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T J Martin

Publications and source records attributed to T J Martin.

At least 253 records · Page 14Linked to original sources
PubMed1991

Synthetic human parathyroid hormone-related protein and rat renal electrolyte transport.

The effect of parathyroid hormone (PTH)-like peptide PTH-related protein (PTHrP)(1-34) from a human cancer cell line on renal electrolyte transport was compared with human PTH(1-34) in a thyroparathyroidectomized anesthetized rat model. Comparing submaximal, maximal and supramaximal phosphaturic concentrations of hPTH with the same PTHrP concentrations, no significant difference could be demonstrated in the urinary excretion of calcium, magnesium, inorganic phosphate or cAMP. Even the small (30.3%) and brief (45 min) reduction in fractional water excretion with the maximal (1 nM/kg/h) hPTH concentration was approximated by PTHrP. It is concluded that the structural homology between hPTH and PTHrP allows a similar action on renal electrolyte transport, including the partial agonist effect of higher concentrations of PTH on vasopressin-induced water transport.

Animals↗
PubMed1990

Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer.

Parathyroid hormone-related protein (PTHrP) is known to be a causative factor in humoral hypercalcemia of malignancy. A polyclonal rabbit antiserum directed against the amino-terminal region of the protein and immunoperoxidase methods have been used to locate the presence of PTHrP in a series of 102 consecutive invasive breast tumors removed surgically from normocalcemic women. Positive PTHrP staining was detected in 60% of the tumors but not in the accompanying normal breast tissue. Positive staining was related to the progesterone receptor status of the tumor (P = 0.039) and to the prognostic index of the patient (P = 0.046) and not to estrogen receptor status, patient age, tumor size, histological grade, or nodal status.

Age Factors↗
PubMed1990

Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines.

This study describes the synergistic interaction of two biochemical modulators, cyclosporin A (CyA) and verapamil (Vp), in multidrug-resistant cells, the highly resistant and moderately resistant variants (CEM/VLB 1000 and CEM/VLB 100) of the parental drug-sensitive T-cell leukemia cell line CEM/CCRF. In the absence of either modulator, the 50% inhibitory concentration for Adriamycin in these cell lines was 270 +/- 10.6 (SD) micrograms/ml, 96 +/- 8.5 micrograms/ml, and 1.5 +/- 0.1 micrograms/ml, respectively. CyA and Vp dramatically reduced multidrug resistance in CEM/VLB 100 and CEM/VLB 1000 in a dose-dependent manner but had no effect on the sensitivity of the parental line to Adriamycin. At a CyA concentration of 8.3 mumol (10 micrograms/ml), the 50% inhibitory concentration of Adriamycin of CEM/VLB 1000 and CEM/VLB 100 fell to 5.9 +/- 0.9 micrograms/ml and 3.3 +/- 0.6 micrograms/ml, respectively. Similarly at a Vp concentration of 10 mumol the 50% inhibitory concentration of Adriamycin of CEM/VLB 1000 and CEM/VLB 100 fell to 23.7 +/- 3.7 micrograms/ml and 5.7 +/- 0.2 micrograms/ml, respectively. More importantly, CyA and Vp showed significant synergism when tested in combination in the moderately resistant line at concentrations normally seen after the clinical administration of these modulators. Synergy was also present when both drugs were tested in the highly resistant variant. These data indicate the need for in vivo studies, given the potential clinical importance of these observations.

Cyclosporins↗
PubMed1990

Interactive regulation of signalling pathways in bone cells: possible modulation of PGE2-stimulated adenylyl cyclase activity by protein kinase C.

We have reported previously that tumour-promoting phorbol esters modulate both basal and vasoactive intestinal polypeptide (VIP)-stimulated adenylyl cyclase activity in GH3 (an established pituitary cell line). Here, we probe the receptor and cell specificity of this response. Experiments were performed in the presence of isobutylmethylxanthine. Unlike the response in GH3 cells, the tumour-promoting phorbol ester (tetradecanoyl phorbol acetate (TPA] did not affect either basal adenylyl cyclase activity nor VIP-stimulated activity in the rat osteosarcoma subclones UMR 106-01 and UMR 106-06. In addition, the cyclase responses to parathyroid hormone (PTH), and, in the case of UMR 106-06, to calcitonin were unaffected by tumour-promoting phorbol ester. However, prostaglandin E2-stimulated cyclase activity in both of these subclones was attenuated in a dose-dependent manner.

Adenylyl Cyclases↗
PubMed1990

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children.

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

Administration, Oral↗
PubMed1990

Identification of plasminogen activator in osteoclasts.

Plasminogen activator (PA) was located in newborn rat osteoclasts using a single-cell assay. Immunohistochemistry using biotin-streptavidin-peroxidase indicated the presence of both tissue-type plasminogen activator (tPA) and urokinase (uPA) within the cytoplasm of osteoclasts isolated from newborn rat long bones. Electron microscopic immunohistochemistry using the biotin-streptavidin-colloidal gold system on L.R. Gold thin resin sections of undecalcified, newborn rat tibial metaphyseal trabecular bone identified these proteases in the lysosomal network of osteoclasts. uPA was also localized in marrow macrophage lysosomes, but tPA was not detected in these cells. The localization of these enzymes within osteoclasts may imply their involvement in bone resorption.

Animals↗
PubMed1990

Insulinlike growth factor 1 regulates mRNA levels of osteonectin and pro-alpha 1(I)-collagen in clonal preosteoblastic calvarial cells.

A nontransformed rat clonal cell line (UMR-201) with phenotypic characteristics of osteoblastic precursor cells was found to respond to insulinlike growth factor 1 (IGF-1) by increased osteonectin and pro-alpha 1(I)-collagen mRNA expression. Cells were treated for 24 h with insulin, growth hormone, or IGF-1 to study the regulation of messenger RNA for osteonectin and pro-alpha 1(I)-collagen using Northern blot hybridization. UMR-201 cells possess specific high-affinity receptors for growth hormone, although there were no significant effects of growth hormone (10(-9)-10(-7) M) or insulin (10(-9)-10(-6) M) on mRNA species for osteonectin or pro-alpha 1(I)-collagen. However, IGF-1 increased both mRNA species from a concentration of 10(-9) M. The effect on osteonectin mRNA expression was likely due to increased transcription; when 5' flanking osteonectin (ON) genomic fragments were linked to the bacterial reporter gene chloramphenicol acetyltransferase (CAT) and introduced by transfection into UMR-201 cells, the transcriptional activity of the ON-CAT construct was increased 235 and 270% by 10(-8) and 10(-7) M IGF-1, respectively. In contrast, growth hormone did not change the transcriptional activity of the ON-CAT construct. In confirmation of other work, transforming growth factor beta (TGF-beta, 0.1-2.5 ng/ml) increased mRNA for osteonectin and pro-alpha 1(I)-collagen in a dose-dependent manner. Transforming growth factor alpha (TGF-alpha) at 0.1-10 ng/ml had no consistent effects in repeated experiments on osteonectin and pro-alpha 1(I)-collagen mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Osteoblasts display receptors for and responses to leukemia-inhibitory factor.

Specific binding of leukemia-inhibitory factor (LIF) to osteoblasts, but not multinucleated osteoclasts, was demonstrated by receptor autoradiography by using cells isolated from newborn rat long bones. The clonal rat osteogenic sarcoma cells, UMR 106-06, which have several phenotypic properties of osteoblasts, expressed 300 LIF receptors per cell, with an apparent KD of 60 pM. Treatment of calvarial osteoblasts or UMR 106-01 cells with LIF resulted in a dose-dependent inhibition of plasminogen activator (PA) activity. Both calvarial osteoblasts and osteogenic sarcoma cells were shown by Western blotting and reverse fibrin autography to produce plasminogen activator inhibitor-1 (PAI-1), the production of which was increased by LIF treatment. Northern blot analysis revealed that LIF treatment resulted in a rapid (peak 1 hour), dose-dependent increase in mRNA for PAI-1. LIF treatment of the preosteoblast cell line, UMR 201, enhanced the alkaline phosphatase response of these cells to retinoic acid. Each of the osteoblast-like cell types (calvarial osteoblasts, UMR 106-06, and UMR 201) was shown to produce LIF by bioassay and, by using the polymerase chain reaction (PCR), was shown to express low levels of mRNA for LIF. These data establish that cells of the osteoblast lineage are targets for LIF action. The reported anabolic effects of this cytokine on bone formation in vivo could be related to inhibition of protease activity. LIF may be an important paracrine modulator in bone, or perhaps an autocrine one, based on the evidence for its production by osteoblasts and osteoblast-like cells.

Alkaline Phosphatase↗
PubMed1990

Cloning of an osteoblastic cell line involved in the formation of osteoclast-like cells.

Experiments have been carried out to determine the mechanisms involved in the formation of osteoclast-like cells from spleen cells in mice. Osteoclasts were defined as tartrate-resistant acid phosphatase-positive multinucleated cells (TRACP-positive MNCs) in which specific calcitonin receptors were identified by autoradiography with labeled salmon calcitonin. Furthermore, cultures rich in these cells produced resorption pits when grown on dentine slices. Several clonal cell lines were obtained from fetal mouse calvariae and screened for their ability to induce TRACP-positive MNCs in response to 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25(OH)2D3] in co-cultures with spleen cells. A cell line, KS-4, was identified with the greatest potency in inducing osteoclast-like cell formation in co-culture with spleen cells. The capacity of KS-4 cells to produce this effect was much greater than that of two bone marrow-derived stromal cell lines (MC3T3-G2/PA6 and ST2 cells), which we have previously shown to be effective in this system but to require treatment with dexamethasone in addition to 1 alpha, 25(OH)2D3 (Udagawa et al.: Endocrinology 125:1805-1813, 1989). Parathyroid hormone (PTH) increased cAMP production in KS-4 cells, and PTH and interleukin-1 alpha also induced TRACP-positive MNCs in co-cultures with spleen cells. Contact between living KS-4 and spleen cells was necessary for osteoclast formation to take place, since this did not occur when the two populations were separated by a membrane filter, or when the KS-4 cells were killed by fixation. Separate cultures of either spleen cells or KS-4 cells formed no TRACP-positive MNCs. KS-4 cells synthesized predominantly type I collagen, formed bone nodules without added of beta-glycerophosphate in a long-term culture, and expressed increasing alkaline phosphatase activity after confluence in culture. These results indicate that the KS-4 cells have properties consistent with progression toward the osteoblast phenotype and represent a single cell line with the ability to promote osteoclast formation by a contact-requiring process.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Immunohistochemical localization of parathyroid hormone-related protein in parathyroid adenoma and hyperplasia.

Parathyroid hormone-related protein (PTHrP) is invoked as the cause of humoral hypercalcaemia of malignancy (HHM); it is contained in the keratinocyte layer of normal skin; and there is evidence that is is produced by fetal parathyroids. Antibodies against synthetic PTHrP peptides have been raised in rabbits and sheep. This immunohistochemical study has found that primary parathyroid adenomata and hyperplastic glands from patients with chronic renal failure stain positively with antisera against PTHrP(1-34) and PTHrP(50-69). Primary hyperplastic glands are negative. No staining with anti-PTHrP(106-141) antiserum could be detected immunohistochemically in any of the parathyroid adenomata or hyperplasia.

Adenoma↗
PubMed1990

Comparison of the effects of amino-terminal synthetic parathyroid hormone-related peptide (PTHrP) of malignancy and parathyroid hormone on resorption of cultured fetal rat long bones.

We have compared the effects of of various synthetic amino-terminal forms of human parathyroid hormone-related peptide (PTHrP) of malignancy with synthetic parathyroid hormone (PTH) on the resorptive responses of fetal rat long bones in organ culture. PTH and PTHrP increased 45Ca release at concentrations of 0.1-25 nM. PTHrP (1-40) and bovine PTH (1-34) were more potent than human PTH (1-34) and PTHrP (1-34). However, the slopes of the dose-response curves and the maximal resorptive effects were similar. There was a marked decrease in the potency of amino-terminal PTHrP peptides as the length was decreased. PTHrP (1-29) and PTHrP (1-25) were inactive at 120 nM. Further comparison of bPTH (1-34) and PTHrP (1-34) showed that both could induce bone resorption after a brief (6 hours) exposure and that the response to PTHrP (1-34) was qualitatively similar to that of bPTH (1-34) with respect to enhancement by ACTH and inhibition by calcitonin and glucocorticoids. Hydroxyurea and indomethacin did not block the resorptive response to either agonist. Cyclic AMP production in response to PTHrP (1-34) and (1-40) was similar to that for bPTH (1-34) in ROS 17/2.8 cells. The cyclic AMP (cAMP) response was much smaller in fetal rat long bones and calvariae, and bPTH was more potent than PTHrP. These studies confirm that PTHrP is quantitatively similar in its effects on bone resorption to PTH and are consistent with the two agents acting on the same receptor.

Animals↗
PubMed1990

The salvage of rabbit ischaemic epigastric free flaps using the vasodilator calcitonin gene-related peptide.

The rabbit epigastric free flap, subjected to 21 hours of warm (25 degrees C) ischaemia, was used as an experimental model to test the ability of two endothelium-dependent vasodilators, calcitonin gene-related peptide (CGRP) and carbamyl beta-methylcholine chloride (MCh, bethanechol chloride, the stable acetylcholine analogue) to improve flap viability. After the period of ischaemia, flaps were infused intra-arterially with either Hanks balanced salt solution (controls), CGRP or MCh for 30 minutes, and received additional intravenous boluses of these drugs at 2 and 32 minutes after revascularisation. The area of flap surviving improved significantly (p less than 0.025) from 39.9% (n = 18) for controls to 70.2% (n = 14) for CGRP treatment at 2 micrograms/kg, but was unchanged at 47.1% (n = 14) for MCh treatment at 50 micrograms/kg. Both CGRP and MCh significantly increased blood flow (p less than 0.05) resulting in 34% lower peripheral resistances compared with controls. These results suggest that CGRP has considerable clinical potential for the salvage of ischaemic flaps. CGRP must have several, as yet undefined, beneficial effects on the ischaemic tissue, since MCh invoked a vasodilatory response but failed to salvage ischaemic flaps.

Abdominal Muscles↗
PubMed1990

Humoral hypercalcemia of malignancy.

Studies on humoral hypercalcemia of malignancy have shown that tumors produce a protein that acts through the parathyroid hormone (PTH) receptor but is immunologically distinct from PTH. We have recently purified and cloned a parathyroid hormone-related protein (PTHrP) from a human lung cancer cell line. Full length cDNA clones were isolated and found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino terminal residues are identical with human PTH, although antisera directed at the amino terminus of PTHrP do not recognize PTH. A 34-amino acid synthetic peptide, PTHrP(1-34), was several times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of cAMP and plasminogen activity in osteogenic sarcoma cells and activation of adenylate cyclase in chick kidney membranes. PTHrP(1-34) was also more potent than PTH(1-34) in stimulating cAMP and phosphate excretion and reducing calcium excretion in the isolated perfused rat kidney. PTHrP has been consistently demonstrated by immunohistochemistry in squamous cell carcinomas and in keratinocytes present in normal skin, but not in normal or hyperplastic parathyroid tissues or other tumors. PTHrP-like activity has been extracted from ovine placenta and fetal parathyroid tissue, suggesting that PTHrP may play a role in fetal calcium homeostasis.

Amino Acid Sequence↗
PubMed1990

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly.

In a double-blind, randomized, crossover study, the H1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 +/- SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 +/- 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 +/- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 +/- 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 +/- 13% to 60 +/- 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 +/- 15% to 78 +/- 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 +/- 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 +/- 11% to 37 +/- 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 +/- 14% to 46 +/- 19% at 2, 5, and 6 hours (p less than 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H1-receptor-antagonist ingestion.

Aged↗
PubMed1990

Effect of cyclosporin and verapamil on the cellular kinetics of daunorubicin.

Both cyclosporin and verapamil modulate the multidrug-resistant (MDR) phenotype in the classical MDR cell lines, CEM/VLB100 and CEM/VLB1000. Initial studies demonstrated a significant reduction in daunorubicin accumulation in the two resistant lines compared with the drug-sensitive parent line CEM/CCRF. Both cyclosporin and verapamil increased drug accumulation in the resistant lines. This effect was dose-dependent although a plateau occurred in CEM/VLB100 cells at concentrations of cyclosporin exceeding 4.2 mumol/l. Cyclosporin 4.2 mumol/l and verapamil 10 mumol/l significantly increased daunorubicin uptake and reduced drug efflux in the CEM/VLB100 and CEM/VLB1000 lines. At low clinical concentrations of cyclosporin (0.8-1.6 mumol/l and verapamil (1-2 mumol/l), there was a synergistic increase in drug accumulation in the two resistant cell lines (P less than 0.007). These data suggest that cyclosporin modulates the classical MDR phenotype by altering the cellular kinetics of daunorubicin. The in vitro synergistic action of cyclosporin and verapamil could be interesting clinically.

Cell Line↗
PubMed1990

Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells.

We previously reported that osteoclast-like cells were formed in cocultures of a mouse marrow-derived stromal cell line (ST2) with mouse spleen cells in the presence of 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. In this study, we developed a new coculture system to determine the origin of osteoclasts. When relatively small numbers of mononuclear cells (10(3)-10(5) cells per well) obtained from mouse bone marrow, spleen, thymus, or peripheral blood were cultured for 12 days on the ST2 cell layers, they formed colonies with a linear relationship between the number of colonies formed and the number of hemopoietic cells inoculated. Tartrate-resistant acid phosphatase (TRAPase)-positive mononuclear and multinucleated cells appeared in the colonies (TRAPase-positive colonies) in response to 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. When hemopoietic cells suspended in a collagen-gel solution were cultured on the ST2 cell layers to prevent their movement, TRAPase-positive colonies were similarly formed, indicating that each colony originated from a single cell. All of the colonies consisted of nonspecific esterase-positive cells. The monocyte-depleted population prepared from peripheral blood failed to form colonies, whereas the monocyte-enriched population produced a large number of TRAPase-positive colonies. In addition, alveolar macrophages formed TRAPase-positive colonies most efficiently on the ST2 cell layers in the presence of the two hormones. Salmon 125I-labeled calcitonin specifically bound to the TRAPase-positive cells. Resorption lacunae were formed on dentine slices on which cocultures were performed. When direct contact between the peripheral blood cells and the ST2 cells was inhibited by a collagen-gel sheet, no TRAPase-positive cells were formed. These results indicate that osteoclasts are also derived from the mature monocytes and macrophages when a suitable microenvironment is provided by bone marrow-derived stromal cells.

Acid Phosphatase↗