Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes.

AIM: This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes. METHODS: This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial. RESULTS: Haemoglobin A(1c), the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: -0.32, 95% confidence interval (CI) (-0.48; -0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: -0.79, 95% CI (-1.17; -0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies. CONCLUSIONS: This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.

Vitamin D supply to the rat fetus and neonate.

The prevention of neonatal rickets by oral supplementation with vitamin D2 (ergocalciferol) has tended to obscure our ignorance of the natural mechanism by which young mammals receive an adequate supply of vitamin D. To investigate the possibility of specific intrauterine transfer and storage of vitamin D in fetal tissues, vitamin D-deficient female rats were given depot injections of 3H- or 14C-labeled vitamin D3 (cholecalciferol) before mating and the 3H-labeled animals were killed at stages during the last third of gestation. Analysis of lipid extracts from whole fetuses revealed a linear increase in the concentration of 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and D3 itself between days 14 and 19 of gestation. During this period the elimination half-time of 3H-labeled molecules in maternal plasma fell from 27.1 to 4.4 d, suggesting that a specific mechanism was transferring vitamin D molecules into the fetuses. The vitamin was stored predominantly as 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3, with the highest concentrations in fetal muscle. Immediately after birth, pups from 3H- and 14C-labeled mothers were exchanged and later killed after 1-3 wk of suckling. Analysis of total lipid extracts for 3H and 14C content determined the relative contributions of vitamin D supplied before birth via the placenta and after birth in the maternal milk. The vitamin D content of the rat milk was relatively high, between 1.0 and 3.5 micrograms/liter. Nevertheless, the supply of vitamin D in utero, rather than from milk, was the main determinant of vitamin D status in early neonatal life. This is the first indication in a mammal of a specific transfer mechanism that allows the fetus to accumulate vitamin D from the mother during the last third of gestation.

Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients.

The effect of mutations at codon 804 in the RET protooncogene is disputed. Some studies have suggested that the V804L mutation causes the low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others have reported that V804L and V804M have an aggressive potential. In this paper, we report three apparently unrelated medullary thyroid carcinoma cases homozygous for these mutations. To clarify the phenotypic heterogeneity associated with these mutations, we compare the clinical data and age of diagnosis among these three homozygous patients, six other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data are consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804.

Recovery from sensorineural deafness in Wegener's granulomatosis.

Wegener's granulomatosis may present with deafness or other aural symptoms. This report describes two patients with histological evidence of Wegener's granulomatosis who developed reversible sensorineural hearing loss during the course of their illness. The first patient showed complete recovery of a sensorineural hearing loss averaging 50 dB after ten months treatment with cyclophosphamide and high-dose prednisolone. The second patient, who was on maintenance haemodialysis, achieved a 40 dB improvement in sensorineural hearing loss within two weeks of adding cyclophosphamide to pre-existing corticosteroid therapy. These findings suggest that the prognosis of sensorineural hearing loss in Wegener's granulomatosis can be improved with suppression of the vasculitic process by early treatment with combined cytotoxic-immunosuppressive therapy.

A new mechanism for induced vitamin D deficiency in calcium deprivation.

Synthesis of vitamin D in the skin in response to ultraviolet light is the main determinant of vitamin D status in man and it is therefore surprising that rickets and osteomalacia, clinical signs of vitamin D deficiency, remain common in tropical and subtropical countries. Skin pigmentation can reduce vitamin D formation but this is a negligible limitation in people exposed to abundant ultraviolet light. Earlier studies in animals and man suggested that another environmental factor, the low calcium/high cereal diet typical of susceptible populations, might affect the efficiency of vitamin D utilization. We show here in rats that the rate of inactivation of vitamin D in the liver is increased by calcium deprivation. The effect is mediated by 1,25-dihydroxyvitamin D, produced in response to secondary hyperparathyroidism, which promotes hepatic conversion of vitamin D to polar inactivation products that are excreted in bile. This finding has widespread implications both for understanding the pathogenesis of endemic rickets and in that it provides a unifying mechanism for the development of vitamin D deficiency in many clinical disorders.

Enterohepatic circulation of vitamin D: a reappraisal of the hypothesis.

Vitamin-D metabolites in bile were investigated after oral and intravenous doses of radioactively labelled vitamin D had been given to six patients with T-tube biliary drainage after cholecystectomy. The vitamin was mainly excreted as highly polar inactivation products and less than 4% of the metabolites in bile were present as 25-hydroxyvitamin D or its glucuronide conjugate. There was insufficient vitamin D or 25-hydroxyvitamin D in bile for the reabsorption of these metabolites to make a significant contribution to normal vitamin-D status. Therefore interference with an enterohepatic circulation of vitamin-D metabolites cannot be a cause of vitamin-D deficiency.

Tumoral calcinosis: clinical and metabolic response to phosphorus deprivation.

Two patients with extensive tumoral calcinosis were treated with aluminium hydroxide. Initial metabolic studies showed positive calcium and phosphorus balances which became negative with aluminium hydroxide treatment. One subject, who had renal impairment, developed transient hypercalcaemia, parathyroid suppression, low levels of 1,25-dihydroxyvitamin D and calcium malabsorption during treatment with aluminium hydroxide. The second patient developed calcium malabsorption due to vitamin D deficiency. When she was replete with vitamin D there were supranormal levels of 1,25-(OH)2D in the serum and enhanced calcium absorption during treatment with aluminium hydroxide. Both subjects developed hypercalciuria and there was dissolution of many of the calcific tumours. The patient with renal impairment accumulated aluminium in the bone.

Giant cell tumours in mandible and spine: a rare complication of Paget's disease of bone.

The case of a man who was diagnosed as having polyostotic Paget's disease at the age of 52 years is described. He developed a rare neoplastic complication of Paget's disease--a giant cell tumour in his mandible, which was excised. Nine years after the diagnosis of this tumour he developed a new giant cell tumour arising from the L3 vertebral body. He was born in Avellino in Italy, from where five other cases of giant cell tumours arising from Pagetic bone disease have been reported. No family relationship between our patient and the other cases was established. His Paget's disease was particularly aggressive and resistant to treatment with two single high dose infusions of pamidronate almost two years apart.

Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism.

1. The elimination half-time of 25-hydroxyvitamin D in plasma was estimated after intravenous injection of the radioactively labelled metabolite in seven patients with primary hyperparathyroidism before and after excision of a parathyroid adenoma. 2. The elimination half-time of 25-hydroxyvitamin D was significantly shortened in primary hyperparathyroidism and reverted towards normal after parathyroidectomy. 3. The increased metabolic clearance of 25-hydroxyvitamin D in primary hyperparathyroidism was accounted for by an increased excretion of vitamin D-derived inactivation products in the faeces. 4. Enhanced hepatic inactivation of 25-hydroxyvitamin D may be important in the development of vitamin D deficiency in primary hyperparathyroidism.

The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency.

OBJECTIVE: We wished to assess the effect of changes in the plasma concentration of 1,25-dihydroxyvitamin D on the plasma elimination half-time for 25-hydroxyvitamin D in man. DESIGN: The turnover of 25-hydroxyvitamin D in plasma was investigated after intravenous doses of the radioactively labelled metabolite had been given to a group of patients (n = 17) with disorders of bone and mineral metabolism before and after oral treatment with calcium or 1,25-dihydroxyvitamin D. PATIENTS: Seven patients with post-menopausal osteoporosis, five with hypoparathyroidism, three with hypophosphataemic osteomalacia, one with renal osteodystrophy and one patient with coeliac disease were studied. MEASUREMENTS: Intravenous injections of 3H-labelled 25-hydroxyvitamin D were given and plasma elimination half-time assessed over periods of 4-14 days during which frequent measurements of plasma calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were made. Changes in the plasma elimination half-time for 3H-25-hydroxyvitamin D before and after treatment with calcium and 1,25-dihydroxyvitamin D were evaluated by non-parametric statistical analysis. RESULTS: The elimination half-time for 3H-25-hydroxyvitamin D in plasma was significantly shortened by raising the circulating concentration of 1,25-dihydroxyvitamin D. Conversely, in a patient with intestinal malabsorption of calcium, the metabolic clearance of 3H-25-hydroxyvitamin D was prolonged when the concentration of 1,25-dihydroxyvitamin D in plasma was decreased by suppressing secondary hyperparathyroidism with large calcium supplements. In the longer-term studies (n = 10) there was a highly significant inverse relation (r = -0.88, P < 0.001) between the change in the plasma concentration of 1,25-dihydroxyvitamin D and the induced change in the elimination half-time of 3H-25-hydroxyvitamin D. There was also a significant correlation (r = 0.66, p < 0.0025) between the observed fall in the plasma concentration of unlabelled 25-hydroxyvitamin D and the predicted fall calculated from the measured value for the half-time of the 3H-labelled metabolite. In acute studies in patients with post-menopausal osteoporosis (n = 7), enhanced metabolic inactivation of 3H-25-hydroxyvitamin D was detectable within 24 hours of oral administration of 1,25-dihydroxyvitamin D. CONCLUSIONS: The effect of 1,25-dihydroxyvitamin D on the catabolism of 25-hydroxyvitamin D can contribute to the development of vitamin D deficiency in many clinical disorders. When the natural supply of vitamin D is limited by sunlight deprivation, a sustained increase in the plasma concentration of 1,25-dihydroxyvitamin D due to primary or secondary hyperparathyroidism will lead to accelerated depletion of vitamin D stores.