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Biomedical subjects

A D Care

Publications and source records attributed to A D Care.

At least 19 recordsLinked to original sources
PubMed1992

Parathyroid gland hormones in the skeletal development of the ovine foetus: the effect of parathyroidectomy with calcium and phosphate infusion.

It has been confirmed that the foetal parathyroid glands are important in development and that thyroparathyroidectomy (TXPTX) of the ovine foetus with thyroxine (T4) replacement leads to hypocalcaemia, retarded skeletal development, depressed calcification and rickets, relative to thyroidectomy plus T4 replacement. Histomorphometric and biochemical (urinary excretion of deoxypyridinoline) indices of bone resorption are also reduced. However, skeletal calcification can be restored to normal by long-term infusion of the TXPTX foetuses with phosphate and calcium sufficient to normalise the plasma Ca2+ x Pi ion product. Nevertheless, depressed resorption, reduced osteoblast numbers and delayed development persisted. The evidence suggests that the abnormally low number of resorption cavities and osteoclasts may result from the reduction in circulatory parathyroid-hormone-related protein consequent upon the removal of the foetal parathyroid glands and that this hypercalcaemic factor has a direct effect upon the process of resorption and primary trabecular remodelling of the foetal skeleton.

Amino Acids↗
PubMed1992

The effects in the rat of two fragments of parathyroid hormone-related protein on uterine contractions in situ.

Synthetic parathyroid hormone fragment PTH(1-34) has been reported recently to inhibit uterine contractions stimulated by a variety of agonists. We have studied the effect in this system of the parathyroid hormone-related protein fragment PTHrP(1-34) which shows 60% homology with PTH over the first thirteen amino acid residues. The effects of two different PTHrP fragments on acetylcholine-stimulated uterine contractions in vitro were studied. Whereas synthetic hPTHrP(75-86 amide) (10(-9)-10(-7) M) was without effect, synthetic hPTHrP(1-34) (10(-9)-10(-7) M) was capable of inhibiting, in a dose-related fashion, uterine muscle contractions precontracted with 10(-6) M-acetylcholine. In a second series of experiments the bovine PTH(3-34) fragment itself was shown to have no stimulatory effect on acetylcholine-stimulated contractions. Also this fragment in an equimolar concentration (10(-7) M) failed to antagonize the effects of PTHrP(1-34) on acetylcholine-stimulated uterine contractions. However, a 100-fold excess molar concentration of bPTH(3-34) (10(-6) M) completely abolished the inhibitory action of hPTHrP(1-34) (10(-8) M) on acetylcholine-stimulated uterine contractions. These results clearly show that the inhibitory action of PTH(1-34) and PTHrP(1-34) on uterine contractions depends on the integrity of the amino-terminal region of the molecule.

Acetylcholine↗
PubMed1992

Production of parathyroid hormone-related protein by the mammary gland of the goat.

Parathyroid hormone-related protein (PTHRP) has been quantified by sensitive specific immunoassays in mammary venous blood and milk from 7 days before to 7 days after parturition in the goat. A significant venous-arterial concentration gradient in plasma PTHRP 1-86 concentrations was demonstrated across the mammary gland, indicating that PTHRP enters the maternal circulation and may have a role in calcium homoeostasis during lactation. Significant and sustained increases in mammary venous and milk PTHRP 1-86 concentrations were found from 1 day before parturition to 7 days afterwards, with peak concentrations of 1.57 +/- 0.58 pmol/l (plasma) and 8.69 +/- 2.95 nmol/l (milk) (mean +/- S.E.M.) occurring on day -1 and the day of parturition respectively. Estimates of the mammary output of PTHRP into plasma in four goats averaged 9% (range 1-25%) of that secreted into milk. Suppression of maternal prolactin concentrations by bromocriptine significantly reduced milk yield and the mammary venous PTHRP concentration, without affecting the concentration of PTHRP in milk. In conclusion, parturition in the goat is associated with a sustained increase in secretion of PTHRP into both plasma and milk; the former may be involved in maternal calcium homoeostasis, whereas the latter may have a role in the neonate.

Animals↗
PubMed1991

Stimulation of calcitonin secretion in the pig by calcitonin gene-related peptide.

Pig thyroid glands were surgically isolated in situ and perfused with autologous blood to which was added known concentrations of calcitonin gene-related peptide (alpha CGRP). When thyroids were perfused with measured concentrations of CGRP within the range of 0.6-600 nM, the secretion rate of calcitonin (CT) was stimulated while the release of T3, T4, and somatostatin remained unchanged. Specific binding of 125I-CGRP to pig thyroid plasma membranes was demonstrated, and binding was inhibited by unlabelled CGRP but not by CT or by other peptides unrelated structurally to CGRP. The findings indicate that the pig thyroid gland contains plasma membrane binding sites for CGRP and that CGRP is capable of stimulating the secretion of CT.

Animals↗
PubMed1991

Role of the fetal parathyroid glands and parathyroid hormone-related protein in the regulation of placental transport of calcium, magnesium and inorganic phosphate.

The plasma Ca concentration of the fetus is maintained higher than maternal levels by active placental transport. Ca, Mg and PO4 accumulation by the fetus is mainly associated with skeletal growth. The fetal parathyroid glands are essential for maintenance of elevated plasma Ca, which is necessary for the stimulation of fetal osteoblasts and mineralization of cartilage and osteoid. Fetal thyroparathyroidectomy (TxPTx) results in a decreased activity of the placental Ca pump. The presence of a parathyroid hormone-related protein (PTHrP) has been demonstrated in fetal parathyroid glands and placental tissue. Extracts of fetal parathyroid glands and purified PTHrP, as well as recombinant PTHrP (1-84, 1-108 and 1-141), stimulate Ca and Mg but not PO4 transport across the placenta of TxPTx-ized fetuses perfused with autologous blood in the absence of the fetus. Parathyroid hormone (PTH) and the N-terminal region of PTHrP do not stimulate placental Ca and Mg transport. It is concluded that a mid-molecule region of this novel hormone may be required to stimulate placental Ca transfer and contribute to the regulation of fetal Ca homeostasis.

Animals↗
PubMed1990

Measurement of plasma osteocalcin in sheep: assessment of circadian variation, the effects of age and nutritional status and the response to perturbation of the adrenocortical axis.

An assay for plasma osteocalcin (BGP) in ruminants is described. Satisfactory cross-reaction was obtained for bovine BGP in several species, namely ovine, cervine, caprine and human. Sample stability at room temperature, after freezing and thawing and after lyophilization and reconstitution is described. Sheep of both sexes have been used throughout and no significant sex effect has been noted. A series of experiments showed a lack of circadian rhythm of plasma BGP concentration in sheep. Plasma BGP values from sheep ranging in age from 0.25 to 7 years fell exponentially from 300 ng/ml at 0.25 years to approximately 50 ng/ml at 1.25 years of age where it remained until the end of the study at 7 years. Long-term administration of adrenocorticotrophic hormone (ACTH) depressed plasma BGP concentrations, although plasma BGP levels were not affected sufficiently by short-term administration of ACTH to increase plasma cortisol concentrations 10-fold during a period of 4 h. It was confirmed that dietary phosphate deficiency depressed plasma BPG concentrations. It is concluded that neither circadian variation nor the short-term stress of handling and bleeding untrained animals need be considered in sampling sheep for measurement of plasma BGP concentration and that the change with age reflected the pattern of development of skeletal maturity in sheep. Values in both growing and mature sheep were at least 6 times higher than in human subjects, which may reflect the 10-fold higher skeletal growth rate in sheep than in humans. This high skeletal activity in sheep may have been selected for in the development of highly productive breeds.

Adrenocorticotropic Hormone↗
PubMed1990

Stimulation of ovine placental transport of calcium and magnesium by mid-molecule fragments of human parathyroid hormone-related protein.

Perfusion in situ of the placenta of intact or previously parathyroidectomized fetal lambs has been used to assess the ability of three mid-molecule fragments of the human parathyroid hormone-related protein (PTHrP) molecule to stimulate the placental transport of calcium and magnesium. PTHrP(67-86 amide) was most effective but some activity was also shown by PTHrP(75-86 amide) and by PTHrP (75-84) in decreasing order. This placental action of PTHrP(67-86 amide) was rapid and could be observed using the placenta from an intact fetus, whereas it was necessary to use the placenta from a previously parathyroidectomized fetus to demonstrate stimulation of placental calcium transport by PTHrP(1-84). PTHrP(67-86 amide) may resemble the molecule that activates the placental calcium pump.

Animals↗
PubMed1990

Fetal magnesium homeostasis in the sheep.

The fetal plasma magnesium concentration exceeds that of the mother but the difference is small compared to that of ionized calcium concentration. Although not fully independent of changes in maternal magnesaemia, fetal magnesaemia showed a high degree of autonomy during both hypermagnesaemic and hypomagnesaemic changes induced in the ewe. As with calcium, the placental gradient is reversed after fetal thyroparathyroidectomy (TXPTX) with thyroxine replacement. During perfusion in situ of the placenta from such TXPTX fetuses isolated from the fetus itself, a stable positive placental gradient of magnesium concentration could be re-established between the perfusing blood and the maternal circulation. As with calcium, this gradient could be increased by fetal calf parathyroid extract, parathyroid hormone-related protein (PTHrP 1-141), PTHrP (1-84) but not by PTHrP (1-34). It was concluded that a mid-molecule portion of PTHrP can stimulate a putative placental pump which is responsible for the gradients of both calcium ions and magnesium across the ovine placenta.

Animals↗
PubMed1989

Effect of estrogen on calcium homeostasis and pituitary hormones in the growing chick.

An experiment was carried out to investigate the effect of a range of estradiol (E2) doses (0.1-6.5 micrograms/g body wt/day) on vitamin D metabolism and the plasma levels of growth hormone (GH) and prolactin (PRL) in the growing chick. Doses of 0.5-0.7 microgram/g E2, which are insufficient to raise the plasma calcium level, did induce an increase in growth rate, an increase in 25-hydroxyvitamin D 1 alpha-hydroxylase (1-hydroxylase) and 24-hydroxylase activities, and an increase in plasma GH level. These parameters leveled off or fell over the dose range 1-2 micrograms/g E2 but there was evidence of a second peak in 1-hydroxylase activity at 6 micrograms/g E2. At this high dose rate, the plasma Ca level rose to 8 mM, as it does in the laying hen; 24-hydroxylase activity, growth rate, and plasma GH and plasma PRL levels all decreased. It was concluded that the dose response to estrogen in the growing chick is not linear and, in the case of 1-hydroxylase activity, may even be biphasic.

Animals↗
PubMed1989

The parathyroid glands in the skeletal development of the ovine foetus.

The ionized plasma calcium concentration in foetal lambs during the last third of gestation is greater than that in the ewe. Since foetal plasma immunoreactive parathyroid hormone is less than that in the ewe the role of the foetal parathyroid glands is not clear. The effects of foetal parathyroidectomy (PTX) on the foetal:maternal gradient and on skeletal development are examined. The histomorphometry and ash content of six PTX lambs was compared with that of 11 intact animals. A reversal of the plasma ionized calcium gradient took place within 3 days without significant change in the foetal plasma inorganic phosphate or 1,25-dihydroxycholecalciferol content. Skeletal changes consistent with rickets were observed and increased in severity with the time after PTX. It is concluded that the foetal parathyroid glands play an important role in placental calcium transfer and skeletal calcification. However, the agent may be a hypercalcaemic substance other than parathyroid hormone.

Animals↗
PubMed1989

Parathyroid hormone-related protein: isolation, molecular cloning, and mechanism of action.

Many factors, such as interleukin 1, TGF alpha, tumor necrosis factor alpha and beta, and PGs, have been implicated in etiological roles in HHM (Martin and Mundy, 1987). Much interest in the past has also centered upon the likelihood of ectopic secretion of PTH in this condition. We have purified a protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and were found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino acids were identical with human PTH, although antisera directed to the NH2 terminus of PTHrP do not recognize PTH; this homology is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone, possibly related to the PTH gene by a gene duplication mechanism. In support of this notion, the PTHrP gene has been localized to the short arm of chromosome 12; it is believed that chromosome 11, containing the PTH gene, and chromosome 12 are evolutionarily related. In addition, the human PTHrP gene has been isolated, characterized, and shown to have a similar intron--exon organization as the PTH gene. It is possible that the original ancestral gene is indeed the PTHrP gene; resolution of this question awaits studies in lower species. Peptides synthesized to the predicted protein sequence have enabled detailed structure-function studies that have identified NH 2-terminal sequences to be responsible for the biological effects of the molecule. Antibodies raised against the various synthetic peptides have led to the immunohistochemical localization of PTHrP in many human squamous cell carcinomas as well as in a subpopulation of keratinocytes of normal skin. The availability of these antibodies has opened the way for the development of a radioimmunoassay to detect PTHrP in the sera of cancer patients at risk of developing hypercalcemia. The recent characterization of PTHrP-like activity in the ovine fetus suggests some physiological function for PTHrP. It is possible that PTHrP, as the fetal counterpart of PTH, has the role of maintaining the maternal-fetal calcium gradient. The isolation and characterization of PTHrP have added to our understanding of the mechanisms of hypercalcemia and may contribute to the understanding of other metabolic bone diseases, such as osteoporosis and Paget's disease. Finally, and perhaps most importantly, PTHrP may play a hitherto unrecognized role in normal cell physiology.

Amino Acid Sequence↗
PubMed1989

Development of endocrine pathways in the regulation of calcium homeostasis.

The mammalian fetus is maintained hypercalcaemic relative to its mother by the action of a calcium pump believed to be located at the basement membranes of the epithelial cells of the fetal chorion. It has recently been demonstrated that the activity of this putative pump is stimulated by a new fetal hormone, parathyroid hormone-related protein, described originally as the product of a human BEN cell line which was derived from a lung tumour associated with hypercalcaemia of malignancy. Whereas the circulating level of immunoreactive parathyroid hormone in the fetus is very low, in keeping with the hypercalcaemia, the plasma concentrations of bioactive parathyroid hormone and parathyroid hormone-related protein can be measured using a sensitive cytochemical bioassay and the separate concentrations assessed by pre-incubation with appropriate antisera. The total plasma concentration of both hormones is inversely related to the prevailing calcium ion concentration but the set point of parathyroid hormone-related protein is probably higher than that for parathyroid hormone. Probably as a result of the hypercalcaemia, the circulating concentration of calcitonin is also higher than in maternal plasma and may serve to limit bone resorption to favour net bone accretion as part of the overall growth of the fetus. Vitamin D and its most active metabolite, 1,25(OH)2D, can pass across the placenta in either direction, in contrast to most peptide hormones. In addition to the supply of some 1,25(OH)2D by the mother to her fetus, the fetal placenta and fetal kidneys can all synthesize 1,25(OH)2D. The relative concentrations circulating in maternal and fetal plasma pools vary with the species, presumably as a result of differing importance of the three sources of supply to the fetus and the relative concentrations of vitamin D-binding protein circulating in mother and fetus. The importance of parathyroid hormone-related protein derived from fetal parathyroid glands has been clearly demonstrated in the fetal sheep. Such animals develop rickets following the removal of their parathyroid glands, despite the demonstration of this substance in fetal placental membranes. However, the relative importance of the parathyroid glands versus the placenta and its membranes as the principal source of parathyroid hormone-related protein remains to be elucidated and may vary with species.

Animals↗
PubMed1989

Comparison of effects of verapamil, low calcium diet and betamethasone on duodenal calcium absorption efficiency in the chick.

The results indicate that oral administration of verapamil for 2 weeks to the chick is followed by an increase in the efficiency of the duodenal absorption of calcium. In these chicks both a decrease in serum calcium level and an increase in the activity of renal 1 alpha-hydroxylase were observed. The increased calcium absorption following prolonged treatment with verapamil resembles that induced by a low calcium diet. The mechanism of both responses presumably involves an increased production of 1,25-dihydroxyvitamin D3. Both verapamil- and low calcium diet-induced adaptations are capable of overcoming the inhibitory action of betamethasone on intestinal calcium absorption. No effects on calcium absorption were noted if verapamil was administered intraperitoneally which suggests that verapamil exerts its action directly on the intestinal mucosa.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1989

The effect of ruminal phosphate concentration on the absorption of calcium, phosphorus and magnesium from the reticulo-rumen of the sheep.

1. The absorption rates of calcium, inorganic phosphate (Pi) and magnesium were determined from buffered solutions placed in the temporarily isolated and washed reticulo-rumen of conscious sheep. The basic composition of these solutions was similar to that found in supernatant fractions of ultracentrifuged rumen contents. 2. The Pi concentrations studied in these solutions were 2, 8.7, 14, 17.3 and 38 mmol/l. The initial concentration of Ca was 2.0 mmol/l and that of Mg was 2.5 mmol/l in all experiments. 3. Increasing the Pi concentration in the rumen solution from 2 to 38 mmol/l resulted in increases in the net absorption rates of both Ca and Pi, and a decrease in the potential difference across the wall of the rumen. 4. Similarly, increasing the Pi concentration from 2 to 17.3 mmol/l resulted in an increase in the net absorption rate of Mg from the rumen. 5. Mineral analysis of strained rumen fluid or a 30,000 g centrifugate of strained rumen fluid revealed a reduced Pi concentration in sheep fed on frozen spring grass as opposed to the pellet + hay diet. The values obtained were within the range studied.

Animals↗
PubMed1989

Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations.

Perfusion in situ of the placenta of previously thyroparathyroidectomized fetal lambs has been used to compare the ability of various forms of parathyroid hormone-related protein (PTHrP) to stimulate placental calcium transport. Whereas PTHrP (1-34) was without effect, PTHrP (1-141) was active but usually after a delay of up to 1 h, in common with the effect noted when using extracts of fetal parathyroid glands. In contrast, PTHrP (1-84) and PTHrP (1-108), tended to show a more rapid stimulatory action. It is suggested that post-translational processing of PTHrP (1-141) may occur as an activating step in the placenta in vivo.

Animals↗