Biomedical subjects
Publications and source records attributed to P W Ho.
A young boy presented with history of abdominal trauma. History and initial clinical findings suggested a soft tissue injury. Due to increasing abdominal pain and fever, we proceeded with an exploratory laparotomy with a diagnosis of intra-abdominal injury, at which we found a perforated appendix. Appendicitis following blunt abdominal trauma needs high index of suspicion.
Intrauterine parathyroid hormone-related protein (PTHrP) concentrations are reduced in association with growth restriction in the spontaneously hypertensive rat (SHR) compared to those of its normotensive control, the Wistar Kyoto (WKY) rat, implicating PTHrP as a pivotal fetal growth factor. The aim of this study was to examine, by embryo cross-transplanation between SHR and WKY, whether the mother, fetus, or both, are responsible for the suppressed SHR amniotic fluid PTHrP. One-day-old SHR embryos were gestated in either an SHR (SHR-in-SHR) or WKY (SHR-in-WKY) surrogate, similarly one-day-old WKY embryos were gestated in either an SHR (WKY-in-SHR) or WKY (WKY-in-WKY) mother. At 20 days gestation, maternal plasma and amniotic fluid samples were collected and assayed for PTHrP concentrations. Data were analysed by two-way ANOVA (mean+/-sem, n=5-9 mothers/group). There were no differences in litter number or maternal plasma PTHrP concentrations. Fetal weight (P< 0.009), fetal/placental weight ratio (P< 0.004) and amniotic fluid PTHrP concentrations (P< 0.001) were lower and amniotic fluid volume (P< 0.0001) was higher with an SHR fetus compared to the WKY fetus irrespective of maternal strain. Thus, the SHR fetus is growth restricted and has suppressed amniotic fluid PTHrP, which are largely determined by the fetus or gestational tissues and are independent of maternal hypertension or maternal PTHrP. We suggest that the low SHR amniotic fluid PTHrP may play a role in the development of SHR growth restriction.
PTH and ionized calcium levels were measured in 131 patients with advanced prostate cancer, all of whom had received at least first-line hormone therapy. Patients were classified into those in remission, those with stable disease, or those with progressive disease according to their prostate-specific antigen response and their clinical status. Thirty-four percent of all patients had PTH levels above the upper level of normal for controls of similar age (7.0 pmol/liter), and in 44% of these patients this was associated with a normal ionized calcium. Patients with proven bone metastases had significantly higher PTH levels than those without. (7.3 +/- 0.5 vs. 4.3 +/- 0.4 pmol/liter, P < 0.0005). There was evidence for a difference in the PTH levels between the three response groups. The PTH levels tended to be higher in patients with progressive disease. Thirty-seven of 65 patients (57%) with both progressive disease and proven bone metastases had elevated PTH levels. Mean levels of urinary deoxypyridinoline and cAMP were significantly greater in patients with high PTH than in those with a normal PTH. Treatment with oral calcium supplements in 32 patients with a high PTH seemed to have only a transient effect on elevated PTH or low ionized calcium levels. These data show that secondary hyperparathyroidism occurs frequently in patients with advanced prostate cancer, particularly in those with both progressive disease and bone metastases. The increased PTH levels are associated with an increase in bone resorption markers. These findings raise important questions about the role of PTH in progression of prostatic cancer in bone and the potential limitations of the use of bisphosphonates in patients with a raised PTH or low serum calcium.
OBJECTIVE: Parathyroid hormone-related protein has roles in normal fetal growth, placental calcium transport, and vascular tone regulation; these factors are compromised in growth-restricted fetuses. Our objective was to determine whether intrauterine parathyroid hormone-related protein expression was increased in association with fetal growth restriction. STUDY DESIGN: The expression of parathyroid hormone-related protein was examined in intrauterine tissues from women with idiopathic fetal growth restriction with preterm (n = 8-10) and term (n = 8-10) gestations and from gestation-matched control subjects. The abundance and immunoreactive content of parathyroid hormone-related protein messenger ribonucleic acid were determined by Northern blot and radioimmunoassay, respectively, in the placenta, amnion, and chorion-decidua. RESULTS: The expression of parathyroid hormone-related protein messenger ribonucleic acid was increased in the amnion (placental and reflected) in association with preterm fetal growth restriction (P <.05). Both parathyroid hormone-related protein messenger ribonucleic acid and protein expression were increased in chorion-decidua in association with preterm fetal growth restriction (P <.05). In term gestations both parathyroid hormone-related protein messenger ribonucleic acid and protein expression were greater in amnion over placenta than in reflected amnion (P <.05); these in turn were greater than those in chorion-decidua (P <.05). No significant changes were detected in parathyroid hormone-related protein messenger ribonucleic acid or in protein expression in association with term fetal growth restriction. CONCLUSION: Either parathyroid hormone-related protein messenger ribonucleic acid or protein expression, or both, was increased in the fetal membranes in association with fetal growth restriction in preterm but not term gestations, suggesting that parathyroid hormone-related protein may be involved in the pathogenesis of preterm fetal growth restriction.
Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) in stimulating cell growth and differentiation, placental calcium transport, and placental vasodilatation. As spontaneously hypertensive rat (SHR) fetuses are growth restricted compared with those of its normotensive control, the Wistar Kyoto (WKY) rat, we examined intrauterine PTHrP and total and ionic calcium concentrations in these rats. Fetal plasma PTHrP concentrations, but not total calcium concentrations, were lower in the SHR compared with WKY (P < 0.05). SHR placental concentrations of PTHrP were lower than in WKY (P < 0.03) and failed to show the increase observed in WKY near term (P < 0.05). PTHrP concentrations in amniotic fluid from SHR were not raised near term and were lower compared with WKY (P < 0.0005). The increased ionic calcium concentrations in amniotic fluid in the WKY near term (P < 0.05) were not detected in the SHR. Thus SHR fetal plasma, placental, and amniotic fluid PTHrP concentrations were reduced and associated with fetal growth restriction. We suggest that PTHrP may play a role in the etiology of both growth restriction during pregnancy and hypertension later in life.
Parathyroid hormone-related protein (PTHrP) is present in fetal and gestational tissues, in which its proposed roles include stimulation of epithelial growth and differentiation, vasodilatation of the uteroplacental vasculature, relaxation of uterine muscle and stimulation of placental calcium transport. The aim of this study was to determine whether the release of PTHrP from gestational tissue explants was tissue specific. In addition, PTHrP concentrations were measured in maternal plasma, umbilical artery and vein plasma, and amniotic fluid from term, uncomplicated pregnancies before the onset of labour. PTHrP was detected in low concentrations in the mother, fetus and placental tissue. Amniotic fluid had ten times the PTHrP concentration compared with that in the maternal or fetal circulations. Using late pregnant human gestational tissues in an in vitro explant system, we found that amnion over placenta, choriodecidua, reflected amnion, and placenta released PTHrP into culture medium in progressively greater amounts over 24 h (P<0.05). This release was not associated with a loss of cell membrane integrity, as indicated by measurement of the intracellular enzyme, lactate dehydrogenase, in the incubation media. After 24 h incubation, the fetal membranes released significantly (P<0.05) greater amounts of PTHrP than did the placenta (placenta 3. 7+/-0.5 pmol PTHrP/g protein). Amnion over placenta released significantly more PTHrP (139.3+/- 43.1 pmol PTHrP/g protein) than did reflected amnion (29.0+/-8.3 pmol PTHrP/g protein) (P<0.05). This study unequivocally demonstrated that human gestational tissues release PTHrP and it was concluded that the main contributors to PTHrP in amniotic fluid were the human fetal membranes, particularly amnion over placenta. Fetal membrane-derived and amniotic fluid PTHrP are proposed to have stimulatory effects on epithelial growth and differentiation in fetal lung, gut, skin and hair follicles and paracrine effects on placental vascular tone and calcium transport.
Maternal hypertension, vasoconstriction and placental insufficiency are features of pre-eclampsia. Alterations in calcium homeostasis and in the production of calciotropic hormones and vasoactive agents have also been described in association with pre-eclampsia. Parathyroid hormone-related protein (PTHrP) is abundantly expressed in intrauterine tissues during normal pregnancy and has roles in fetal growth and calcium homeostasis, placental calcium transport and vascular tone regulation. Intrauterine PTHrP mRNA expression and tissue PTHrP content were determined by Northern blot analysis and radio-immunoassay, respectively, in preterm and term pre-eclamptic women. PTHrP mRNA expression and PTHrP content in placenta, amnion over placenta, reflected amnion and choriodecidua from preterm pre-eclamptic women (n=8-10) were not different from preterm controls (n= 10-12). PTHrP mRNA expression and content in amnion over placenta and reflected amnion were significantly greater in term compared to preterm pre-eclamptics (P<0.05). PTHrP mRNA expression was significantly lower in choriodecidua from term pre-eclamptic women (n=8) compared to term controls (n=28, P<0.05), but was not different in placenta or amnion. PTHrP content was not altered in term pre-eclamptic women (n=8) compared to controls (n=25) for any tissue. In summary, PTHrP expression in placenta and amnion was not increased in pre-eclamptic women in association with maternal hypertension, placental insufficiency and vasoconstriction. PTHrP mRNA expression was decreased in choriodecidua in association with term but not preterm pre-eclampsia, however, levels of the protein were not decreased. The data suggest that PTHrP is not involved in the placental pathophysiology of pre-eclampsia in late gestation.
Parathyroid hormone-related protein (PTHrP) is highly expressed in normal skin keratinocytes, and its involvement in growth and differentiation processes in these cells has been implicated by several lines of evidence which include the use of antisense PTHrP (Kaiser et al., 1994, Mol. Endocrinol., 8:139-147). In this study, we have investigated whether PTHrP expression and its subcellular localization is linked to cell cycle progression in a human keratinocyte cell line (HaCat), which constitutively expresses and secretes PTHrP. PTHrP mRNA and immunoreactive PTHrP were assessed in asynchronous dividing cells and in cells blocked at G1 or G2 + M phases of the cell cycle using several different protocols. The response of PTHrP mRNA expression was examined following readdition of serum in the continued presence of cycle blockers, and after release from cell cycle block, or from cell synchronization by serum deprivation. PTHrP expression was greatest in actively dividing cells when cells were in S and G2 + M phases of the cell cycle and were lowest in quiescent G1 cells. Most notable were the high levels of PTHrP mRNA and protein in cells at G2 + M phase of the cell cycle at division. Furthermore, PTHrP was localized to the nucleolus in quiescent cells, but redistributed to the cytoplasm when cells were actively dividing. Taken together, these results support a role for PTHrP in cell division in keratinocytes. In asynchronously growing cells, PTHrP expression fell as cells became confluent at a time when cell growth is inhibited and cells begin to differentiate. Mitogen stimulation of HaCaT cells resulted in a rapid increase in PTHrP mRNA expression, but was dependent upon cells being in the G1 phase of the cell cycle. Cells blocked in G1 responded to mitogen both in the continued presence of aphidicolin or when released from block. Cells blocked at G2 + M with colcemid expressed high levels of PTHrP mRNA and protein, and PTHrP mRNA did not respond further to mitogen in the continued presence of blocker. However, in cells released from block at G2 + M by addition of serum, an increase in PTHrP expression was seen coincident with the progression of cells into G1. In contrast, in a squamous cancer cell line (COLO16), basal PTHrP expression was high and was not altered during the cell cycle or by cell cycle block, consistent with association of its dysregulated expression in malignant cells. The results of this study suggest that PTHrP may have two roles in the cell cycle; one in G1 in response to mitogen, and a second at cell division when its expression is high and it is relocated from the nucleolus to the cytoplasm.
Parathyroid hormone-related protein (PTHrP) gene expression and/or immunoreactive protein have previously been identified in the uterus and intrauterine gestational tissues. The putative roles of PTHrP during pregnancy include vasodilatation, regulation of placental calcium transfer, uterine smooth muscle relaxation and normal fetal development. The aims of this study were 1) to determine the tissue-specific and temporal expression of PTHrP mRNA and immunoreactive protein in human gestational tissues collected at preterm and term; and 2) to determine the effect of labour on PTHrP expression by collecting these tissues from women undergoing elective caesarean section (before labour), intra-partum caesarean section during spontaneous-onset labour (during labour), and women with spontaneous labour and normal vaginal delivery (after labour). Total RNA and protein were extracted from placenta, amnion (over placenta and reflected) and choriodecidua for analysis by Northern blot (using a specific human PTHrP cDNA probe), and by N-terminal PTHrP RIA respectively. In amnion over placenta, reflected amnion and choriodecidua both PTHrP mRNA relative abundance and immunoreactive protein were significantly elevated at term compared with preterm (P < 0.01). At term, both PTHrP and its mRNA were significantly greater in amnion than in placenta and choriodecidua (P < 0.05). Also, both PTHrP and its mRNA were significantly elevated in amnion over placenta compared with reflected amnion (P < 0.05). The expression of PTHrP and its mRNA did not change in association with term labour or rupture of the fetal membranes, therefore this study provides no evidence for a specific PTHrP role in the onset and/or maintenance of term labour. However, the significant up-regulation of PTHrP mRNA and protein in the fetal membranes at term compared with preterm suggests an important role in late human pregnancy.
The expression of parathyroid hormone-related protein (PTHrP) was studied in a range of cell cultures representative of the osteoblast lineage and in rat calvarial sections. Primary newborn rat calvarial cells, a rat preosteoblastic cell line (UMR 201), a mouse stromal cell line (ST 2), a mouse calvaria-derived osteoblastic cell line (KS 4), and rat osteosarcoma cell lines (UMR 106-01 and -06), all expressed PTHrP when examined by reverse transcription polymerase chain reaction (RT-PCR). Using a radioimmunoassay we also demonstrated PTHrP in the conditioned medium of the cultured cells, with the exception of UMR 106-01 and -06 cells. Treatment of UMR 201 cells with all-trans-retinoic acid which induces them to acquire a more differentiated phenotype, also led to a time-dependent decrease in PTHrP mRNA levels as determined by RT-PCR, Northern blot analysis, and in situ hybridization. Decreased PTHrP levels in the conditioned medium of the treated cells was also observed. These results suggested that PTHrP production might be greater in less mature osteoblasts. Examination of the populations obtained from newborn rat calvariae by sequential collagenase digestion revealed that the early digests exhibited low ALP activity, low expression of PTH/PTHrP receptor mRNA, and no adenylate cyclase response to PTHrP(1-34). These populations showed the highest level of mRNA and production of PTHrP. Cells from later digests, the "osteoblast-rich" populations, had reduced PTHrP expression. Immunohistochemistry and in situ hybridization in sections of newborn rat calvariae showed PTHrP expression in cuboidal osteoblasts located adjacent to bone and in spindle-shaped cells in the periosteal region. It is concluded that PTHrP is produced by cells of the osteoblast lineage, supporting the hypothesis that PTHrP may function physiologically as a paracrine factor in bone.
To establish the changes associated with gestational age and labour status in parathyroid hormone-related protein (PTHrP) concentrations in the amniotic fluid, human amniotic fluid was collected from non-labouring and labouring women at < 37 weeks of gestation (preterm) and at term (> or = 37 weeks). PTHrP was assayed by a specific N-terminal radioimmunoassay. PTHrP concentrations in amniotic fluid obtained from non-labouring women were significantly lower at preterm (15-36 weeks; 14.1 +/- 2.5 pmol L(-1); n = 11) than at term (37-42 weeks; 39.3 +/- 7.6 pmol L(-1); n = 16; P < 0.0009). Concentrations of PTHrP in amniotic fluid obtained from labouring women were also significantly lower at preterm (27-36 week; 12.2 +/- 4.7 pmol L(-1); n = 4; P < 0.01) than at term (37-42 weeks; 63. 8 +/- 19.6 pmol L(-1); n = 9). There were no significant changes in concentration associated with labour status, either at preterm or at term. The physiological significance of elevated amniotic fluid concentrations of PTHrP has yet to be established, but the data are consistent with the suggestion that PTHrP plays a role in fetal membrane function during late gestation.
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Production of parathyroid hormone-related protein by the rat mammary gland in pregnancy and lactation. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E1077-E1085, 1992.--Production of parathyroid hormone-related protein (PTHrP) by the mammary gland of Sprague-Dawley rats has been examined using immunohistochemistry and in situ hybridization to detect PTHrP and PTHrP mRNA, respectively. PTHrP and PTHrP mRNA could be demonstrated in nests of epithelial cells of the developing mammary gland at day 14 of pregnancy and in the epithelial secretory cells lining the alveoli during the latter stages of pregnancy and during lactation. A specific radioimmunoassay was also used to measure the concentration of PTHrP secreted in the milk throughout lactation. The concentration of PTHrP in milk was relatively low initially but increased during the latter stages of lactation, whereas calcium concentrations remained virtually constant throughout lactation. No correlation was found between the concentrations of calcium and PTHrP in rat milk. These results show that PTHrP is present in rat milk and also in mammary tissue before parturition, and therefore it may assist in the development of the mammary gland during pregnancy.
The effect of lowering ionized calcium on circulating parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) was assessed in twenty patients with hypercalcemia of malignancy following treatment with Pamidronate Disodium. Ionized calcium levels fell rapidly in all treated patients. PTH concentrations were initially suppressed below normal in 18 patients, but rose from 0.48 +/- 0.42 pmol/L to 3.63 +/- 3.13 pmol/L (p less than 0.01) after treatment, reaching higher than normal values in some patients even in the presence of persistent hypercalcemia. PTHrP concentrations did not change significantly after treatment. These findings are consistent with an increased sensitivity of parathyroid tissue to changes in ionized calcium following prolonged exposure to hypercalcemia. Regulation of tumor secretion of PTHrP by calcium was not apparent within the range of calcium concentrations in this study.
Parathyroid hormone-related protein (PTHrP) has been shown to be present in milk of various mammals. We have assayed PTHrP in milk of various species by radioimmunoassay and estimated the molecular weights by Western blot analysis. PTHrP concentrations in bovine, ovine and human milk were 59.2 +/- 18.5, 74.1 +/- 35.0 and 36.6 +/- 20.7 micrograms/l (mean +/- S.D.) respectively, in pooled samples collected at various stages of lactation. PTHrP in mammalian milk was found to exist in two forms with molecular weights of 17.5 kDa and 21.5 kDa approximating those of PTHrP(1-108) and (1-141) respectively. In comparison, marsupial milk PTHrP appeared as a single low molecular weight form of 14.4 kDa which approximated to that of PTHrP(1-84). We performed a longitudinal study measuring the concentration of PTHrP in milk throughout lactation in cows, and found it to increase with the duration of lactation (r = 0.669, n = 91). We further examined the relationship between the concentration of PTHrP and total calcium in bovine milk, and the differences between these constituents in milk from Friesian and Jersey cows. PTHrP concentrations correlated positively with total milk calcium (r = 0.346, n = 105). The mean milk concentration of PTHrP of the Jerseys was significantly higher than that of the Friesians (52.6 +/- 5.4 micrograms/l compared with 41.0 +/- 4.8 micrograms/l, P less than 0.01), as was the mean milk calcium concentration (30.5 +/- 3.0 mmol/l compared with 26.7 +/- 2.7 mmol/l, P less than 0.01). We therefore postulate that production of PTHrP by the mammary gland may be associated with calcium transport from blood to milk. Also PTHrP may play a role in the development of milk fever in Jerseys which are predisposed to this condition.
Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. [Nle8,Nle18,Tyr34]bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with [125I]PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself.(ABSTRACT TRUNCATED AT 250 WORDS)
The absorption kinetics of intranasal salmon calcitonin were assessed in 4 normal subjects and 9 patients with Klinefelter's syndrome. After administration, absorption occurred within 5 minutes. There was a highly significant correlation between the amount administered and the amount absorbed (r = -0.83, P less than 0.0005).
Vitamin D deficiency leads to secondary hyperparathyroidism initially and then to mild osteomalacia, both of which conditions may be aymptomatic and may predispose to bone fracture. To assess the importance of vitamin D deficiency in predisposing to fractured neck of femur, we studied the vitamin D status, dietary intake and socio-economic characteristics in 69 patients with fractured neck of femur (group A), 28 normal subjects with age above 60 (group B), and 101 normal volunteers (group C). Patients with fractured neck of femor had significantly lower levels of serum 25-hydroxy-cholecalciferol compared with subjects of groups B and C. There is no statistically significant difference in other biochemical parameters, including calcium, phosphate, and alkaline phosphatase. Patients with fractured neck of femur and with 25-hydroxycholecalciferol below 20 ng/mL were characterized by a home-bound and/or institutionalized life-style, smaller living place, and limited access to open space. To conclude, hypovitaminosis D is a common problem among elderly patients with fractured neck of femur in Hong Kong. The fact that such vitamin D deficiency is associated with muscle weakness may contribute to falls, and thus indirectly account for an increased rate of hip fractures over the normal control.