanisms and management of pain will include preparations and formulations designed to assist with the palliative-care principle of individualisation of symptom control. There is much research on the horizon for better clinical outcomes for palliative patients.

Deborah A Campbell MB BS, FAChPM · David C Currow BMed, FRACP, FAChPM

Plastic surgery has seen many changes in the past five years. Advances in our knowledge of genetic coding, growth factors, and tissue engineering offer the potential for new treatment options in the near future. Prevention. Craniofacial surgery has undergone an explosion of new discoveries over the past five years, which has the potential to lead to dramatic improvements in diagnosis and treatment of craniofacial disorders. Recent studies have demonstrated that mutations in the genes that code for fibroblastic growth factor receptors (FGF-R) are at least partially responsible for both syndromic and non-syndromic craniosynostoses.1 To date, four FGF-R subtypes have been identified. These tyrosine kinase transmembrane proteins function as high-affinity receptors for fibroblast growth factors and have been implicated in the regulation of cellular proliferation, differentiation, chemotaxis and apoptosis. Clinical applications of these findings are currently limited to genetic testing for some of the common craniosynostosis syndromes, but the hope is that these conditions will one day be treated with a combination of minimally invasive procedures and gene therapy. In a similar way, the complex cascade that determines upper-limb development is being unravelled. A number of important protein signals have been discovered and their role in upper-limb growth may provide therapeutic options in prevention of upper-limb anomalies. Diagnosis. Malignant melanoma is one of the most common cancers in Australia, with the estimated risk of developing a melanoma before the age of 75 years in Australia being one in 26 for men and one in 36 for women. Management of melanoma saw dramatic changes through the 1990s, in particular with regard to safe excision margins. However, it remains an intense area of research. Studies are now in progress to look at the role of sentinel-node biopsy. This technique, first described in 1992,2 involves identification of the first draining lymph node from the primary melanoma site using a combination of radioactive tracer and patent blue dye. The technique has already been shown to be a good indicator of spread of melanoma to draining lymph nodes. This could provide prognostic information and direct adjuvant therapies, potentially treating early disease spread. It has the advantage of causing less morbidity than traditional block dissections. Currently, sentinel-node biopsy should be considered for any melanoma thicker than 1 mm, but only in the context of a controlled clinical trial. Intervention. Chronic and other difficult-to-manage wounds remain a huge treatment challenge and cost burden to the community. One of the greatest advances has been the development of low-pressure dressings.3 These dressings consist of a non-collapsible evacuation tube connected to a sub-atmospheric pressure system, which is embedded within medical-grade reticulated polyurethane ether foam dressing. This technique removes excess interstitial fluid, increases vascularity, decreases bacterial colonisation and aids the natural tendency of the wound to contract. Additionally, it is only changed every 72 hours, thus decreasing labour costs and patient discomfort. Another area of wound care that is being developed and used by plastic surgeons is the determination of the precise biochemical processes that control wound healing. Already, the roles of a number of growth factors and cytokines have been defined. It is envisaged that during the 21st century new treatments will be developed to change cell function in a favourable way with the addition of positive growth factors and the removal or inhibition of negative growth factors. Some clinical trials have already been conducted using platelet-derived growth factor.4 Biochemical modification of wounds will have implications not only for treating chronic wounds, but also in preventing or controlling scarring. Bioresorbable plating systems represent an enormous development, particularly in the area of craniofacial surgery. Previous systems consisted of plates and screws made of stainless steel or Vitallium. Although these materials provide rigid fixation, have excellent tissue compatibility, and are corrosion resistant, they are permanent unless surgically removed, and thus carry long term potential for infection, migration and limitation of growth. Polyglycolic acid and poly-l-lactic acid fixation systems maintain their strength long enough to allow healing, and are then broken down completely by the body, thus eliminating these long term complications. Tissue engineering is one of the most exciting advances, and may lead to a new era in medicine: the potential to create new tissues or induce their regeneration. The basic requirements for this process are cells, a scaffold for the cells to grow on, and cellular signals or growth factors, which differentiate and stimulate cell growth. For the new tissue to be incorporated into the body, a blood supply then needs to be established. Although plastic surgeons have been "engineering" tissues for decades, these new developments raise the possibility of manufacturing tissues and organs ex vivo. This technology is already used in the area of burns surgery to create skin replacements when donor sites are limited by the extent of the injury.

Richard J Bloom MB BS · Kirstie MacGill MB BS, FRACS

Three recent developments of outstanding international significance have occurred in psychiatry. First, The global burden of disease report,1 which showed that depression, bipolar disorder, alcoholism, schizophrenia and obsessive compulsive disorder were among the leading causes of worldwide disease disability and burden, has had major ramifications for government prioritisation of health services. Second, significant research in Alzheimer's disease has revealed the specific molecular defects underpinning the rare familial early-onset form of this condition. Third, major advances in pharmacotherapy have led to dramatic shifts in treatment, particularly for depression and schizophrenia, but also for dementia and bipolar disorder. Nationally, a major epidemiological study — the National Survey of Mental Health and Well-being of Adults2 — confirmed the high prevalence and disability of mental illnesses, with depression and anxiety accounting for considerable morbidity. These international and national findings prompted the Federal Government to establish the National Depression Initiative "beyondblue". Diagnosis. In psychiatry, diagnoses continue to be made on the grounds of pattern recognition (ie, by delineation of clinical syndromes). However, as the pathophysiological mechanisms underlying the various mental illnesses gradually become apparent, the prospect of diagnostic tests comes closer. Most noticeably, there is an air of excitement surrounding aetiological research into Alzheimer's disease. The abnormal degradation of amyloid precursor protein (present on all cells) releases the β protein fragment that polymerises to form amyloid, which, over some decades, results in the formation of plaques. In the past decade, the first animal model of Alzheimer's disease has been developed in mice; abnormal genes on chromosomes 1 (coding for presenilin 1), 14 (coding for presenilin 2) and 21 (coding for an altered amyloid precursor protein, APP) have been identified in families with early-onset Alzheimer's disease. It has also been recognised that some alleles of the gene for apolipoprotein E increase the risk of the late-onset form. These findings may lead to an understanding of the key events in the genesis of the disease, and possibly to prevention or cure. Interventions. For depression, the selective serotonin re-uptake inhibitors have become the most commonly prescribed antidepressants, probably reflecting their greater tolerability and safety. Meta-analyses suggest that the recently available agents that act on both noradrenaline and serotonin (ie, venlafaxine and mirtazapine) may have greater efficacy. Other antidepressants likely to become available in the next few years include the selective noradrenergic agent reboxetine, and antagonists of corticotropin-releasing factor. For bipolar disorder, the anticonvulsants valproate and carbamazepine have proven to be of similar efficacy to lithium. Newer anticonvulsants, such as lamotrigine and topiramate, are showing promise as future potential mood stabilisers. The second generation (atypical) antipsychotic drugs — clozapine, risperidone, olanzapine and quetiapine — are being prescribed for schizophrenia (and for bipolar disorder) at ever-increasing rates because of their beneficial side-effect profiles, and, in the case of clozapine, superior efficacy in treatment-resistant disease. In the next five years, newer antipsychotic drugs, such as ziprasidone, iloperidone and aripiprazole, are likely to be in routine clinical use. A further major advance is the advent of drug treatments for Alzheimer's disease.3 Currently, the only drugs approved are the cholinesterase inhibitors donepezil, rivastigmine and galantamine, which work by blocking the enzyme that destroys acetylcholine, the major neurotransmitter for memory. While their clinical effects are modest but significant, their major impact has been in stimulating earlier diagnosis and raising doctors' awareness. The cholinesterase inhibitors may improve or maintain cognition, as well as having positive effects on behaviour and function. Cholinesterase inhibitors provide symptomatic relief only. Increased attention is needed to the integration of psychosocial and pharmacological treatments. A major Australian contribution to management of mental illness has been the development of the concept of "mental health literacy" (community knowledge of mental disorders),4 which is now recognised as a major determinant of the effectiveness of any intervention. Prevention. This is a goal that is yet to be realised. Promising avenues include early intervention (secondary prevention) for schizophrenia, and the (more distant) possibility of vaccination as primary prevention for Alzheimer's disease. Studies in Melbourne of early intervention in schizophrenia have received considerable international attention.5 The focus on early detection and intervention in psychiatry is likely to grow stonger.

Philip B Mitchell MD, FRANZCP, FRCPsych · Henry Brodaty AO, MD, FRACP, FRANZCP · David L Copolov PhD, FRACP, FRANZCP

Public health is crucial for the promotion and protection of health. Links between preventive action and improved health status (eg, in the case of smoking-related cancers, the decline in sudden infant death syndrome and rates of cardiovascular disease) present strong arguments for increased investment in public health infrastructure. The Public Health Education and Research Program1 has ensured a well-trained public health workforce to support national, state and local initiatives. Partnerships. The importance of partnerships in public health has been recognised and institutionalised. Australia's success in containing the HIV/AIDS epidemic resulted from partnerships between government, the gay community and healthcare workers. The National Public Health Partnership, involving State and Commonwealth governments and non-government organisations, coordinates the national public health effort. Its work is exemplified in the development of model public health legislation, particularly on passive smoking, and definitions of public health core functions. A further example is the EnHealth Council, which includes non-government organisations, industry and governments, and promotes coordinated approaches to environmental health. At State/Territory and local levels, partnerships between government and non-government sectors, communities and public health professionals have been formed to tackle Indigenous health issues, alcohol and drug issues, and for public health planning. Health-status inequities. Worsening inequities in health status are a major concern, especially in regard to Indigenous Australians. Socioeconomic differences in health status are being researched. Factors including employment, education, geographical location, access to health services, transport, levels of social capital and living conditions are recognised as crucial in ameliorating socioeconomic health differences, in contrast to earlier beliefs that behavioural changes would improve health status. Primary care. The Commonwealth has invested heavily in general practice. The Divisions of General Practice and initiatives from the federal Department of Health and Aged Care have encouraged greater involvement of GPs in population health. Increasing vaccination and cervical cancer screening rates are notable successes. The involvement of other primary healthcare workers (community nurses, physiotherapists, dietitians, speech pathologists, pharmacists, social workers and psychologists) needs more encouragement. Some of these groups are more suited, through their training and orientation, to facilitate community participation and develop health-promotion strategies involving sectors such as transport, local government and housing. Drug use. Harm-reduction principles are recognised as progressive and effective.2 In Australia, however, harm minimisation is compromised by the focus on controlling illicit drugs, while insufficient attention is paid to tobacco and alcohol, which account for greater disease burdens. Governments need to commit to long term drug policies, accepting that successful implementation may not achieve short term political recognition. Mental health. Mental illness is recognised by the World Health Organization in its 2001 report as one of the most urgent global health problems. Rates of disease are increasing, but treatment options are limited and preventive strategies inadequate. Australia has responded through a National Mental Health Strategy that sees mental health as a population-wide problem, with individual and community solutions.3 Programs funded under this strategy (and others) are tackling depression and seeking to reduce the rates of suicide among men aged under 35 or over 65 years. The next five years. Economic globalisation presents threats to public health. Chief among these is the growth in the power of multinational companies and the power of international treaties to override national legislation designed to protect health. Deregulation of industry practices threatens food safety. Food scares in Europe (eg, mad cow disease) and Australia (eg, haemolytic–uraemic syndrome in Adelaide)4 indicate problems with relaxing the regulation of food production and retailing. Inequities in health status, especially relating to Indigenous health, will remain a central issue. Other critical issues include the effects of globalisation and environmental deterioration, translation of public health research into policy and practice, food safety, and genetics. There is increasing recognition of the impact of environmental deterioration on health:5 global warming and pollution have both direct and indirect effects on health. Maintaining our environment will remain an important concern for public health.

Fran E Baum PhD · Helen Keleher PhD

Radiotherapy is one of the cornerstones of cancer treatment, being a component of management in at least half of all cancer patients. Increasingly, radiotherapy is used in multimodal treatment protocols in combination with surgery and chemotherapy. The best outcomes are achieved when specialists in each of these disciplines work in a multidisciplinary way, understanding the benefits and limitations that each brings to the patient's management. The aim is to individualise treatment using the best evidence available while continually advancing our knowledge through clinical trials. The Trans-Tasman Radiation Oncology Group has taken a leadership role in this regard. Advances in radiation oncology have historically been linked to developments in technology and biology. Never has this been more evident than in the present era. Technology. The power of ionising radiation as a therapeutic tool lies in its ability to penetrate non-invasively to any part of the body. The challenge is to target tumour tissue and minimise normal tissue toxicity. This requires sophisticated techniques for disease localisation, treatment planning, delivery and verification. Excellence in oncological imaging is at the heart of modern radiation oncology. The advent of fast, multislice CT scanners, new MRI techniques, metabolic imaging with PET and the advent of machines producing fused CT and PET scans has revolutionised radiation oncology. Patients can now be more accurately staged, their disease can be precisely localised, and treatment can be planned accordingly.1 Modern planning for radical radiotherapy involves the delineation on cross-sectional scans of the target volumes to be irradiated and the normal tissues to be excluded from the high dose volume. The ability to achieve three-dimensional conformal dose distributions allows critical normal tissues to be spared from injury and tumour doses to be increased safely. In the case of prostate cancer this has been shown to translate into improved outcomes.2 The ability to sculpt the high dose radiation volume to match tumour localisation is maximised by intensity-modulated radiation therapy. This technique uses a computer-controlled beam-shaping device in the head of the linear accelerator, which changes the beam shape continually during radiation exposure to produce any desired dose distribution. This is a far cry from the situation only a few years ago, when the only method of protecting normal tissues was to insert a lead block in the radiation beam, external to the treatment machine. For treatment verification and quality assurance, electronic portal imaging systems that provide a real-time digital image of each treatment field are now available. These allow detection of variations from the intended treatment set-up. Unfortunately, these technologies are available at only a few Australian centres, and use is severely restricted because of the under-resourcing of radiation oncology departments. A balance has to be struck between offering sophisticated treatment to some patients and forcing longer waiting times for treatment on others. Our goal for the next five years must be to redress the shortfalls in infrastructure so the advantages of existing technology will become more widely available.3 Biology. In the past five years, many of the seeds of earlier research have come to fruition with proven clinical benefit in randomised trials. Perhaps the best example is the development of integrated protocols combining radiotherapy with chemotherapy4 or hormonal therapy for many cancers, including lung, cervix, rectum, larynx/pharynx, breast and prostate cancer. The explosion of knowledge in molecular biology and genetics has led to new understanding of how ionising radiation causes cell death and has provided the rationale for trials combining radiation with designer-made inhibitors of molecular pathways, such as those mediated by EGFR and Ras oncogenes. Intensive research into the molecular determinants of radiation-induced apoptosis has created the possibility of selectively manipulating these mechanisms to improve the therapeutic ratio. Another major research focus is to identify predictively patients who are genetically predisposed to radiation injury and who, if treated with radiotherapy, are at risk of severe complications. Excluding this small group of patients would allow dose escalation for others, resulting in increased local cure rates. The next five years will see a revolution in the molecular phenotyping of tumour and normal tissues, using gene-array microchip technology. Within each anatomical/histological subtype, tumours will be characterised at the molecular level in a way that will permit rational application of the most effective treatment modalities, including radiation. The ultimate aim is to combine molecular characterisation with the technological sophistication of radiation treatment to use this powerful anti-cancer weapon to maximum benefit.5

Lester J Peters MD, FRANZCR · Lizbeth M Kenny MB BS, FRANZCR

Major advances in radiology in recent years can be attributed to the change from analogue to digital imaging and to advances in electronics and computing.1 Digital imaging. Modalities such as ultrasound, computed tomography, magnetic resonance imaging and nuclear medicine are digital, but have been displayed in analogue format (ie, film) for easy manipulation with conventional radiographs. However, digital radiography units, digital screening units and scanning of conventional films (computed radiography) are now accepted technologies, with resolution similar to that of film/screen techniques. Digitisation itself is a critical advance, as it allows manipulation of the images. Digital images can be transferred within a hospital's network as part of a picture-archiving and communication system (PACS), or examined from remote locations via telecommunication networks (teleradiology), which obviates the need to physically transport films to a reporting location and better enables distance radiology services for outlying communities. Radiology still uses techniques similar to those discovered by Roentgen in 1895. Film is exposed, developed, coded and placed in packets, reported, and then stored for review. With PACS, a clinician (or many clinicians simultaneously) can review the images as soon as they have been processed, and consultation between physicians can take place without physical meetings. The PACS connects to the Radiology Information System (RIS) and the Hospital Information System (HIS), avoiding multiple entering of patient data and allowing planning for patient bookings. Future PAC systems will be able to track patient progress via the RIS and HIS and pre-emptively fetch images from the electronic archive to the appropriate clinical workstations for outpatient lists or operative lists. Cross-sectional imaging. Advances in electronics and computing, combined with helical CT technology and the development of fast-gradient coils in MRI, has made possible rapid high-resolution scanning. The consequent reduction in motion and respiratory artefacts leads to: The ability to optimise the timing of intravenous contrast medium enhancement, which enables relatively non-invasive CT and MR angiography and multiphasic post-contrast scan acquisition, such as in liver imaging; The capability for volume-acquisition of data, leading to multiplanar reformatting from data acquired in a single plane, and three-dimensional reformatting for surgical planning or for endoluminal navigation (eg, "virtual endoscopy"); and Functional imaging, such as perfusion CT and MR imaging of the brain and MR spectroscopy. Current multidetector-array CT scanners have four rows of detectors. Scanners with larger arrays will be released soon, enabling finer, morphologically detailed three-dimensional and even four-dimensional imaging (virtually real-time functional imaging). MRI has diversified from its original musculoskeletal and neurological applications.3,4 Many of the potential benefits of MRI are limited only by availability of scanners and funding. For example, MR cholangiopancreatography could replace many diagnostic endoscopic cholangiopancreatograms. MR spectroscopy has tremendous potential for assessing tumour spread and recurrence, and an MRI-equipped operating theatre enabling perioperative guidance of surgical resection of tumour tissue is already a reality. It is also possible to guide and monitor percutaneous tumour ablation with MRI. New tissue-specific MR contrast agents, such as those taken up by lymph nodes, are likely to become available. This could lead to targeted therapy, with the therapeutic agent attached to a tissue-specific contrast agent. The next five years are likely to see expansion of the accepted applications for MRI. Interventional radiology. Many recent advances relate to the increasing sophistication of hardware such as catheters, stents and embolisation materials. Percutaneous access to small vessels is now possible, expanding the range of therapeutic options (eg, stenting of intracranial arteries, treatment of intracranial aneurysms and thrombolytic therapy). Other innovations likely to affect therapeutic practices include imaging-guided radiofrequency tumour ablation, percutaneous aortic aneurysm stenting, percutaneous vertebroplasty, and uterine fibroid embolisation. These emerging technologies need critical appraisal to avoid the risks attending uncontrolled introduction. Such "horizon scanning" by government agencies working with medical experts has been instituted in Australia and elsewhere. With such a choice of expensive imaging modalities, evidence-based guidelines are needed more than ever for cost-effective imaging. The education of clinicians is a priority of the Royal Australian and New Zealand College of Radiologists and is addressed by the latest edition of Imaging Guidelines.5

Brendan D Adler · Richard M Mendelson

Disorders of the kidney and related disturbances are being explored at the cellular and molecular level, and advances are moving apace. Hypertension and the kidney. Kidney disease and high blood pressure are closely linked. Hypertension is multifactorial in origin and not previously considered a single gene disorder. However, although most people with high blood pressure do not have kidney disease, there have now been at least six single gene mutations linked to families with hypertension, all at sites of renal tubular proteins responsible for salt and water balance.1 These genotype studies both lead us to novel causes of hypertension, and provide a potent source of likely targets for treating hypertension. Delineation of the structures of salt transporters in the renal tubules, their alteration and genetic control has created an environment that suggests gene insertion and alteration may be possible and may be applicable to a variety of inherited renal transport disorders. Gene manipulation in such disorders as nephrogenic diabetes insipidus should not be far away. A wide range of genetic abnormalities have been identified in these rare familial salt-handling disorders, and they can be easily identified in babies within days of birth. Whether "salt-sensitive" hypertensive people who respond to salt restriction will be able to have their salt balance altered by genetic manipulation of the renal tubule remains unclear. Patients with high blood pressure and proteinuria have a poor prognosis. Recent observations in such individuals have shown that the use of angiotensin-converting enzyme inhibitors and blocking agents not only controls blood pressure, but reduces proteinuria and improves prognosis by slowing the progression of the vascular dysfunction.2 This is true in patients with diabetes and extends to patients with hypertension but no diabetes. In acute (but reversible) toxaemia of pregnancy, studies are now unlocking the process that elevates blood pressure and damages the kidney (usually reversibly). Understanding this process, which involves vasoactive factors and the interleukins, will lead to a new approach to managing high blood pressure. The interrelationship between these vascular and immune reactive proteins has wider application in looking at the antecedents of "essential hypertension" and deciphering the reasons for end-organ (renal) damage. Autosomal-dominant polycystic kidney disease (ADPKD). This disorder is responsible for 15%–20% of people on dialysis. Recent studies have recognised that people with ADPKD have normal kidneys at birth, and that the cysts develop later. ADPKD is being viewed as a neoplasm in disguise, so that expanding therapies for malignancy may affect the development of the cysts by reducing the rate of mutations. At the same time, recognition of the abnormal polycystins that may interfere with cell–cell interactions could provide a target for future interventions. Growth-factor tyrosine-kinase inhibitors are now entering trials in the management of malignancy that may be applicable in ADPKD. Glomerulonephritis. There have been few developments in the understanding or management of most causes of glomerulonephritis. Poststreptococcal glomerulonephritis persists only in disadvantaged communities with poor access to medical care. IgA nephropathy, probably the commonest cause of glomerulonephritis in our community, remains largely a mystery. There is increasing evidence that the IgA is abnormal in its chemical and spatial structure, and that its deposition triggers the inflammatory response.3 In the future, this may allow us to target the precipitant and prevent the disease. Renal transplantation: allografts and xenografts. Organ replacement is the ideal management strategem for organ failure. Unfortunately, organ availability does not meet demand, and, even in successful transplants, chronic rejection remains a long term problem. The first issue has been approached by encouraging more family and unrelated "friends" to consider donations. The ethics of paying donors remain unresolved, especially in countries where payment provides a significant financial "win" for donors. It is illegal to pay for organs in Australia. An alternative is xenografting, and an increasing understanding of the process of hyperacute rejection and the ability to manipulate the antigenicity of the donor tissue opens the way for "designer" organs.4 Xenografts may be possible in the next decade. Potential problems such as unknown infective agents, longevity of grafts related to the natural life of the animal donor, different physiological and pharmacological responses do not seem overwhelming in the short term — if organs can be manufactured for specific recipients then replacements may be possible with little problem. Chronic rejection is also a major problem for successful allografts. Understanding the process of tolerance that occurs in some individuals should unlock this process and make possible treatments to facilitate tolerance. The two areas of xenografting and tolerance induction and maintenance will be closely linked and should see increased organ availability and longevity.

David J Tiller AO, MB BS, FRACP · Annemarie Hennessy PhD, MB BS FRACP

New advances have reinforced our understanding of respiratory disease as a complex interaction between environment, genetic predisposition and host responses.1 We describe recent advances in diseases that are a major cause of morbidity and mortality. Prevention. Smoking cessation, pollution control, vaccination, medical review and education represent important advances in respiratory disease prevention. Effective interventions for nicotine addiction include replacement therapy (eg, transdermal patches, nasal spray, gum) and antidepressants (bupropion, nortriptyline).2 Both are efficacious when used correctly, but more so in conjunction with behavioural modification.2,3 Epidemiological studies have identified the importance of reducing exposure to occupational dusts and chemicals, air pollution and passive smoking.1,2 Reduction of pollution has required public policy, altered workplace practices and individual protective strategies. The characterisation of the genetic basis of disorders such as cystic fibrosis (CF) and a1-antitrypsin deficiency has made a major impact on their prevention by identifying at-risk individuals.1,2 The emergence of multidrug-resistant strains of Streptococcus pneumoniae has led to the development of a 23-valent pneumococcal vaccine, effective in preventing pneumococcal bacteraemia and pneumonia in high-risk patients.4 Influenza vaccination appears to reduce serious illness and death in chronic obstructive pulmonary disease (COPD).2 Diagnosis. Innovative technologies have enabled the rapid diagnosis of many respiratory disorders.1 Computed tomography (thin-section and spiral) is used to diagnose lung cancer, pulmonary embolus and to assess emphysema.1 The detection of bacterial DNA in clinical samples by polymerase chain reaction (PCR) permits rapid identification of the infection. PCR is also being used to monitor viral load (eg, cytomegalovirus) in immunosuppressed individuals. Invasive surgical techniques include video-assisted thoracoscopy, a procedure with low morbidity, high diagnostic accuracy and short postoperative recovery time.1 Interventions. Treatment of asthma in high risk patients should be aligned to the degree of airway inflammation.4 Inhaled anti-inflammatory drugs are effective maintenance treatment, reducing symptoms and improving quality of life.3,4 Adding a long-acting b2-agonist to inhaled corticosteroids is as effective as increasing the dose of inhaled steroids.4 Combined therapy may have a significant disease-modifying effect on inflammation and remodelling. Leukotriene modulators may be useful for patients when inhaled corticosteroids fail to control asthma.4 Treatment of COPD is still controversial. No current therapy modifies the long-term decline in FEV1.2 Bronchodilators control symptoms,2 and combining a long-acting b2-agonist and an anticholinergic drug or theophylline may produce additional benefits in lung function.2,4 Oxygen therapy and multidisciplinary rehabilitation programs improve survival, symptoms and quality of life.2 Surgical treatments include lung volume reduction surgery (LVRS) for regional emphysema, and bullectomy for giant bullous emphysema. Randomised controlled trials are being conducted to compare LVRS with optimal medical therapy,2 but patients at high risk of death after LVRS have recently been identified. No successful medical therapy has been found to treat interstitial lung disease. However, one study reported significant improvement after 12 months of treatment with interferon-g1b and corticosteroids compared with corticosteroids alone.3 Treatments such as laser methods, endobronchial radiation and airway stents offer palliation for terminal lung cancer.1 The recognition in recent years that mild to moderate obstructive sleep apnoea is a major risk factor in cardiovascular morbidity and mortality represents a major advance. Although S. pneumoniae is the most common pathogen in cases of community acquired pneumonia, other pathogens, such as Legionella species, Staphylococcus aureus, Pseudomonas aeruginosa and Mycoplasma pneumoniae, are also implicated.3 Early therapy with penicillin or third-generation cephalosporin with a macrolide is important.3 Meta-analysis shows that neuraminidase inhibitors are effective in preventing influenza A and B and in shortening the duration of illness.5 The recognition that hyaline membrane disease of the newborn is caused by a surfactant deficiency and subsequent intratracheal administration of surfactant has been estimated to save 2000 neonates per year in the United States.1 Advances in surgical technique and perioperative management have led to improved survival for patients undergoing lung transplantation. In carefully selected patients with advanced lung disease (eg, COPD, CF, ILD or bronchiectasis), lung transplantation has also been reported to improve quality of life and functional capacity.1,2 Ventilatory support includes both non-invasive negative-pressure or positive-pressure ventilation and invasive mechanical ventilation.4 Advances in ventilation have reduced mortality from respiratory failure resulting from acute respiratory distress syndrome, congestive heart failure, asthma and COPD with acute carbon dioxide retention.1 Conclusion. Increasing understanding of the mechanisms of respiratory disease, particularly at the cellular and molecular level, will enable improved diagnosis and treatment. Prevention remains a key strategy.

John H Alpers MB BS, FRACP · Josephine M Cranston BSc(Hons) · Alan J Crockett MPH

Recent major advances in rheumatology have been given further impetus by the declaration of 2000–2010 as the Bone and Joint Decade. This initiative, endorsed by the United Nations, aims to improve health-related quality of life for people with musculoskeletal disorders worldwide. Prevention. The imperative to prevent chronic disability from musculoskeletal conditions is increasingly being recognised. For instance, beliefs and behaviour associated with acute back pain, which may have potentially costly and prolonged sequelae in the workplace, can be altered with early appropriate intervention.1 The incidence and severity of knee osteoarthritis, the most important cause of musculoskeletal disability, can be reduced by better weight control and avoiding excessive deep-knee bending, while corticosteroid-induced osteoporosis can be prevented by concomitant use of bisphosphonates.2 Diagnosis. Assessment of osteoporosis and monitoring of response to interventions will be improved by combining bone densitometry with ultrasound (to define other important bone characteristics, including fragility) and better methods of determining biochemical markers of bone turnover. The difficulty of identifying osteoarthritis at an early stage (when interventions are most effective) will be overcome by refining the use of MRI and other imaging techniques and developing specific markers of cartilage breakdown and repair, such as proteoglycans. Likewise, early intervention in rheumatoid arthritis significantly affects symptom control, joint damage and functional ability. Both MRI and ultrasound will soon be used to accurately detect early inflammation and joint damage in rheumatoid arthritis and allow for stratification of different intervention strategies. Intervention. Osteoporosis management has been significantly improved by the newer-generation bisphosphonates (alendronate, risedronate). The selective oestrogen-receptor modulators (SERMs), such as raloxifene, also offer fracture protection, lower lipid levels and a reduced risk of breast cancer. Newer SERMs will provide more selective and potent effects in bone and breast tissue. Pulsed daily parathyroid hormone therapy, which increases bone mineral density and possibly reduces fracture rates, and osteoprotegerin, a potent inhibitor of osteoclast action, will both improve management of osteoporosis. Glucosamine may reduce knee cartilage loss, but the full significance of its effect on osteoarthritis has yet to be established.3 More definitive osteoarthritis treatment may be possible within the next five years, with progress in elucidating the mechanisms of cartilage breakdown and repair. Several potential agents are currently undergoing clinical trials. Selective COX-2 inhibitors suppress joint inflammation and, compared with non-selective agents, significantly decrease rates of major gastrointestinal adverse events. They do not affect platelet function, but provide no advantage in regard to salt and water retention.4 Selective inhibitors of inflammation-induced isoforms of the upstream precursors of phospholipase A2 may have equivalent anti-inflammatory effects, with less disturbance of homoeostasis. Methotrexate remains the baseline medication of choice for early intervention in rheumatoid arthritis, with current trends being to use higher doses and drug combinations. Leflunomide, a pyrimadine pathway inhibitor, provides significant benefits, especially when introduced early and in combination with methotrexate. The effectiveness of cyclosporin is also improved by combining with methotrexate, but it must be used with care because of its adverse effects on blood pressure and renal function. Suppression of specific components of the rheumatoid arthritis inflammatory cascade has proved effective. Tumour necrosis factor (TNF) suppression by TNF fusion protein (etanercept), chimeric anti-TNF antibody (infliximab) or human monoclonal anti-TNF (adalimumab) all result in significantly less inflammation and reduced joint damage in the short term. Early data on safety and cost-effectiveness are encouraging.5 Suppression of interleukin-1 by the IL-1-receptor antagonist anakinra may decrease bone damage proportionally more than inflammation. Combinations of such agents will target the different components of the rheumatoid arthritis process. Future development of less expensive, oral agents with similar specificity will permit broader application of targeted therapies. Longer-term toxicity issues may yet emerge. Applying pharmacogenomics (the study of genes relevant to drug therapy) and modulation of pro-inflammatory intracellular enzymes will further refine possibilities for modifying inflammatory processes. Recognition that corticosteroids act via these pathways has opened this field to the development of novel broad-spectrum immunomodulatory agents, some of which are in early-phase clinical trials. Drugs that modulate the sensitised pain mechanisms of fibromyalgia and regional pain syndromes include, among others, derivatives of gabapentin and inhibitors of the 5-hydroxytryptamine receptor. Clinical trials suggest that these approaches will provide useful ancillary treatments. Conclusion. With the impetus that the Bone and Joint Decade will bring to research in rheumatic diseases, we can expect further elucidation of disease mechanisms, and an increase in management options.

Geoffrey O Littlejohn MD, MPH, FRACP · Eric F Morand PhD, FRACP

The practice of urology continues to be affected by the compulsory wearing of seatbelts, resulting in less trauma, and antismoking initiatives. Bladder cancer is an occupationally related tumour, but cigarette smoke is by far the most significant environmental carcinogen, so a recent report suggesting that smoking rates may be declining1 is heartening. Prostate cancer. The trend to earlier diagnosis of prostate cancer continues. Detection of an elevated serum prostate specific antigen (PSA) level is usually followed by biopsies guided by transrectal ultrasound (TRUS). PSA analysis has been expanded to give more information; rate of change of total PSA (PSA velocity) and the percentage of free PSA (unbound) are most often used (lower percentages of free enzyme being associated with a higher likelihood of malignancy, especially for total PSA levels 4–10 g/L). TRUS-guided sextant prostatic biopsies are not new, but, particularly with larger prostates, repeat biopsies after negative findings have increased detection rates up to 30%.2 Consequently, eight or more biopsy samples are now often obtained. As well as pre-TRUS–PSA, Gleason score and number of tumour-containing cores (with percentage involvement) serve to predict the likelihood of cancer being localised. Thus, the PSA–transrectal ultrasound approach appears to have reached maturity and a change in direction, such as molecular characterisation of ejaculate, is now required to advance early diagnosis and natural history prediction. The focus on PSA by patients has contributed to androgen suppression starting earlier, despite unwanted side effects with all forms of hormonal treatment and a lack of convincing evidence that earlier intervention improves survival. Intermittent androgen blockade does not adequately compensate for early commencement of androgen suppression, as, certainly in the short-term, many unwanted effects, including testosterone suppression, are not always reversible. The popularity of maximal androgen blockade has waned since the publication of unsupportive meta-analysis data.3 Notwithstanding its major advantage of avoiding contrast media, spiral computed tomography (CT) serves as an adjunct to, rather than a replacement for, intravenous urography, which remains the first-line investigation for most ureteric colic patients. Non-contrast CT does not provide functional information, but may detect other abnormalities. Female urinary incontinence. This is one of the conditions managed by both urologists and gynaecologists. The mainstay of treatment for patients with overactive bladders (frequency and urgency with or without urgency incontinence in the absence of attributable local, pathological or metabolic factors4) is anticholinergic drugs, with doses limited by dry mouth and constipation especially. Recently evaluated uroselective agents have shown a considerable reduction in unwanted effects without loss of efficacy. The tension-free vaginal tape (TVT) procedure was recently introduced for stress incontinence. Its low rate of short-term complications has been attributed to its wide-mesh monofilament polypropylene composition, reputed to retain flexibility and admit macrophages, fibroblasts, blood vessels and collagen into its pores to permit elimination of infiltrating bacteria. Whether such attributes translate into lower complication rates and continued success in the longer term (more than two years) remains to be seen. Concerns about an uncritical adoption of the TVT procedure, paralleling initial enthusiasm for needle suspension operations in the 1980s, are justifiable. TVT operations are often performed as day procedures — a not insignificant attraction given the current shortage of hospital beds. Lower urinary tract symptoms (LUTS). LUTS, even when categorised as storage or emptying, are poor indicators of underlying LUT dysfunction. A third of men with LUTS do not have bladder outflow obstruction (BOO), accurate diagnosis of which is problematical. Consequently, there is a tendency to treat LUTS with medications and to identify BOO only when considering more invasive therapies. This approach relates particularly to the commonly used saw palmetto berry (Serenoa repens) extract, which affords LUTS relief for many men. Treatment by α1-blockade (doxazosin, prazosin, terazosin) is well established for benign prostatic hyperplasia (BPH) causing BOO. BPH is predominantly a stromal condition and these drugs target prostatic and bladder-neck smooth muscle. Improvements in symptom scores and flow rates often persist long-term. Seventy per cent of prostatic adrenoreceptors are of the α1A receptor subtype. Tamsulosin, a selective α1A antagonist, has a safety profile superior to non-selective α1 antagonists, with comparable effects on LUTS. However, dizziness and abnormal ejaculation may still occur. Male sexual dysfunction. The adverse impact of sexual dysfunction on quality of life has only recently been acknowledged. Papaverine and prostaglandin E1 intracavernosal injections were a significant advance. However, a dramatic change came with the serendipitous discovery of sildenafil, which prolongs nitric oxide-induced cavernosal muscle relaxation. While sildenafil therapy represents a revolution in impotence treatment, it does not address underlying pathogeneses.5 Infertility. One of the most remarkable milestones of the 1990s was intracytoplasmic sperm injection (ICSI). Despite the possibility that sperm with suboptimal genetic characteristics may be selected for this process, ICSI has become established as a valuable option in infertility management. Conclusion. Urology is continuing to evolve at a rapid rate. Consequently, urologists are tending to subspecialise rather than practise in the broad range of conditions which constitute this fascinating yet practical specialty.

Robert A Gardiner MB BS, MD, FRCS, FRACS

The prevalence of vascular disease in our society has led to innovations in vascular surgery that focus increasingly on less invasive techniques to diagnose and treat disease. Prevention. There has been little progress with prevention of arterial or venous disease. Conventional risk factors for atherosclerosis appear to be as prevalent as ever, but new risk factors have emerged. Homocysteinaemia may be just as important as lipid disorders, is present in 10% of the population, and can be controlled by vitamin supplements. Other factors identified are metalloproteases for aneurysms, and cytokines, growth factors and inflammatory cells responsible for atherogenesis and venous ulceration, yet none have yet led to tangible therapeutic advances. Diagnosis. Duplex ultrasound scanning is replacing angiography for preliminary assessment and may become the definitive investigation for some conditions. It is simple, relatively inexpensive, and non-invasive, and can be applied to disease at most sites. It is used by many surgeons in Australasia as the sole investigation to select patients for carotid endarterectomy.1 Computer analysis of carotid plaque echogenicity by ultrasound promises to better define plaques that pose an increased risk for stroke. Ultrasound scanning can be used to select techniques for femoral artery bypass grafting, and most surgeons now use it to predict whether endovascular therapy is a realistic option. Regular ultrasound surveillance improves results after femoral artery vein bypass grafting, although its value for other interventional techniques has yet to be proven. For chronic venous disease, up to 30% of important deep to superficial connections can be missed by clinical examination alone, inviting early recurrence.2 Many surgeons now scan most patients before treating varicose veins. Treatment. There has been great interest in endovascular therapy. Until recently, surgeons' enthusiasm has outstripped the manufacturers' ability to produce suitable systems, resulting in valid criticism. A Sydney team leads the world in assessing outcome for endoluminal grafting for aortic aneurysms.3 Relatively atraumatic insertion of a stent or graft through the femoral arteries is a most attractive alternative to major open repair for abdominal or thoracic aortic aneurysms. The technique has been limited by difficulties in sealing grafts to normal arteries above and below aneurysms to prevent "endoleak" into the aneurysm sacs. Surgeons in Perth and Adelaide have pioneered innovative techniques to incorporate vital arterial branches (just above and below most aneurysms) with side stents or grafts.4 This will allow the main graft to be taken above the renal and visceral arteries in the abdomen or carotid arteries in the thorax. Studies show that aneurysms can shrink to produce strains on grafts that can lead to their late disruption, and this has influenced newer graft designs. It has yet to be determined whether the current fabric cover and stent scaffold is sufficiently strong to withstand repeated pulse deformation over long periods. The debate is even more lively as to whether endovascular stenting for carotid stenosis has advantages over conventional carotid endarterectomy.5 The open operation is far less traumatic than that for aneurysms and is probably safer than current techniques for carotid stenting, so that enthusiasm for the latter has evolved slowly. However, new filter devices that trap embolised material passing up the carotid arteries after balloon dilatation have advanced the endovascular approach in its inevitable incursion into traditional management. A more prosaic but potentially explosive development has been the introduction of minimally invasive techniques to treat varicose veins. Ultrasound follow-up after all forms of treatment has shown that residual or recurrent connections are frequent. Surgical stripping is not universally popular with patients, although specialist phlebologists obtain excellent long-term results with good cosmetic appearance and minimal morbidity. Endovenous alternatives are attractive but have not been objectively assessed. These began with sclerosant injection into major saphenous veins under ultrasound guidance. This gained considerable impetus when it was appreciated that the detergent sclerosants can be injected as a foam which stays in the vein for far longer and is easy to track with ultrasound. More recently, techniques are being evaluated for obliterating the saphenous vein with radiofrequency or laser probes introduced by percutaneous puncture. Quality. ASERNIPS (the Australian Safety and Efficacy Register of New Interventional Procedures – Surgical) has done well to introduce an effective audit for assessing safety and efficacy after endoluminal grafting for aorto-iliac aneurysms. The challenge for the vascular surgical community is to better audit and evaluate all existing and new techniques for diagnosis and treatment to ensure that they are effective.

Kenneth A Myers MS, FRACS, FACS