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Biomedical subjects

I W Caple

Publications and source records attributed to I W Caple.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Ontogeny of parathyroid hormone-related protein in the ovine parathyroid gland.

PTH-related protein (PTHrP) has been implicated in calcium regulation during fetal life. In this study the ontogeny of PTHrP was examined in ovine parathyroid glands. Immunohistochemical techniques, Western blot analysis, and a RIA with antisera raised against synthetic fragments of human (h) PTHrP (i.e. 1-34, 1-40, 50-69, and 107-141) were used to detect the presence of immunoreactive PTHrP in parathyroid glands from fetal and neonatal lambs and maternal ewes. Positive immunostaining for PTHrP was observed in fetal (from 116 days of gestation) and lamb (up to 180 days post birth) but not maternal parathyroid glands with the PTHrP(50-69) antiserum. Fetal and lamb parathyroid glands consisted entirely of one cell type in which PTHrP immunoreactivity to PTHrP(50-69) antiserum was found. In contrast, immunoreactivity to PTHrP could not be detected in sections of fetal, lamb, or maternal parathyroid glands with antisera raised against PTHrP(1-34) or PTHrP(107-141). However, PTHrP immunoreactivity in urea/acid extracts of newborn lamb parathyroid glands could be detected by Western blot analysis and RIA with antisera raised against the N-terminal portion of PTHrP. Western blot analysis with the PTHrP(1-34) antisera revealed that urea/acid extracts of newborn lamb parathyroid glands contained a substance with a mol wt of 14.4K, which corresponded in size to that of hPTHrP(1-84). Newborn lamb parathyroid glands contained 0.35 ng PTHrP/micrograms extract, whereas maternal parathyroid glands contained only 0.035 ng PTHrP/micrograms extract when tested in a RIA employing recombinant hPTHrP(1-84) as standard and an antibody raised against hPTHrP(1-40). The detection of immunoreactive PTHrP in the developing ovine parathyroid gland provides further evidence to support the suggestion that PTHrP produced in the parathyroid gland is involved in the normal hormonal regulation of calcium metabolism in the mammalian fetus and neonate.

Animals↗
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↗
PubMed1990

Measurement of parathyroid hormone-related protein in extracts of fetal parathyroid glands and placental membranes.

A radioimmunoassay based on an antiserum to human parathyroid hormone-related protein PTHrP(1-16) was used with PTHrP(1-34) standard to measure the concentration of immunoreactive PTHrP in extracts of fetal parathyroid glands from lambs and calves and also placental membranes obtained from several species, including man. Dilution curves from these sources were parallel to those obtained for PTHrP(1-34) standard. It was demonstrated that this parallelism was not the result of tracer damage caused by enzymic activity in the tissue extracts. Extracts of human placental membranes were subjected to high-pressure liquid chromatography with a linear acetonitrile gradient. Co-elution of cytochemical biological activity with 125I-labelled PTHrP(1-34) was noted. These results provide further evidence for both the fetal parathyroid glands and the placenta containing material resembling PTHrP which may be responsible for sustaining the activity of the placental calcium pump which maintains the fetus hypercalcaemic relative to its mother.

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

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↗
PubMed1989

Osteocalcin as an index of osteoblast function during and after ovine pregnancy.

Fetal and neonatal calcium requirements impose heavy demands on maternal bone and mineral homeostasis. The functional response of maternal osteoblasts to this stress is poorly understood. Therefore, plasma osteocalcin (OC) levels were measured by homologous RIA in age-matched nonpregnant, pregnant, and postpartum ewes to evaluate osteoblast function. In pregnant ewes from day 35 of gestation to term, the plasma OC level was suppressed to 8.2 +/- 0.5 micrograms/liter (mean +/- SEM; n = 36) compared with age-matched nonpregnant ewes (18.3 +/- 1.1 micrograms/liter; n = 39; P less than 0.0005). Plasma OC rose to the nonpregnant value by day 20 postpartum and was elevated above this level for the following 40 days (e.g. 44.0 +/- 5.0 micrograms/liter at 48-53 days; P less than 0.0005). The timing of changes in plasma OC levels and weaning did not correlate. The validity of plasma OC measurement as a marker of osteoblast function was assessed by determining the OC plasma production and clearance rates using an [125I]ovine OC infusion method. The OC plasma production rates in matched controls (n = 6), pregnant (n = 9), and 48-53-day postpartum sheep (n = 7) were 1.5 +/- 0.2, 0.5 +/- 0.04 (P less than 0.001 vs. control), and 3.6 +/- 0.6 mg/day (P less than 0.005 vs. pregnant sheep), respectively. In one ewe studied longitudinally, the OC plasma production rate increased by 15 days after parturition and achieved a 10-fold elevation at 49 days postpartum. The OC plasma clearance rate (3.3 +/- 0.3 liters/h) was the same in control, pregnant, and postpartum ewes. It is concluded that 1) changes in plasma OC levels during and after ovine pregnancy reflected changes in OC production, 2) plasma OC measurements are likely to be a useful index of osteoblast function in pregnancy, and 3) osteoblast function appears to be depressed during ovine pregnancy and enhanced markedly in the interval 20-60 days postpartum. The relationship between osteoblast function, as indicated by OC production, and bone formation remains to be clarified.

Aging↗
PubMed1978

Blood glutathione peroxidase activity in horses in relation to muscular dystrophy and selenium nutrition.

The activity of glutathione peroxidase, a selenium containing enzyme, was measured in the blood of horses to determine its usefulness as an indicator of selenium status. In 15 horses the enzyme activity was positively related to the blood selenium concentration (P less than .001, r-0.98) over the range of enzyme activities of 8.2 to 140 units (mumoles NADP-oxidised/min/gHb) and selenium concentrations of 0.24 to 2.74 mumol/l. In a group of 8 horses which 2 foals had died with lesions of muscular dystrophy the enzyme activity increased from a mean of 11.8 units before treatment with selenium to 34.5 units after 2 intravenous injections of sodium selenite given one month apart. Another group of 8 horses grazing paddocks adjacent to this affected group did not receive any selenium treatment and had a mean enzyme activity of 11.9 units. Blood glutathione peroxidase activity was measured in 50 pasture-fed horses and 180 stall-fed horses. The range of activities found (7 to 158 units) indicated that selenium intake in horses varied widely between localities. All pasture-fed horses grazing areas where muscular dystrophy had occurred in foals had low activities (less than 20 units). In stall-fed horses the enzyme activity was influenced by selenium treatment, and horses which had been treated usually had higher activities than horses in the same stable with no history of selenium treatment. It was concluded that blood glutathione peroxidase is a suitable indicator of selenium status in horses.

Animals↗
PubMed1978

Some clinico-pathologic findings in elephants (Elephas maximus) infected with Fasciola jacksoni.

Severe submandibular and ventral abdominal oedema was observed in an Asian elephant (Elephas maximus) in which liver flukes (Fasciola jacksoni) were recovered from the bile ducts at post-mortem examination. Clinico-pathologic examination of blood samples and serum from this elephant and another 8 elephants showed that most had anemia and hypoproteinemia. Fecal samples from 6 of the elephants contained from 6 to 83 eggs per gram. Treatment of elephants with nitroxynil (10 mg/kg) by subcutaneous injection produced severe local reactions at the injection site. Feces collected 2 and 4 months after treatment were free of trematode eggs. Hematologic values measured 4 months after treatment showed that the hemoglobin concentration, packed cell volume, erythrocyte count and plasma protein concentration had increased to within the normal range.

Animals↗
PubMed1978

Changes in the concentration of copper in serum of sheep during halothane anaesthesia.

Concentrations of serum copper and caeruloplasmin were measured in jugular blood samples of sheep before, during and after halothane anaesthesia. Significant decreases were recorded in the concentration of serum copper during anaesthesia, but caeruloplasmin activity did not change significantly. The serum copper concentration increased when the sheep were allowed to recover, and returned to pre-anaesthetic values after 3 h.

Anesthesia↗