Letters

Jim Stockigt Senior Endocrinologist, Alfred Hospital, Melbourne; and Professor of Medicine, Monash University, VIC 3004. jrsATnetspace.net.au To the Editor: In May 2004, Sigma, the sole Australian supplier of l-thyroxine sodium, instructed pharmacists that thyroxine tablets should be stored refrigerated, both in pharmacies and after dispensing. Thyroxine bottles now carry explicit labels: “keep refrigerated” or “refrigerate at all times”. This instruction seems to have been accepted by health professionals, but patient-support groups immediately questioned the refrigeration directive. In response, Sigma conceded that thyroxine tablets can be stored at room temperature (< 25°C) for up to 4 weeks, with refrigeration still the preferred option. There are major unresolved issues about the potency, stability and bioavailability of various thyroxine preparations that are marketed competitively in the United States.1 With a single supplier in Australia, we can avoid between-preparation variations, provided that stability and consistency are maintained. The instruction to refrigerate thyroxine tablets seems to be uniquely Australian. None of my co-authors of the website <www.thyroidmanager.org>2 is aware of a refrigeration directive in any other country. The local instruction seems to have followed interaction between the Therapeutic Goods Administration and the manufacturer, so that unopened bottles could be marketed with a longer shelf life. Is the rest of the world missing out on something important? Is there something peculiar about the Australian formulation that makes it unstable at room temperature? Could this directive be without firm basis, or even dangerous? There is currently no evidence on whether thyroxine in already-opened, unsealed bottles is more or less stable at 4°C than at room temperature, but the need to keep the tablets dry has been widely emphasised.3 Consider the condensation that will occur during 200 daily openings of a refrigerated glass bottle, whatever it contains. If damp tablets lose potency, this would lead to apparent under-treatment. In the months since refrigerated storage was recommended in Australia, preliminary observations suggest that apparent under-dosage (ie, unexpected rises in serum TSH) may indeed occur in previously compliant patients (personal observation). If dosage were increased, the adjustment could result in over-treatment after a change to a fresh preparation. Thyroxine has a narrow therapeutic window, and excessive dosage can have serious effects, especially if there is associated cardiac ischaemia. While refrigeration of sealed bottles of thyroxine might extend the shelf life, the instruction to refrigerate unsealed bottles seems ill-advised. When an existing formulation is modified, it is generally the obligation of a manufacturer to demonstrate safety. The stability of tablets in sealed bottles and those in current use are quite separate issues. To establish how tablets in current use are influenced by refrigeration, it is necessary to measure the thyroxine content of remaining tablets from bottles of 200, opened and used daily for up to 6 months. Without such data, it is preferable to instruct patients not to store currently used bottles of thyroxine at refrigerator temperature.

Jim Stockigt

Ovais Siddiqui Regulatory and Medical Manager, Sigma Pharmaceuticals, Locked Bag 268, South Croydon, VIC 3136. ovais.siddiquiATsignet.com.au In reply: Sigma Australia acquired Oroxine (thyroxine sodium) from the original manufacturer in 1999, and launched Eutroxsig, an identical product, in 2002. During 2002–03, as a result of advances in analytical technology for some pharmaceutical products, product specifications, including shelf life and storage conditions, were updated, so that the product’s quality, safety and efficacy could be maximised or maintained throughout the claimed shelf life. For Oroxine and Eutroxsig, the new stability data showed a loss of up to 10% of thyroxine sodium in the first 6 months when stored below 25°C, with some plateauing thereafter. As an interim measure, Sigma, in agreement with the Therapeutic Goods Administration (TGA), decided to immediately reduce the shelf life from 24 to 12 months (“store below 25°C”) and set the lower release to 98.0% (up from 92.5%), while investigating reasons behind the loss in potency. The manufacturing process was confirmed to consistently yield tablets with very reproducible chemical and physical attributes in accordance with the release criteria. During manufacturing, however, about 2% of the thyroxine sodium is lost, with a corresponding similar increase in degradants. To limit the degradants responsible for the reduction in potency of thyroxine at room temperature, it was agreed with the TGA that thyroxine should be stored at 2°– 8°C (“Refrigerate. Do not freeze”), based on good stability data generated at this temperature. Consumer Medicine Information (CMI) and Product Information (PI) were updated in May/June 2004 to reflect this change. The new stability studies support the storage of Oroxine and Eutroxsig in the refrigerator; however, repeated in-use handling may result in an increase in condensation and microbial contamination. This may lead to changes in the physical characteristics of these products, including the growth of mould. There may be a further increase in condensation if the lid is not tightly closed. One possible solution is for patients to place up to 4 weeks’ supply of tablets in a spare, previously used, Oroxine or Eutroxsig amber-coloured bottle and store out of the fridge (below 25°C) for current use, while keeping the remaining stock in the fridge. Sigma is looking at options to improve the packaging so that the above problems are minimised or eliminated. Oroxine and Eutroxsig, manufactured by Sigma, are sold in Australia only. Sigma does not have access to formulation details, stability results and justification for the storage conditions used in other countries; therefore, we are unable to comment on such issues. As an Australian company, we are obliged to follow the regulatory guidelines of the Therapeutic Goods Act 1989 (Cwlth). Sigma recommends that the label instructions regarding storage conditions after opening be strictly followed to maximise the quality, safety and efficacy of the product.

Ovais Siddiqui

Christopher M MacIsaac,* Mark A Page,† Beverley-Ann Biggs,‡ Kumar Visvanathan§ * Associate Intensivist, † Registrar, ‡ Associate Professor, The Royal Melbourne Hospital, Grattan Street, Melbourne, VIC 3050; § Senior Research Fellow, Murdoch Children’s Research Institute, Melbourne, VIC. Christopher.macisaacATmh.org.au To the Editor: We report a recent case of toxic shock syndrome associated with menstruation which illustrates that this syndrome still occurs, even when tampons are used appropriately. A potential diagnostic test for the syndrome is also discussed. An 18-year-old woman presented with a 1-day history of fever, chills and severe back pain, with no other focal symptoms. On examination, she was febrile with a blood pressure of 75/40 mmHg, and had begun vomiting. She was treated empirically with intravenous ceftriaxone and flucloxacillin and resuscitated with intravenous fluids. Over several hours, the back pain resolved, and a widespread erythrodermic rash developed, centred mainly on the trunk. Further questioning revealed that the patient had removed a tampon shortly before presentation, as she had just ceased menstruating. Renal ultrasound examination, chest x-ray and blood cultures were non-diagnostic. She was treated with intravenous antibiotics for 4 days and discharged home with a further 10-day course of oral amoxycillin and clavulanic acid. At outpatient follow-up 3 weeks after admission, she reported desquamation of the skin of her palms and soles. Toxic shock syndrome was first described in 1978,1 and a strong association with Staphylococcus aureus, menstruation and tampon use was established in 1980.2 Toxic shock syndrome toxin-1 (TSST-1), a protein secreted by S. aureus, was the first of many toxins associated with the syndrome to be identified. The term “superantigen” was adopted to describe the ability of these toxins to cause a remarkable expansion of T lymphocytes displaying specific β chain variable regions of the T-cell antigen receptor. Superantigens bypass normal antigen presentation and can stimulate over 20% of all T cells, whereas a conventional antigen stimulates only in the order of 1 in 10 000 T cells. The signature feature of superantigen activity is the expansion of lymphocyte populations bearing the particular Vβ chains that bind the superantigen. In the case of TSST-1, this is Vβ2.3 Our patient consented to blood being sampled to investigate the Vβ profile of her T cells at follow-up. This investigation was part of a broader study on superantigens in sepsis that was approved by the Ethics Committee of the Royal Melbourne Hospital. The blood was stained with monoclonal antibodies against 24 Vβ families4 and analysed by flow cytometry. This showed a massive expansion of Vβ2 cells, which accounted for 28% of all CD4 lymphocytes (Box). Currently, there is no diagnostic test for toxic shock syndrome. Toxin production from cultured organisms can be established in vitro by some laboratories, but does not confirm toxin production in vivo. Detection of a “skewed” Vβ repertoire is a potential diagnostic test. Clearly, the sensitivity and specificity of the assay would need to be established before general application. To date, we have found skewed Vβ T-cell profiles in six independent cases of toxic shock syndrome. This patient had used tampons appropriately, including replacing tampons at least every 4 hours and not using them overnight, but nevertheless developed a life-threatening disease. The incidence of toxic shock syndrome peaked in the United States in 1980 and has since fallen substantially, as a result of factors including changed tampon absorbency. However, the incidence may be now increasing.5 Our case serves to remind us all to be vigilant for toxic shock syndrome in association with menstruation, and to consider the diagnosis in all patients with severe sepsis. Vβ profile of the T-cell antigen receptor of CD4 lymphocytes in a patient with toxic shock syndrome Vβ profile of CD4 cells from a patient 21 days after onset of toxic shock syndrome compared with the mean profile from 11 adult intensive-care patients with no evidence of infection. Note the massive expansion of cells carrying Vβ 2, for which toxic shock syndrome toxin-1 has known affinity.

Christopher M MacIsaac · Mark A Page · Beverley-Ann Biggs · Kumar Visvanathan

Patrick M Schlievert Professor, Microbiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA. patsATlenti.med.umn.edu Comment: As noted by MacIsaac et al above, my colleagues and I recently reported an increase in the incidence of staphylococcal toxic shock syndrome (TSS) in Minneapolis–St Paul in the United States, from 0.8 per 100 000 (in January 2000) to 3.4 per 100 000 (in December 2003).1 We noted that physicians across the United States were reporting TSS cases in increasing frequency. There are two major categories of staphylococcal TSS, menstrual and non-menstrual.2,3 Menstrual TSS is defined as occurring during menstruation or within the 2 days preceding its onset or the 2 days following its cessation; the illness is primarily, but not exclusively, associated with tampon use. Menstrual TSS is nearly always caused by the superantigen exotoxin, TSS toxin-1 (TSST-1).4 Superantigens significantly overactivate the human immune system to release cytokines that cause the clinical features of TSS (interleukin-1β [endogenous pyrogen]; tumor necrosis factor-α and β [capillary leak]; and interferon-γ and interleukin-2 [rash]).5 Non-menstrual TSS may occur in anyone, young or old, male or female, and today commonly follows superinfection of the upper respiratory tract after viral infection. Non-menstrual TSS is caused by TSST-1 (50%) or by staphylococcal enterotoxin B or C (together nearly 50%). The important question is what accounts for the fourfold rise in TSS that was reported in our 2004 study? We proposed several hypotheses. First, the increase in incidence partly results from the emergence of three strains of methicillin-resistant Staphylococcus aureus (MRSA), at least two of which are emerging worldwide. These strains are termed (by Centers for Disease Control [CDC] nomenclature) USA 1100 (TSST-1 positive), USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive), and USA 300 (positive for an unknown superantigen as well as PVL). In our studies, USA 1100 strains currently comprise 20% of submitted isolates, compared with none before the year 2000. These isolates may produce 10 to 100 times more TSST-1 in vitro than their methicillin-sensitive S. aureus counterparts matched by pulsed-field gel electrophoresis profile. Thus, these organisms rapidly produce high levels of TSST-1, leading to TSS even when lower-absorbency tampons are used. In addition, the USA 400 and USA 300 strains are also emerging and are associated with increases in non-menstrual TSS. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts. Secondly, in our 2004 study, physicians who submitted cultures to our laboratory defined cases of TSS based on patient presentation and the presence of an S. aureus strain producing one of the three causative exotoxins. Our TSS definition is likely to be broader than the strict CDC definition. Finally, we also noted that it is possible that women are beginning to menstruate and to use tampons at earlier ages. In addition, teenagers are bombarded with media advice that TSS is no longer a problem; failure to recognise the illness may lead to it becoming more severe before presentation. These lifestyle and awareness changes, combined with the emergence of high-toxin-producing strains and the expanded definition of TSS, may account for the observed increase in TSS. The increase does not appear to be caused by changes in tampon composition or absorbency.

Patrick M Schlievert

Andrew Firestone Psychiatrist; and Honorary Senior Lecturer, Monash University, Clayton, VIC 3168. afireATtpg.com.au To the Editor: Emerging evidence suggests that the so-called second-generation antipsychotics (SGAs), especially olanzapine and clozapine, can cause abnormal weight gain and increase the risk of diabetes mellitus.1-3 In Australia, there are calls for a prospective multicentre trial to compare the rates of weight gain and diabetes between SGAs.4,5 The Australian data presented here underline the pressing need for such a study. Data were examined for the 10-year period January 1994 to December 2003 for: Total prescriptions dispensed by the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme for 12 antipsychotic drugs; and Reactions reported in the same period to the Adverse Drug Reactions Advisory Committee (ADRAC) for each of these drugs, involving excessive weight gain or obesity, and diabetes mellitus or hyperglycaemic reactions. Reports were included in the survey only when it was considered that no other drug could be responsible. As clozapine is dispensed and recorded differently from other SGAs in Australia, complete data on numbers of prescriptions dispensed were not available. However, total Australian expenditure was available for each tablet strength of clozapine for the full 10-year study period, along with number of prescriptions dispensed and costs for the private hospital sector for the 4 years July 2000 to June 2004. Therefore, I calculated the average script cost for each tablet strength, and extrapolated the script numbers for the 10-year period, as shown in Box 1. Box 2 shows the “report rate” for each SGA for the side effects of weight gain or obesity, and diabetes or hyperglycaemia. The report rate for side effects was greater for clozapine than for any other SGA. Unfortunately, the true situation may be still worse. Clozapine is usually prescribed a month at a time, while the other drugs are prescribed for up to 6 months. Adjusting for this would widen the gap further. Moreover, as ADRAC promotes reporting for new drugs, the report rates for the five drugs introduced during the study period are probably inflated. Clozapine is not one of them. The limitations of ADRAC data are well known.4 Nevertheless, these are currently our best Australian data and strongly suggest that SGAs, of which risperidone has the most favourable profile, cause weight gain and diabetes much more often than the older antipsychotic agents. These data accord with previously published studies1 and support the US advice to avoid olanzapine and clozapine if possible. Recent PBS approval in Australia for use of olanzapine in bipolar disorder further underlines the urgent need for a prospective multicentre study to compare weight gain and glucose metabolism in patients taking antipsychotic drugs. Meanwhile, I suggest that: Patients who have abnormal weight gain with an SGA might be treated with chlorpromazine, trifluoperazine or haloperidol. PBS regulation of clozapine might be amended, to discourage its prescription until after failure of a “first-generation” as well as a second-generation antipsychotic drug. 1 Estimation of the total number of clozapine scripts in Australia Tablet strength (mg) Private hospitals data (Jul 2000–Jun 2004) Total clozapine used (Jul 1994–Jun 2004) Total prescriptions Cost ($) Average cost/ prescription ($) Cost ($) Estimated total prescriptions 25 3 650 230 929 63.27 9 636 814 152 313 50 25 1 443 57.72 85 980 1 490 100 21 057 6 632 499 314.98 153 276 771 486 624 200 69 24 392 353.51 463 131 1 310 Total 24 801 6 889 263 – 163 462 696 641 737 2 Report rates for side effects of antipsychotic drugs No. of years* No. of prescriptions dispensed No. of ADRAC reports Report rate (per million prescriptions dispensed) Weight gain† Diabetes‡ Weight gain† Diabetes‡ Chlorpromazine 10 950 221 0 0 0 0 Fluphenazine 10 327 126 0 0 0 0 Trifluoperazine 10 937 605 1 0 1.07 0 Pericyazine 10 657 514 0 0 0 0 Thioridazine 10 1 983 915 1 3 0.50 1.51 Haloperidol 10 1 499 254 2 0 1.33 0 Flupenthixol 9 121 132 0 0 0 0 Zuclopenthixol 8 93 839 0 1 0 10.66 Olanzapine 6 2 786 334 47 19 16.87 6.82 Quetiapine 4 271 957 1 4 3.68 14.70 Risperidone 9 1 298 156 6 2 4.62 1.53 Clozapine 10 641 737§ 41 61 63.89 95.05 ADRAC = Adverse Drug Reactions Advisory Committee. * Number of years with data available (as some drugs were introduced only after the start of the 10-year period). † Weight gain or obesity. ‡ Diabetes mellitus or hyperglycaemia. § Estimated number (see Box 1).

Andrew Firestone

To the Editor: The interesting case report by Currie and colleagues describes a variable cutaneous eruption of uncertain aetiology in a cluster of methadone-dependent patients.1 The rash was described as including pruritic, exanthematous, purpuric and eventually desquamative components, and typically as involving the trunk and extremities, particularly palms and soles. Secondary syphilis classically presents in a similar fashion, but no mention was made as to whether this had been excluded by serological testing. Indeed, the histology of the rash (perivascular inflammation, including plasma cell infiltrate, progressing to endarteritis) is similar to that seen in skin biopsies from methadone patients with secondary syphilis. However, an allergic or toxic cause appears to be implicated, in view of previous, well documented reports of hallucinogenic or other drug-related vasculitis published by ourselves2 and others.3-5

Vernon J Heazlewood

To the Editor: As a Victorian always on the lookout for something new, I read with interest the report by Currie and colleagues of a syndromic rash in patients attending methadone clinics in New South Wales.1 From the title I expected to read about a rash occurring as part of a syndrome, yet no group of concurrent symptoms was described. In fact, there was a long list with each patient of negative findings. I also had trouble deciding whether the four patients described indeed had the same rash. While the “lumpers” among us may consider it pedantic to split “rash” into more than one category, some doctors make an occupation of it quite successfully. For example, Patient 1 had petechiae and purpura, but no erythema and no involvement of the palms and soles. No photo, but nevertheless a nice description of vasculitis — common among intravenous drug users. Patient 2 had, from the look of the photo, a toxic erythema that resolved with desquamation of the palms and soles. No petechiae or purpura. Therefore, must be a different rash to Patient 1. Patient 3 is described as having “ a prominent purpuric rash involving both lower limbs”. However, the photo shows a macular erythema with some associated purpura that looks almost certainly to be an incidental manifestation of dependency. Difficult to say from a photo, as touch is so important in the diagnosis of true purpura. Of course, a 2 mm punch biopsy of the skin could resolve this almost instantly. Again, it is not clear whether this rash is similar to that seen in either Patient 1 or Patient 2. Patient 4 is described as having a red and itchy rash (erythematous and pruritic), but, from the photograph, we can clearly see that the rash is urticarial. This raises the possibility of urticaria, or urticarial vasculitis, or even erythema multiforme. Again, a skin biopsy would be very useful. The severe palmar peeling almost seems incongruous, but it does give me faith that buried in this report there might actually be a new desquamating rash associated with methadone use. In summary, I am still not clear whether the four patients described had the same rash, but I concur with the authors that several of these patients might warrant specialist assessment. Let’s hope they get it.

Rodney D Sinclair

In reply: The purpose of our report1 was to alert the wider medical community to the recent outbreak of a “syndrome” (“a group of symptoms and signs, which, when considered together, are known or presumed to characterise a disease or lesion”2) that included the development of various forms of rash in patients taking methadone syrup. Our report included four cases illustrating the different types of rash encountered to date. From October 2004, over 400 cases were reported from methadone clinics in New South Wales, although very few new cases have been reported since February 2005, presumably reflecting the success of preventive measures instituted by the NSW Health department. To date, the cause of this methadone-associated syndrome has not been elucidated. Skin biopsies of rash lesions have been performed in a number of our patients. All have shown chronic perivascular inflammation, with most demonstrating hyperkeratosis. A small number of patients have had a true leukocytoclastic vasculitis. As Heazlewood has commented, both secondary syphilis and illicit drugs such as amphetamines and cocaine have been reported to cause vasculitic rashes. However, none of the more than 50 patients in whom we have performed syphilis serological testing has had positive results, and few of our affected methadone patients have had urine drug-test results positive for amphetamine or cocaine use. We therefore believe that the syndrome we have described remains specific to the patients’ current use of methadone syrup. We are unaware of a rash that is “an incidental manifestation of dependency”, as suggested by Sinclair, but we would assure him that specialists from a wide variety of fields, including dermatology, immunology, immunopathology, infectious diseases, addiction medicine and epidemiology, have all been involved in the assessment and treatment of patients with this syndrome, and in the wider investigation of its pathogenesis.

Jon N Currie · Lisa Snell · Elizabeth M Benson

Huy A Tran Director and Associate Professor, Department of Clinical Chemistry, University of Newcastle, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New Lambton Heights, NSW 2310. huy.tranAThnehealth.nsw.gov.au To the Editor: The interesting article by Gordon et al1 warrants further discussion with regard to the hypophosphataemia, “inappropriately” high level of serum 25‑hydroxyvitamin D, biochemical diagnosis of pancreatitis and management of hypercalcaemia. Fibroblast growth factor-23 (FGF-23) is a recently described 254‑amino-acid peptide that has been shown to have significant phosphaturic effect. It probably plays a major role in phosphate metabolism and homeostasis by rising after an oral phosphate load and falling after dietary phosphate restriction. In the patient discussed by Gordon et al, elevated FGF-23 level may, hypothetically, have been a major contributing factor to the low serum phosphate level. Although the understanding of this factor is still in its infancy, measuring the serum level of FGF-23 in the patient might have shed more light on the role of FGF-23 in phosphate homeostasis. However, FGF-23 levels do not correlate directly with serum phosphate levels, suggesting that FGF-23 exercises control via renal tubular cells, regulation of calcitriol levels or intestinal phosphate absorption. FGF-23 levels are also markedly elevated in chronic renal failure, partly in response to the chronic hyperphosphataemia and partly because of reduced renal clearance.2 Its action is independent of the traditional and better understood regulators of phosphate level, including parathyroid hormone and parathyroid hormone-related protein. The triad of high vitamin D level, hypercalcaemia and hypophosphataemia points strongly to a diagnosis of vitamin D intoxication, despite a patient history to the contrary. An alternative explanation is an inaccurate vitamin D assay from the supporting laboratory. This issue, which has been highlighted recently, has therapeutic relevance in monitoring vitamin D replacement therapy.3 In supporting the diagnosis of pancreatitis, serum lipase level remains the best biochemical test and is more specific than amylase level.4 The practice of dual amylase and lipase ordering in the investigation of such conditions is excessive, confusing and costly to the community and should be discouraged. The indication for bisphosphonate treatment in milk-alkali syndrome remains unclear and contradicts the underlying pathogenesis, which is believed to be that of excessive calcium ingestion. In the patient in question, excessive calcium ingestion overwhelmed the calcium homeostatic mechanism, resulting in severe hypercalcaemia. In such a milieu, osteoclasts would be heavily suppressed and inhibited, and thus the use of a bisphosphonate, whose major action is also by osteoclastic suppression, would be of little value other than in precipitating hypocalcaemia.5 Thus, expectant management as outlined by the authors would be sufficient to achieve normocalcaemia. As bisphosphonates are not without adverse effects,6 they should only be used after a clear diagnosis of hypercalcaemia has been made.

Huy A Tran

Adam P Morton Physician, Mater Hospital, Raymond Terrace, Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: I read with interest the Lessons from Practice article on milk-alkali syndrome during pregnancy.1 I would like to offer the following comments. The patient’s alkalosis was in fact more impressive than presented, as the authors used the reference range for serum bicarbonate in non-pregnant patients. During pregnancy, serum bicarbonate levels typically fall by about 4 mmol/L to compensate for the respiratory alkalosis caused by elevated progesterone levels stimulating respiratory drive. Given the patient’s life-threatening calcium level on presentation, I am interested to know whether calcitonin treatment or even dialysis was considered while waiting for the pamidronate to take effect. An important aspect that the authors did not discuss in relation to this case is the reassuring data on the safety of both proton-pump inhibitors and H2-receptor antagonists in pregnancy. While there is more experience with the latter, two recent studies found no evidence of teratogenicity in almost 900 cases of exposure to proton-pump inhibitors in the first trimester.2,3 Clinicians should feel comfortable about prescribing these medications in pregnancy. After reporting a similar case,4 I wrote to Walco, the manufacturers of Quick-Eze, who subsequently changed their product labelling to include a warning about the number of tablets that could be safely taken each day. Disappointingly, they did not include a warning about ingestion during pregnancy, as I suggested.

Adam P Morton

Michelle V Gordon,* P Shane Hamblin,† Lawrence P McMahon‡ * Registrar, † Head, Department of Endocrinology, Western Hospital, Private Bag, Gordon Street, Footscray, VIC 3011; ‡ Head, Department of Obstetric Medicine, Sunshine Hospital, St Albans, VIC. hamblin1ATbigpond.net.au In reply: Our case appears to be consistent with typical milk-alkali syndrome. While measuring fibroblast growth factor-23 (FGF-23) level might have been of hypothetical interest, it is unlikely that it would have influenced management. Vitamin D intoxication was considered once the 25-hydroxyvitamin D results became available, and we closely questioned our patient in relation to this possibility. She was insistent that she had not taken any vitamin D supplements. It is possible either that the patient did not wish to admit to taking vitamin D or that the assay was misleading, as suggested by Tran. We agree that bisphosphonate therapy should not be advocated when the diagnosis of milk-alkali syndrome is clear. In this case, however, the patient was drowsy and very ill; the full history relating to antacid ingestion was not obtained until after the bisphosphonate therapy had been given. With regard to Morton’s comments, the hypercalcaemia settled promptly, so fortunately calcitonin treatment and other measures did not need to be considered. Drug safety in pregnancy is a difficult issue, as the effects of fetal or neonatal damage may carry lifelong implications, and even relatively rare associations need to be considered with care. In addition, many pregnant women are uncomfortable about taking prescription medications during pregnancy, even though their doctors may have a more relaxed view. Currently, over-the-counter antacids are classed as category A drugs for pregnancy, whereas H2-receptor antagonists and proton-pump inhibitors are category B1 and B3, respectively. Cimetidine has been associated rarely with neonatal hepatic abnormalities,1 and it is still too early to state with confidence that proton-pump inhibitors are “safe”, despite promising initial analyses. Ironically, the potential dangers of over-the-counter calcium-containing antacids, as demonstrated in this case report and others, are not currently adequately acknowledged. We have written to the manufacturers of Rennie tablets requesting a package label warning advising consumers not to exceed six tablets a day.

Michelle V Gordon · P Shane Hamblin · Lawrence P McMahon

Tulsi Menon Resident Medical Officer, Department of Orthopaedic Surgery, Royal Perth Hospital, 19 Morgan Road, Redcliffe, WA 6104 kaltulAToptusnet.com.au To the Editor: I report an infection with Dracunculus medinensis diagnosed incidentally on x-ray. The patient was a Sudanese immigrant, who had sustained a left knee joint effusion after falling. During management at Royal Perth Hospital, a calcified lesion with a serpentine appearance was seen on x-ray within soft tissues near the left knee joint. Its characteristic appearance, combined with the patient’s background, led to a diagnosis of D. medinensis (known as guinea-worm), a nematode parasite which causes dracunculiasis. The patient’s knee effusion was managed conservatively and improved within a few weeks. The effusion was secondary to the fall and believed to be unrelated to the calcified D. medinensis. Transmission of dracunculiasis is through consumption of contaminated water. The guinea-worm larvae mature and migrate towards the skin surface over 1 year (during which the patient remains asymptomatic), with over 90% of the worms appearing from the lower limbs. When in contact with water, the exposed guinea-worm releases larvae, and the lifecycle is completed when people ingest contaminated water.1 If the guinea-worms die before maturation, they usually calcify. The Global Dracunculiasis Eradication Campaign was established in 1981 with the aim of eliminating dracunculiasis through water sanitation efforts.1 With no vaccine or treatment, prevention is the only method of eliminating dracunculiasis. Since the campaign was established, the number of people affected by dracunculiasis has decreased by 98%. Currently, Sudan alone accounts for 73% of cases.1 Our patient migrated to Australia as a refugee from Sudan during the civil war. Her village in Sudan had only one source of water used for daily activities, including drinking. The patient knew many people with dracunculiasis, but did not know she had been infected. When calcified guinea-worms are discovered during routine radiological examination, they usually do not need treatment. Many people are not aware they have been infected. Muller reported 89% of patients with calcified guinea-worms were asymptomatic.2 No known previous case of a radiologically diagnosed calcified guinea-worm has been reported in Australia. The consequences of war and famine, with a resultant increase in refugees and immigrants from affected nations, is likely to increase the number of incidental calcified guinea-worms found in non-endemic countries. This disease may have a significant impact if affected immigrants arrive during the incubation period (when asymptomatic) and the parasite emerges from the skin after immigration (rather than calcifying), similar to the patient described by Spring.3 Thus, it is important for health personnel to be aware of dracunculiasis, including its radiological manifestations. Lateral view of left knee joint and distal left thigh A calcified lesion, representing Dracunculus medinensis within the soft tissues, is visible posterior and lateral to the distal femur near the knee joint. The calcification has a serpentine appearance: the proximal part coiled in appearance, the middle having a string-like linear appearance, and the distal part having dense curvilinear opacity.

Tulsi Menon

Simon J Vanlint Lecturer, Department of General Practice, University of Adelaide, SA 5005. simon.vanlintATadelaide.edu.au To the Editor: The Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia are to be commended for their clear and succinct position statement on vitamin D and bone health.1 This statement highlights an important public health issue which is under-recognised in this country. Of particular value is the box of recommendations on high-risk groups, testing and treatment. However, I believe an important high-risk group has been omitted, a group which too often escapes the notice of the broader medical community. People with intellectual disability have been shown to be at particularly high risk of low vitamin D levels, reduced bone density and fractures.2-5 The reasons for this are multifactorial and include poor mobility, insufficient sun exposure, reduced muscle mass and strength, problems with dietary intake, and medications which interfere with vitamin D metabolism.3,4 There is also some evidence that people with intellectual disability are prone to premature ageing, together with the health problems associated with older age in the general population.3 Some conditions which cause or are associated with intellectual disability are also linked with hypogonadism and reduced peak bone mass.4 To add to all of this, several of the above risk factors, vitamin D deficiency itself, and the increased incidence of epilepsy in the population with intellectual disability, also result in an increased incidence of falls and trauma.5 This unfortunate combination of poor bone health and increased risk of falls and trauma results in a markedly increased incidence of fracture when compared with age- and sex-matched controls from the general population.2-5 In conclusion, people with intellectual disability, particularly those with poor mobility or who are also being treated for epilepsy, should be added to the list of high risk groups. It is likely that the relatively simple steps set out in the position statement (screening for vitamin D deficiency and supplementation) will result in substantial health benefits for this small but particularly vulnerable group of people.

Simon J Vanlint

Alvin L K Chia,* Stephen Shumack,† Peter Foley‡ * Research Fellow, † Dermatologist, St George Dermatology and Skin Cancer Centre, Level 3, 22 Belgrave St, Kogarah, NSW 2217; ‡ Dermatologist, St Vincent’s Hospital, Melbourne, VIC. sshumackATbigpond.com To the Editor: We read with alarm the extraordinary statements in the position statement on vitamin D and adult bone health published recently in the Journal.1 The suggestion that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight” is not true. The suggested basis for this statement is an extraordinary extrapolation from a single study in which a small number of volunteers had whole body exposure on one occasion for 10–15 minutes to midday summer sun in Boston. It is not possible to extrapolate in such a way from this single demonstration, as the effect of shorter exposure times or repeated daily exposures were not examined. In fact, a study in Australia showed that the adult population (including those aged over 70 years) received sufficient sunlight while using sunscreen to ensure that no-one was found to have vitamin D deficiency during the study period.2 While it is well accepted that ultraviolet B (UVB) radiation is essential for the formation of vitamin D3 in the skin, it is equally well established that continued exposure of vitamin D to UVB radiation results in its degradation. Hence, the importance of knowing the effect of lower sun exposures on vitamin D production. It is intriguing that the authors of the position statement recommended a daily sun exposure dose that they calculate will produce 1000 IU of vitamin D, but, if sun exposure is not possible, a vitamin D supplement of at least 400 IU per day. The high prevalence of vitamin D deficiency among institutionalised older Australians is a tragedy, but this cannot be used as the basis of advice for the general population who do receive daily sun exposure and appear to be the target of the statement. Nor can the mild vitamin D deficiency found in a single study in southern Victoria be used to recommend sun exposure in more northern Australian climes. Finally, while vitamin D supplementation has been shown to reduce the risk of fractures in the elderly, the proposed beneficial effect of deliberate sun exposure has not been demonstrated. Recently, a joint position statement was approved by the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, the Australasian College of Dermatologists and the Cancer Council Australia. This included the statement that “The majority of Australians generally have sufficient ultraviolet radiation exposure to enable adequate vitamin D production . . . to form and maintain healthy, strong bones”.3 This statement, endorsed only a few weeks ago, is in obvious conflict with the position statement from the same organisations that was published in this Journal. The latter puts the vast majority of Australians at further risk of skin cancers, which are already epidemic in our country.4

Alvin L K Chia · Stephen Shumack · Peter Foley

Terrence H Diamond,* John A Eisman,† Rebecca S Mason,‡ Caryl A Nowson,§ Julie A Pasco,¶ Philip N Sambrook,** John D Wark†† * Associate Professor, Endocrinology, University of NSW, Sydney, NSW; † Professor and Director, Bone and Mineral Research Program, Garvan Institute of Medical Research, Sydney, NSW; ‡ Associate Professor of Physiology, ** Professor of Rheumatology, University of Sydney, NSW; § Associate Professor, School of Health Sciences, Deakin University, Melbourne, VIC; ¶ Senior Research Fellow, Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, PO Box 281, Geelong, VIC 3220; †† Professor of Medicine, The University of Melbourne, VIC. juliepATbarwonhealth.org.au In reply: We agree with Vanlint that any individual who has limited mobility, or is housebound or institutionalised, is at risk of vitamin D deficiency, as highlighted in Box 3 of the position statement.1 Disability in general is likely to be a risk, with motor disability as well as intellectual disability liable to limit sun exposure. The problem may be further exaggerated by any increased risk of falls or convulsions. Chia and colleagues have raised important issues. After a number of meetings, the Cancer Council of Australia, the Australasian College of Dermatologists and the Australian and New Zealand Bone and Mineral Society developed a considered consensus statement on vitamin D deficiency, risk of skin cancers and sunlight exposure, which was published at <http://www.cancer.org.au/documents/Risks_Benefits_Sun_Exposure_MAR05.pdf>. This document refers to the position statement published in this Journal in relation to sun-exposure guidelines for vitamin D. Chia and colleagues’ objection to the abstract of this position statement appears ill-founded. If “a significant number of Australians are deficient in vitamin D”, then it follows logically that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight”, as sunlight is the main source of vitamin D in Australia. The significant number of Australians deficient in vitamin D are not the majority, as was clearly shown in the article, so this statement does not conflict with the complementary statement in the risks and benefits statement. We stand by our original claim that a number of groups in the Australian community have a high prevalence of vitamin D deficiency, including elderly men with hip fracture (63%), Muslim women (68%), elderly ambulant men with prostate cancer (34%), “healthy” elderly men living in Southern Sydney (16%), healthy community-dwelling, ambulatory women in Geelong (20% in the age group 20–39 years, increasing to 53% in older age groups), men and women (some with psychiatric disorders) in south-east Queensland (23%), and even pregnant women in south-eastern Australia (7%) (references are available from the authors on request). As noted in the position statement, and by Chia and colleagues, continued exposure to ultraviolet (UV) radiation may lead to degradation of pre-vitamin D, so that short exposures are likely to be more efficient. This degradation is marked only at relatively high UV doses.2 Studies that used lower UV doses2,3 produced indirect UV equivalence data similar to those quoted in the position statement.1 As the relationship between UV exposure and vitamin D dosage varies from person to person, and as sun exposure is also likely to be variable and on most days, rather than every day, the recommendation that vitamin D supplementation be at least 400 IU/day in people likely to be at risk of inadequate skin-derived vitamin D is entirely appropriate. We strongly agree with Chia and colleagues about the need to avoid sun damage while still obtaining the small amount of sun exposure needed to make adequate vitamin D, which is why the position statement advocates short exposures, easily achieved by casual exposure, and reiterates other Sun-Safe messages, such as avoidance of exposure in peak UV periods and the use of sunscreens where appropriate.

Terrence H Diamond · John A Eisman · Rebecca S Mason · Caryl A Nowson · Julie A Pasco · Philip N Sambrook · John D Wark

Elizabeth A Hender,* Corrine R Balit† * Scientific Officer, Hazardous Substances Section, Environmental Health Service, Department of Health, PO Box 6 Rundle Mall, Adelaide, SA 5000; † Research Pharmacist, New South Wales Poisons Information Centre, The Children’s Hospital, Westmead, NSW. elizabeth.henderAThealth.sa.gov.au To the Editor: Although there are few deaths due to poisoning in Australian children, from 1993 to 1997 there was an average of more than 2500 admissions to hospital per year for assessment of poisoning with medicines in children younger than 5 years.1 Child-resistant packaging has been effective in preventing accidental poisoning with prescription medicines and aspirin in young children in the United States.2,3 In the US, both reclosable and non-reclosable (blister or strip) packaging used for pharmaceuticals required to be in child-resistant packaging is tested to confirm its effectiveness in preventing access by children.4 In Australia, only reclosable packaging is required to be child-tested. Blister or strip packaging, which has not usually been child-tested, is accepted as an alternative to child-resistant reclosable packaging.5 We conducted a study at the New South Wales Poisons Information Centre (NSWPIC) over 9 weeks from 18 July to 17 September 2003. Our aims were to ascertain which medicines children younger than 5 years access directly from blister or strip packaging, and whether assessment at a hospital was recommended. The study was approved by the Ethics Committee of the Children’s Hospital, Westmead. Callers ringing about a suspected accidental ingestion of a solid dose medicine in a child younger than 5 years were asked whether the child accessed the medicine directly from a blister or strip pack. There were 318 accidental exposures to solid dose medicines in these children during the study period. In 186 exposures (58%), the caller said the medicine was normally in a blister or strip pack and the child obtained it directly from the pack. A wide range of medicines (40 different drugs or drug groups) were associated with the exposures; the most common were oral contraceptives (49 exposures) and paracetamol (27 exposures). Some of the exposures involved medicines that can cause severe toxicity when children ingest a small number of dose units, such as clonidine, olanzapine, narcotic analgesics, and tricyclic antidepressants. In 36 exposures where the child obtained the medicine directly from the pack, the caller was advised to take the child to hospital (Box). Many of the medicines associated with these exposures (eg, paracetamol, preparations containing narcotic analgesics, antidepressants, antihistamines, iron and clonidine) are required to be in child-resistant packaging.5 Our study shows that blister or strip packs currently in use did not prevent children accessing drugs. This finding calls into question whether blister or strip packaging that has not been child-tested presents an adequate safety barrier. No outcomes of drug ingestion are known in this study, which is a limitation. However, assessment of these children in hospital represents a financial burden to the health care system regardless of the outcome. Further studies would be required to quantify the harm associated with exposures to medications packaged in blister or strip packaging in young children and to assess the effectiveness of such packaging in the prevention of poisoning. Drugs accessed from blister or strip packs where child required referral to hospital Drug or drug group Number of exposures Paracetamol 8 Paracetamol/narcotic combination analgesics 3 Selective serotonin re-uptake inhibitors 3 Antidepressant: other/unknown 2 Antiemetics 2 Antihistamines 2 Cough/cold preparations, no paracetamol 2 Iron 2 Other (eg, clonidine, olanzapine) 12 Total 36

Elizabeth A Hender · Corrine R Balit

Timothy C Crowe,* David Cameron-Smith† * Lecturer, † Senior Lecturer, School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125. tcroweATdeakin.edu.au To the Editor: Low-carbohydrate diets have re-emerged into the public spotlight and are enjoying widespread popularity. However, current evidence indicates that low-carbohydrate diets have no significant advantage over more traditional energy-restricted diets for long-term weight loss and maintenance.1-3 While these diets have shown short-term efficacy in modifying some lipid parameters and measures of insulin sensitivity, questions remain about the risk of adverse effects with long-term carbohydrate restriction.4 The scientific literature has not addressed the questions of how the general public perceive these diets, and what dieting approaches they adopt. Dieting perceptions and practices within the community may be far removed from the strictly controlled situation of published research. A national telephone survey of 1200 adults aged 18 years and over was conducted by the private market research company Newspoll from 6 to 8 August 2004. The survey asked about knowledge of and attitudes to carbohydrates and dieting. Telephone numbers were randomly selected, with a quota for capital city and non-capital city areas. Selection of an individual in each household was based on the last birthday. Response rate to the survey was 11%. Sex, age, marital status and working status demographics were representative of the Australian adult population. The main findings are summarised in the Box. Most of those surveyed correctly identified foods such as pasta and bread as “carbohydrate foods”. Only a third of people identified soft drinks and lollies as carbohydrate foods, and 20% incorrectly identified cheese and eggs as carbohydrate foods. Almost 17% of people had either tried, or intended to try, a low-carbohydrate diet, with women more likely to have tried this diet. Half of those surveyed believed that carbohydrate foods should make up a quarter or less of the daily diet (current health recommendations are that about half the diet should comprise carbohydrates). Almost 70% of those surveyed believed they needed to cut back on carbohydrates to lose weight. Based on this survey, low-carbohydrate dieting practices are as widespread in Australia as in the United States.5 Interestingly, the US study noted a greater propensity to use carbohydrate-reduced diets among those who were obese, had diabetes, hypertension or high cholesterol. Our data demonstrated widespread misunderstanding of what constitutes a high-carbohydrate food, which may leave many individuals at risk of choosing a diet that selectively excludes wholegrain foods, fruits and some dairy products. Health professionals should be aware that low-carbohydrate diets remain popular, that the people who are following these diets may represent a more “at risk” population, and that the food choices made by those following this dietary pattern may have adverse long-term health effects. Respondents’ knowledge of and attitudes to carbohydrate foods and low-carbohydrate dieting Question Total (n = 1200) Men (n = 600) Women (n = 600) Which of the following foods, if any, do you regard as carbohydrate foods? Bread 89% 85% 93% Pasta 90% 88% 93% Rice 80% 76% 83% Breakfast cereal 79% 77% 80% Lollies 35% 36% 35% Soft drink 34% 31% 36% Cheese 20% 22% 19% Eggs 18% 20% 16% Have you tried or do you intend to try the Atkins diet, or some other low-carbohydrate diet? 17% 11% 22% Based on official recommended guidelines for a healthy diet, about how much of a person’s diet should be made up of foods such as bread, breakfast cereal, pasta and rice? Less than a quarter 7% 7% 7% About a quarter 43% 34% 51% About half 29% 31% 26% About three quarters 6% 8% 4%

Timothy C Crowe · David Cameron-Smith

Ian W Boyd Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australian Government Department of Health and Ageing, PO Box 100, Woden, ACT 2606. ian.boydAThealth.gov.au To the Editor: Labate and colleagues note that tramadol is the most frequently suspected cause of provoked seizures at their First Seizure Clinic.1 Early in 2003, the Adverse Drug Reactions Advisory Committee (ADRAC) reported to Australian prescribers the results of the first 4 years of experience with tramadol in Australia.2 At the time, ADRAC noted that 26 cases of convulsions had been reported among a total of 354 reports on tramadol. By January 2005, ADRAC had received a total of 921 reports involving tramadol, of which 66 described convulsions. (Labate et al reported that 83 cases of convulsions associated with tramadol had been reported to ADRAC. This is incorrect, but the mistake probably resulted from an error in interpretation of information supplied by the Adverse Drug Reactions Unit.) In 27 cases, tramadol was the only suspected drug, but in the other 39 cases there were various other suspected drugs. This included 20 reports in which there was a suspected drug interaction. Both oral and injected tramadol have been implicated. The product information for tramadol states that convulsions have been reported in patients using tramadol at the recommended dose levels and that the risk may be greater when doses of tramadol exceed the recommended limits.3 In addition, tramadol may increase the seizure risk in patients taking other medications that lower the seizure threshold. Drugs specifically mentioned in this context include the selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs. In the 39 cases reported to ADRAC in which there were one or more suspected drugs in addition to tramadol, tramadol was being used with selective serotonin reuptake inhibitors (10 cases), tricyclic antidepressants (6 cases) and, in 13 cases, other drugs that may also have the potential to lower the seizure threshold, such as pethidine (2 cases), venlafaxine (2), propofol (2) and bupropion (2). In two of the cases in which tramadol was the only suspected cause and two of the cases with multiple suspected causes, the patients were also taking anticonvulsant drugs for seizure control. ADRAC data indicate that, although tramadol alone can induce seizures, these are more likely to occur in the setting of the concomitant use of other drugs that also have the potential to lower the seizure threshold.

Ian W Boyd

Graham R Wicks Medical Hypnotherapist, Department of Psychological Medicine, Women’s and Children’s Hospital, North Adelaide; 9 Collins Street, Collinswood, SA 5081. grwicksATbigpond.net.au To the Editor: I was interested to read the article about managing nocturnal enuresis in children,1 but was surprised and disappointed that there was no mention of the place of medical hypnotherapy. Hypnotherapy can be particularly valuable in the treatment of monosymptomatic nocturnal enuresis in children aged from 7 or 8 years upwards, and has the advantage of being completely non-invasive with no side effects. It focuses on empowering the children to take control of their own bodily functions.2 Hypnotherapy is also of value in the management of nocturnal enuresis associated with day-time symptoms, such as urgency with or without incontinence, and can also be used to enhance the efficacy of treatments like enuresis alarm systems. While there are few well documented comparative studies3 on the benefits of hypnosis versus other treatments for nocturnal enuresis, there are numerous anecdotal reports and studies involving a series of patients being successfully treated with hypnotherapy. Hypnosis should only be used by properly trained doctors or psychologists who have access to the full range of medical investigations. Hypnosis is of course not a panacea, but is an excellent first-choice treatment for monosymptomatic nocturnal enuresis, the commonest type seen by general practitioners. If, after three or four treatment sessions, hypnosis is not effective, other approaches can be employed. A quick search of the internet using the terms “enuresis and hypnotherapy” will reveal over 700 sites with information on the subject, and there are several highly respected professional journals that publish clinical and research papers and articles on the use of hypnosis in medicine and psychology. All of these are published by reputable professional societies whose membership is limited to registered health professionals. The Australian Society of Hypnosis (http:// www.ozhypnosis.com.au) conducts ongoing training courses in all states of Australia for graduates in medicine, psychology and dentistry. Hypnotherapy is now becoming more and more accepted worldwide as a valuable and legitimate tool that can be used, in conjunction with the more traditional approaches, in a wide variety of medical and psychological problems. It is a great pity that many clinicians are either not aware of its value or are still loathe to accept it because of negative connotations associated with its use for entertainment purposes and in the hands of non-professional therapists.

Graham R Wicks

Patrina H Y Caldwell,* Denise Edgar,† Elisabeth Hodson,‡ Jonathan C Craig§ * Staff Specialist and Lecturer, † Head, Department of Nephrology, § Associate Professor and Head of Clinical Research, NHMRC Centre of Clinical Research Excellence in Renal Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145; ‡ Clinical Nurse Consultant, The Continence Foundation of Australia in NSW, Sydney, NSW. PatrinacATchw.edu.au In reply: Thank you for your interesting comments regarding hypnotherapy in the treatment of nocturnal enuresis in children. There are a number of therapies, such as hypnotherapy, electrotherapy and acupuncture, which show great promise for the management of nocturnal enuresis. We only included in our article1 treatments that were supported by evidence from well documented comparative studies. Using comprehensive search strategies, we have not found comparative studies for these complementary therapies. We would be very interested to be directed to studies that have formally evaluated other interventions. There is a huge need for randomised controlled trials comparing alternative treatment strategies with conventional therapy in this area.

Patrina H Y Caldwell · Denise Edgar · Elisabeth Hodson · Jonathan C Craig

Edwin P Kirk,* Annette Hattam,† Anne Turner‡ * Co-ordinator of Advanced Training, † Chair, Specialist Advisory Committee in Clinical Genetics, Royal Australasian College of Physicians; and Geneticists, Department of Medical Genetics, Sydney Children’s Hospital, High Street, Randwick, NSW 2031; ‡ Chairperson, Board of Censors in Genetic Counselling, Human Genetics Society of Australasia. kirkedATsesahs.nsw.gov.au To the Editor: Genetic risk estimation is a key element of the practice of clinical geneticists and genetic counsellors. Given this, it was with some concern that we read the findings of Bonke and colleagues regarding the performance of (mainly European) geneticists and counsellors in the application of Bayesian analysis to risk estimation.1 Bayesian analysis is taught as part of Australasian training in both clinical genetics and genetic counselling, and has been for as long as there have been formal programs. Thus, most Australian geneticists and counsellors should be familiar with the application of Bayes’ theorem to risk estimation. In actual clinical practice, it is rare to need to perform this type of analysis. This is partly because of the rapid progress in molecular genetic testing, which often obviates the need for such calculations, and partly because situations in which Bayesian analysis is clinically helpful are uncommon. Pedigrees like those in the study by Bonke et al do not come along often; when they do, the modification of prior risk by Bayesian analysis is not often important. For example, modification of a risk from 50% to 33% or from 25% to 17% (as in two of the examples used by Bonke et al) is unlikely to alter decision-making for the families involved. Specifically, as these examples all involve testing for Huntington’s disease, in which molecular analysis is usually quite straightforward, we would expect very few individuals would decide whether to proceed with testing based on being given information about modification of risk expressed this way. Moreover, when you are not performing this type of calculation regularly, it is time-consuming to do. It seems possible that many of those who completed the questionnaire would have taken greater care, and achieved greater accuracy, if faced by a real clinical situation. Nonetheless, for those of us who are involved in training clinical geneticists and genetic counsellors, the article is a useful reminder of the importance of this skill, and we will communicate with supervisors to reinforce the importance of teaching Bayesian analysis to our trainees.

Edwin P Kirk · Annette Hattam · Anne Turner

In reply: Geneticists and counsellors must be able to calculate risks according to professional standards, regardless of whether modified risks lead to decision changes. Does training in genetic risk calculation help? Only 21% of our respondents who had had such training recently (< 3 years ago) estimated all target risks correctly. In response to Kirk et al, calculating conditional risks need not be time-consuming in scenarios similar to our target pedigrees,1 and is often helpful when at-risk (grand)parents do not wish to be tested but their offspring do. Given n children at 25% prior risk tested negative and no other (grand)children tested, the conditional risk for at-risk individuals in generation g (with g = 0 at 50% prior risk, g = 1 at 25% prior risk, etc) is 1/[2g(2n+1)]. Thus, in target #4 (n = 1), the father’s risk (g = 0) equals 1/[20(21+1)] = 0.33. In target #9 (n = 2), the unborn’s risk (g = 2) equals 1/[22(22+1)] = 0.05. Similar formulas for more complicated scenarios are available upon request. In calculating risks, however, care must be taken that the pedigrees and target individuals are comparable to our scenarios. In target #7, for instance, the risk for the untested aunt does not increase simply because of the decreased risk for her brother (gambler’s fallacy).2

Benno Bonke · Aad Tibben · Dick Lindhout · Angus J Clarke · Theo Stijnen

Scott Kinlay Director, Vascular Medicine and Endovascular Therapy, Veterans Affairs Medical Center and Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. skinlayATpartners.org To the Editor: Wang and Hoy1 deserve much credit for highlighting yet again the poor state of health of Indigenous Australians. However, their conclusion that the Framingham equation underestimated risk and that better prediction equations are needed may miss the point. The Framingham equations work well in other populations if the aim is to rank groups of individuals into higher or lower risk categories. Box 4 in the article by Wang and Hoy shows that they do this pretty well across increasing age groups. Framingham equations fall down when they are used to estimate absolute risk in populations whose coronary heart disease (CHD) rates are different from those in the Framingham study. Some years ago, we showed that adjusting the Framingham risk estimates in line with the overall incidence of CHD in the population modestly improved their performance.2 This is all very nice, but is better risk estimation the solution? We don’t estimate risk in other high-risk groups (eg, patients with CHD), because all are at high risk and all need risk factor reduction. A brief look at the risk factor profile in Box 2 of Wang and Hoy’s article reveals an alarming picture of uncontrolled CHD risk factors in a relatively young population (average age, 33–36 years). Cigarette smoking, dyslipidaemia, diabetes and overweight prevail. Perhaps, rather than concentrating on quantifying the exact risk in such a high-risk population, we should look at the reasons for the high rates of risk factors. What motivates some Indigenous people to smoke more, be more overweight and have a higher incidence of dyslipidaemia and diabetes than other Australians?3,4 Do they feel disenfranchised when governments infer they are “dirty” by tying financial aid to face-washing?5 Do they have attractive employment opportunities? Do they have enough sense of control over their lives to reduce their need to indulge in cigarettes and other short-term pleasures? Are there adequate supplies of healthy foods that they like? These factors may differ, as some rural Abori-ginal communities have much lower rates of smoking, overweight and diabetes6 than others. Exploring these issues will aid preventive methods aimed at the whole community. In the meantime, I would suggest that the Framingham equation does rank members of this community — into modest, high, and very high risk (the average 45–54-year-old has a 20% risk of a CHD event over 10 years1). This may help guide the medical treatment of risk factors and the pursuit of the medical model of prevention while social changes dictated by Aboriginal communities take effect.

Scott Kinlay

In reply: We agree with Kinlay that it is important to prevent risk factors at the population level (a population strategy). However, there is also a need to properly identify high-risk individuals who require immediate medical intervention (a high-risk strategy) and to understand the full spectrum of factors that determine such risk. The primary focus of our study was to assess whether the widely used Framingham risk functions were applicable to Aboriginal people in remote communities. Our data show that the Framingham functions significantly underestimated the risk of coronary heart disease (CHD). 1 The high CHD risk in Aboriginal people cannot be fully explained by traditional risk factors. Some major risk factors such as abnormal total cholesterol level and obesity in the study population are actually not as prevalent as those in the general Australian population. 2 Evaluation of traditional risk factors and identification of novel factors in this population are useful for the development of intervention strat-egies. Novel factors such as infection, inflammation, albuminuria and low birthweight have been suggested as predictors of CHD risk in this population. 3,4 Kinlay suggests that Framingham functions should be used to predict CHD risk in Aboriginal people. We disagree. Guidelines for the management of Aboriginal people need to recognise the serious underestimation of risk that the Framingham formulas provide. We agree that some high-risk groups, such as patients with established CHD, do not need additional risk estimates. With our current knowledge, however, we can not say whether the whole Aboriginal community should be treated as a very high-risk population.

Zhiqiang Wang · Wendy E Hoy

Anna Peeters,* Reannan L Cashen,† Paul E O’Brien‡ * Senior Research Fellow, † Honours Student, Epidemiology and Preventive Medicine, ‡ Director, Centre for Obesity Research and Education, Monash University, The Alfred Hospital, Commercial Road, Melbourne VIC 3004. anna.peetersATmed.monash.edu.au To the Editor: We support the warning of Talbot and colleagues regarding the inequities of the current system for provision of bariatric surgery to the morbidly obese in Australia.1 We recently analysed data on the number of separations for bariatric surgery for morbid obesity in Australia. The two most common procedures in Australia are gastric reduction surgery (procedure code 30511, which includes gastric stapling, laparoscopic adjustable gastric banding [LAGB] and gastroplasty) and gastric bypass surgery (procedure code 30512). The number of separations for procedure 30512 has remained quite stable and relatively low (around 200 a year) over the past few years. By contrast, the number of separations for procedure 30511 has been continually increasing. While the exact number of LAGB procedures can not be identified from this single code, it is assumed that the majority of the increase is due to LAGB, as it is a less invasive pro-cedure and therefore generally more acceptable to patients.2 However, the number of separations for gastric reduction surgery in public hospitals is low and has remained so. In the financial year 2000–01 there were 1529 separations for gastric reduction for morbid obesity across Australia, only 194 (13%) of which were performed in public hospitals (see Box). In 2001–02 the total number increased to 2351, but the number performed in public hospitals increased only marginally, to 238 (10% of the overall number). In 2002–03, the last year of available data, there were 2612 separations, of which only 287 (11%) were performed in public hospitals (unpublished data, courtesy of the Australian Institute of Health and Welfare). Clearly, if this issue is not addressed systematically, it will only serve to widen the socioeconomic inequalities in health associated with obesity in Australia. Separations for all gastric reduction surgery for morbid obesity, Australia

Anna Peeters · Reannan L Cashen · Paul E O’Brien