Editorials

Editorial Migraine: then and now Better understanding of the neurobiology of migraine is leading to better treatment MJA 1996; 164: 519-520 Migraine is debilitating for its victims and frustrating for their friends and relatives. The Australian National Health Survey of 57 000 people in 1989-1990 found that 12.2% had experienced a headache in the preceding two weeks.1 Extrapolation to the entire Australian population implies that 280 000 people suffered a migraine attack and two million some lesser form of headache in that two-week period. The annual cost of migraine to the community, considering loss of productivity and cost of medical services, has been estimated at $302-$721 million by the Centre for Applied Economic Research, University of New South Wales.2National Migraine Week (12-18 May) may help to increase public awareness of this problem. In addition, the Migraine Foundation, a subsidiary of the Australian Brain Foundation, has recently been established to promote education and to encourage research and the formation of self-help groups in the community. When is a headache a migraine? Whether migraine has a place at one end of a headache spectrum or is a separate entity remains controversial. The International Headache Society has established criteria for the diagnosis of migraine, to standardise headache classification for surveys and clinical trials.3The Classification Committee's general description of migraine is "an idiopathic headache disorder manifesting in attacks lasting 4-72 hours", with the characteristics of common unilateral location, pulsating quality, moderate or severe intensity, aggravation by physical activity and association with nausea and photophobia. Nevertheless, a third of migraine headaches are bilateral, and not all throb or are accompanied by nausea and photophobia. About 25% of those affected describe premonitory symptoms the night before -- a feeling of elation, craving for sweet foods or excessive yawning. Between 25% and 40% experience a visual aura at some time, but only 10% describe typical fortification spectra (zigzag visual hallucinations) or spreading scintillating scotomas. Such neurological symptoms usually precede the headache, but may occur without an ensuing headache or may appear while a headache is in progress. However, most migraine headaches occur without such symptoms. Varieties of migraine are designated hemiplegic, basilar, ophthalmoplegic or retinal, depending on the area of the brain rendered ischaemic. A migraine headache lasting longer than 72 hours is termed "status migrainosus". Neurological symptoms persisting for more than seven days indicate a migrainous infarction. Genetic factors contribute about half of the susceptibility to migraine, and the gene for some kinships with familial hemiplegic migraine has been localised to chromosome 19.4 Neurobiology of migraine Modern techniques have improved our knowledge of both aura and headache mechanisms. Aura: Regional cerebral blood flow studies show a reduction in cortical perfusion, starting in the parieto-occipital region during a visual aura and spreading forward at 2-3 mm/min. This corresponds to the speed at which fortification spectra appear to move over the field of vision and that of "spreading cortical depression" observed by Leâo as an artefact in experimental animals in the 1940s.5 Recently, magnetic resonance imaging and positron emission tomography (PET) showed a similar spreading pattern of diminished metabolism in a patient with migraine with blurred vision but no classical aura.6 Although needing confirmation, this raises the possibility of cortical oligaemia in migraine attacks that lack an aura; this would account for the impaired vision, loss of concentration and poor memory that often accompany migraine headache. Headache pain: Since the work of Wolff and his colleagues in the 1940s and 1950s, dilatation of the superficial temporal artery and its branches has been regarded as the main cause of headache pain. However, recent studies have shown that this applies to only about a third of migraine patients. Measurements of velocity of blood flow with transcranial Doppler ultrasound have shown that the middle cerebral artery dilates during migraine headache and returns to normal when the headache resolves after the injection of sumatriptan.7 Cerebral oedema may also be a feature of some migraine attacks, as there have been two reports of skull defects bulging during the headache phase.8 "Neurogenic inflammation" (with extravasation of protein from dural vessels) has been implicated, brought about by release of vasodilator peptides, such as calcitonin gene-related peptide (CGRP) and substance P.9,10 This effect can be blocked by sumatriptan and dihydroergotamine. It is also possible that the blood-brain barrier breaks down during migraine headache, allowing access of drugs that are normally excluded. When sumatriptan is administered during the aura phase it does not prevent the ensuing migraine headache, despite its prompt action once headache is established, suggesting that it can enter the brain only after the headache starts. How can we link the initiating cerebral events and the vascular changes? Stimulation of the brainstem nuclei, locus coeruleus and raphe dorsalis has been shown in animals to alter both intracranial and extracranial blood flow.11 In humans, some patients with implanted electrodes which stimulate the periaqueductal grey matter or thalamus for relief of bodily pain have developed migraine-like headaches, some associated with visual symptoms.12 PET scans during and after migraine headache have shown increased metabolic activity in the region of the periaqueductal grey matter and locus coeruleus on the side of the migraine headache, which persisted after the headache.13 What has happened to the "serotonin story"? It is now thought that the discharge of serotonin (5-hydroxytryptamine, 5-HT) by platelets at the onset of migraine headache14 may reflect similar changes in the central nervous system, as serotonin plays a key role in pain control. Serotonin is also a potent vasoconstrictor in the cranial circulation. Increase in knowledge of the many 5-HT receptors has led to the synthesis of agents which act as agonists of these receptors. Prophylactic medications, such as pizotifen and methysergide, act predominantly on 5-HT2 receptors in the central nervous system. The newest antimigraine drug, sumatriptan, is a highly selective agonist of the D-subtype of 5-HT1 receptors. It constricts cranial arteries, interferes with the release of vasodilator peptides and may also have central actions (as yet unknown), if, as has been proposed, the blood-brain barrier breaks down during migraine headache. Already other 5-HT1D agonists, such as 311C90 (zolmitriptan) and MK462, are undergoing clinical trials for the management of migraine headache. Continued research on these drugs and on the receptor sites for serotonin and other neurotransmitters involved in the migraine syndrome promises new therapeutic avenues in the treatment of migraine. James W Lance Consultant Neurologist, Institute of Neurological Sciences Prince Henry and Prince of Wales Hospitals, Sydney, NSW Australian Bureau of Statistics. National Health Survey: summary of results. 1989-1990. Canberra: ABS, 1991. (Catalogue No. 4364.0.) Parry TG. The prevalence and costs of migraine in Australia. Centre for Applied and Economic Research working paper. Sydney: CAER, University of New South Wales, 1992. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7: 13-96. Merikangas KR. Sources of genetic complexity of migraine. In: Sandler M, Ferrari M, Harnett S, editors. Migraine: pharmacology and genetics. London: Chapman and Hall, 1996: 254-274. Leâo AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359-390. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689-1692. Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet 1991; 338: 13-17. Lance JW. Swelling at the site of a skull defect during migraine headache. J Neurol Neurosurg Psychiatry 1995; 59: 641. Moskowitz MA, Cutrer EM. Trigeminovascular system and migraine. Semin Headache Manage 1996; 1: 7-9. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48-56. Lance JW, Lambert GA, Goadsby PJ, Zagami AS. Contribution of experimental studies to understanding the pathophysiology of migraine. In: Sandler M, Collins GM, editors. Migraine: a spectrum of ideas. Oxford: Oxford University Press, 1990: 21-39. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache 1987; 27: 416-420. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995; 1: 658-660. Anthony M, Hinterberger H, Lance JW. Serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552. ©MJA 1999 © 1999 Medical Journal of Australia.

James W Lance

Haemophilia -- darkest hours before the dawn We have the technology to make plentiful and relatively safe supplies of coagulation factors, and a cure may be within our grasp MJA 1996; 164: 453 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Reducing viral transmission - Replacement therapy - Immune complications - References - - ©MJA1997 Introduction Haemophilia is often considered to be our community's most expensive disease because of the life-long need for frequent replacement of coagulation factors VIII (haemophilia A) and IX (haemophilia B). The incidence of haemophilia in Australia is one in 7000 males -- the same in all ethnic groups. Its prevalence is much reduced because of premature death from bleeding in pre-replacement- therapy days and past transmission of infections such as HIV and hepatitis B and C through unsterilised pooled plasma concentrates. History's most famous person with haemophilia, the Tsarevitch Alexei, had almost reached his likely lifespan of 20 years when he was murdered in 1917. His frequent crippling haemarthroses and muscle bleeds are obvious from photographs. Today, because of major technical advances in coagulation factor production, most boys born in Australia with haemophilia can expect a normal lifespan and lifestyle, with neither plasma-derived viral infection nor disabling progressive arthropathy. Reducing viral transmission In Australasia, concentrates are prepared from plasma collected and screened for viral markers by State Red Cross Blood Banks, fractionated by CSL Ltd and sterilised by terminal dry heating at 80ûC for 72 hours. No case of HIV transmission from concentrates has been identified in the haemophilia population since 1985. Between 1981 and 1984, 245 people with haemophilia contracted HIV, at least 98 of whom have died (figures courtesy of the Mark Fitzpatrick Trust), and patients in all Australian States and Territories have received recompense payments for HIV infection. Because of the high prevalence of hepatitis C virus in pooled plasma before appropriate screening and increased heat technologies became available, most patients who received concentrates before 1989 were also infected with this virus, leading to serious comorbidity with HIV infection, chronic liver disease and hepatocellular carcinoma. Despite many improvements and sequential application of multiple virucidal technologies, some human viruses, such as parvovirus B19, may remain in plasma concentrates. Novel techniques, such as viral nanofiltration and partitioning during fractionation, are being developed, but a threat known as the TNV (the next virus!) to the safety of human-derived products always remains. The genes for factor VIII and IX, which occur on the tip of the long arm of the X chromosome, were sequenced in 1984 and 1985.1 By 1988 recombinant human factor VIII expressed in rodent cell lines was available for human trial.2 This product is now licensed and has been used in Australia since January 1995, so with political goodwill and financial support the supply of factor VIII may finally match demand. The possibility of human virus transmission is not completely abolished as, presently, recombinant factor VIII is resuspended in human serum albumin (although this product has not yet been reported to transmit such infec tions). Recombinant factor IX concentrates are now in clinical trial overseas. Replacement therapy In the past, the approach to haemophilia treatment was to arrest bleeding after it had occurred. This is called "on-demand" therapy. Unfortunately, this strategy is like shutting the gate after the horse has bolted, as it fails to prevent the significant joint damage caused by the reaction of the synovial membrane to blood. It is possible, however, to shut the gate somewhat earlier with "prophylactic therapy". In patients whose factor VIII level is greater than 1%, there is seldom spontaneous bleeding into joints. Hence, prophylactic therapy aims to maintain factor VIII levels at more than 1% at all times. As the factor VIII half-life is approximately 12 hours, this can be achieved by giving factor VIII concentrates in a dose of 25-40 IU/kg body weight three times a week. Reports from Sweden3 and the United States4 have demonstrated the effectiveness of such a regimen, and virtually all eligible children in Australia can now potentially receive prophylaxis, although Victoria is the only State to have matched Commonwealth Government funding for this therapy to date. A recent review of the results of prophylactic treatment at the Royal Children's Hospital, Melbourne, has confirmed a dramatic reduction in the incidence of joint bleeding and the number of hospital visits and, consequently, a reduction in morbidity from haemophilia (H E, unpublished results). The cost to the community of treating haemophilia patients prophylactically, in current costs for recombinant factor VIII, is no less than $100 000 per year (for an average of 100 000 units per patient). There are, however, significant cost savings from a reduced need for medical and allied health professional treatment, and the prospects that, without joint damage, young men will be able to pursue active and productive lives without the need for pension support. Immune complications Despite the advances in treatment, there are patients with severe haemophilia who develop allo-antibodies to infused factor VIII, and then do not respond to human factor VIII. In some instances, these patients face forms of treatment which are barely superior to those which were practised in the days of Rasputin, and suffer high morbidity and mortality compared with patients who do not develop these antibodies or inhibitors. While 20% of individuals with severe haemophilia (factor VIII activity < 1%) develop such antibodies, only half of those have high enough levels of antibodies to inactivate the infused factor VIII. Thus, one in 10 patients with severe disease are at risk of having no effective factor VIII replacement therapy. At present, Australians with this problem are more disadvantaged than similar patients in countries such as the United States, Canada or Western Europe. The only product available for treating their life-threatening or organ-threatening bleeds is porcine factor VIII. Its use has to be approved by the Therapeutic Goods Administration (TGA), and its usefulness is often offset by the development of antiporcine factor VIII antibodies, which restricts its use to bleeds that threaten life, limb or an organ and, even then, for a short time only. The only other products presently available are activated prothrombin complex concentrates, which are of unpredictable efficacy and can only be obtained with TGA approval. Because these products are costly and infrequently used, they are not always available in Australia. A new and recombinant product, activated factor VIIa (Novo Seven), has been shown to be the most effective in the treatment of inhibitors, including cover for surgery -- this product is not currently registered by the TGA5 and is no longer available for compassionate use. This is a serious situation for patients who are otherwise "untreatable". Treating bleeding in patients with activated prothrombin complex concentrates or recombinant VIIa is a form of on-demand therapy. European workers have shown conclusively that, in most patients newly diagnosed as having factor VIII inhibitors, giving factor VIII in a daily dose of 100-200 IU/kg body weight can often suppress the inhibitor to non-detectable levels, with normal factor VIII recovery in the plasma. 6 This is known as "tolerising therapy" and is a form of prophylaxis. Unfortunately, there is insufficient factor VIII in Australia to use it for this indication, even though tolerising is the most logical way to prevent the morbidity associated with poorly controlled bleeding, and it is cost-effective in comparison with on-demand therapies. It is to be hoped that the working parties currently convened by Australian Health Ministers to investigate optimum therapies for patients with haemophilia and factor VIII inhibitors will recommend funding for tolerising therapy in all newly diagnosed patients with inhibitors. These patients are usually children, thus small, requiring much less product than adults with established inhibitors. Genetic technology can be used to detect female relatives who are at risk of being carriers, and to detect haemophilia antenatally. In the long term the tantalising prospects of "cure" of this molecular disease by gene therapy is stimulating much research into mechanisms of vector biology which allow efficacious, safe and continuous expression of factors VIII and IX. Fortunately, the days when patients with haemophilia could be treated only by Rasputin are over. Comprehensive care centres in each State coordinate surgical, medical and dental management while providing counselling and diagnostic services. With the potential for plentiful and safe factor supplies for prophylactic, surgical and inhibitor- suppressing programs, and hope of a cure by gene therapy, the future for our children with haemophilia is bright. Alison M Street Head, Haematology Unit, Alfred Healthcare Group, Melbourne, VIC Henry Ekert Senior Consultant, Department of Haematology/Oncology, Royal Children's Hospital, Melbourne, VIC References Mandel JL, Willard HF, Nussbaum RL, et al. Report of the committee on the genetic constitution of the X chromosome. Cytogenet Cell Genet 1988; 49: 107-128. White GC, McMillan CW, Kingston HS, Shoemaker CB. Use of recombinant antihemohilic factor in the treatment of two patients with classic hemophilia. New Engl J Med 1989; 320: 166-170. Nilsson IM, Berntrop E, Lofqvist T, Pettersson H. Twenty-five years experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 23-32. Aledort LM. Experience with prophylactic treatment in the USA. Clinical benefits; a multi-center view. Round Table Series 1991; 25: 26-32. McPherson J, Teague L, Lloyd JV, et al. Experience with recombinant factor VIIa in Australia and New Zealand. Haemostasis 1996; 26 (Suppl 1): 109-117. Brackman HH. Induced immune tolerance in factor VIII inhibitor patients. Prog Clin Biol Res 1983; 150: 181-195. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Alison M Street · Henry Ekert

Editorial Of mice and (wo)men: the obesity (ob) gene, its product, leptin, and obesity Ground-breaking discoveries in obesity demonstrate that research can pay big dividends for society MJA 1996; 164: 393-394 Scientists are a unique breed whose research may seem to have little relevance to human health. Often, they are unable to communicate effectively what they are actually doing (particularly to economic rationalists intent on slashing research budgets), and especially when, as with obesity, the research appeared to have "hit the wall", with little hope of an imminent breakthrough. Then, along comes a discovery in obese mice1 so stunning that it opens up a new era in obesity research, with possible spin-offs for management of obesity and other associated disorders such as non-insulin-dependent diabetes mellitus (NIDDM). Obesity is epidemic in developed nations, including Australia2 and the United States,3 and is rapidly becoming so in many developing countries (particularly Pacific Island nations), as a penalty of modernisation,2 and in disadvantaged communities in developed countries (e.g., Afro-Americans and Mexican Americans).3 The annual cost of obesity to the United States is close to US$69 billion4 and this includes the cost of morbidity and mortality from cardiovascular disease, gallbladder disease, NIDDM, cancer and musculoskeletal disorders. Who can guess the personal cost to millions of obese people who splurge US$33 billion annually on new diet books or new "fad" diet programs?5 There has been no lack of effort or interest in obesity research, but the tangible results for clinical practice have been disappointing. This explains the community focus on each new miracle diet. We know about the importance of nutrition, exercise, community lifestyle interventions and pharmacotherapy for obesity, and the role of surgery for morbid obesity. Also, the genetic, sociocultural and behavioural risk determinants of obesity are well understood,6 but the basic physiological mechanisms that regulate body weight and adipose tissue have largely remained a mystery. Then, in late 1994 came the cloning of the mouse ob gene and its human homologue,1 followed within months by reports that injections of the ob protein/hormone expressed by the ob gene (named leptin, from the Greek root leptos, meaning thin) make obese mice thin.7-9 Based on research involving parabiosis (joining of the mice by anastomosis of the skin, which allows cross-circulation experiments) of obese (ob/ob) and diabetes mutant (db/db) mice, Coleman suggested over 20 years ago that a satiety factor produced in adipose tissue circulated in plasma and affected appetite through interaction with the hypothalamus.10 He further suggested that ob/ob mice lacked the satiety factor that could regulate adiposity by modulation of appetite and metabolism. There the suggestion remained until Friedman and his colleagues cloned the ob gene.1 They and other researchers subsequently prepared the recombinant ob protein, leptin; injecting ob/ob mice with leptin resulted in diminished food intake, increased energy expenditure, and dramatic weight reduction.7-9 After two weeks of treatment, there was a reduction of body fat from 12.2% to 0.7%!8 The ob gene is overexpressed in adipose tissue of obese human subjects,11,12 and overexpression and hyperleptinaemia have now been demonstrated in the best animal model of human NIDDM, Psammomys obesus.13 We are currently exploring the role of leptin in the high frequency of hyperglycaemia, hyperinsulinaemia and obesity which occurs in this rodent model. Thus, research begun over 20 years ago has culminated in findings that have set the obesity field alight and opened up new possibilities in pharmacotherapy of obesity. A look into the crystal ball reveals a vista to be explored in intermediary metabolism. It could revolutionise our knowledge of appetite control and energy regulation, and the interaction of leptin with other key hormones, such as insulin and glucagon in insulin sensitivity and resistance, remains to be explored. How many other unknown hormones are being produced by adipose tissue? Already we know that leptin administration to mice lowers blood glucose and insulin levels in obese mice.7 While assays for leptin are still in the early stages of development, high blood leptin concentrations (four to five times higher than in non-obese persons) have been demonstrated in obese subjects,14,15 and we have recently confirmed this and demonstrated a highly significant direct correlation between leptin, body mass index and serum insulin (Zimmet et al., unpublished data). Whether leptin itself is the "magic bullet" to cure obesity remains to be established, as studies in humans suggest that the problem in obese subjects may be decreased sensitivity to leptin (i.e., leptin resistance). The significance of this will become apparent as research moves to the next phase: the search for and study of the hypothalamic leptin receptor, and human clinical trials. The pace at which new developments are emerging is breathtaking, and in the space of a few weeks publications have appeared on the identification and cloning of the leptin receptor in mice,16 and a mutation has been identified in the leptin receptor of the db/db mouse.17 There will undoubtedly be concern about misuse of therapeutic agents with so much promise -- either leptin itself or drugs directed at the hypothalamic leptin receptor -- particularly with the possibility of a person gorging and then having an injection or taking a tablet to undo the consequences of the indulgence! While these concerns are important, this discovery provides a quantum leap in our understanding of the pathophysiological mechanisms leading to obesity and has clearly defined an avenue for its prevention. This then leads to exciting possibilities for understanding the aetiology and reducing the morbidity and mortality of a host of chronic conditions associated with obesity, including coronary artery disease, the insulin resistance metabolic syndrome (or syndrome X) and NIDDM. Coleman's elegant parabiosis experiments and Friedman's relentless search for the ob gene and leptin bring hope to hundreds of millions of obese people around the world. Debate about the appropriateness of animal experimentation will continue forever, but here is one classic example where such research may pay huge human dividends. This discovery may help the community understand how medical research works for society's ultimate benefit, and gives researchers a tangible result to convince politicians that funds applied to long term basic medical research can be an excellent investment! Paul Zimmet Chief Executive Officer, International Diabetes Institute Melbourne, VIC Greg R Collier Senior Lecturer, School of Nutrition and Public Health Deakin University, Geelong, VIC Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432. Segal L, Carter R, Zimmet P. The cost of obesity. The Australian perspective. PharmacoEconom 1994; 5(Suppl 1): 45-52. VanItallie TB. Worldwide epidemiology of obesity. PharmacoEconom 1994; 5(Suppl 1): 1-7. Wolf AM, Colditz GA. The cost of obesity: the US perspective. PharmacoEconom 1994; 5(Suppl 1): 34-37. Berg FM. Diet industry hard hit since 1990, hopes for recovery. Healthy Weight Journal 1994; 8: 67-68. Lissner L. Causes, diagnosis and risks of obesity. PharmacoEconom 1994; 5 (Suppl 1): 8-17. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540-543. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546. Campfield LA, Smith FJ, Guisez Y, et al. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546-549. Coleman DL. Effects of parabiosis of obese with diabetic and normal mice. Diabetologia 1973; 9: 294-298. Masuzaki H, Ogawa Y, Isse N, et al. Human obese gene expression: adipocyte- specific expression and regional differences in the adipose tissue. Diabetes 1995; 44: 855-858. Lšnnquist F, Arner P, Nordfors L, et al. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995; 1: 950-953. Walder K, Zimmet P, Collier GR. Expression of the ob (obese) gene in Psammomys obesus, an animal model of obesity and non-insulin dependent diabetes mellitus (NIDDM). Proceedings of the 3rd Scientific Meeting of the Australasian Association for the Study of Obesity [abstract]. Melbourne: Australasian Association for the Study of Obesity, 1995: 42. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155-1161. Ionsidine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83: 1263-1271. Lee G-W, Proenca R, Montez JM, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996. In press. Reprints: Professor P Zimmet, Chief Executive Officer, International Diabetes Institute, 260 Kooyong Road, Caulfield, VIC 3162.

Paul Zimmet · Greg R Collier

Approximately one-quarter of adult Australians are "active" smokers, but almost everyone is a "passive" smoker at some time. The right of adults to make a fully informed decision to begin or to continue smoking is not in question, but there is widespread concern about the risks carried by non-smokers who breathe environmental tobacco smoke (ETS) from others' cigarettes. If passive smoking really does harm health, then a strong case can be made for limiting the places and situations in which smoking is permitted. In November 1995, the National Health and Medical Research Council (NHMRC) released for public comment a new report on the effects of passive smoking on health.1 It reviewed the scientific evidence on the risks to health from exposure to ETS, gave an estimate of the total burden of illness attributable to passive smoking in Australia, and gave 25 recommendations for measures to reduce this burden. (The main recommendations are shown in the Box.) The report concluded that the evidence relating ETS to several important categories of illness had strengthened considerably since the last NHMRC review in 1986.2 It found that ETS is firmly linked, as a likely causal factor, to lower respiratory tract illness in young children, asthma, lung cancer and cardiovascular disease, and provided detailed calculations of the numbers and costs of additional cases of these conditions attributable to passive smoking in Australia. Evidence since 1986 implicates exposure to ETS as a cause of sudden infant death syndrome, "glue ear" in childhood, acute irritation of the respiratory tract, and low birth weight (as a consequence of non-smoking mothers being exposed to ETS during pregnancy). However, the report found insufficient evidence concerning these conditions to include them in estimates of the burden of illness. Each year, according to the NHMRC report, passive smoking leads to more than 5400 extra hospital admissions in Australia and costs the country about $21 million. The brunt of this excess morbidity -- 51 600 episodes of asthma (about 9% of all cases) in people aged less than 15 years, and about 2000 admissions to hospital in the first 18 months of life because of chest illness -- is borne by children. There are approximately 10 attributable cases of lung cancer among adults who have never smoked and 100 deaths from coronary disease. These figures are likely to be underestimates. The effects of passive smoking on current and ex-smokers have not been included, any effects of low levels of exposure in causing or exacerbating asthma have been ignored, and it has been assumed that passive smoking does not cause other respiratory problems in children over 18 months of age. Evidence from overseas indicates that the burden of adult illness from exposure outside the home is likely to be at least as great as that from domestic exposure,3 but the NHMRC estimates include domestic exposure only. The term "passive smoking" was coined 25 years ago,4 but scientific and public interest in the issue accelerated sharply in 1981 when Hirayama published evidence that exposure to ETS went beyond being a source of annoyance to non-smokers and actually caused lung cancer.5 The NHMRC working party was able to find 31 separate studies of ETS and lung cancer in non-smokers published before 1995, as well as 41 investigations of the impact of passive smoking on various respiratory complaints in childhood. As the report by Doyle et al. in this issue of the Journal shows, the evidence linking ETS with impairment and illness continues to grow. This prospective study of a cohort of very low birthweight children found that those who had been exposed to tobacco smoke since birth had worse respiratory function than their non-exposed peers when tested at 11 years of age. The findings exhibit a dose-response relationship, despite a somewhat crude assessment of exposure to ETS, and cannot be explained by differences in the socioeconomic circumstances. The results are based on small numbers of children, but are consistent with other published studies. It should be noted also that active smokers never regain the decrement in respiratory function that they accumulate, even if they give up smoking.6 There is a clear message to doctors and parents: passive smoking is the most readily preventable cause of respiratory impairment in childhood. Vulnerable groups in society -- infants, children and adults with asthma and other respiratory conditions, and individuals with established cardiac disease -- are most affected by exposure to ETS. Workplaces where smoking is still allowed, including hotels and restaurants, are also a special case because the passive smoking by employees in these enterprises is often involuntary. Progress has been made in the provision of smoke-free workplaces, but about 40% of Australian indoor workers are still exposed to tobacco smoke at work.7 What is now the appropriate public policy response to more than two decades of careful scientific research into the risks associated with passive smoking? We probably can do little better than be guided by John Stuart Mill's oft-quoted essay On liberty:8 "The only purpose for which power can be rightfully exercised over any member of a civilised community, against his will, is to prevent harm to others." Alistair Woodward Professor of Public Health Wellington School of Medicine, New Zealand Konrad Jamrozik Associate Professor, Department of Public Health University of Western Australia References National Health and Medical Research Council. The health effects of passive smoking: The draft report of the NHMRC Working Party, November 1995. Canberra: NHMRC, 1995. National Health and Medical Research Council. Effects of passive smoking on health. Canberra: AGPS, 1987. United States Environmental Protection Agency. Respiratory health effects of passive smoking: lung cancer and other disorders. Washington DC: Office of Research and Development, 1992. Harke HP. Zum problem des "passiv-rauchens". Munch Med Wochenschr 1970; 51: 2328-2334. Hirayama T. Nonsmoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. BMJ 1981; 282: 183-185. Fletcher CM, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1: 1645-1648. Borland R, Mullins R. The increasing prevalence of workplace smoking bans in Victoria, 1994. J Occup Health Safety Aust N Z 1994; 10: 35-40. Mill JS. On liberty. London: Watts & Co., 1941: 11.

Alistair Woodward · Konrad Jamrozik

Is cryotherapy treating or infecting? The preservation of microorganisms (especially viruses) in liquid nitrogen means that without adherence to proper infection control common cryotherapeutic procedures are an infection risk MJA 1996; 164: 263 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 Cryotherapy has become an indispensable tool in the treatment of benign dermatological lesions and some premalignant and malignant lesions.1 As early as the mid-1800s, clinicians used freezing agents as ablative therapy; initially using a salt-ice mixture which was later replaced by liquefied gases, such as air, oxygen and nitrogen. Other freezing agents still in use include liquid refrigerants and solid carbon dioxide.1 Of all the cryotherapeutic freezing agents, liquid nitrogen is the agent of choice. The properties which have made liquid nitrogen popular in clinical medicine include its low boiling point (-196oC) and inertness, relatively easy availability and handling, affordability and good compliance. Liquid nitrogen causes cellular death by formation of intracellular and extracellular crystals (inducing dehydration), and damage to blood vessels.2,3 Irreversible vascular occlusion results from erythrocyte accumulation, thrombus formation and diapedesis of blood elements, eventually causing tissue necrosis.2,3 Of all the cryotherapeutic freezing agents, liquid nitrogen is the agent of choice. In clinical practice, liquid nitrogen can be applied by various methods: cryosurgical spray units, cryoprobes or cotton-tipped swabs.4 Swabbing is the simplest method of application, but cryospray units or cryoprobes are more appropriate in settings where liquid nitrogen or nitrous oxide is used more frequently. It is often not recognised that, apart from causing tissue necrosis, liquid nitrogen is also an excellent agent for cryo preservation of biological material (e.g., for forensic analysis)5 and, in particular, preservation of infectious microorganisms (including viruses).6-8 Therefore, without adherence to correct infection control procedures when using cryotherapy (and without adequate sterilisation of cryotherapy accessories), staff could transmit infection from patient to patient (see Box). For example, if a common receptacle filled with liquid nitrogen is used for every patient throughout a clinic and multiple swabs are dipped into it, the receptacle can be contaminated with patients' microbial flora. Moreover, if any unused liquid nitrogen is returned to the main storage container, the entire tank can become contaminated. A recent study from the United Kingdom,9 where infection control procedures broke down, reported hepatitis B virus contamination of a cryopreservation tank used for storage of bone-marrow or stem cells. Six patients developed icteric acute hepatitis B infection subsequent to transplantation.9 Other studies have also shown that infectious viruses can be isolated from the liquid nitrogen in containers storing vials of preserved virus and without any drop in viral titre.8,10 Transmission of viruses, particularly human papillomavirus (HPV), via contaminated inanimate objects has also been confirmed.11 Liquid nitrogen was implicated in cases of HPV cross-infection when liquid nitrogen swabs were used to treat patients with warts and then used to treat other patients with non-infectious dermatological lesions.12 The risks of cross-infection in medical procedures have recently become a critical public health issue in Australia after four people were diagnosed HIV positive allegedly following simple surgical procedures in a doctor's office,13 and in the United States where transmission of HIV from health care worker to patient occurred in a dental practice.14 Therefore, it is essential that all health care workers understand the principles of infection control and practise them at all times. Sepehr N Tabrizi Senior Research Officer Department of Microbiology, The Royal Women's Hospital, Carlton, VIC. Suzanne M Garland Director of Microbiology Department of Microbiology, The Royal Women's Hospital, Carlton, VIC. References Kuflick EG. Cryosurgery updated. J Am Acad Dermatol 1994; 31: 925-944. Kreyberg L. Local freezing. Proc R Soc Lond [Biol] 1957; 147: 546-547. Kreyberg L. Statis and necrosis. Scand J Clin Lab Invest Suppl 1963; 15 Suppl 71: S1-S26. Allington HV. Liquid nitrogen in the treatment of skin disease. Calif Med 1950; 72: 153-155. Camp FR, Ellis FR, Shields CE, Werline MM. Long-term preservation of biologicals for the forensic laboratory and their areas of application. J Forensic Sci 1968; 13: 419-432. Hildebrant RJ, Sever JL, Anderson B. Preservation of infectious cytomegalovirus. Proc Soc Exp Biol Med 1968; 129: 504-506. Jarvis JD, Wynne CD, Telfer ER. Storage of bacteria in liquid nitrogen. J Med Lab Technol 1967; 24: 312-314. Schafer TW, Everett J, Silver GH, Came PE. Biohazard potential: recovery of infectious virus from liquid nitrogen of a virus repository. Health Lab Sci 1976; 13: 23-24. Tedder RS, Zukerman MA, Goldstone AH, et al. Hepatitis B transmission from contaminated cryopreservation tank. Lancet 1995; 346: 137-140. Jones SK, Darville JM. Transmission of virus particles by cryotherapy and multi-use caustic pencils: a problem to dermatologists? Br J Dermatol 1989; 121: 481-486. Massing A, Epstein W. Natural history of warts; a two-year study. Arch Dermatol 1968; 87: 300-310. Charles CR, Sire DJ. Transmission of papovavirus by cryotherapy applicator. JAMA 1971; 218: 1435. Chant K, Lowe D, Rubin G, et al. Patient-to patient transmission of HIV in private surgical consulting rooms [letter]. Lancet 1993; 342: 1548-1549. Centers for Disease Control. Update: investigations of patients who have been treated by HIV-infected health-care workers. MMWR Morb Mortal Wkly Rep 1992; 41: 344-346. Reprints: Dr S N Tabrizi, Department of Microbiology, The Royal Women's Hospital, Carlton, VIC 3053. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Sepehr N Tabrizi · Suzanne M Garland

How can we reduce heroin "overdose" deaths? MJA 1996; 164: 197 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - - ©MJA1997 Deaths from heroin "overdose" have increased steadily over the past decade in the absence of any public health measures specifically aimed at reducing them. Recent research suggests that many of these deaths may be preventable.1-3 It also calls into question much of the conventional wisdom about the causes of "heroin" overdoses. The toxicological data from the study of Zador and colleagues in this issue of the Journal suggest that heroin "overdose" is a misnomer. In only a minority of cases was morphine (the metabolite of heroin) the only drug detected at autopsy, and in a third of cases blood morphine levels were below the level usually regarded as toxic for opioid-naive individuals. More typically, morphine was found in combination with intoxicating levels of alcohol or other central nervous system depressants, such as benzodiazepines. These data are consistent with the findings of other studies of fatal overdoses1,4,5 and with what heroin users have reported about their use of alcohol and other drugs at the time of their most recent non-fatal overdoses.1,2,6 Opioid overdoses are not confined to inexperienced drug users.2 A recent survey of 329 Sydney heroin users, for example, found that non-fatal opioid "overdoses" are common among experienced users.2,3 Two-thirds of these 30-year-old users had experienced an average of three non-fatal overdoses during their 10 years of heroin use. A third had been given naloxone, and four out of five had been present when someone else had "overdosed".2,3 Opioid overdoses are not confined to inexperienced drug users Contrary to media and drug-user folklore, fatal heroin "overdoses" are probably only rarely a consequence of unexpectedly high purity. Variations in purity can cause overdoses, but they appear to be a minor factor in fatal overdoses. Moreover, the fact that four out of five heroin users had been present when someone else had overdosed2,3 suggests that individuals in a group using the same batch of street heroin commonly experience overdose. A first priority for prevention must be to reduce the frequency of drug overdoses. We should inform heroin users about the risks of combining heroin with alcohol and other depressant drugs. Not all users will act on such information, but if there are similar behavioural changes to those that occurred with needle-sharing7 overdose deaths could be substantially reduced. Heroin users should also be discouraged from injecting alone and thereby denying themselves assistance in the event of an overdose. Increasing the number of heroin users enrolled in methadone maintenance treatment is another useful strategy for reducing overdose deaths, because the risk of such deaths is substantially reduced while heroin users are in methadone treatment.8,9 It has recently been suggested that supervised injectable heroin maintenance programs may also reduce opioid overdose deaths. This argument has been used in favour of the proposed trial of injectable heroin maintenance in the Australian Capital Territory, with media stories suggesting that providing heroin under medical supervision will reduce overdose deaths allegedly caused by uncertainty about the purity of heroin.10 This is one of the least cogent reasons for a "heroin trial", because it exaggerates the contribution of heroin purity to drug overdose, and ignores the role of concurrent alcohol and other drug use. Media misconstructions of the aims of the "heroin trial" also create unrealistic expectations of its outcome. Even if heroin maintenance reduces opioid overdoses, the proposed trial is unlikely to detect such a reduction because only 40 heroin users will be involved in its first phase. As these users will be recruited from the ACT methadone program, their risks of opioid overdose will be small, and hence it will be extremely difficult to detect any reduction in risk. Even in the larger trial proposed in the second phase, the number of heroin users would be too small a fraction of the population of heroin users to have a detectable effect on overall opioid mortality. A second priority for prevention is to reduce the number of fatal overdoses by improving heroin users' responses to the overdoses of their peers. Heroin users could be taught simple cardiopulmonary resuscitation skills so that they can keep comatose users alive until help arrives. Users also need to be encouraged to call an ambulance earlier than they do at present.3 Their understandable fears of police involvement need to be addressed, and relations between ambulance officers and heroin users need to be improved. A serious analysis should also be made of the benefits and costs of distributing the opiate antagonist naloxone to high risk heroin users so that they can reverse the opioid contribution to drug overdoses.11 Peer-based health education programs and the increased availability of clean needles and syringes appear to have maintained low rates of HIV infection among Australian injecting drug users.6 The public health challenge is to ensure that information about the causes of heroin "overdose" is acted upon so that drug overdose deaths can be reduced. Wayne D Hall Director, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW Bammer G, Sengoz A. Non-fatal heroin overdoses. Med J Aust 1994; 161: 572-573. Darke S, Ross J, Cohen J, Hall W. Overdose among heroin users in Sydney, Australia. I. Prevalence and correlates of non-fatal overdose. Addiction 1996. In press. Darke S, Ross J, Cohen J, Hall W. Overdose among heroin users in Sydney, Australia. II. Responses to overdose. Addiction 1996. In press. Davoli M, Perucci CA, Forastiere F, et al. Risk factors for overdose mortality: a case control study within a cohort of intravenous drug users. Int J Epidemiol 1993; 22: 273-277. Frischer M, Bloor M, Goldberg D, et al. Mortality among injecting drug users: A critical reappraisal. J Epidemiol Commun Health 1993; 47: 59-63. Loxley W, Carruthers S, Bevan J. In the same vein: first report of the Australian study of HIV and injecting drug use. Perth: National Centre for Research into the Prevention of Drug Abuse, Curtin University of Technology, 1995. Feachem RGA. Valuing the past . . .investing in the future. Evaluation of the National HIV/AIDS Strategy 1993-4 to 1995-6. Canberra: AGPS, 1995: 92. Caplehorn JRM, Dalton MSYM, Cluff MC, Petrenas AM. Retention in methadone maintenance and heroin addicts' risk of death. Addiction 1994; 89: 203-207. Fugelstad A, Rajs J, DeVerdier MG. Mortality among HIV-infected intravenous drug addicts in Stockholm in relation to methadone treatment. Addiction 1995; 90: 711-716. Lamont L. Heroin trial set to go ahead. The Sydney Morning Herald 1996 Jan 11: 3. Strang J, Farrell M. Harm minimisation for drug users: when second best may be best first. BMJ 1992; 304: 1127-1128. Reprints: Dr W D Hall, Director, National Drug and Alcohol Research Centre, University of New South Wales, PO Box 1, Kensington, NSW 2033. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Wayne D Hall

Editorial Oily fish and asthma - a fishy story? Further studies are required before claims can be made of a beneficial effect of oily fish consumption on asthma Interest in the possible health benefits of dietary fish lipids followed observations that populations with a high dietary intake of fish, such as Greenland Inuit and the Japanese, had low incidences of atherosclerotic disorders and of inflammatory conditions such as rheumatoid arthritis. Our recent understanding of asthma as a chronic inflammatory airway disease has led to speculation that a diet rich in fish oil may also ameliorate asthma. The potential anti-inflammatory effect of fish oil stems from its active ingredient, eicosapentaenoic acid (EPA), which is a competitive substrate with arachidonic acid for the generation of inflammatory mediators. The derivatives of arachidonic acid (an n-6 fatty acid) are leukotriene B4 (LTB4), a potent neutrophil chemoattractant and pro- inflammatory mediator, and the cysteinyl series of leukotrienes (LTC4, LTD4 and LTE4), which produce potent smooth muscle contraction and bronchoconstriction. In contrast, EPA (an n-3 fatty acid), as well as inhibiting arachidonic acid metabolism, is a substrate for the less active prostanoids (e.g., thromboxane A3) and leukotrienes (e.g., LTB5), and so has the potential to reduce airway inflammation and reverse bronchoconstriction. As the most profound anti-inflammatory actions of fish oil are on neutrophil function and mediator generation, it is not surprising that clinical trials of dietary fish oil have been beneficial in diseases where there is a neutrophilic inflammation, such as rheumatoid arthritis, psoriasis, cystic fibrosis and inflammatory bowel disease. However, in asthma the role of neutrophils is much less certain. Eosinophils and mast cells are thought to be the predominant effector cells in asthma (through the release of mediators), with T lymphocytes, macrophages and, possibly, mast cells having initiating and immunomodulatory roles through cytokine secretion. Placebo-controlled interventional studies of high dose fish oil supplementation in patients with asthma have been disappointing. Early short term trials (eight weeks) of up to 4 g/day of EPA in severe asthmatics showed no clinical benefit, despite demonstrating profound suppression of neutrophil chemotaxis and mediator generation.1 In a study in aspirin-intolerant subjects asthma control worsened after six weeks of 3 g/day of EPA, 2 consistent with the known aspirin-like effect of cyclooxygenase inhibition by EPA. Further studies in milder asthmatics with 3.2 g/day for 10 weeks showed no benefit in either clinical symptoms or bronchial hyperresponsiveness,3 despite demonstrating attenuation of allergen-induced late-phase bronchoconstriction induced in the laboratory.4 A more prolonged trial for six months with 3.2 g/day of EPA also showed no clinical benefit in patients with pollen-induced asthma and seasonal hayfever.5 These disappointing results are consistent with in-vitro evidence that EPA does not inhibit eosinophils and mast cells. In contrast to its dampening effect on neutrophils, EPA incubated with cultured murine mast cells produced a marked increase in production of platelet-activating factor, without an effect on histamine release.6 Similarly, stimulated human eosinophils incubated with EPA generated significantly greater amounts of leukotrienes than those incubated with arachidonic acid.7 Furthermore, in asthma there is a complex interaction between cells, cytokines, nerves and lipid and other mediators. Although of the lipid mediators leukotrienes may have the most influential role in asthma, modulating any one group of inflammatory mediators alone may not be sufficient to produce clinical improvement. The only interventional study which has shown positive results was a small placebo-controlled trial of low-dose EPA (1 g/day) for 12 months in 12 adult asthmatic subjects (six taking fish oil and six taking placebo). After nine months a small but significant improvement was found in forced expiratory volume at one second (FEV1).8 However, no details were given of concurrent medication use or assessment of compliance with therapy by leukocyte membrane phospholipid analysis, and there have been no follow-up data since 1991. The question of fish diet and respiratory health has also been investigated from an epidemiological perspective in recent American studies. In a survey of 2526 adult subjects aged 30-70 years, the first National Health and Nutrition Survey found eating fish more than once a week, compared with less than once a week, was associated with a higher level of lung function. However, only 2.9% of subjects in this survey were asthmatic, so no conclusion could be drawn about the effect of fish consumption on asthma.9 The Atherosclerosis Risk in Communities (ARIC) study surveyed 8960 adult current and former smokers10 and reported that a high dietary intake of n-3 fatty acids was inversely related to the risk of chronic obstructive pulmonary disease (COPD). This apparent protective effect is biologically plausible as neutrophilic inflammation is a feature of COPD. The Nurses' Health Study, possibly the largest prospective study of its type, reporting the incidence of adult-onset asthma in 77 866 women aged 34-68 years, found no relationship between dietary intake of fatty acids and the incidence of doctor-diagnosed asthma over a 10-year period.11 With this background, what interpretation can be put on the study by Hodge et al. in this issue of the Journal (page 137)? The novel aspects of this epidemiological survey are that the study population consisted of Australian children aged 8-11, and that the diagnosis of asthma was based both on symptoms and measurement of bronchial hyperresponsiveness. The investigators found an inverse relationship between weekly oily fish intake and prevalence of asthma in 574 schoolchildren. A number of salient points may be made. Firstly, the investigators previously reported an inverse relationship between weekly total fish intake and asthma, which is not evident in this study. This may reflect the inherent variability of food frequency questionnaire data or the different sample sizes of the two studies, but it does raise doubts about the primary hypothesis being tested. Secondly, the estimated mean intake of EPA from a weekly serve of fish10 is about 0.2-0.8 g, which is much lower than the amount that would be expected to have anti-inflammatory effects on leukocyte mediator and cytokine generation. It is possible that it is not the oil in the fish per se but some other dietary or social component associated with families who eat fish which is responsible for these results. Thirdly, a much larger prospective study in adults did not find a similar relationship between dietary fish intake and asthma prevalence.11 Can this discrepancy be explained by subtle effects of low-dose fish oil on the immunological development of asthma in childhood, which are no longer relevant in adulthood? There is currently insufficient understanding of the mechanisms involved to put forward a biologically plausible hypothesis. Finally, the study of Hodge et al. is a cross-sectional study, and thus cannot establish a temporal relationship between oily fish intake and asthma. Nevertheless, these are very interesting data but they need to be confirmed in larger studies. Placebo-controlled prospective intervention studies with dietary manipulation for prolonged periods in childhood are also required before any claim can be substantiated. Until then, unwarranted speculation about the relationship between dietary fats and asthma12 should be avoided as this may have a negative impact on other health outcomes, cause even more confusion about diet and health in the general population and undermine an evidence-based approach to public health initiatives. Francis C K Thien Senior Lecturer Rosalie K Woods Research Fellow E Haydn WaltersProfessor/Director Department of Respiratory Medicine, Alfred Healthcare Group Melbourne, VIC (©MJA 1996; 164: 135-136) Kirsch CM, Payan DG, Wong MYS, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988; 18: 177-187. Picado C, Castillo JA, Schinca N, et al. Effects of a fish oil enriched diet on aspirin intolerant asthmatic patients: a pilot study. Thorax 1988; 43: 93-97. Arm JP, Horton CE, Mencia-Huerta J-M, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988; 43: 84-92. Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139: 1395-1400. Thien FCK, Mencia-Huerta J-M, Lee TH. Dietary fish oil effects on seasonal hay fever and asthma in pollen-sensitive subjects. Am Rev Respir Dis 1993; 147: 1138-1143. Triggiani M, Connell TR, Chilton FH. Evidence that increasing the cellular content of eicosapentaenoic acid does not reduce the biosynthesis of platelet-activating factor. J Immunol 1990; 145: 2241-2248. Thien FCK, Hallsworth MP, Soh C, Lee TH. Effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene C5 by calcium ionophore-activated human eosinophils in vitro. J Immunol 1993; 150: 3546-3552. Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991; 95: 156-157. Schwartz J, Weiss ST. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I). Eur Resp J 1994; 7: 1821-1824. Shahar E, Folsom AR, Melnick SL, et al. Dietary n-3 polyunsaturated fatty acids and smoking-related chronic obstructive pulmonary disease. N Engl J Med 1994; 331: 228-233. Troisi RJ, Willett WC, Weiss ST, et al. A prospective study of diet and adult-onset asthma. Am J Respir Crit Care Med 1995; 151: 1401-1408. Hodge L, Peat JK, Salome C. Increased consumption of polyunsaturated oils may be a cause of increased prevalence of childhood asthma. Aust N Z J Med 1994; 24: 727. (©MJA 1996; 164: 135-136)

Rosalie K Woods

Vaccine-preventable childhood diseases in Australia Too much disease, not enough vaccination: what more can we do? MJA 1996; 164: 61 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 In 1994, there were 17 442 notifications of vaccine- preventable diseases in Australia.1 This disgraceful situation exists despite the ready availability of free, safe and effective vaccines. Particularly damning were the 8661 cases of pertussis, measles, mumps, rubella and Haemophilus influenzae type b notified in children up to school leaving age (19 years old) -- all diseases for which a national immunisation program has been in place for many years! Why do we still have so much disease despite good vaccines and good delivery systems? While there is a lack of uniform reliable data on vaccination coverage, it would seem our national childhood vaccination rates are inadequate. The Australian Bureau of Statistics' 1989-90 National Health Survey reported that, according to parental recall, 53% of children up to six years of age had been vaccinated in accord with the National Health and Medical Research Council (NHMRC) vaccination schedules.2 Unpublished data from State health departments include the report of a 1991 cluster survey in Victoria of 630 children aged 18 months to 3 years which found that 88% were fully vaccinated against diphtheria, pertussis, tetanus, polio and measles (John Carnie, Manager, Infectious Diseases Unit, Victorian Department of Health and Community Services, Melbourne, personal communication); a 1994 ACT report found that only 67% of 236 children at school entry (aged about five years) were fully vaccinated (Ms Ann Kempe, Immunisation Coordinator, ACT Department of Health and Community Care, Canberra, personal communication). Whatever the true vaccination coverage, continuing notifications (in the thousands) of cases of measles, with its well-known risks of encephalitis, bronchopneumonia and subacute sclerosing panencephalitis (SSPE), highlight how much still needs to be done. In the United Kingdom a recent national measles-rubella immunisation program has successfully terminated measles virus circulation in schools; in March and April 1995, there were four confirmed cases of measles in England and Wales; three cases had recently arrived in the country, and the other occurred in an unvaccinated 15-month-old child.3 In Australia there were 229 measles notifications for the same period (National Notifiable Diseases Surveillance System, personal communication). there is still a lack of awareness on the part of parents and even some health practitioners of the benefit-risk equation for vaccination On the other hand, notifications of invasive Haemophilus influenzae type b have decreased from at least 3.5 cases per 100 000 population in 19911 to 1 case per 100 000 in 1994.1 Within three years we may see less than a quarter the number of cases of childhood bacterial meningitis recorded in 1990 -- evidence of the benefit of effective vaccination. The National Childhood Immunisation Committee has implemented a number of initiatives over the past two years to increase vaccination coverage rates in line with the goals of the 1993 NHMRC National Childhood Immunisation Strategy.4 More than 30 000 copies of a kit, which included the fifth edition of the Australian immunisation procedures handbook,5 were distributed to general practitioners and other vaccination service providers. A parents' guide to immunisation, Understanding childhood immunisation,6 was also produced and widely distributed; a recent mass media awareness campaign offers this booklet free to enquirers through a toll-free telephone number (1800 671 811). Such initiatives have received broad professional and community support from organisations such as the Australian Medical Assocation, the Royal Australian College of General Practitioners, the Australian College of Paediatrics, the Australian Institute of Environmental Health, the Sudden Infant Death Association and the NHMRC. Technical considerations also play a role in ensuring the optimal efficacy of vaccines: guidelines and systems for cold-chain maintenance have been implemented (some local studies have suggested that some vaccine providers have difficulty maintaining vaccines at between 2-81/4C7,8 ); knowledge of the thermolability of reconstituted measles-mumps- rubella vaccines and of oral polio vaccine at room temp erature is another important consideration. The safety and efficacy of vaccines are apparent to all but a few. A scheme to record, follow-up and regularly publish significant adverse events following vaccination has been under way since March 1995 (general practitioners and other providers notifying respective State or Territory health authorities by telephone). The data are collated, reviewed and published monthly in Communicable Diseases Intelligence. Adverse event rates of less than 1% have been recorded, although the data are as yet incomplete. Nevertheless, there is still a lack of awareness on the part of parents and even some health practitioners of the benefit-risk equation for vaccination, at least for some vaccines. A few individuals who propagate tired myths of exaggerated vaccination harm, however sincerely, make it more difficult to provide concerned parents with balanced benefit-risk information. To address this problem Commonwealth funding of $24 million has been allocated towards childhood vaccination during 1995-96 and 1996-97. Most of this outlay is provided to the States and Territories to purchase NHMRC standard childhood immunisation schedule vaccines in return for their undertaking to provide a coordinated program. Some of this funding will be used to obtain better information about vaccination coverage via the Australian Childhood Immunisation Register, which commenced on 1 January 1996. Information from the Register will enable resources to be targeted effectively to assist areas with the lowest coverage rates. Combination 4-in-1 (tetravalent) and 5-in-1 (pentavalent) vaccines (e.g., against diphtheria, tetanus, polio, Haemophilus influenzae type b and hepatitis B), less reactogenic acellular pertussis vaccines, as well as a varicella vaccine, are soon to appear on local markets. On the eve of the third millennium, once again we as a nation will need to debate the cost-benefit of disease prevention. In this debate we must acknowledge how far we have come in the two hundred years since Jenner's successful inoculations against smallpox, and how far we have yet to go. Gavin W Frost Senior Medical Adviser, AIDS/Communicable Diseases Branch Commonwealth Department of Human Services and Health, Canberra, ACT Monica Johns Senior Project Officer, National Childhood Immunisation Program Commonwealth Department of Human Services and Health, Canberra, ACT Hargreaves J, Longbottom H, Myint H, et al. Annual Report of the National Notifiable Diseases Surveillance System 1994. Commun Dis Intell 1995; 19: 542-574. Australian Bureau of Statistics. 1989-90 National Health Survey Children's Immunisation Survey, Australia. Canberra: ABS, 1992. (Catalogue No. 4379.0.) Interruption of measles transmission in school schildren, 1995. Wkly Epidemiol Rec 1995; 70: 215-216. National Health and Medical Research Council. National Immunisation Strategy. Canberra: NHMRC/AGPS, 1993. National Health and Medical Research Council. The Australian immunisation procedures handbook. 5th ed. Canberra: AGPS, 1995. Herceg A, Shelley S. Understanding childhood immunisation. Canberra: Commonwealth Department of Human Services and Health, 1995. Liddle JL, Harris MF. How general practitioners store vaccines. A survey in south-western Sydney. Med J Aust 1995; 162: 366-368. Herceg A, Longbottom H. A national immunisation provider survey. Canberra: Commonwealth Department of Human Services and Health, 1995. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Gavin W Frost · Monica Johns

Editorial Hydatid disease: medical problems, veterinary solutions, political obstacles Prevention of human hydatidosis requires new strategies, political support and collaboration between government departments It is to be hoped that in the near future Australia will cease to have the unenviable reputation of being the home of perhaps the most important parasitic disease common to man and domesticated animals, which carries with it the added stigma that it is preventable.1 Seventy years later, the hopes of Sir Ian Clunies Ross, the first chairman of the Commonwealth Scientific and Industrial Research Organisation (CSIRO), have not been fulfilled; the problem is still with us. Australians have been very good at treating human hydatidosis but very poor at preventing it. Notorious under-reporting of cases of hydatid disease has made it easier for authorities to remain inactive to the need for control. In this issue of the Journal, Jenkins and Power (page 18) have effectively documented the failure of the New South Wales (NSW) and Australian Capital Territory (ACT) health care systems to take the problem seriously. Their survey of medical records from hospitals and health care services identified 195 new cases of hydatidosis (172 in NSW, and 23 in the ACT) during the six-year period 1987-1992. This compares with official notifications of 37 and three cases, respectively, during the (partially overlapping) five-year period 1990-1994.2 New cases presented predominantly in the north-eastern and south-eastern Tablelands and in metropolitan areas. Whereas the latter could have included some patients from rural areas, 60% of the urban cases were migrants who had most probably contracted hydatidosis outside Australia. Their presentation to city practitioners may present diagnostic difficulties if medical awareness of hydatidosis is less acute than in endemic rural areas. Would complete notification of all cases (assuming that it could be achieved) alleviate the problem? Apart from causing transient embarrassment, I believe it would have little impact. Certainly, accurate incidence figures are essential for assessing any pattern of change in a disease, but there are other major obstacles interfering with successful hydatid control in mainland Australia. In Tasmania, a concerted campaign involving collaboration between government and community organisations over several decades eliminated transmission of hydatid disease to humans,3 but in the larger mainland areas problems stem from the disease failing to conform to a pattern to which health care systems are designed to respond. Firstly, hydatidosis occurs in a limited number of regions, and centrally directed health programs operate on a state-wide basis (with a strong urban bias). Secondly, hydatidosis, although a human disease, requires veterinary, agricultural and educational expertise for effective prevention. Thirdly, the treatment of hydatidosis is exclusively surgical (and undertaken at a high standard in Australia) but its prevention is not ( in a way, surgery is as relevant to hydatid control as panel beating is to the prevention of road accidents. Fourthly, because successful prevention requires diverse skills, hydatidosis is not accepted as the responsibility of any one bureaucracy. Health, agriculture, education and conservation all have a role, but collaboration across such a range of portfolios to solve a regional problem is apparently unthinkable. And finally, the coup de grace ( there are no votes in hydatids. The largest and longest operating control campaign on the mainland (under the auspices of which the research of Jenkins and Power was undertaken) succumbed after a decade in which it received no State funding whatsoever: the Government eliminated the campaign and left the parasite! To what extent would complete prevention of human hydatidosis be attainable if political support and collaboration between government departments were coupled with the enthusiasm of many in rural communities who have attempted the task in the past? Ongoing investigations of hydatidosis epidemiology in Australia indicate that the textbook description of the life cycle of Echinococcus granulosus is no longer comprehensive.4 Surveys of parasite prevalence in regions with a high incidence of human hydatidosis consistently reveal a high prevalence of infection in wild dogs (including dingoes) as definitive hosts, and in macropods (kangaroos and wallabies) and feral pigs as intermediate hosts.5 In the light of these findings, the practice of baiting pigs in national parks, and thus providing an appetising source of echinococcal infection for wild dogs, may require re-examination. Contrary to earlier beliefs, foxes have been found to carry the parasite,6 and they frequent urban locations such as barbecue areas where their habit of demarcating territories by depositing faeces may introduce a significant human hazard.7 Dogs living in Perth suburbs but used for recreational pig hunting have been found to carry the parasite.8 It is not clear whether these new patterns of hydatidosis represent changes in the parasite, in its ecosystem, or in both. The extent to which human activity has contributed to the changes is also unclear. Increasingly, there are indications that the concept of separate wildlife and domestic animal strains of the parasite is breaking down and that a single strain, albeit manifesting host-determined phenotype variation, may have the capacity to infect both types of host in each of the traditional wildlife and domestic cycles. The domestic and wildlife strains of E. granulosus do not appear to be genetically distinguishable.9 Consequently, the wildlife cycle is likely to be of considerable human health importance. A case of hydatidosis in a child from the Southern Tablelands was the first documented instance of human disease produced by the wildlife strain.10 When a serious decision to combat hydatidosis is taken, it is clear that new strategies will be required. Peter J McCullagh Senior Fellow, Division of Clinical Sciences John Curtin School of Medical Research Australian National University, Canberra, ACT 1. Clunies Ross I. A survey of the incidence of Echinococcus granulosus (Batsch) or hydatid disease in New South Wales. Aust Vet J 1926; 2: 56-67. 2. Longbottom H, Hargreaves J. Human hydatid surveillance in Australia. Commun Dis Intell 1995; 19: 448-451. 3. Goldsmid JM, Pickmere J. Hydatid eradication in Tasmania. Point of no return. Aust Fam Physician 1987; 16: 1672-1674. 4. Constantine GC, Thompson RCA, Jenkins DJ, et al. Morphological characterization of adult Echinococcus granulosus as a means of determining transmission patterns. J Parasitol 1993; 79: 55-61. 5. Schartz PM, Chai J, Craig PS, et al. Epidemiology and control of hydatid disease. In: Thompson RCA, Lymbery AJ, editors. The biology of Echinococcus and hydatid disease. Wallingford, UK: CAB International, 1995: 233-302. 6. Obebdorf DL, Matheson MJ, Thompson RCA. Echinococcus granulosus infection of foxes in south-eastern New South Wales. Aust Vet J 1989; 66: 123-124. 7. Jenkins DJ, Craig NA. The role of foxes, Vulpes vulpes, in the epidemiology of Echinococcus granulosus in urban environments. Med J Aust 1992; 157: 754-756. 8. Thompson RCA, Lymbery AJ, Hobbs RP, Elliot AD. Hydatid disease in urban areas of Western Australia: an unusual cycle involving western grey kangaroos (Macropus fuliginosus), feral pigs and domestic dogs. Aust Vet J 1988; 65: 188-190. 9. Lymbery AJ, Thompson RCA, Hobbs RP. Genetic diversity and genetic differentiation in Echinococcus granulosus (Batsch, 1786) from domestic and sylvatic hosts on the mainland of Australia. Parasitology 1990; 101: 283-289. 10. Thompson RCA, Nott DB, Squire J, Rennell D. Evidence that the Australian sylvatic strain of Echinococcus granulosus is infective to humans [letter]. Med J Aust 1987; 146: 396-397.

Peter J McCullagh

Editorial Enter the Web: an experiment in electronic research peer review The MJA is exploring new protocols for publishing medical research See also the Internet peer review study home page for subsequent developments. The World Wide Web is a system for electronic publishing on the Internet. Electronic documents created for the Web can have many features not possible in printed documents. They include hyperlinks: marked text or images within the document that link to other related documents, wherever they might be stored in the Internet. Click on a link and the linked document is brought to your computer screen. Hence the name, "World Wide Web": documents from all over the world join into a web of information that can be rapidly traversed, across national and disciplinary boundaries, to wherever the reader wishes to go. Web documents can include animated images, sound recordings and various interactive elements, such as the capacity to send an immediate e-mail response to the author, or search a computer database. The Web has the potential to create a closer communication between authors and readers, or even a communication space in which everybody is both author and reader. Since its inception in 1990, the Web has rapidly grown in size and function to become the "hottest of the hot" applications for the Internet. Governments, universities, businesses, hospitals, courts, single individuals, newspapers and learned journals have rushed to create "Web pages" announcing their existence to the entire (networked) world. Publishing on the Web is not technically difficult (which is why many individuals have created their own Web pages) but not free, as both the publisher and the reader must pay the costs of connecting to the Internet. However, the publisher has none of the costs associated with printing and distributing a paper publication, and has an effective worldwide distribution that takes seconds rather than weeks. So, for reasons of economy and utility, there is an incentive to move information publishing from print to the Web. Against this, there is the obvious objection that most readers are not connected to the Internet, plus a problem for publishers in establishing how they will be paid. At present, most Web pages are freely available to anyone who is connected to the Internet. For instance, one can browse Web sites for Nature,1 the British Medical Journal2 or the Journal of the American Medical Association3 without paying a subscription to any of these journals. Of course, what is available on the Web is no substitute for the paper journal. At the BMJ site, for instance, there are contents lists and the full text of selected articles, plus details of how to subscribe to the printed publication. Such Web sites function more as advertising for or adjuncts to print ( and how indeed could they be anything else, until such time as large numbers of readers demonstrate a willingness to pay for an electronic journal? It is technically possible to make Web pages available only to paying subscribers, but as yet this is a rarity, with most publishers testing the market and the technology with freely distributed material. Meanwhile, there are those who hope that the journals will die a natural death and that the Web will provide a new publication system entirely free of publishers.4 One such vision describes a "global health information server", a Web site where all medical writers could publish their writings, and where editorial selection and peer review processes would be replaced by an automatic system of scoring articles by the number of readers they had attracted.4 Such a system is described as more "democratic" and would not refuse publication to anybody. The authors of this proposal ask "How will the world of health information look when every original paper, letter of criticism, and review article, as well as every form, chart, and database in the computerised world, is accessible with a couple of dozen clicks of a mouse?" The answer might well be "Hopelessly overloaded". Anyone who currently uses the Web to find information has had the experience of losing a grain of sense in a mountain of chaff; medical journals may have a great future on the Web precisely because they offer a selection of material that is intelligently tailored to the needs of particular readers. At the MJA, we have been as excited as anyone about the potential of the Web and have been looking for ways to exploit it. How can a journal be improved by using the Web? If the Web is to be used for faster or wider electronic publication of research, can this be done within the framework of reliable editorial control and peer review? Or, to put this question the other way around, can using the Web overcome criticisms of editorial control and peer review (i.e., that these processes may clog the progress of research,5 that they themselves are uncontrolled and potentially arbitrary, unscientific or unfair4-7)? To address these questions, we are going to conduct an experiment this year in electronic publication and open peer review. The project has been made possible by the cooperation of the University of Sydney Library (USL), which is providing essential expertise and support in Web publishing, and by a grant from the Electronic Publishing Working Group of the Australian Vice Chancellors' Committee. The purpose of the AVCC grants is to encourage innovative models of electronic publication for the creation and distribution of Australian research. The MJA and the USL are working in partnership on this initiative to develop and evaluate such a model. The project provides opportunities for both partners to develop technical and management skills, investigate the complex issues around electronic publication and position themselves to take further advantage of these new technologies. The USL is also working with the University's Faculty of Medicine in the use of electronic resources for medical teaching and research. In brief, a Web site will be created for the MJA where selected research articles that have gone through our traditional peer review process and have been accepted by the MJA will be published, together with comments provided by our peer reviewers. The papers will undergo minimal editing at this stage, and the effort will be to achieve rapid electronic publication, without the delays necessary to print. Readers on the Internet will be able to review the articles and reviewers' comments and, using a response mechanism built into the Web site, e-mail their own comments to the MJA. These comments will be filtered editorially to remove irrelevant material, then passed on to the authors and peer reviewers as feedback. Selected comments may be electronically published with the papers and reviews as additional commentary; authors will be able to respond or revise their paper in response. After a period on the Web, papers will undergo their "definitive" editing and be published in print in the MJA. Quantitative data (number of participants, number of Web readers, and so on) will be collected via the computer system, and qualitative assessments will be sought from authors, reviewers, editorial staff and an external Project Review Group. Participation in the open peer review experiment by authors and reviewers will be voluntary, and one thing we look forward to discovering is how many wish to be involved. Authors will be offered more rapid and more international publication, so we expect that most will be keen ( but will our peer reviewers, who have been used to the cloak of anonymity, be willing to have their comments on papers made public? Will this opening up of the review process to wider scrutiny have an effect on the quality (already excellent) of the reviews we receive? And will the comments posted to our Web site represent a valuable extension of the peer review process, leading to further improvements in papers before their appearance in print? All these questions and many related questions of detail and method introduce the MJA to a new world of electronic research publishing. We do not yet know the shape of the terrain, but we are set to explore. Craig Bingham Publication Coordinator, MJA Ross Coleman Collection Management Librarian University of Sydney Library, Sydney, NSW (©MJA 1996; 164: 8-9) Nature Web home page. http://www.nature.com/ British Medical Journal Web home page. http://www.bmj.com/bmj/ Journal of the American Medical Association Web home page. http://www. ama-assn.org/journals/standing/jama/jamahome.htm La Porte RE, Marler E, Akazawa S, et al. The death of biomedical journals. BMJ 1995; 310: 1387-1390. Horrobin DF. The philosophical basis of peer review and the suppression of innovation. JAMA 1990; 263: 1438-1441. Matthews R. Storming the barricades. New Scientist 17 June 1995: 38-41. Lock S. A difficult balance. Editorial peer review in medicine. London: BMJ, 1991: 23-55.

Craig Bingham · Ross Coleman