Biomedical subjects
Publications and source records attributed to I MacIntyre.
(1) Vitamin D is the precursor of an extremely potent calcium regulating hormone, 1,25(OH)2D3, which is secreted by the kidney. (2) The secretion of 1,25(OH)2D3 by the kidney is influenced by the calcium and phosphorus content of the diet, parathyroid hormone, and 1,25(OH)2D3 itself. (3)Prolactin and growth hormone are importnat regulators of vitamin D metabolism during pregnancy and growth.
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The influence of estrogen on the metabolism of 25-hydroxyvitamin D3 was studied in 2- to 5-wk-old chicks. Single injections of at least 500 microgram diethylstibestrol (DES) increased the conversion of 25-hydroxyvitamin D3 to 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) and suppressed the production of 24,25-dihydroxyvitamin D3 in chick kidney homogenates. Acute (one 5-mg) injections of testosterone or progesterone did not enhance the 25-hydroxyvitamin D3-1alpha-hydroxylase, indicating specificity. However, chronic pretreatment with DES appeared to allow the potentiation of previously unstimulatory steroids such as progesterone and testosterone. In addition, the hormonal metabolite of vitamin D3, 1alpha,25-(OH)2D3, was measured in 4- to 6-wk chick plasma after steroid treatment. Greater than 1 mg DES per day for 5 days was necessary to enhance the circulating level of 1alpha,25-(OH)2D3; testosterone alone had no effect. This elevation was rapid, occurring within 12--24 h after injection. These data suggest that estrogen (as evidenced by DES treatment) is a modulator of vitamin D metabolism along with other known regulators such as parathyroid hormone, phosphate, and 1alpha,25-(OH)2D3. The mechanism of the regulation is as yet unknown.
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Antibodies to the central fragments 9-20 dodecapeptide sequence of CCK were used for specific immunostaining of the CCK cells of the mammalian gut. The use of high specific antibodies to synthetic fragment, essential when there is a possibility of immunochemical cross reactions between antisera and hormones of similar molecular structure provides the key to increased understanding of the nature and relationships of peptide hormones.
Many factors influence the production of 1,25(OH)2D3 (1,25-dihydroxycholecalciferol) by the kidney. One important factor seems to be feedback regulation by 1,25(OH)2D3 itself. Administration of 1,25(OH)2D3 to vitamin D-deficient chicks abolishes renal 25(OH)D3(25-hydroxycholecalciferol)1-hydroxylase activity and induces the appearance of 25(OH)D3 24-hydroxylase activity. It is likely that these effects are mediated via a nuclear effect, as they are prevented by pretreatment with actinomycin D and alpha-amanitin. Further, 1,25(OH)2D3 has a marked effect on gene transcription in the kidney cell, as assessed by measurement of RNA polymerase activities. RNA polymerase I and II activities are 80-90% inhibited by 12.5nmol of 1,25(OH)2D3 within 30min of subcutaneous administration, indicating an immediate and massive decrease in total gene transcription. By 4h RNA polymerase II activity has returned to control values, but RNA polymerase I activity is markedly enhanced. These results are consistent with the view that regulation of cholecalciferol metabolism in the kidney is associated with an effect of the active metabolite on the kidney nucleus.
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A total of 107 patients with bronchial carcinoma have been studied for the presence of potential circulating tumour markers which might be used as indicators of recurrence after primary treatment. Plasma carcinoembryonic antigen (CEA) levels were estimated in every patient and, after a preliminary hormone screening study, plasma calcitonin (CT) and parathyroid hormone (PTH) levels were assayed in 66 patients. Oat-cell tumours proved to be of particular interest in that CEA levels greater than 40 microgram/l were measured (initially or subsequently) in 40.6 percent and CT levels were elevated in 75 percent. Longitudinal studies point towards the possible use of elevated marker levels as guides to therapy when all other features of recurrent disease are lacking. It is clear that no ideal tumour marker exists for bronchial carcinoma but in an individual case an abnormal level of one or more marker substances may provide a valuable aid to treatment.
In eight patients with symptomatic Paget's disease, radiographs and radioisotope bone scans have been compared before treatment by high dose synthetic human calcitonin (CIBA 47175-Ba) and three months and 12 months later. In six patients quantitative radioisotope scans allowed calculation of relative radioactivity in normal bone, Paget's disease and bone adjacent to osteoarthritic joints. Comparison of radiographs and scans showed 69 sites diagnosed as Paget's disease on both examinations; nine sites showed radiographic changes of Paget's disease but had negative radioisotope scans and two sites were abnormal on the scan but radiologically normal. One of these two reverted towards normal during treatment with calcitonin. Comparison of analogue scans done at three months and 12 months with initial scans showed diminished uptake in Paget's disease compared with normal bone, and quantitation showed this was due to decreased absolute uptake in Paget's disease and a slight increase in normal bone. Osteoarthritic bone showed no significant response to calcitonin.
Two children with bone dysplasia with hyperphosphatasemia (juvenile Paget's disease) were treated with synthetic human calcitonin. The progress of bone disease was monitored radiographically and histologically. Pretreatment radiographs showed markedly abnormal bone, characterized by lack of discrete cortex and absence of normal modeling. During treatment a discrete cortex was formed composed of compact bone, and more normal modeling occurred. This coincided with a histologic change from woven bone before treatment to a more lamellar type during treatment.
Inhibition of osteocytic osteolysis in bats given calcitonin injections during late hibernation supported previous morphologic evidence that the bone loss during hibernation is associated with decreased calcitonin and increased parathormone activity.
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The regulation of vitamin D metabolism by the kidney is now known to be multifactorial. Three regulatory factors are discussed: 1,25(OH)2D3 itself; parathyroid hormone, and phospate. The influence of 1,25(OH)2D3 probably depends on new protein synthesis, while the mode of action of phosphate is unknown. Parathyroid hormone is not essential for regulation but may have an important biological role. The direction of its effect varies, perhaps due to a complex interrelation of changes in calcium and phosphorus metabolism and the level of kidney adenyl cyclase activity.