Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism.

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterized by uniglandular or multiglandular parathyroid tumours that occur in the absence of other endocrine tumours. The disorder may represent either an early stage of multiple endocrine neoplasia type 1 (MEN1), or an allelic variant of MEN1, or a distinct entity involving another locus. We have explored these possibilities in seven families in whom primary hyperparathyroidism occurred as the sole endocrinopathy. METHODS: Seven FIHP families were ascertained and venous blood samples obtained from 35 members (17 affected and 18 unaffected) for DNA sequence analysis of the MEN1 gene. The mean (+/- SD) follow-up period in the 17 affected members was 15.06 (+/- 8.83) years. RESULTS: Four heterozygous germline mutations of the MEN1 gene were identified. These consisted of two 4-bp intragenic deletions that would result in prematurely truncated proteins, and two missense (Asp153Val and Ala411Pro) mutations. Furthermore, analysis of parathyroid tumour DNA from one individual revealed a loss of the wild-type allele and retention of the mutant allele, consistent with Knudson's 'two-hit' model of hereditary cancer and a tumour suppressor role for MEN1 in FIHP. CONCLUSIONS: Our results provide further support for FIHP being a distinct allelic variant of MEN1, and an analysis of the 16 mutations reported to date indicate that FIHP is associated with a higher frequency of missense MEN1 mutations.

Kimura's disease and membranous nephropathy.

An interesting association of Kimura's disease and membranous nephropathy is reported in a 71-year-old Chinese patient, 40 years after emigrating to the UK from Hong Kong. Significant blood eosinophilia and a very high serum IgE level were detected, the latter with a moderate level of specificity to Candida albicans. Light microscopy of renal biopsy was unremarkable despite a proteinuria of nephrotic proportions; diffuse subepithelial dense deposits compatible with membranous nephropathy were identified on electron microscopy. The atopic nature of Kimura's disease is confirmed and C. albicans is suggested as a possible causative agent.

Changes in platelet membrane fatty acids after myocardial infarction.

Myocardial infarction (MI) is a common cause of morbidity and mortality, and platelets may contribute to its development. Platelet membrane composition can influence platelet function. In this study changes in platelet membrane fatty acids with time following MI were explored. Platelet membrane fatty acid profiles were studied in 40 patients after MI, at a mean of 8 days, and compared with a control group of 17 subjects awaiting minor surgery. They were restudied at 1 month and 3 months. Significant changes were found within the patient group in 18:1, which fell with time (19.99% +/- 1.24 to 18.73% +/- 1.16 at 3 months, P less than 0.001), 22:3 + 24:1, which also fell (1.97% +/- 0.48 to 1.46% +/- 0.49, P less than 0.001), and in 18:2, which increased (3.92% +/- 0.77 to 5.04% +/- 1.15 P less than 0.001). Comparison with controls showed no significant differences at baseline, a small increase in 22:4 at 1 month and 3 months in MI group and a decrease in 22:3 + 24:1 in MI group at 3 months. No changes were noted in 20:4, 20:5 or in the polyunsaturated/saturated fatty acid ratio. The explanation for these findings is not known. The possible influence of diet and other factors is discussed.

Prednisolone and chlorambucil treatment in idiopathic membranous nephropathy with deteriorating renal function.

Eight patients with idiopathic membranous nephropathy whose renal function was deteriorating were given a 6-month course of alternating monthly cycles of prednisolone and chlorambucil. Proteinuria was reduced in all eight, from a mean (SD) of 15.3 (5.9) g/24 h at the start of treatment to 2.1 (1.5) g/24 h at follow-up (p less than 0.05). Creatinine clearance increased in six, and the rate of decline was reduced in the other two (group mean 51.6 [17.8] ml/min at the start of treatment and 81.4 [36.8] ml/min at follow-up; p less than 0.05). Adverse effects of chlorambucil were severe, and the daily dose had to be reduced. Prednisolone and chlorambucil treatment can change the natural course of membranous nephropathy even when renal function has started to deteriorate, so treatment can be reserved for high-risk patients.

The effect of intravenous epoprostenol (prostacyclin, PGI2) on cerebral blood flow and cardiac output in man.

Epoprostenol (prostacyclin, PGI2) was given intravenously to seven healthy volunteers in a dose of 4 ng kg-1 min-1 over a 30 min period. Diastolic blood pressure fell but there was no change in cardiac output. The mean PGI2 concentration at the end of the infusion was 0.43 ng/ml (1.1 nM) and a significant inhibition of ADP-induced platelet aggregation occurred. Although obvious facial flushing occurred in all subjects and some subjects complained of headache, cerebral blood flow tended to fall. The results do not support the hypothesis that PGI2 acts as a physiological vasodilator involved in the homeostasis of normal cerebral blood flow.