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.

Modulation of the biological activity of thyrotrophin by anti-human thyrotrophin monoclonal antibodies.

The mechanism by which monoclonal antibodies enhance the biological activity of a number of hormones is poorly understood. One such antibody (GC73), which binds to human but not bovine TSH, enhances the bioactivity of human TSH in vivo. We have investigated whether GC73 enhancement of TSH bioactivity involves potentiation of hormone-receptor activation assessed by the cyclic AMP (cAMP) responses of both primary human thyrocyte cultures and a TSH-responsive human thyrocyte cell line (SGHTL-45). GC73 had no effect on basal cAMP production. In contrast to its enhancement of the bioactivity of human TSH in vivo, it markedly inhibited the cAMP response to 1 and 10 mU human TSH/ml in primary thyrocytes. This effect was dose-dependent with neutralization of the bioactivity of TSH occurring at 2 mg GC73/ml. GC73 had no effect on the bioactivity of bovine TSH. In contrast, a second anti-TSH monoclonal antibody (TC12), which binds to both human and bovine TSH, inhibited the bioactivity of both species of TSH. Similar results were obtained using SGHTL-45 cells, although the peak concentrations of cAMP were lower. We conclude that binding of GC73 to human TSH resulted in inhibition rather than enhancement of the in-vitro biological activity of human TSH. We suggest that GC73 enhancement of human TSH bioactivity seen in vivo does not result from a mechanism involving potentiation of receptor activation by human TSH.

Cytotoxic effects of amiodarone and desethylamiodarone on human thyrocytes.

Since recent in vivo evidence suggests that the benzofuran antiarrhythmic drug amiodarone has a direct toxic effect on the human thyroid gland, we have investigated the effects of both amiodarone and its metabolite desethylamiodarone on a novel immortalized functional human thyrocyte line (SGHTL-34 cells). Desethylamiodarone markedly reduced cell number as assessed from both DNA and protein content. Few cells were left after 24 hr exposure to 12.5 micrograms/ml; the concentration producing death of 50% of cells (EC50) was 6.8 +/- 1.1 micrograms/ml (mean +/- SE, N = 15). Amiodarone was much less potent, producing a maximum decrease in cell number of approximately 25% at concentrations up to 50 micrograms/ml. The effect of desethylamiodarone was seen within 24 hr of culture. T3 in concentrations up to 0.75 micrograms/ml had no effect on the action of amiodarone or desethylamiodarone on SGHTL-34 cells. Light microscopy demonstrated vacuolation of SGHTL-34 cells after 4-day culture with either the drug or its metabolite. Studies using primary cultures of human retroorbital fibroblasts demonstrated that the greater cytotoxicity of desethylamiodarone was not confined to thyrocytes. When SGHTL-34 cells were incubated with 2.5 micrograms/ml desethylamiodarone for 4 days, 71.7 +/- 0.9% was taken up by the cells; there was no detectable conversion to amiodarone. Incubation of thyrocytes with 50 micrograms/ml amiodarone for 4 days resulted in the uptake of 80.1 +/- 2.1% by the cells. In addition, 5.0 +/- 0.1% of the amiodarone was converted to material with the same retention time as desethylamiodarone standard; of this material, 72.9 +/- 2.8% was taken up by the cells. We conclude that desethylamiodarone, at concentrations near those found in the plasma of patients on long-term amiodarone therapy, exerts a direct cytotoxic effect on human thyroid cells in short-term culture. This effect may play a role in the aetiology of clinical thyroid disease during amiodarone therapy. We suggest that, since the effect is not restricted to thyrocytes, desethylamiodarone may play a role in the aetiology of amiodarone toxicity which occurs clinically in many tissues.

Effects of ageing on the growth and differentiated function of transfected human thyrocytes.

Senescence in primary cultures of mammalian cells is characterised by cessation of growth after a number of cell divisions; this may be associated with loss of some differentiated functions. Recent studies on bovine adrenocortical cells have suggested that expression of simian virus-40 (SV40) early region in these cells may prevent phenotypic losses due to senescence. We report here data on growth and differentiated function of two human thyrocyte cell lines (SGHTL-34 and -45) generated by the transfection of primary thyrocytes with the plasmid pSV3neo which contains the SV40 early region. Growth was assessed by fluorometric DNA estimations and calculation of cell population doubling time; function was assessed by binding studies using 125I-bovine thyrotrophin (TSH) and measurement of cyclic adenosine 3',5'-monophosphate (cAMP) response to stimulation with TSH, forskolin and cholera toxin. After 3-12 months in stable culture there was a gradual increase in the doubling time of both cell lines over a 3-month period (SGHTL-34 cells, early 34.5 +/- 4.5 h, late 301 +/- 111.6 h; SGHTL-45 cells, early 53.4 +/- 4.4 h, late 148.3 +/- 26.3 h; mean +/- SEM). Scatchard analysis demonstrated a loss of the high affinity TSH receptor over the same time period. The increase in cAMP in response to 1000 microU/ml TSH declined until the cells became unresponsive (SGHTL-34 early, cAMP 10.3 +/- 0.7 pmol/well; late, cAMP -0.4 +/- 0.3 pmol/well; SGHTL-45 early, cAMP 11.3 +/- 1.1 pmol/well, late, cAMP 0.3 +/- 0.1 pmol/well). The cAMP responses to forskolin and cholera toxin were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Thyroid storm in a young woman resulting in bilateral basal ganglia infarction.

We describe a 30 year old woman who presented with thyroid storm. She had non-specific symptoms and few clinical signs of hyperthyroidism despite markedly raised thyroid hormone concentrations. Soon after admission her behaviour became abnormal and her level of consciousness deteriorated. Despite the rapid restoration of thyroid hormone concentrations to normal using conventional therapies, and correction of hypoxia resulting from acute pulmonary oedema, her level of consciousness did not improve. Cranial CT scanning revealed extensive bilateral basal ganglia infarction, a previously unreported complication of thyroid storm. This observation suggests that thyroid storm may predispose to hypoxic neurological damage.

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.

A progressive pericardial effusion caused by psittacosis.

A patient developed signs of a progressive pericardial effusion over a period of eight days. Diagnostic and therapeutic pericardiocentesis was performed. Viral titres to psittacosis rose from less than 1:8 to greater than 1:256 indicating recent infection.

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.

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 oxytocin on the plasma glucagon response to insulin-induced hypoglycaemia in man.

The presence of the classical neurohypophyseal hormone oxytocin has recently been described in the human pancreas in considerably higher concentrations than those found in peripheral plasma. Evidence in animals and man suggests that oxytocin can directly stimulate the secretion of glucagon from pancreatic islets. In order to investigate a possible paracrine role for oxytocin in the regulation of glucagon secretion we have studied the effect of oxytocin on the plasma glucagon response to insulin-induced hypoglycaemia in 10 lean fasted male subjects. Intravenous insulin tests were performed in random order with or without oxytocin infusion (2 U bolus injection; 111 mU/min for 2 hours). Blood sugar nadir occurred at the onset of symptoms (time S) with no significant differences between oxytocin and saline infusions (saline S = 24 +/- 2.3 min; oxytocin S = 23.3 +/- 2.7 min). There was no significant change in peripheral plasma oxytocin concentrations during saline infusion. During the oxytocin infusion plasma oxytocin concentrations rose from 1.05 +/- 0.1 (mean +/- SEM) pmol/l to a peak of 632 +/- 179 pmol/l and remained elevated throughout the study. Peak plasma glucagon concentrations occurred at S + 10 mins with no significant differences in peak values (saline 200 +/- 26.3 pg/ml; oxytocin 207 +/- 23.6 pg/ml) between saline and oxytocin infusions. The data suggest that oxytocin at concentrations up to 6.3 X 10(-10) M has no effect on the decline or recovery of blood glucose concentrations or on the plasma glucagon response to insulin-induced hypoglycaemia.

Responses of plasma oxytocin and arginine vasopressin to nausea induced by apomorphine and ipecacuanha.

Apomorphine, a centrally-acting emetic, was administered subcutaneously (50 micrograms/kg) to nine normal subjects (four male, five female; aged 22-36 years) and four patients with idiopathic diabetes insipidus (DI) (one male, three female; aged 24-49 years). In the normal subjects this stimulus caused nausea (and vomiting in seven of nine) with a latency of 9.5 +/- 0.9 min which was followed by a large increase in plasma arginine vasopressin (AVP) concentration (from 0.9 +/- 0.2 pmol/l to 249 +/- 104 pmol/l at 15 min after the onset of symptoms; mean +/- SEM, P less than 0.01). There was a small but significant increase in plasma oxytocin (OXT) concentration (from 1.6 +/- 0.4 pmol/l to 6.2 +/- 3.4 pmol/l; P less than 0.05). Mean arterial pressure (MAP) fell slightly (from 87 +/- 1.9 mm Hg to 71 +/- 4.4 mm Hg; P less than 0.05) 15 min after the onset of nausea; there was no change in blood haematocrit or plasma osmolality and sodium concentration. In the DI patients apomorphine produced nausea (with vomiting in three of four) with a latency of 10.0 +/- 1.4 min but failed to cause an increase in either plasma AVP or OXT. In the DI patients the fall in MAP did not reach statistical significance (83 +/- 4 mm Hg to 71 +/- 11 mm Hg); there was also no change in haematocrit, osmolality or sodium concentration. Ipecacuanha, an emetic with both peripheral and central actions, was administered orally to seven normal subjects (three male, four female; aged 22-36 years) six of whom also underwent apomorphine tests.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oxytocin infusion on adenohypophysial and adrenal cortical responses to insulin-induced hypoglycaemia.

The responses of plasma adrenocorticotrophin (ACTH), cortisol, growth hormone (GH) and prolactin to insulin-induced hypoglycaemia were studied in six lean male subjects (age 22-29 years). Intravenous insulin tests were performed with and without oxytocin infusion. Blood sugar nadir occurred at the onset of symptoms (time S) with no significant differences between oxytocin and saline infusion. During the oxytocin infusion mean plasma oxytocin increased from 1.9 pmol/l to 138 pmol/l. Peak increase in plasma ACTH (oxytocin 266 +/- 54 ng/l; saline 281 +/- 43 ng/l, mean +/- SEM) was at S + 10 min while peak plasma cortisol (oxytocin 680 +/- 47 nmol/l: saline 656 +/- 40 nmol/l) was measured at S +/- 60 min, peak GH (oxytocin 96 +/- 17.8 mU/l; saline 106 +/- 18.6 mU/l) at S + 60 min and prolactin (oxytocin 1332 +/- 239 mU/l; saline 1242 +/- 273 mU/l) at S + 30 min. There were no significant differences in plasma concentrations of ACTH, cortisol, GH or prolactin between saline and oxytocin infusion. The results indicate that oxytocin has no effect on plasma ACTH, cortisol, GH and prolactin responses to insulin-induced hypoglycaemia. In particular they fail to support previous studies which suggested an inhibitory role for oxytocin in ACTH secretion.

The response of plasma oxytocin to surgical stress.

Recent evidence suggests that oxytocin (OXT) and arginine vasopressin (AVP) are involved in the response to stress. We have examined the changes in peripheral plasma OXT during abdominal surgery in eight patients (six males, two female; ages 60-82 years) undergoing hemicolectomy and compared the results with those for AVP to the same stimulus. There was no significant change in systolic blood pressure, blood haematocrit or plasma sodium, osmolality or glucose. AVP rose significantly after premedication (from 1.8 +/- 0.3 pmol/l to 5.5 +/- 2.3 pmol/l; P less than 0.05) but the greatest increase (to 35.8 +/- 6.6 pmol/l) occurred after gut manipulation. Plasma OXT concentrations fell slightly with premedication (from 5.7 +/- 2.0 pmol/l to 3.3 +/- 0.9 pmol/l; P less than 0.05) but rose markedly (to a peak of 33.5 +/- 11.4 pmol/l) after gut manipulation. The data support the concept that OXT like AVP may play a role in the neuroendocrine response to surgery. The stimulus to OXT release and its function remain to be determined.

Premature coronary artery disease and the Prader-Willi syndrome.

A 28 year old woman with the Prader-Willi syndrome developed chest pain and loss of anterior R wave amplitude on the electrocardiogram. Cardiac catheterization demonstrated a severe proximal stenosis of the left anterior descending artery with delayed antegrade flow together with antero-apical akinesia consistent with myocardial infarction. Physicians involved in the management of patients with the Prader-Willi syndrome should be aware of this association with premature coronary artery disease.

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.