Rhabdomyolysis in association with simvastatin and dosage increment in clarithromycin.

Clarithromycin is the most documented cytochrome P450 3A4 (CYP3A4) inhibitor to cause an adverse interaction with simvastatin. This particular case is of interest as rhabdomyolysis only occurred after an increase in the dose of clarithromycin. The patient developed raised cardiac biomarkers without any obvious cardiac issues, a phenomenon that has been linked to rhabdomyolysis previously. To date, there has been no reported effect of rhabdomyolysis on the structure and function of cardiac muscle. Clinicians need to be aware of prescribing concomitant medications that increase the risk of myopathy or inhibit the CYP3A4 enzyme. Our case suggests that troponin elevation could be associated with statin induced rhabdomyolysis, which may warrant further studies.

Profile of the distal femur anterior cortex--a computer-assisted cadaveric study.

INTRODUCTION: Accurate positioning and sizing of the femoral component in total knee arthroplasty is important for stability and functional outcome. The purpose of the study was to evaluate the bony profiles of the distal anterior femoral cortex (AFC). MATERIALS AND METHODS: Anatomical bony landmarks on 50 adult cadaveric femora were collected. Critical points were used to identify the distal AFC surface. RESULTS: There were four anterior cortex profiles: (1) lateral side highest and medial side lowest (56%); (2) lowest height in median area (26%); (3) highest height in median area (14%); (4) medial side highest and lateral side lowest (4%). DISCUSSION: Anterior referencing in TKA needs to represent the anterior shape of the distal femoral cortex to prevent notching, femoro-patellar overstuffing or flexion gap mismanagement. Due to the variability of the AFC, surgeons have to carefully select the AFC landmark to be sure of avoiding complications.

Candesartan: widening indications for this angiotensin II receptor blocker?

Candesartan cilexetil is one of a number of drugs of the angiotensin II receptor blocker (ARB) class. Their principal mode of action involves competitive blockade of the angiotensin II type 1 receptor, thereby modulating the activity of the rennin-angiotensin-aldosterone system. Angiotensin II receptor blocker therapy has been proven to be well tolerated and effective in the management of hypertension, chronic heart failure with left ventricular dysfunction and the prevention and progression of diabetic renal disease. Candesartan is a highly potent, long-acting and selective angiotensin II type 1 receptor blocker. It was launched in 1998 for the treatment of hypertension. Its use has increased dramatically, with recently published data suggesting benefit in the treatment of stroke, heart failure, diabetic renal disease and most recently in preventing the development of or delaying the progression of diabetic retinopathy. In this article we review the literature on the use of ARB drugs in general before focusing on candesartan.

Familial hyperinsulinaemia associated with epilepsy and mental retardation--a syndrome of familial insulin resistance.

BACKGROUND: Variants of type A insulin resistance, characterized by female hyperandrogenism and 'acromegaloid' features, have been ascribed to genetic defects of the insulin receptor or post-receptor pathways via autosomal dominant or recessive inheritance patterns. Whilst a variety of congenital syndromes of insulin resistance are identified by their characteristic clinical phenotypes, an association with epilepsy and mental retardation has not previously been reported. CASE REPORT: We describe three female siblings (aged 12, 19 and 21) with fasting hyperinsulinaemia (116-443 pmol/l; normal range < 80 pmol/l) and mental retardation. Two siblings also have epilepsy. The eldest has features of severe insulin resistance with dyslipidaemia, acanthosis nigricans, 'acromegaloid features' and diabetes requiring high dose insulin therapy in combination with a glitazone. Their mother has fasting hyperinsulinaemia (113 pmol/l), mental retardation and epilepsy. None had clinical or biochemical features of hyperandrogenism or evidence of pigmentory retinopathy, deafness or renal insufficiency. Autoantibody screens were negative. Interestingly, there is no evidence of mental retardation or epilepsy among males in the family. CONCLUSION: This family suggests the presence of a yet-undefined syndrome of familial insulin resistance affecting female kindred. Further studies are being undertaken to clarify the genetic defects and mode of inheritance.

A randomized double-blind study to compare the effects of nasal fluticasone and betamethasone on the hypothalamo-pituitary-adrenal axis and bone turnover in patients with nasal polyposis.

Treatment of nasal polyposis with topical betamethasone is associated with suppression of the hypothalamo-pituitary-adrenal (HPA) axis and, potentially, has adverse effects on bone turnover. Fluticasone propionate is a potent corticosteroid with negligible absorption across the nasal mucosa and extensive first-pass hepatic metabolism. We performed a randomized double-blind study, in patients with nasal polyposis, comparing the effects of 8 weeks' treatment with betamethasone drops or fluticasone nasules on the HPA axis using the 1 micro g tetracosactide test, and on bone turnover using two serum markers. Nine patients were allocated to each treatment. Betamethasone resulted in significant suppression in the tetracosactide test (P = 0.006), but fluticasone did not (P = 0.113). There were no differences in bone turnover or treatment efficacy between treatments. Treatment of nasal polyposis with topical betamethasone drops, but not with fluticasone nasules, suppresses the HPA axis and, given comparable efficacy, fluticasone administered via nasule should be the preferred agent.

Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus.

The generation of an autoimmune response against islet beta-cells is central to the pathogenesis of type 1 diabetes mellitus, and this response is driven by the stimulation of autoreactive lymphocytes by components of the beta-cells themselves. Reactive oxygen species (ROS) have been implicated in the beta-cell destruction which leads to type 1 diabetes and may modify beta-cell components so as to enhance their immunogenicity. We investigated the effects of oxidation reactions catalysed by copper or iron on the major beta-cell autoantigen glutamic acid decarboxylase (GAD). Lysates of purified rat islets were exposed to copper or iron sulphate with or without hydrogen peroxide or ascorbic acid. Immunostaining showed that these treatments generated high molecular weight covalently linked aggregates containing GAD. These are not formed by intermolecular disulphide bonds between cysteine residues since they cannot be resolved into monomeric form when electrophoresed under extreme reducing conditions. There was no modification of insulin or pro-insulin by ROS. The same oxidative changes to GAD could be induced in viable islet cells treated with copper sulphate and hydrogen peroxide, and thus the modifications are not an artefact of the catalysed oxidation of cell-free lysates. Sera from patients with type 1 diabetes and stiffman syndrome containing GAD antibodies reacted predominantly with the highest molecular weight modified protein band of GAD: normal human sera did not precipitate GAD. Thus, oxidatively modified aggregates of GAD react with serum antibodies of type 1 diabetes patients and some SMS patients: this is consistent with oxidative modifications of autoantigens being relevant to the pathogenesis of type 1 diabetes.

Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial.

AIMS/HYPOTHESIS: The management of charcot neuroarthropathy, a severe disabling condition in diabetic patients with peripheral neuropathy, is currently inadequate with no specific pharmacological treatment available. We undertook a double-blind randomised controlled trial to study the effect of pamidronate, a bisphosphonate, in the management of acute diabetic Charcot neuroarthropathy. METHODS: Altogether 39 diabetic patients with active Charcot neuroarthropathy from four centres in England were randomised in a double-blind placebo-controlled trial. Patients received a single infusion of 90 mg of pamidronate or placebo (saline). Foot temperatures, symptoms and markers of bone turnover (bone specific alkaline phosphatase and deoxypyridinoline crosslinks) were measured over the 12 months, in 10 visits. All patients also had standard treatment of the Charcot foot. RESULTS: Mean age of the study group (59 % Type II (non-insulin-dependent) diabetes mellitus) was 56.3 +/- 10.2 years. The mean temperature difference between active and control groups was 3.6 +/- 1.7 degrees C and 3.3 +/- 1.4 degrees C, respectively. There was a fall in temperature of the affected foot in both groups after 2 weeks with a further reduction in temperature in the active group at 4 weeks (active and placebo vs baseline; p = 0.001; p = 0.01, respectively), but no difference was seen between groups. An improvement in symptoms was seen in the active group compared with the placebo group (p < 0.001). Reduction in bone turnover (means +/- SEM) was greater in the active than in the control group. Urinary deoxypyridinoline in the pamidronate treated group fell to 4.4 +/- 0.4 nmol/mmol creatinine at 4 weeks compared with 7.1 +/- 1.0 in the placebo group (p = 0.01) and bone-specific alkaline phosphatase fell to 14.1 +/- 1.2 u/l compared with 18.6 +/- 1.6 u/l after 4 weeks, respectively (p = 0.03). CONCLUSION/INTERPRETATION: The bisphosphonate, pamidronate, given as a single dose leads to a reduction in bone turnover, symptoms and disease activity in diabetic patients with active Charcot neuroarthropathy.

Adverse metabolic and cardiovascular risk following treatment of acute lymphoblastic leukaemia in childhood; two case reports and a literature review.

We report two patients who survived childhood acute lymphoblastic leukaemia (ALL) following treatment with chemotherapy, total body irradiation (TBI) and bone marrow transplantation (BMT). The first case presented with an acute cerebral infarction at 23 years of age and was found to have non-ketotic diabetes and gross mixed hyperlipidaemia; the second presented with non-ketotic diabetes, hypertension, proteinuria and dyslipidaemia at age 16 years. The association of glucose intolerance with other vascular risk factors in young adult survivors of BMT was recently highlighted in a follow-up study of 23 survivors of BMT [1], but none presented with such gross mixed hyperlipidaemia. The improving survival rates of childhood malignancy over the last two decades will present adult physicians with patients who have accelerated vascular risk at a young age who will require early treatment to modify it.

The effect of six weeks topical nasal betamethasone drops on the hypothalamo-pituitary-adrenal axis and bone turnover in patients with nasal polyposis.

Betamethasone topical nasal drops may have systemic corticosteroid activity and cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis and impairment of bone turnover. The aim of this study was to assess the effect of a standard 6-week regime of betamethasone topical nasal drops on the HPA axis (using a physiological dose (1 microg) ACTH test) and on bone turnover (using markers of bone turnover, urinary deoxypyridinoline and serum bone specific alkaline phosphatase). Eleven patients with nasal polyposis were included in a prospective cohort study. Plasma cortisol was lower after betamethasone treatment at all time intervals (P < 0. 0001). There was no change in urinary deoxypyridinoline corrected for creatinine or bone specific alkaline phosphatase. Six weeks' treatment with recommended doses of betamethasone suppresses the HPA axis, but has no significant effect upon markers of bone turnover. Topical betamethasone in subjects with nasal polyps should be viewed as systemic corticosteroid administration and the long and short-term sequelae should be borne in mind.

Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus.

AIMS: Vascular endothelial dysfunction, an early marker of atherosclerosis, has been demonstrated in Type 2 diabetes mellitus (DM). Vitamin E preserves endothelial function in animal models of diabetes and reduces cardiovascular risk. We examined endothelial function and the effect of vitamin E supplements in uncomplicated Type 2 DM. METHODS: Forty-eight subjects with Type 2 DM and 21 controls had endothelial function assessed using forearm venous occlusion plethysmography with endothelium-independent (sodium nitroprusside) and dependent (acetylcholine, bradykinin) vasodilators. Those with diabetes received 1600 i.u. daily oral alpha-tocopherol or placebo, double-blind for 8 weeks, and had endothelial function reassessed. RESULTS: The diabetic group had higher HbA1c (6.9+/-1.4 vs 4.8+/-0.6%; P<0.01) and systolic (145+/-15 vs. 130+/-16 mm Hg; P<0.01) but not diastolic blood pressure (79+/-8 vs. 76+/-9 mm Hg; P = 0.15). There was blunted vasodilation to acetylcholine (15 microg/min; P<0.01) in subjects with diabetes. Vasodilation to sodium nitroprusside and bradykinin was similar (all P>0.1). Alpha-tocopherol did not affect vasodilation to nitroprusside (P>0.1), acetylcholine (P>0.1) or bradykinin (P>0.1). CONCLUSIONS: There may be receptor-specific endothelial dysfunction in subjects with uncomplicated Type 2 DM. This is not improved by treatment with alpha-tocopherol.

A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism.

OBJECTIVE: The optimal dosage regimen for carbimazole (CBZ) in the treatment of hyperthyroidism remains uncertain, despite clinical use of the drug for approximately fifty years. We have compared the early clinical and biochemical responses to 20 or 40 mg/day of CBZ given as initial treatment for hyperthyroidism. DESIGN: Prospective open multicentre trial. PATIENTS: Sixty-three patients presenting with hyperthyroidism. MEASUREMENTS: Serum total and free thyroid hormones, serum TSH and SHBG were measured at baseline and at 4 and 10 weeks after start of therapy. Weight, pulse and a symptom questionnaire were also monitored at 6 and 12 weeks. RESULTS: Patients randomized to a starting dose of 40 mg/day CBZ had lower total (98 +/- 10 vs 158 +/- 11 nmol/l, P < 0.001) and free T4 (19.4 +/- 2.6 vs 35.2 +/- 3.7 pmol/l, P < 0.001) and total (2.6 +/- 0.3 vs 4.3 +/- 0.4 nmol/l, P < 0.001) and free T3 (8.3 +/- 1.0 vs 13.7 +/- 1.2 pmol/l, P < 0.01) at 4 weeks than those receiving 20 mg/day. Clinical responses at 6 and 12 weeks (weight, pulse, symptom score) and SHBG concentrations were similar. Drug-related hypothyroidism was less likely to occur at 4 and 10 weeks in those patient who initially received 20 mg CBZ/day, but this dose was less effective at controlling hyperthyroidism in those with more severe hyperthyroidism with baseline TT4 > 260 nmol/l. CONCLUSIONS: In treating hyperthyroidism, 20 mg/day carbimazole is effective, convenient and has a lower risk than 40 mg/day of iatrogenic hypothyroidism in patients with mild or moderate hyperthyroidism. Higher doses are required for those with severe hyperthyroidism.

Microalbuminuria screening in the UK: are we meeting European standards?

European guidelines recommend annual screening for microalbuminuria in patients with Type 1 (insulin-dependent) diabetes mellitus (IDDM) of greater than 5 years' duration and in those with Type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) from diagnosis. To determine the current provision of screening for microalbuminuria we performed a postal survey of all diabetologists in the United Kingdom. Of 556 questionnaires sent, 326 (59%) were returned (246 adult, 57 paediatric, 3 adolescent clinics) and of these 306 (55%) were suitable for analysis. Screening programmes have been established by 210 (69%) diabetologists: 70 of these in the last 2 years. 46 more plan to screen patients with IDDM within 2 years. 155 (92%) of 169 adult programmes perform annual screening in IDDM, 74% according to European guidelines (39% in NIDDM). Other clinics use age, type of diabetes or criteria such as blood pressure to target screening. An albumin/creatinine ratio (52%) on an early morning urine (56%) or random (29%) urine sample is most commonly requested. Financial constraint was the principal reason given in 32 (33%) of 96 clinics that do not currently screen. Other reasons included implementation of other developments with a higher priority (24%) and doubts about the medical value of screening (46%). Assuming respondents are representative of current UK practice, we conclude that microalbuminuria screening is available to patients in many clinics, but is neither universal nor always performed according to European guidelines.

Microbial contamination of harvested bone marrow and peripheral blood.

The incidence and clinical consequences of microbiological contamination of autologous bone marrow and peripheral blood progenitor cells are not well documented. We therefore retrospectively analysed our experience with bacterial or fungal contamination of harvested bone marrow and/or peripheral blood. From January 1987 to the end of January 1994, 499 patients were harvested or which 301 were transplanted. A total of 3910 specimens obtained during three stages in the processing were assessed for microbial contamination: (1) in the operating room immediately after harvesting (1662 bags) with 2.1% culture positivity, (2) after processing for cryopreservation (1039 bags) with a further 1.1% cultures positive, and (3) after thawing at the time of reinfusion (1209 bags) of which 2.2% were culture positive. There were no culture positive specimens obtained from any peripheral blood progenitor cell products. The vast majority of the 85 culture positive specimens obtained from marrow were skin flora (89%) and 35% of all positive harvest specimens remained positive following processing and freezing. At least 36% of culture positive specimens were thought to have arisen as a result of exogenous contamination of blood culture bottles. Potentially pathogenic enteric organisms were present in nine (0.2%) specimens and infusion of these organisms occurred in four cases. A further seven patients were reinfused with marrow culture positive for skin organisms. No adverse clinical sequelae were noted following infusion of any contaminated products. However, clinical decision making continues to be influenced by culture results and multistage microbial culture continues to be of value in the management of our marrow recipients.

Raised ambulatory blood pressure in type 1 diabetes with incipient microalbuminuria.

Whether raised blood pressure precedes, follows or develops in parallel with the onset of microalbuminuria, remains unclear. Previous studies, using conventional blood pressure recordings, have yielded discrepant results. Ambulatory blood pressure (ABP) monitoring detects borderline hypertension more reliably, and correlates more closely with end-organ damage. We have therefore compared ABP and left ventricular dimensions in normotensive insulin-dependent diabetic patients with or without microalbuminuria, and matched nondiabetic control subjects. Those diabetic patients with microalbuminuria, and to a lesser extent those without, had higher 24 h mean arterial blood pressure than matched non-diabetic control subjects, with corresponding increases of left ventricular mass, interventricular septal width and posterior wall thickness. These observations suggest that raised arterial blood pressure is present at an early stage of 'incipient' microalbuminuria.

The prevalence of coeliac disease in adult diabetes mellitus.

Coeliac disease occurs more commonly in children with insulin-dependent diabetes mellitus (IDDM) than in the general population, but the prevalence of coeliac disease in adults with diabetes is unknown. We therefore screened an adult hospital-based diabetic population using IgA antigliadin antibody (IgA-AGA) to identify those patients requiring intestinal biopsy. In 1 year, 1789 patients (43% IDDM, 57% NIDDM) were screened, and 73 had raised IgA-AGA. Of these patients, 49 agreed to duodenal biopsy and 13 (10 IDDM) had coeliac disease. Selective IgA deficiency was found in eight patients, one of whom had coeliac disease. Of these 14 patients with newly diagnosed coeliac disease, four had microcytic anaemia, nine a low serum ferritin, and four a low albumin-corrected calcium. Eight patients had symptoms which improved on gluten withdrawal. Dietary compliance was maintained in 6/8 symptomatic patients, but only in 1/6 without symptoms. Included in the 1789 patients were four (all IDDM) with known coeliac disease. The overall prevalence of coeliac disease in adult patients with IDDM was 1:50 compared with 1:340 in NIDDM. Coeliac disease is common in adults with IDDM and may cause malabsorption and ill health. It should be suspected in any IDDM patient with gastrointestinal symptoms or unexplained anaemia.