Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.
Aims To examine active and passive tobacco smoke exposure in children and adolescents attending a diabetic clinic. Methods Salivary cotinine concentrations were measured by gas chromatography and questionnaire data on the smoking habits of patients, families and friends were analysed as well as recording of glycosylated haemoglobin (HbA1c), body mass index (BMI) and social deprivation score. Results Salivary cotinine concentrations identified 7% of the patients as active smokers and 72% as passive smokers. The mean cotinine concentration in those with no identifiable source of exposure was 0.10 (95% confidence interval 0.05–0.14) ng/ml, 2.81 (2.24–3.38) ng/ml in the passive smoking group and 103.69 (55.96–151.41) ng/ml in the active smokers. Cotinine concentrations in passive smokers increased with the number of sources of exposure. The mean cotinine concentration was also higher when the mother was the sole source compared to other sources. There was no statistically significant correlation to smoking exposure and HbA1c, BMI and deprivation scores. Conclusion Tobacco smoke exposure may pose serious health risks to children and adolescents with diabetes and additional public health measures are required to reduce overall exposure. Diabet. Med. 16, 31–34 (1999)
Abstract A sensitive HPLC method for the determination of ranitidine in small-volume (0.5 mL) paediatric plasma samples is described. Plasma samples were extracted using a simple, rapid solid phase extraction (SPE) technique developed using disposable copolymer packed SPE cartridges. Chromatographic separation was achieved by reverse-phase HPLC with isocratic elution using a μBondapak C18 column and a phosphate buffer (10 mm, pH 3.75)-acetonitrile (87:13 v/v) mobile phase with UV detection at 313 nm. The HPLC system exhibited linearity in the range 8–800 ng mL−1. Intraday % CV and % bias values were in the range 1.28–8.09% (% bias %-4.33 to %-0.87) and interday % CV and % bias values were in the range 0.73–15.28% (% bias %-1.80 to +1.65). The limits of detection and quantitation obtained were 2 ng mL−1 and 8 ng mL−1, respectively, and ranitidine extraction recoveries from plasma ranged from 92.30 to 103.88%. In this study, the developed HPLC and SPE methodologies have been successfully applied to the determination of ranitidine concentrations in 68 paediatric plasma samples. The sampled population was drawn from patients already receiving the study drug therapeutically. Patients recruited had received ranitidine by two main routes - oral and intravenous. The plasma concentrations of ranitidine encountered in paediatric samples following oral or intravenous administration of a range of prescribed doses are presented graphically. These profiles are based on analysis of the first 68 plasma samples obtained from the first 35 patients recruited to the study receiving ranitidine by the oral or intravenous route.
Abstract Aims To determine whether children with infections in early life (recorded routinely in general practice) have a reduced risk of Type 1 diabetes, as would be expected from the hygiene hypothesis. Methods Children with Type 1 diabetes and up to 20 matched (on year of birth, sex and region) control subjects were selected from a cohort of children born in the UK at General Practice Research Database practices. For each child, the frequency of general practitioner consultations for infections and prescriptions for antibiotics in the first year of life were determined. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using conditional logistic regression. Results The main analysis included 367 case and 4579 matched control subjects. There was no evidence of any reduction in the subsequent risk of Type 1 diabetes in children with at least one infection in the first year of life (OR = 1.03, 95%CI 0.79, 1.34) or in children prescribed antibiotics in the first year of life (OR = 1.03, 95%CI 0.82, 1.29). Further analyses also revealed little evidence of a difference in subsequent risk of Type 1 diabetes after different types of infection in the first year of life (including gastrointestinal, conjunctivitis, otitis media and upper and lower respiratory tract). Analyses of infections in the first 2 years of life reached similar conclusions. Conclusions This study provides no evidence of an association between infections in early life and subsequent risk of childhood‐onset Type 1 diabetes and therefore does not support the hygiene hypothesis.
SUMMARY A young male patient demonstrated unusual features of Cushing's syndrome, atrial myxomas and freckled skin pigmentation. At 4.5 years of age he presented with intermittent swelling of his face and abdomen associated with weight gain and mild hypertension. A left atrial myxoma, suspected from routine physical examination, was surgically removed at 6.1 years of age. The initial mild symptoms clinically thought to be due to Cushing's syndrome, persisted intermittently without any consistent biochemical abnormality. At 10 years of age height velocity decreased and at 12 years early osteoporosis was observed radiologically. Repeated dexamethasone tests revealed a paradoxical increase in cortisol and corticotrophin from normal basal levels. Further investigation showed a cyclical pattern of hypercortisolism. The removal of a pituitary microadenoma failed to correct the features of Cushing's syndrome or prevent intermittent hypercortisolism. At 15.3 years a second left atrial myxoma was removed. This was followed by bilateral adrenalectomy. Histologically the features were consistent with primary pigmented nodular adrenocortical disease. This is the first patient described with cyclical Cushing's syndrome as part of this unusual complex of disorders.
Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism, characterised by defective transport of the cationic amino acids lysine, arginine and ornithine. To date there are few reported necropsy cases. This report describes the necropsy findings in a 21 year old female patient originally diagnosed as having LPI in 1973. Liver function tests deteriorated and immediately before death jaundice, hyperammonaemia, coma, metabolic acidosis, and a severe bleeding diathesis developed. At necropsy, there was micronodular cirrhosis of the liver with extensive fatty change in hepatocytes. The lungs showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy revealed the presence of a glomerulonephritis with predominant IgA deposition. These necropsy findings reflect the spectrum of lesions reported in LPI, providing further evidence of an association between this condition and pulmonary alveolar proteinosis, cirrhosis and glomerulonephritis.
SUMMARY An 11 ‐year‐old male presented with a 2‐year history of headache and lethargy. Serum PRL was elevated at 14 000 mU/1 and computerized tomography showed a pituitary macroadenoma. Visual fields and fundi were normal and the testes showed early pubertal changes. There was normal responsiveness of serum Cortisol but absence of GH response to hypoglycaemia. After bromocriptine therapy for 4 months serum PRL had fallen to 90 mU/1 and the tumour was not visible on repeat computerized tomography. After 7 months treatment, repeat pituitary function testing showed restoration of GH response to hypoglycaemia. Treatment with bromocriptine was continued and there was spontaneous progression of normal puberty; the serum testosterone continued to rise, and height maintained the 50th centile. Bromocriptine therapy should be considered as initial therapy in the management of prolactinomas in prepubertal patients.
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