Sequential therapy for Helicobacter pylori Sequential antibiotic therapy against Helicobacter pylori may result in a better eradication rate than standard triple-drug therapy, an Italian randomised controlled trial has shown. A total of 295 patients with proven H. pylori infection underwent endoscopy, biopsy, and bacterial culture of biopsy specimens. One group of patients received a 10-day sequential regimen of pantoprazole, amoxycillin, clarithromycin, and tinidazole. The other group was given standard 10-day therapy of pantoprazole, clarithromycin, and amoxycillin, each given twice daily. After treatment, patients underwent a second diagnostic 13C-urea breath test to detect presence of H. pylori. Sequential therapy resulted in a greater eradication rate and was significantly more effective in the treatment of clarithromycin-resistant strains. Ann Intern Med 2007; 146: 556-563 Salt and the heart Reducing dietary sodium intake can lower the risk of cardiovascular disease overall as well as leading to a significant reduction in blood pressure, according to US researchers. Two large randomised trials involving over 3000 patients were performed, and the incidence of myocardial infarction, stroke, coronary revascularisation, and cardiovascular death were recorded. The Trials of Hypertension Prevention studied adults aged 30–54 years with prehypertension, who were randomly assigned to a sodium reduction intervention group or a control group. The risk of a cardiovascular event was found to be 25% lower in the intervention group in the 10 to 15 years after the trial. The reduced risk persisted after adjustment for confounding factors such as age, race, and sex. The researchers comment that their study, despite being relatively small as a trial of clinical outcomes, has several strengths. These include objective measurement of dietary sodium intake, a heterogenous study population, and the use of a prehypertensive population at risk of negative cardiovascular outcomes. BMJ Online, 20 April 2007 Chocoholic Daily intake of cocoa can cause a significant reduction in blood pressure, according to a meta-analysis of 10 randomised controlled trials. In contrast, consumption of green or black tea is not shown to have a significant lowering effect on systolic and diastolic blood pressure. The review, which included trials performed over a 10-year period, reveals that an intake of between 46 and 100 mg of polyphenol-containing dark chocolate per day results in a pooled decrease of −4.7 mmHg in systolic blood pressure. Polyphenols, present in both cocoa and tea, act by causing arterial vasodilation. The authors of the meta-analysis comment that the reduction in blood pressure on the cocoa-including diet is similar to that achieved using β-blockers or angiotensin-converting enzyme inhibitors. The researchers hypothesise that the difference observed between cocoa and tea in blood-pressure lowering properties is due to the varying types of polyphenols present in chocolate and tea. Arch Intern Med 2007; 167: 626-634 Killing pain softly Morphine still suffers from “bad press”, despite its proven efficacy as a pain-relieving drug in the palliative care setting, according to a commentary by a UK palliative care physician. Dr Nigel Sykes, from St Christopher’s Hospice in London, gives a brief history of morphine use at the end of life and debunks some of the myths surrounding the risk of addiction and respiratory complications. Dr Sykes comments that morphine remains underused due to negative perceptions long held by both the medical community and the public, and that under-prescription of opioids remains a major barrier to effective pain management, particularly in the dying patient. Lancet 2007; 369: 1325-1326 Right brain — right weight Obesity may well prove to be all in the mind, or in the right prefrontal cortex (PFC), if new studies by US scientists continue to shed light on the complex aetiology of weight gain. Researchers from Beth Israel Medical Centre and Harvard Medical School claim that the right PFC is a critical area in the cognitive control of eating. The PFC is a centre in the brain where sensory, limbic and autonomic information converge, making it an essential area in the “top-down” control of behaviour. Using repetitive transcranial magnetic stimulation, which allows non-invasive interference with cortical activity, the neurologists were able to influence their subjects’ decision-making ability. Disrupting the activity of the right dorsolateral PFC induces a disregard for the adverse consequences of choices in the long term. Obese individuals are found to perform more poorly on tasks involving activation of such pathways, leading to the hypothesis that under-functioning of the PFC may result in an inability to project the consequences of poor food choices into the future. The role of the right PFC in mediating self-recognition and promoting physical activity over sedentarism and apathy may also support its role in the development of obesity. JAMA 2007; 297: 1819-1822

Tanya Grassi

Objective: To determine whether remoteness category of residence of Indigenous women affects the perinatal outcomes of their newborn infants.Design and participants: A population-based study of 35 240 mothers identified as Indigenous and their 35 658 babies included in the National Perinatal Data Collection in 2001–2004.Main outcome measures: Australian Standard Geographical Classification remoteness category, birthweight, Apgar score at 5 minutes, stillbirth, gestational age and a constructed measure of perinatal outcomes of babies called “healthy baby” (live birth, singleton, 37–41 completed weeks’ gestation, 2500–4499 g birthweight, and an Apgar score at 5 minutes ≥ 7).Results: The proportion of healthy babies in remote, regional and city areas was 74.9%, 77.7% and 77.6%, respectively. After adjusting for age, parity, smoking and diabetes or hypertension, babies born to mothers in remote areas were less likely to satisfy the study criteria of being a healthy baby (adjusted odds ratio [AOR], 0.87; 95% CI, 0.81–0.93) compared with those born in cities. Babies born to mothers living in remote areas had higher odds of being of low birthweight (AOR, 1.09; 95% CI, 1.01–1.19) and being born with an Apgar score < 7 at 5 minutes (AOR, 1.63; 95% CI, 1.39–1.92).Conclusions: Only three in four babies born to Indigenous mothers fell into the “healthy baby” category, and those born in more remote areas were particularly disadvantaged. These findings demonstrate the continuing need for urgent and concerted action to address the persistent perinatal inequity in the Indigenous population.

Simon Graham BIS · Lisa R Jackson Pulver PhD, MPH, GradDipAppEpi · Yueping Alex Wang MB BS; MPH · Paul M Kelly DTM · Paula J Laws BA(Hons) · Narelle Grayson BA(Hons) · Elizabeth A Sullivan MB BS, MPH, MMed(Sexual Health)

Objective: To determine the incidence of type 2 diabetes mellitus (T2DM) in 2001–2006 in young people < 19 years and the characteristics of T2DM in the Indigenous group.Design and setting: Prospective population-based incidence study, New South Wales.Participants: Primary ascertainment was from the Australasian Paediatric Endocrine Group NSW Diabetes Register, with secondary ascertainment from the National Diabetes Register (Australian Institute of Health and Welfare).Main outcome measures: Incidence of T2DM in young people in NSW; incidence of T1DM and T2DM in Indigenous young people; characteristics at diagnosis.Results: There were 128 incident cases of T2DM (62 boys, 66 girls) in the study period. The median age at diagnosis was 14.5 years (interquartile range, 13.0–16.4), and 90% were overweight or obese (body mass index > 85th percentile for age). Mean annual incidence was 2.5/100 000 person-years (95% CI, 2.1–3.0) in 10–18-year-olds. Of the ethnic groups represented, white Australian comprised 29%, Indigenous 22%, Asian 22%, North African/Middle Eastern 12% and Māori/Polynesian/Melanesian 10%. The incidence of T2DM was significantly higher in the Indigenous than the non-Indigenous group (incidence rate ratio, 6.1; 95% CI, 3.9–9.7; P < 0.001), but incidence rates of T1DM were similar (15.5 v 21.4/100 000, respectively).Conclusions: T2DM accounts for 11% of incident cases of diabetes in 10–18-year-olds, and the majority are overweight or obese. The high rate among Indigenous Australian children supports screening for T2DM in this population.

Maria E Craig PhD, FRACP, MMed · Giuseppe Femia BSc · Vitali Broyda BSc, MB BS · Margaret Lloyd RN · Neville J Howard FRACP, FRCP

Objective: To determine whether primary care management of chronic heart failure (CHF) differed between rural and urban areas in Australia.Design: A cross-sectional survey stratified by Rural, Remote and Metropolitan Areas (RRMA) classification. The primary source of data was the Cardiac Awareness Survey and Evaluation (CASE) study.Setting: Secondary analysis of data obtained from 341 Australian general practitioners and 23 845 adults aged 60 years or more in 1998.Main outcome measures: CHF determined by criteria recommended by the World Health Organization, diagnostic practices, use of pharmacotherapy, and CHF-related hospital admissions in the 12 months before the study.Results: There was a significantly higher prevalence of CHF among general practice patients in large and small rural towns (16.1%) compared with capital city and metropolitan areas (12.4%) (P < 0.001). Echocardiography was used less often for diagnosis in rural towns compared with metropolitan areas (52.0% v 67.3%, P < 0.001). Rates of specialist referral were also significantly lower in rural towns than in metropolitan areas (59.1% v 69.6%, P < 0.001), as were prescribing rates of angiotensin-converting enzyme inhibitors (51.4% v 60.1%, P < 0.001). There was no geographical variation in prescribing rates of β-blockers (12.6% [rural] v 11.8% [metropolitan], P = 0.32). Overall, few survey participants received recommended “evidence-based practice” diagnosis and management for CHF (metropolitan, 4.6%; rural, 3.9%; and remote areas, 3.7%).Conclusions: This study found a higher prevalence of CHF, and significantly lower use of recommended diagnostic methods and pharmacological treatment among patients in rural areas.

Robyn A Clark MEd, FRCNA · Kerena A Eckert MPH · Simon Stewart PhD, FCSA · Susan M Phillips DPhil · Julie J Yallop NZRN · Andrew M Tonkin MD, MRACP, FRACP · Henry Krum PhD, FRACP

Prediabetes, the presence of impaired fasting glucose/glycaemia and/or impaired glucose tolerance, affects about 16.4% of Australian adults. People with prediabetes are at increased risk of developing diabetes, and cardiovascular and other macrovascular disease. Management includes reducing cardiovascular disease risk factors, specifically lipid and blood pressure abnormalities, and smoking-cessation counselling. To help prevent progression to diabetes, people with prediabetes who are overweight or obese require intensive lifestyle intervention. Medication to help prevent diabetes may also be used, but only after a minimum of 6 months of lifestyle intervention. In people with prediabetes, there is no role for routinely testing: capillary blood glucose; glycated haemoglobin (HbA1c) levels; serum insulin or pancreatic C-peptide levels; or testing for ischaemic heart disease or the microvascular complications of diabetes. Follow-up assessment of glycaemia in prediabetes requires a formal 75 g oral glucose tolerance test, initially performed annually, with subsequent individualised testing frequency.

Stephen M Twigg MB BS, FRACP, PhD · Maarten C Kamp FRACP, MHA · Timothy M Davis FRACP · Elizabeth K Neylon DAA, CDE · Jeffrey R Flack FRACP, MMed

Objective: To assess whether a diagnosis of the metabolic syndrome (MetS) improves the prediction of cardiovascular disease or total mortality beyond that already provided by conventional risk factors.Design and setting: A longitudinal cohort study conducted in Dubbo, New South Wales.Participants: 2805 men and women aged 60 years and older living in the community, first assessed in 1988–1989 and followed for 16 years.Main outcome measures: Coronary heart disease (CHD) events, ischaemic stroke events, and total mortality.Results: MetS was present in 31% of men and 34% of women. Crude CHD, ischaemic stroke, and total mortality rates were higher in the presence of MetS in men and women. In proportional hazards models that included conventional risk factors, but excluded variables used to define the presence of MetS, MetS was a significant predictor of CHD, stroke and total mortality. In men, the respective hazard ratios were 1.64 (95% CI, 1.37–1.96), 1.31 (95% CI, 0.97–1.77), and 1.53 (95% CI, 1.30–1.79). In women, the respective hazard ratios were 1.70 (95% CI, 1.43–2.02), 1.37 (95% CI, 1.04–1.82), and 1.35 (95% CI, 1.15–1.59). The use of MetS variables on an ordinal scale produced broadly similar conclusions.Conclusions: A diagnosis of MetS provides additional prediction of CHD events, stroke events, and total mortality beyond that provided by other conventional risk factors.

Leon A Simons MD, FRACP · Judith Simons MACS · Yechiel Friedlander PhD · John McCallum DPhil

Clinical record A 44-year-old man underwent coronary artery bypass surgery in 2004. He had been in satisfactory health as an adult apart from hypertension, for which he was receiving treatment. He ate a normal diet, including dairy products, meat and other high protein food. At age 44 years, he developed acute central chest pain while exercising at a gymnasium. An angiogram showed coronary artery occlusions. Forty-eight hours after successful coronary artery bypass surgery, during which time he received intravenous sodium but not glucose, he felt unwell, and the following day he became delirious. Computed tomography of the brain, initially reported as appearing normal, was later thought to show cerebral oedema. Plasma ammonium level was 110 μmol/L (reference range [RR], 10–50 μmol/L), but the timing of this sample was unclear. Wilson’s disease was initially considered because of elevated liver enzyme levels, but serum copper and ceruloplasmin levels were not measured. Eight days after the bypass surgery, a urine sample was sent to the NSW Biochemical Genetics Service, for metabolic screening. This showed gross elevations in glutamine and orotic acid (orotic acid, 14.8 μmol/mmol creatinine; RR, 1.23 μmol/mmol creatinine), indicating a likely diagnosis of ornithine transcarbamylase (OTC) deficiency. Plasma glutamine level was 3527 μmol/L (RR, 385–862 μmol/L). Plasma tyrosine and methionine levels were also moderately elevated, which was consistent with liver dysfunction. Plasma citrulline level was mildly elevated at 57 μmol/L (RR, 10–45 μmol/L), but this finding was difficult to interpret in the light of the other elevated amino acid levels. (Citrulline level is very low in neonatal OTC deficiency, but not necessarily low in late-onset phenotypes.) The patient was by then gravely ill, requiring maximum life support, and under consideration for liver transplantation. His condition progressively deteriorated despite introduction of intravenous sodium benzoate and l-arginine, and life support was withdrawn. He died 8 days after surgery. The diagnosis of OTC deficiency was subsequently confirmed by mutation analysis which showed hemizygosity for the c.622G>A (p. A208T) mutation in exon 6 of the OTC gene (as males have only one X chromosome, they are said to be hemizygous with respect to X-linked genes). Cascade testing of family members (Figure) showed that the patient’s mother (person II-2) was a carrier, heterozygous for the c.622G>A (p. A208T) mutation, while his asymptomatic brother (III-2) was hemizygous for the same mutation. Random biochemical testing of the brother showed normal levels of plasma glutamine, citrulline, arginine and urinary orotic acid. No information was available on causes of death of first-generation relatives. Past history revealed that, at age 7 years, the patient had an episode of acute encephalopathy following a 2-month history of intermittent nausea, vomiting and frontal headache. There was no preceding febrile illness, intercurrent infection or history of trauma. The symptoms reappeared after a 2-week period of apparent recovery. On admission to hospital, he was drowsy, disorientated and restless, but quickly settled and made a satisfactory recovery. No haematological or biochemical results were evident in his medical records. He was discharged with a diagnosis of viral meningitis/encephalitis. We report a 44-year-old man who presented with fatal hyperammonaemia after coronary artery bypass surgery. He had previously been asymptomatic, apart from a possible episode of unrecognised hyperammonaemia in childhood. The diagnosis of ornithine transcarbamylase (OTC) deficiency was made too late for successful intervention. Inborn errors of metabolism are frequently unrecognised or diagnosed late in adults. OTC deficiency is the most common disorder affecting the urea cycle. In New South Wales, the incidence is of the order of one in 70 000 births.1 It is an X-linked disorder leading to potentially lethal hyperammonaemia. The clinical severity ranges from acute neonatal hyperammonaemic coma to symptom onset at any time from infancy to adulthood, depending on environmental triggers and residual enzyme activity.2 The timing of episodes in late-onset OTC is dictated by environmental factors that increase nitrogen turnover, including dramatic increase in protein intake, medications affecting protein catabolism, viral illness or other generalised stress, rapid weight loss, and poor nutritional intake.3 Lessons from practice Inborn errors of metabolism are frequently unrecognised or diagnosed late in adults. Postoperative catabolism with insufficient calorie intake may unmask previously asymptomatic, but potentially lethal, inborn metabolic errors. Patients with acute onset of unexplained neurological or psychiatric symptoms need urgent metabolic investigation, including measurement of plasma ammonia level, to exclude metabolic causes. The first step in ureagenesis is the production of carbamyl phosphate from ammonium and bicarbonate. OTC then catalyses the biosynthesis of citrulline from ornithine and carbamyl phosphate. Thus, a deficiency of OTC leads to accumulation of ammonia and glutamine (the major extrahepatic source of ammonia for ureagenesis), and a reduction in citrulline. The accumulating carbamyl phosphate enters the pyrimidine synthetic pathway, resulting in increased excretion of orotic acid. The missense mutation p. A208T, replacing alanine with threonine at codon 208 of exon 6 in the OTC gene, has been previously reported in a late-onset OTC patient we investigated,4 and in others.5-7 This group showed an extremely wide phenotype, ranging from encephalopathy at age 4 months7 to no symptoms at age 97 years.5 Our patient developed hyperammonaemia following postoperative catabolism, caused by surgical stress and fasting with inadequate calorie supply from intravenous fluids pre- and postoperatively. In addition, a high nitrogen load from bleeding sites, tissue trauma or tissue protein breakdown could have overwhelmed urea synthesis and promoted the excessive ammonia production. OTC deficiency is not the only inborn error of metabolism that can result in fatal postoperative decompensation. Another example is medium-chain acyl-CoA dehydrogenase deficiency, which appears more prevalent, with several recorded cases (eg, Raymond et al8). Other mild fatty-acid oxidation defects and, perhaps, intermittent maple syrup urine disease could behave similarly. Death during an initial episode seems frequent in patients with late-onset OTC deficiency, as lack of familiarity with the disorder in the adult setting delays diagnosis and appropriate treatment.9-11 Treatment of hyperammonaemia is well established, and includes aggressive calorie support to counteract catabolism, early use of intravenous sodium benzoate as an ammonia sink, and intravenous arginine.2 It was unfortunate that no objective evidence was gathered on the cause of the patient’s episode of encephalopathy during childhood. While the cause could have been viral encephalitis, the clinical course, and appearance of the cerebrospinal fluid on microscopy and the brain on computed tomography did not strongly support this diagnosis. Assessment of plasma ammonia level would most likely have led to the diagnosis of OTC deficiency. Establishment of the correct diagnosis in the patient led to the finding that his mother and brother were also affected, enabling them to be advised about precautions. The genetic implications for the family’s younger generation were not critical, as the proband had no children, and his brother’s children were both male and could not have inherited their father’s X chromosome (Figure). This case illustrates the difficulty of diagnosing late-onset OTC. The X-linked inheritance may be obscured, even when more than one family member is affected, as some patients remain asymptomatic. Patients with acute onset of unexplained neurological or psychiatric symptoms need urgent metabolic investigation, including measurement of plasma ammonia level, to exclude metabolic causes. Cascade testing of family members The G-to-A base change in exon 6, which results in an amino acid substitution from alanine to threonine at position 208 (p. A208T), was identified in DNA from the blood of the patient with late-onset ornithine transcarbamylase deficiency (person III-1) and his brother (III-2). Their mother (II-2) was found to be heterozygous for the p. A208T mutation.

Mary Anne Chiong MD · Bruce H Bennetts PhD · Simone I Strasser MD, FRACP · Bridget Wilcken FRACP, FHGSA

Objective: To assess the prevalence of obesity in patients undergoing coronary artery bypass grafting, heart valve surgery, or both procedures, and its association with postoperative outcomes.Design and setting: Retrospective analysis of data, collected by the Australasian Society of Cardiac and Thoracic Surgeons Victorian Cardiac Surgery Database Project, on patients undergoing coronary artery bypass grafting, heart valve surgery, or both procedures, between 1 June 2001 and 31 January 2006.Participants: 11 736 patients divided into four groups: underweight (body mass index [BMI], < 20), normal weight (BMI, 20–30), obese (BMI, > 30 to < 40), and morbidly obese (BMI, ≥ 40).Main outcome measures: Prevalence of obesity (compared with the age- and sex-matched adult Australian population); associations between obesity and morbid obesity in cardiac patients and adverse postoperative outcomes.Results: 30.4% of patients had a BMI > 30 (28.6% obese, 1.8% morbidly obese) compared with an expected prevalence of 21.2%. Morbid obesity was associated with prolonged ventilation (adjusted odds ratio [OR], 2.4; 95% CI, 1.6–3.7), readmission to intensive care (adjusted OR, 2.2; 95% CI, 1.2–4.1), and length of stay > 14 days (adjusted OR, 2.1; 95% CI, 1.4–3.3). Both obesity and morbid obesity were associated with renal failure (adjusted ORs, 1.4 [95% CI, 1.1–1.7] and 2.9 [95% CI, 1.7–4.9], respectively) and deep sternal wound infection (adjusted ORs, 2.4 [95% CI, 1.5–3.8] and 7.2 [95% CI, 2.8–18.7], respectively).Conclusions: Obesity is 1.4 times more prevalent in patients having coronary artery bypass grafting or heart valve surgery in Victoria compared with the general adult Australian population. Both obesity and morbid obesity are associated with early morbidity, but not mortality, after operation.

Cheng-Hon Yap MB BS, MS · Morteza Mohajeri FRACS · Michael Yii FRACS, MS

Objective: To describe the prevalence, characteristics and outcomes of amphetamine-related presentations to a tertiary hospital emergency department (ED).Design, setting and participants: Prospective observational study of amphetamine-related presentations to the ED of the Royal Perth Hospital (RPH), an adult, inner-city, tertiary referral hospital, between 3 August and 2 November 2005. For all patients presenting to the ED, the treating doctors were automatically prompted by the computerised data entry system to consider amphetamine use.Main outcome measures: Proportion of ED presentations related to amphetamine use; demographic features and usage practices of amphetamine users; characteristics of presentations and admissions; associated psychiatric illnesses and use of other drugs.Results: Over the study period, there were 13 125 presentations, of which 156 (1.2%) were judged to be causally related to amphetamine use. Of those 156 patients, over half were habitual drug users (89 [57.1%] used amphetamines at least weekly), and the majority were men (111 [71.2%]). The mean age was 28 years (range, 16–55 years). Presentations were of high acuity: 104 patients [66.7%] were rated 1, 2 or 3 on the Australasian Triage Scale; 50 (32.1%) arrived by ambulance; and 25 (16.0%) arrived with police. The mean time spent in the ED was 6 h (range, 0.5–24 h). Fifty patients (32.1%) required sedation, and the likelihood of requiring sedation increased almost threefold if the heart rate was over 100 beats/min on presentation. Sixty-two patients (39.7%) were admitted and 58 (37.2%) required psychiatric evaluation. Repeat attendance was common, with 71 patients (45.5%) having previous amphetamine-related presentations to the RPH ED.Conclusions: Amphetamine-related presentations comprise 1.2% of all ED attendances and have a major impact on hospital EDs. Patients are often agitated and aggressive, require extensive resources, and frequently re-attend. The burden of amphetamine-related illnesses on EDs is likely to increase in the future.

Suzanne D Gray MB BS · Daniel M Fatovich MB BS, FACEM · David L McCoubrie MB BS, FACEM · Frank F Daly MB BS, FACEM

The Confederation of Postgraduate Medical Education Councils launched the Australian Curriculum Framework for Junior Doctors in October 2006. The curriculum framework: balances the major areas of clinical management, communication and professionalism, and highlights the importance of an integrated approach to prevocational learning and teaching; supports practice-based, opportunistic and continuous learning, and specifies performance and supervision requirements for junior doctors; and has been published in both Internet and printable versions, to make the document accessible and easily usable by junior doctors and supervisors. The implementation of the curriculum framework will be overseen by a steering group that includes representatives from key stakeholder groups, including junior doctors and medical students.

Ian S Graham MB BS, MHP, FRACMA · Andrew J Gleason MB BS(Hons), BSc · Gregory W Keogh MB BS, FRACS · Deborah Paltridge BApplSci(Phyt), MHSc(Ed) · Ian R Rogers MB BS, FACEM · Merrilyn Walton BA, MSW, PhD · Caroline De Paola PhD · Jagdishwar Singh PhD · Barry P McGrath MB BS, MD, FRACP