Warwick Bagg

Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C

Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non‐compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.

Cushing's Syndrome Due to Interaction Between Inhaled Corticosteroids and Itraconazole

OBJECTIVE: To report a case of an interaction between inhaled corticosteroids and itraconazole causing iatrogenic Cushings syndrome and provide a review of the relevant literature. CASE SUMMARY: A 70-year-old white woman on long-term treatment with high-dose inhaled corticosteroids for asthma was diagnosed as having Scedosporium apiospermum infection of the skin and subcutaneous tissues. As a result, she was treated with itraconazole for 2 months. She subsequently developed Cushings syndrome due to a probable cytochrome P450–mediated interaction between itraconazole and budesonide. She also had secondary adrenal insufficiency requiring prolonged treatment with replacement hydrocortisone. DISCUSSION: Budesonide is a potent glucocorticoid that is metabolized in the liver by the CYP3A4 isoenzyme to inactive metabolites. Itraconazole is a potent cytochrome P450 inhibitor. It can inhibit the metabolism of oral or inhaled corticosteroids, producing cortisol excess leading to Cushings syndrome and adrenal insufficiency. An assessment of causality indicated a possible adverse interaction between itraconazole and budesonide. CONCLUSIONS: The combination of itraconazole and inhaled corticosteroids is increasingly being used to treat conditions such as allergic bronchopulmonary aspergillosis. Clinicians need to be aware of the potential for an interaction between such a combination.

Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes

Background: Patients with type 2 diabetes have abnormal endothelial function but it is not certain whether improvements in glycaemic control will improve endothelial function.

Screening for left ventricular hypertrophy in patients with type 2 diabetes mellitus in the community

BackgroundLeft ventricular hypertrophy (LVH) is a strong predictor of cardiovascular disease and is common among patients with type 2 diabetes. However, no systematic screening for LVH is currently recommended for patients with type 2 diabetes. The purpose of this study was to determine whether NT-proBNP was superior to 12-lead electrocardiography (ECG) for detection of LVH in patients with type 2 diabetes.MethodsProspective cross-sectional study comparing diagnostic accuracy of ECG and NT-proBNP for the detection of LVH among patients with type 2 diabetes. Inclusion criteria included having been diagnosed for > 5 years and/or on treatment for type 2 diabetes; patients with Stage 3/4 chronic kidney disease and known cardiovascular disease were excluded. ECG LVH was defined as either the Sokolow-Lyon or Cornell voltage criteria. NT-proBNP level was measured using the Roche Diagnostics Elecsys assay. Left ventricular mass was assessed from echocardiography. Receiver operating characteristic curve analysis was carried out and area under the curve (AUC) was calculated.Results294 patients with type 2 diabetes were recruited, mean age 58 (SD 11) years, BP 134/81 ± 18/11 mmHg, HbA1c 7.3 ± 1.5%. LVH was present in 164 patients (56%). In a logistic regression model age, gender, BMI and a history of hypertension were important determinants of LVH (p < 0.05). Only 5 patients with LVH were detected by either ECG voltage criteria. The AUC for NT-proBNP in detecting LVH was 0.68.ConclusionsLVH was highly prevalent in asymptomatic patients with type 2 diabetes. ECG was an inadequate test to identify LVH and while NT-proBNP was superior to ECG it remained unsuitable for detecting LVH. Thus, there remains a need for a screening tool to detect LVH in primary care patients with type 2 diabetes to enhance risk stratification and management.

A community-based model of care improves blood pressure control and delays progression of proteinuria, left ventricular hypertrophy and diastolic dysfunction in Māori and Pacific patients with type 2 diabetes and chronic kidney disease: a randomized controlled trial

BACKGROUND In this study, our main goal was to determine whether an integrated, community-based model of care using culturally appropriate health-care assistants to manage hypertension in Māori and Pacific patients with diabetes and chronic kidney disease (CKD) is more effective than conventional care in achieving blood pressure (BP) targets and delaying progression of cardiac and renal end-organ damage. METHODS Sixty-five Māori and Pacific patients (aged 47-75 years) with type 2 diabetes, moderate CKD (>0.5 g proteinuria/day, serum creatinine 130-300 µmol/l) and hypertension were randomized to usual care (n = 32) or community/intervention care (n = 33) for 12 months. Community care patients were visited monthly by a nurse-led health-care assistant for BP measurement. Antihypertensives were adjusted using a stepwise protocol, aiming for a BP <130/80 mmHg. Office BP and renal and echocardiographic parameters were measured at baseline and 12 months. RESULTS Baseline characteristics including office BP, renal and echocardiographic parameters, and number of antihypertensives were well matched in both groups. By 12 months, the community care patients had achieved a significantly greater reduction in office systolic BP (-21 ± 26 mmHg vs -12 ± 20 mmHg, P = 0.04) and in 24-h urine protein (-1.4 ± 2.6 g vs +0.1 ± 2.8 g, P = 0.04). The number of prescribed antihypertensives was greater in these patients at 12 months (3.4 ± 1.1 vs 2.3 ± 1.0, P < 0.01). Left ventricular (LV) mass and left atrial (LA) volume progressed in the usual care group, but not in the intervention group (P < 0.05). CONCLUSION This novel model of care is more effective than conventional care in lowering systolic BP and reducing cardiac and renal end-organ damage in these high-risk patients.

The effects of intensive glycaemic control on body composition in patients with type 2 diabetes

SUMMARY

Training the intern: The value of a pre-intern year in preparing students for practice

Aims: To evaluate the clinical and professional development that occurs during a New Zealand trainee intern year in preparation for the first house officer role. Methods: A quantitative questionnaire was distributed to all trainee interns (year 6) and year 5 medical students in New Zealand at the end of the 2007 academic year. This survey assessed self-reported competency and performance across clinical, professional and role development domains. Results: Response rate was 65% (457/702). Compared to year 5 students, trainee interns reported significantly greater competence and performance levels across all three domains. The greatest improvement occurred in the independent performance of procedural skills (trainee interns: 77%, year 5: 35%, p < 0.001) and clinical tasks (trainee interns: 94%, year 5: 56%, p < 0.001) and in the level of clinical responsibility taken (p < 0.001). At the end of the trainee intern year, 92% of students felt prepared to be a junior doctor, versus only 53% at the end of their 5th year (p < 0.0001). Conclusions: The trainee intern year is important in preparing graduates for the intern role. The year affords increased responsibility and practical experience, whilst retaining an educational focus, facilitating the move from competence towards performance. Preparedness for practice was substantially higher following the New Zealand trainee intern year than has been reported with other pre-intern placements.

Early Detection and Significance of Structural Cardiovascular Abnormalities in Patients with Type 2 Diabetes Mellitus

Cardiovascular disease is the leading cause of death among patients with Type 2 diabetes mellitus. The main forms of structural heart disease associated with diabetes are coronary heart disease and diabetic cardiomyopathy, which is characterized by left ventricular hypertrophy, left ventricular diastolic and systolic dysfunction. Asymptomatic structural heart disease is common and associated with a poor prognosis in patients with diabetes. Contemporary practice guidelines do not recommend screening of asymptomatic individuals for structural heart disease. Potential screening modalities, such as echocardiography, are costly and inaccessible. A simple, inexpensive blood test for brain natriuretic peptide is a useful marker of structural heart disease and is a prime candidate for screening patients with Type 2 diabetes mellitus and prioritizing referral for echocardiography.

The current state of undergraduate medical education in New Zealand

The two medical schools in New Zealand (NZ) are responding to the challenges of increasing healthcare demands and a worldwide doctor shortage, despite an environment of relatively scarce resource. Admissions to medical school are being increased and curricula examined and modified so that graduates are able to meet the healthcare needs of all New Zealanders. Affirmative pathways are in place for people of Maori, Pacific and rural origin to enter medical programmes and aim towards a broad demographic representation in future doctors. Additionally, there is a strong focus on Maori (indigenous) health in curricula. Medical undergraduate programmes have common learning outcomes and assessment but there are different pathways to achieve these, delivered at geographically dispersed sites. The final (Trainee Intern) year of the programme is an apprenticeship year which serves as a ‘work hardening’ year, but remains under the auspices of the respective universities. One of the greatest challenges that NZ faces with respect to healthcare is the long-term retention of high quality, local medical graduates, whose services are in high demand internationally.

Role of echocardiographic left ventricular mass and carotid intima‐media thickness in the cardiovascular risk assessment of asymptomatic patients with type 2 diabetes mellitus

Background: Standard cardiovascular (CV) risk assessment may underestimate risk in people with type 2 diabetes mellitus (T2DM). Cardiac and vascular imaging to detect subclinical disease may augment risk prediction. This study investigated the association between CV risk, left ventricular hypertrophy (LVH) and carotid intima‐media thickness (CIMT) in patients with T2DM free of CV symptoms.