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T J Martin

Publications and source records attributed to T J Martin.

At least 199 records · Page 11Linked to original sources
PubMed1993

Parathyroid hormone-related protein is a factor in normal fish pituitary.

Using antibodies to the amino-terminal region of human parathyroid hormone-related protein (PTHrP) we have demonstrated PTHrP immunoreactivity in pituitaries and plasma of the sea bream (Sparus aurata). Pituitary cells at two distinct locations contained immunodetectable PTHrP; an anterior group in the rostral pars distalis which also contained immunoreactive thyroid stimulating hormone (TSH), and a posterior group lying at the border of the pars intermedia and proximal pars distalis between cells which stained with antibody to human corticotrophin-like intermediate lobe peptide. By Western blot analysis pituitary extracts contained two immunoreactive isoforms of PTHrP, one of 29 kDa and the other of 26 kDa. Media of pituitaries incubated for up to 14 days in Krebs-Ringer bicarbonate also had several isoforms of immunodetectable PTHrP, two of them corresponding to the 29- and 26-kDa molecular forms but there were in addition both larger and smaller molecules. The concentration of PTHrP in sea bream plasma was comparable with levels observed in human subjects with humoral hypercalcaemia of malignancy. There was no reaction between pituitary cells or pituitary extracts and antibody to human parathyroid hormone. Thus sea bream pituitary contains immunoreactive PTHrP, which appears to be released into medium during in vitro incubation and which may be a significant source of plasma immunoreactive PTHrP in vivo.

Animals↗
PubMed1993

Synthesis of phosphites and phosphates of neuraminic acid and their glycosyl donor properties--convenient synthesis of GM3.

The importance and requirements for catalytic activation of sialyl donors are discussed, leading to the acid sensitive phosphite and phosphate moiety, respectively, as leaving group and nitriles as solvent. Therefore, from readily available N-acetylneuraminic acid, derivative 1 with phosphochloridites 2a-f and Huenigs' base sialyl phosphites 3a-f were prepared and isolated in high yields. Oxidation of 3a,c with tert-butyl-hydroperoxide afforded the corresponding phosphates 4a,c. As expected, phosphites 3 could be activated in acetonitrile by catalytic amounts of TMSOTf; thus, from 3a-e as donors and lactose derivatives 8A,B as acceptors the ganglioside building blocks 9A and 9B, respectively, were obtained in good yields. The best results were obtained with diethyl phosphite derivative 3a as sialyl donor, which exceeded by far the results obtained with the corresponding phosphate derivative 4a. Trisaccharide 9B was transformed into known 9A and into the fully O-acetylated GM3-trisaccharide 10.

Carbohydrate Sequence↗
PubMed1993

Transforming growth factor beta stimulation of parathyroid hormone-related protein (PTHrP): a paracrine regulator?

The regulation of PTHrP expression and production by transforming growth factor-beta (TGF beta) has been investigated in an epidermal squamous cancer cell line COLO 16. TGF beta 1 treatment increased steady-state levels of PTHrP mRNA and concentrations of PTHrP immunoreactivity in conditioned medium in a time- and dose-dependent manner with a half-maximal effect at 40 pM. An effect of TGF beta 1 on PTHrP mRNA was observed first after 4 h treatment and continued to increase up to 48 h with a concomitant increase in PTHrP immunoreactivity in the culture medium. TGF beta 1 was found to stabilize PTHrP mRNA as assessed by actinomycin C1 experiments. In addition, a direct effect of TGF beta to increase PTHrP transcription was indicated by nuclear run-on and transient transfection experiments using a CAT promoter/expression construct encompassing the region -1100 bp to -20 bp from the initiating AUG of the human PTHrP gene. The conditioned medium from COLO 16 cells was also shown to contain both latent and active TGF beta at concentrations of 160 pM and 16 pM, respectively, in 72 h conditioned medium. A neutralizing antibody to TGF beta 1 (and TGF beta 2) decreased the level of immunoassayable PTHrP in the medium.

Base Sequence↗
PubMed1993

Hypercalcaemia in small cell lung cancer: report of a case associated with parathyroid hormone-related protein (PTHrP).

Although hypercalcaemia is frequently associated with malignancy, it is very rare in small cell lung cancer despite the high incidence of lytic bone metastases. We report a patient with extensive small cell cancer who presented with hypercalcaemia. Investigations suggested parathyroid hormone (PTH) receptor stimulation, although the serum PTH level was not elevated. PTH related protein (PTHrP) was localised in a biopsy specimen from the tumour. Although hypercalcaemia is rare in small cell lung cancer, when hypercalcaemia does occur, PTHrP may be a causal factor.

Aged↗
PubMed1993

Comparison of thromboelastography to bleeding time and standard coagulation tests in patients after cardiopulmonary bypass.

This prospective study of 36 adult patients undergoing cardiopulmonary bypass (CPB) was conducted to determine the utility of thromboelastography (TEG) versus platelet studies (bleeding time, platelet count, mean platelet volume) and standard coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen) to more effectively discriminate patients likely to benefit from platelet or fresh frozen plasma (FFP) transfusion. Although the sensitivities of the bleeding time (71.4%) and platelet count (100%) were similar to the TEG (71.4%), the specificity (89.3%) of the TEG was greater than that of the bleeding time (78.5%) and platelet count (53.6%). Seven patients experienced clinically significant hemorrhage; 5 (71.4%) had an abnormal TEG. Three of 8 (38%) other patients with an abnormal TEG had no abnormal bleeding. Only 2 of 27 (7.4%) patients with a normal TEG had abnormal bleeding requiring platelet or FFP transfusion. Therefore, it is suggested that post-CPB patients with a normal TEG should not receive platelet or FFP transfusions empirically. If excessive bleeding is noted in a patient with a normal TEG, this suggests a surgically correctable etiology. Data from this series suggest that patients displaying an abnormal TEG appear to be at increased risk for hemorrhage; therefore, appropriate blood product support should be initiated at the first sign of accelerated bleeding.

Adolescent↗
PubMed1993

Effects of thyroparathyroidectomy, parathyroid hormone, and PTHrP on kidneys of ovine fetuses.

The fetal parathyroid glands and parathyroid hormone-related protein (PTHrP) have been shown to be important regulators of fetal calcium metabolism through their actions on the placenta and bone. This study examined the effects of fetal thyroparathyroidectomy (with thyroxine replacement) and exogenous infusion of human parathyroid hormone [PTH-(1-34)], PTHrP-(1-34), and PTHrP-(1-141) on the urinary excretion of calcium in chronically cannulated ovine fetuses during the last one-fifth of gestation. Fetal plasma total and ionized calcium concentrations were significantly lower in thyroparathyroidectomized (TxPTx) fetuses when compared with intact fetuses, but there were no significant differences in urinary excretion rates of total calcium. However, TxPTx produced a significant increase in the fractional excretion rate of total calcium and a significant decrease in the excretion of adenosine 3',5'-cyclic monophosphate (cAMP) compared with intact fetuses. Infusions of PTH-(1-34), PTHrP-(1-34), and PTHrP-(1-141) into the jugular vein of TxPTx fetuses (n = 5) at the rate of 1 nmol/h for 2 h, after a 1-nmol loading dose, significantly decreased the excretion rate of total calcium and increased the excretion rate of cAMP in fetal urine. Infusions of all three peptides resulted in significant increases in the concentration of total calcium in fetal plasma but had no effect on the plasma concentrations or urinary excretion rates of phosphate. Infusion of either PTH-(1-34), PTHrP-(1-34), or PTHrP-(1-141) also resulted in an increase in fetal urine osmolality and pH and a decrease in free water clearance in TxPTx fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1993

Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.

Bisphosphonates are generally considered to act on bone resorption by binding to bone mineral and subsequently inhibiting the activity of the osteoclasts which ingest them. This has been supported by the fact that bisphosphonates adsorbed on mineralized tissue inhibit the resorbing activity of isolated osteoclasts in vitro. However, the effectiveness of different bisphosphonates determined in this system does not reflect their relative potencies in vivo. Employing the well-described isolated osteoclast resorption pit assay, with ivory as the resorption substrate, we show here that this lack of correlation prevails only when the bisphosphonates are added to the mineral before addition of osteoclasts, but not when the cells are treated for a short time (5 min) before allowing them to adhere onto ivory. By using this approach with five different bisphosphonates, a stringent correlation of relative potencies was obtained with those found, both in the rat and in the human, in vivo. Furthermore, by using an osteoblastic cell line (CRP 10/30) which is a powerful promoter of osteoclastic resorption in vitro, we obtained evidence that the inhibitory effect of bisphosphonates was the result of an action on osteoblasts rather than on osteoclasts. Thus, in experiments in which the osteoblastic cells were pretreated for 5 min with bisphosphonates and then cocultured with osteoclasts, inhibition of osteoclastic resorbing activity was obtained. Moreover, it was found that this treatment resulted in a decrease of the stimulatory effect found in CRP 10/30-conditioned medium. In conclusion the present study shows that part of the osteoclast inhibiting action of the bisphosphonates is mediated through an action on osteoblasts.

Alendronate↗
PubMed1993

Infusions of a novel calcitonin gene-related peptide (CGRP) derivative at the time of reperfusion to salvage ischaemic rabbit skin flaps.

Rabbit epigastric skin flaps were subjected to 21 h of ischaemia at 25 degrees C. In the first 40 min of reperfusion the flaps were infused intraarterially with either Hanks' balanced salt solution (controls), chicken CGRP or a derivative DADA-CGRP. Skin biopsies and blood specimens were taken immediately before and after 1-h reperfusion. The aim was to observe the effect of CGRP derivatives on compromised skin-flap survival and to help elucidate the critical biochemical mechanisms. It was found that chicken CGRP and DADA-CGRP produced a dose-dependent increase in blood flow, significant at and above 0.1 microgram/kg, but only the 0.1 microgram/kg DADA-CGRP infusion produced a statistically significant increase in flap survival (75.1%) as compared with controls (41.6%). CGRP infusions caused significantly more rapid restoration of tissue ATP levels and resulted in a smaller rise in blood thromboxane as compared with controls. However, CGRP caused no significant change in the tissue levels of myeloperoxidase, a measure of neutrophil infiltration, and lipid peroxidation, an indicator of free-radical activity. It is concluded that intraarterial CGRP infusions to ischaemic flaps at the time of reperfusion are indicated. However, an ideal infusion solution would also need to counteract free radicals and neutrophils which are believed to also play a major role in the inflammatory response leading to flap failure.

Animals↗
PubMed1993

The plasminogen activator and inhibitor system in bone remodelling.

The neutral protease, plasmin, is generated by plasminogen activators, and is ascribed an important role in several physiological and pathological circumstances characterized by tissue remodelling and cell motility. The two types of plasminogen activator, tissue-type (tPA) and urokinase-type (uPA), are produced by osteoblasts, as is the specific PA inhibitor, PAI-1. Some hormones which activate bone resorption increase PA activity produced by osteoblasts, by decreasing the production of PAI-1. The increased PA activity has been suggested to facilitate bone resorption by activating latent collagenase, thus preparing the bone surface for osteoclastic resorption. Targeted and regulated production of plasmin might also contribute to the coupling of bone formation to resorption, by activating latent TGF beta in bone, and activating IGF-1 by freeing it from association with inhibitory binding protein. TGF beta itself is a powerful inhibitor of PA activity, an effect achieved by enhancing mRNA and protein for PAI-1. Thus the PA system is a potentially important regulatory system in bone remodelling, whose local activity is controlled through concerted actions of hormones and locally generated growth factors and cytokines.

Animals↗
PubMed1993

Effects of intracerebroventricular administration of beta-funaltrexamine on [3H]DAMGO binding to rat brain sections.

In spite of an extensive body of knowledge regarding the pharmacological effects of centrally administered beta-funaltrexamine (beta-FNA), little is known about the distribution of mu opiate receptor alkylation produced by i.c.v. administration. This study examines the dose relationship between i.c.v. beta-FNA pretreatment and the affinity and density of mu opioid binding sites in discrete brain regions using in situ binding and quantitative receptor autoradiography. [3H]DAMGO binding was determined in coronal sections obtained from the frontal portion of the brain from animals 24 hr after i.c.v. administration of 0, 1, 5, 10, 20 or 40 nmol of beta-FNA. The Kd and Bmax values of [3H]DAMGO binding were unaltered in animals treated with saline or 1 nmol of beta-FNA, whereas treatment with 5, 10 and 20 nmol of beta-FNA increased Kd and decreased Bmax values. The 40 nmol dose did not affect the Kd but decreased the Bmax value. Administration of 40 nmol of beta-FNA i.c.v. was not found to affect either the Kd or Bmax of delta opioid receptors assessed with [3H]DPDPE. Although some brain regions appeared to be affected to a greater degree than others, the autoradiographic localization of [3H]DAMGO binding at 10 different brain levels revealed a generally homogeneous loss of binding after 40 nmol of beta-FNA. beta-FNA appears to alkylate mu opiate receptors throughout the brain after i.c.v. administration.

Animals↗
PubMed1993

Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein.

We describe a case of hypercalcemia without lytic bone lesions complicating myeloid blast crisis of chronic myeloid leukemia (CML). Serum levels of parathyroid hormone-related protein (PTHrP) were elevated during the initial hypercalcemic period and became undetectable during chemotherapy-induced chronic phase, only to become elevated again during subsequent recurrent blastic periods repeatedly associated with hypercalcemia. Previously reported cases of hypercalcemia complicating CML are reviewed. It is suggested that PTHrP was responsible for the hypercalcemia in this case and may be an important mediator of hypercalcemia in CML.

Adult↗
PubMed1993

Parathyroid hormone related protein in breast cancers of widely varying prognosis.

Parathyroid hormone related protein (PTHrP) is a novel calcium regulating hormone that may have a significant role in the pathophysiology of breast cancer. We have previously demonstrated a relationship between immunohistochemically detectable PTHrP in primary breast tumours and the subsequent development of bone metastases and hypercalcaemia. The aim of this study was to compare the PTHrP status in the primary tumours from three groups of patients with widely varying prognosis. (1) The favourable outcome group; all patients had a favourable prognosis and minimum 3 years disease free follow up (n = 30). (2) The unfavourable outcome group; all patients presented with localized breast cancer but developed distant disease within 3 years (n = 26). (3) The unfavourable presentation group; all had distant disease at first presentation (n = 26). No differences in PTHrP status of the primary tumour amongst the three patient groups were found (66%, 65% and 61% positive respectively). The development of bone with liver metastases and hypercalcaemia was associated with increased positive PTHrP status of the primary tumor.

Bone Neoplasms↗
PubMed1992

Abundant expression of parathyroid hormone-related protein in human amnion and its association with labor.

In animal models, parathyroid hormone-related protein (PTHrP) increases placental calcium transport and inhibits contraction of uterine smooth muscle. The present studies were undertaken to characterize the expression of PTHrP in human uteroplacental tissues. PTHrP mRNA was identified by Northern analysis as a single species (approximately 1.8 kilobases) in human amnion, chorion, placenta, decidua, and myometrium. The most abundant signal was seen in amnion, where it was 10-400 times that in the other uteroplacental tissues. PTHrP mRNA abundance was decreased in amnion (but not in the other tissues) following the onset of labor (P less than 0.001). PTHrP mRNA in amnion appeared to be translated to a bioactive peptide, as PTHrP bioactivity and immunoreactive PTHrP in amnion correlated closely with PTHrP mRNA content (r = 0.86 and 0.95, respectively; P less than 0.05 and P less than 0.01). Amniotic fluid contained PTHrP, 21 +/- 6 pmol/liter (n = 10) at 16 weeks and 41 +/- 9 pmol/liter (n = 7) at 38 weeks (P = 0.05). These concentrations equaled or exceeded those found in plasma of patients with hypercalcemia secondary to PTHrP. After rupture of the fetal membranes, PTHrP mRNA in amnion was decreased by 78% (P less than 0.0001). This decrease appeared to be specific for PTHrP mRNA, as glyceraldehyde-3-phosphate dehydrogenase mRNA was unchanged following rupture of membranes. Like PTHrP mRNA, PTHrP bioactivity and immunoreactive PTHrP in amnion decreased significantly following rupture of membranes (P less than 0.03 and P less than 0.01, respectively). Since PTHrP is a potent antagonist of uterine muscle contraction, the decrease of PTHrP following rupture of the fetal membranes may play a key role in the onset of labor.

Amnion↗
PubMed1992

Leukaemia inhibitory factor and bone cell function.

A bone-resorbing product of mouse spleen cells found to have differentiation-inducing activity was most probably leukaemia inhibitory factor (LIF). This revealed that LIF is a cytokine active on bone, in addition to its several other sites of action. In organ culture of newborn mouse bone, recombinant LIF promoted bone resorption by a prostaglandin-dependent process. Resorption by isolated rat osteoclasts was also promoted by LIF through an initial action on osteoblasts which was receptor-mediated. Incorporation of [3H]thymidine into DNA was increased by LIF in cells (most probably osteoblasts) of the newborn mouse bones. Osteoblasts have been shown to produce LIF, and the amount is increased by treatment with retinoic acid or TNF-alpha. LIF also acts directly on osteoblasts to inhibit plasminogen activator activity, by stimulating the synthesis of plasminogen activator inhibitor 1 mRNA and protein. The latter actions are very similar to those of TGF-beta. Again like TGF-beta, LIF was ineffective in promoting bone resorption in vitro in fetal rat long bones. These results, together with the in vivo data showing that high circulating levels of LIF in the mouse are accompanied by a substantial increase in trabecular bone mass, indicate that LIF is another cytokine with potent actions on bone and potentially important interactions with other osteotrophic factors.

Animals↗
PubMed1992

Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization.

Parathyroid hormone-related protein (PTHrP) has been identified immunohistochemically in 60% of breast carcinoma and in 92% of breast cancer metastases in bone. To establish whether the localization of the PTHrP antigen reflects protein synthesis and also to investigate the role of PTHrP in metastatic disease, as part of an ongoing study, we used in situ hybridization to study the localization of PTHrP mRNA in a retrospective series of primary breast tumors and their metastatic lesions. Paraffin sections of 17 primary and 26 metastatic lesions, 11 of which were in bone, were available for the study: 10 of the 17 (59%) primary lesions, 8 of 11 (73%) breast cancer metastases to bone, and 3 of 15 (20%) metastases to non-bone sites showed specific localization of PTHrP mRNA. These findings establish that PTHrP is commonly synthesized by primary breast cancers and support previous immunohistochemical studies reporting a higher incidence of PTHrP-positive tumor cells in skeletal metastases than in nonskeletal metastases.

Breast Neoplasms↗
PubMed1992

Plasminogen activator regulation in osteoblasts: parathyroid hormone inhibition of type-1 plasminogen activator inhibitor and its mRNA.

In order to determine the mechanism by which parathyroid hormone (PTH) stimulates plasminogen activator (PA) activity in rat osteoblasts, we investigated the effect of human PTH(1-34) [hPTH(1-34)] on the synthesis of mRNAs for tissue-type PA (tPA), urokinase-type PA (uPA), and PA inhibitor-1 (PAI-1), and on release of PA activity and PAI-1 protein in both normal rat calvarial osteoblasts and UMR 106-01 osteogenic sarcoma cells. hPTH(1-34) (0.25-25 nM) decreased PAI-1 mRNA and protein, and increased PA activity in both cell types in a dose-dependent manner with ED50 of about 1 nM for both responses. Forskolin and isobutylmethylxanthine also stimulated PA activity and decreased PAI-1 protein and mRNA in both cell types. hPTH(1-34) did not show any consistent effect on tPA and uPA mRNA in calvarial osteoblasts, but a modest (two-fold) increase of both mRNAs was observed in UMR 106-01 cells treated with 25 nM hPTH(1-34). However, when protein synthesis was inhibited with 100 microM cycloheximide, the increase of tPA and uPA mRNA by hPTH(1-34) was enhanced in UMR 106-01 cells and became evident in calvarial osteoblasts. Fibrin autography also revealed that hPTH(1-34) increases tPA and uPA activity, especially after cycloheximide treatment in UMR 106-01 cells. These results strongly suggest that PTH increases PA activity predominantly by decreasing PAI-1 protein production through a cyclic adenosine monophosphate (cAMP)-dependent mechanism in rat osteoblasts. The reduction of PAI-1 protein by PTH results in enhanced action of both tPA and uPA, and would contribute to the specific roles of these PAs in bone.

Animals↗