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Biomedical subjects

R Ziegler

Publications and source records attributed to R Ziegler.

At least 253 records · Page 14Linked to original sources
PubMed1993

Cyclic AMP formation in rat bone and kidney cells is stimulated equally by parathyroid hormone-related protein (PTHrP) 1-34 and PTH 1-34.

Parathyroid hormone-related protein (PTHrP) plays a major role in the pathogenesis of humoral hypercalcemia of malignancy. It interacts with the PTH receptor and has therefore a nearly identical effect on bone cells as PTH. However, PTHrP is thought to be less potent than PTH in stimulating adenylate cyclase in canine renal membranes, leading to the hypothesis of a differential efficiency in signal transduction by PTHrP with respect to bone vs kidney. In a homologous model with intact osteoblast-like cells (UMR 106) and primary kidney cells, both from the rat, we have tested N-terminal peptide fragments, based on the rat amino acid sequence 1-34, of PTH and PTHrP. Compared with PTHrP(1-34), rat PTH(1-34) had a similar relative potency in bone cells (85%) and in kidney cells (140%) in its ability to stimulate adenylate cyclase. Human PTH(1-34) was 5.6- to 6.5-fold less potent than rat PTH(1-34) in both cell types. In human osteoblast-like cells (SaOS-2), rat and human PTH were essentially equally potent compared to PTHrP(1-34) (identical sequence in rat and human) in stimulating cAMP accumulation. In conclusion, our study revealed the equipotency of rat PTH(1-34) and PTHrP(1-34) in stimulating intracellular cAMP formation in a homologous system of rat bone and kidney cells. There seemed to be no unique signal transduction mechanism of PTHrP to the adenylate cyclase in rat kidney cells compared with bone cells.

Adenylyl Cyclases↗
PubMed1993

Levels of parathyroid hormone-related protein (PTHrP) in hypercalcemia of malignancy are not lowered by treatment with the bisphosphonate BM 21.0955.

Parathyroid hormone-related protein (PTHrP) is a major cause of hypercalcemia in malignancy and serum levels are elevated in many patients suffering from this syndrome. In 10 patients with hypercalcemia of malignancy the levels of the midregional fragment of PTHrP in serum were determined by radioimmunoassay over 7 days during a calcium-lowering treatment with a single dose of the bisphosphonate BM 21.0955. PTHrP concentrations remained unchanged 6 days after administration of the drug as compared with pretherapeutic values, thus apparently excluding an effect of either the drug itself or the rapid fall in serum calcium on the release of PTHrP by the tumors or on its clearance from the circulation. In the patients with elevated midregional PTHrP levels (n = 6), the calcium-lowering effect of the drug was significantly less pronounced than in patients with normal PTHrP (n = 4) (mean serum calcium of 2.89 vs. 2.51 mmol/l at day 6), despite similar pretherapeutic concentrations. Of the six patients with elevated PTHrP, five were still hypercalcemic, whereas in the group with normal PTHrP one out of four patients remained hypercalcemic. In conclusion, PTHrP levels in hypercalcemia of malignancy remained unchanged after calcium-lowering therapy with bisphosphonates. High serum PTHrP levels were, however, predictive of a lesser effectiveness of the drug in lowering serum calcium.

Adult↗
PubMed1993

Bone loss in experimental diabetes. Comparison with the model of inflammation mediated osteopenia.

Osteopenia occurs in diabetes mellitus. Since bone status is altered in Inflammation Mediated Osteopenia (IMO), it was appropriate to study its course in diabetic animals in order to investigate the mechanism of diabetic osteopenia. To this end, we compared the bone loss in streptozotocin (STZ) diabetes with that of IMO. Female rats were studied in total of 8 groups: Control, IMO, Diabetes, IMO with Diabetes (IMO-DIA) on the 3rd and similar groups on the 6th week after induction of IMO with 8 s.c. injections of talcum suspension. Femoral mineral content as reflected by ash weight per femoral volume after 3 weeks was lower in IMO compared to control rats (p < 0.05) while after 6 weeks this difference was not significant. The femur ash weight per volume of diabetic rats was lower than the one of intact rats with and without IMO both after 3 and 6 weeks. Diabetic rats with and without IMO exhibited no difference in this respect. Spleen weight as a measure of the extent of inflammation per body weight was increased only in the IMO group. The diabetic rats with and without IMO did not differ significantly with regard to spleen weight. Similar changes were observed 6 weeks after the induction of IMO. However the difference between IMO and diabetes rats was of borderline significance and no difference existed between the IMO and IMO-diabetic group. The serum calcium levels of intact, IMO and diabetic rats showed no change during both experimental periods. Those of diabetic rats with IMO were higher than those of the diabetic and IMO animals after 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Neutralizing antibodies against calcitonin.

The use of calcitonin (CT) is established as a treatment of Paget's disease of bone and postmenopausal osteoporosis (PMO). Salmon calcitonin (sCT), which differs in 14 of the 32 amino acids from human calcitonin, has found a wider distribution world wide, although antibody formation against sCT has been reported in more than 70% of the patients on continuous sCT treatment. The clinical significance of these antibodies has been discussed controversially, because the occurrence of antibodies is not always associated with the development of secondary resistance. Using an in vitro bioassay, based on the CT-mediated increase of the cyclic AMP (cAMP) production of the human breast cancer cell line T 47 D we could identify a neutralizing activity against sCT in the serum of a subset of patients with formation of antibodies against sCT which was related to the development of secondary resistance. Antibody formation against human calcitonin (hCT) has been reported only once before. Binding and neutralizing antibodies were now observed in 1 of 33 patients with PMO treated with hCT. Due to a low neutralizing activity, clinical sequelae were not to be expected in this patient. The formation of neutralizing antibodies against calcitonin is common after treatment with salmon but a rare phenomenon after treatment with human calcitonin. We recommend monitoring of patients with postmenopausal osteoporosis and Paget's disease of bone on long term treatment with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment.

Antibodies↗
PubMed1993

Long-term exposure to SMS 201-995 inhibits proliferation and calcitonin release in neoplastic C-cells.

The effect of the long-acting somatostatin analogue SMS 201-995 on cellular proliferation and calcitonin production was examined in rMTC 6-23 cells. A dose-dependent inhibition of calcitonin release and cellular calcitonin content was obtained in cells exposed to SMS 201-995 for 72 hrs. The dose-dependent antiproliferative effect of SMS 201-995 (10(-8)-10(-6) M) was significant after 72 hrs of exposure. SMS 201-995 has an inhibitory effect on calcitonin secretion and synthesis as well as on the growth of C-cells.

Animals↗
PubMed1993

Decreased serum levels of insulin-like growth factors and IGF binding protein 3 in osteoporosis.

OBJECTIVES: The aim of the study was to investigate endogenous growth hormone (GH) secretion in patients with osteoporosis and in patients with degenerative bone diseases or no spinal disease by measuring serum insulin-like growth factors 1 and 2 (IGFs) and their major binding protein 3 (BP-3) as an indirect parameter of GH secretion. DESIGN: A cross-sectional study. SETTING: All patients were seen as out-patients of the Endocrinology Department of the University of Heidelberg where all bone parameters were measured. IGFs and BP-3 serum levels were measured at the Children's Hospital of the University of Tübingen. SUBJECTS: A total number of 310 patients were studied. The group with primary osteoporosis and vertebral fractures (OPO) consisted of 141 patients (98 females, 43 males). Spinal degenerative bone disease or osteoarthritis (DEG) was present in 108 patients (91 females, 17 males). Sixty-one control patients (56 females, 5 males) had no spinal disease on X-ray, but presented with lower back pain. MAIN OUTCOME MEASURES: Serum levels of IGFs, BP-3, PTH and 25-vitamin D3 were measured by radioimmunoassay. Bone mineral density (BMD) was determined using absorptiometry; anthropometric parameters and menopausal status were recorded. RESULTS: There was no difference in age and years after menopause between OPO and DEG, but control individuals were younger. Mean IGFs and BP-3 serum levels in patients with OPO were lower (P < 0.001) than those in patients with DEG or in controls. Patients with DEG had significantly higher BP-3 levels than controls (P < 0.001). There was a significant (P < 0.05) negative correlation of BP-3 with age in females with OPO, but not in controls or in DEG patients. The IGFs did not decrease with age in any of the three groups. Binding protein 3 was positively correlated (P < 0.05) with BMD in postmenopausal women with OPO but not in controls or DEG patients. CONCLUSION: We conclude that systemic IGFs and IGF binding protein 3 are decreased in patients with osteoporosis. Further studies are needed to investigate whether this is as a result of diminished secretion of endogenous GH and whether this reflects the local circumstances of IGFs and IGF binding proteins in bone.

Adult↗
PubMed1993

Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy.

We investigated in humoral hypercalcemia of malignancy whether parathyroid hormone-related protein (PTHrP) elevation causes a rise in 1,25-dihydroxyvitamin D (1,25-(OH)2 D) serum levels. We assessed 41 patients with hypercalcemia of malignancy in a prospective study. There were 19 patients who had serum PTHrP levels in the normal range; 22 patients had elevated serum PTHrP levels. All patients were treated with the bisphosphonate pamidronate resulting in a drop of serum calcium (p < 0.0001) and serum phosphate (p < 0.0023) within 12 days, independent of the group. Parathyroid hormone (PTH) was suppressed at the start of therapy and rose to within the normal range during therapy (p < 0.0001), regardless of the PTHrP levels. PTHrP levels were not influenced by calcium lowering therapy. The serum levels of 1,25-(OH)2 D were either suppressed or in the low normal range at the beginning of the study, without any significant difference between both groups. All patients showed a rise in 1,25-(OH)2 D during bisphosphonate therapy (p < 0.0001), independent of their PTHrP levels. Thus PTHrP did not influence the calcium, phosphate-, or PTH-dependent regulation of 1,25-(OH)2 D during calcium lowering therapy. We conclude, that PTHrP does not stimulate renal 1-hydroxylase activity in humoral hypercalcemia of malignancy.

Adult↗
PubMed1993

Biosynthetic route of locust apolipophorin III isoforms.

Insect apolipophorin III (apoLp-III) plays a key role in the enhanced diacylglycerol transport during insect flight. For apoLp-III of the migratory locust, two different isoforms have been described (apoLp-IIIa and -b), displaying different N-termini and isoelectric points; each of the isoforms is however equally well capable to perform its function in lipid transport. In the present report the biosynthetic route of the apoLp-III isoforms is elucidated. Immunoprecipitation of media from in vitro fat body incubations and analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that the locust fat body synthesized and secreted apoLp-III. ApoLp-III levels in the hemolymph showed that in young adults, apoLp-III concentrations were only very low (1-3 mg/ml). During adult maturation, however, the apoLp-III concentration increased rapidly to approximately 17 mg/ml. During apoLp-III elevation, the apoLp-IIIa:-b ratio remained equal or in the favour of the a-isoform, while in adults from approximately 12 days after adult ecdysis apoLp-IIIb was the most abundant isoform. Analysis of the protein by native polyacrylamide gel electrophoresis showed that only the apoLp-IIIa form was secreted. Injection of radiolabeled apoLp-IIIa into the hemolymph of adult locusts resulted in a slow conversion into apoLp-IIIb.

Animals↗
PubMed1993

Homologous desensitization of calcitonin receptors and calcitonin-dependent adenylate cyclase in T47D cells.

Prolonged use of calcitonin (CT) in vivo leads to a loss of biological response (escape). To understand the molecular basis of this phenomenon, we examined desensitization of calcitonin receptors and down-regulation of adenylate cyclase response to CT in T47CD cells after a preincubation with CT. Preincubation with salmon or human CT (sCT, hCT) for 3 h led to a concentration-dependent loss of [125I]-sCT binding and a similar loss of adenylate cyclase response to a maximal stimulatory dose of sCT. At the same time there was an increased basal activity of the adenylate cyclase. After 24 h preincubation with sCT, basal cAMP levels fell considerably but not to basal levels. Time course experiments showed a delayed decline of maximally sCT-stimulated cAMP levels, which started after 1 h, while binding values declined over the first 60 min to one-third of the original values. Upon removal of CT from the medium, recovery of hormone binding occurred in parallel with the recovery of the adenylate cyclase response to sCT. T47D cells incubated with 25 mumol/l monensin, a lysosomal inhibitor, showed a persistent [125I]-sCT binding after removal of hormone, consistent with diminished intracellular receptor degradation. However, despite persistent binding to the cells, basal and stimulated cAMP levels dropped in the same manner as seen in controls. Our experiments support the view that tight binding of CT to its receptor stimulates adenylate cyclase in T47D cells, until receptors are removed by internalization. The physiological role of internalization of the CT receptor might be to end continuous stimulation of the adenylate cyclase, which occurs after binding.

Adenylyl Cyclases↗
PubMed1993

Characterization of insulin autoantibodies in relatives of patients with type I diabetes.

We studied in detail the anti-insulin autoantibodies in 29 nondiabetic relatives of patients with type I diabetes. The affinity of the autoantibodies for [125I]human insulin was high (1.34 x 10(9)-20.71 x 10(9) L/mol), and the capacity was low (0.84 x 10(-12)-37.80 x 10(-12) M). The product of affinity x capacity of each relative's antibodies directly correlated (r = 0.99) with the level of antibodies determined in our standard radioassay. The autoantibodies from each of the subjects studied had the same rank order of affinities for insulin from different species. Guinea pig, fish insulin, and insulin containing Trp rather than Leu in position 13 of the A-chain inhibited minimally the human insulin binding. Human proinsulin, insulin containing Gln rather than Glu in position 17 of the A-chain, and desoctapeptide insulin (des B23-30) all inhibited binding effectively. Insulin autoantibodies in relatives of patients with type I diabetes share common epitope(s), which suggests a common pathogenic mechanism for production of such antibodies. The epitopes from this initial analysis appear to include amino acids B1-B3 and A8-A13. The region recognized can be distinguished from the insulin receptor binding domain.

Adolescent↗
PubMed1993

Effect of clodronate treatment on bone scintigraphy in metastatic breast cancer.

Because of their high affinity for bone, bisphosphonates are used both in the treatment of benign and malignant bone disease and in radiopharmaceutical bone imaging. A prospective study was undertaken to evaluate whether intravenous clodronate (dichloromethylene bisphosphonate) therapy might affect the results of bone scintigraphy with 99mTc-labeled methylene diphosphonate (MDP). In 11 female patients with breast cancer and metastatic bone disease, quantitative bone scans were obtained using a region of interest (ROI) method on Days 0 and 22. After intravenous clodronate therapy from Day 1 to Day 21, all metastatic bone lesions were still detectable, and median ROI ratios did not differ to a statistically significant extent from baseline values. Serum calcium levels decreased (p = 0.0449), whereas parathyroid hormone concentrations showed an increase (p = 0.0053). Mean serum levels of creatinine, inorganic phosphorus, osteocalcin, gamma glutaminyl-transpeptidase and alkaline phosphatase remained unchanged. However, a more than twofold rise in the serum activity of alkaline phosphatase was measured in three patients. We conclude that 3 wk of intravenous clodronate treatment did not impair the sensitivity of 99mTc-MDP bone scintigraphy in detecting bone lesions in patients with metastatic breast cancer.

Bone Neoplasms↗
PubMed1993

The use of octreotide in the treatment of medullary thyroid carcinoma.

The long-term treatment of metastasizing medullary thyroid carcinoma with octreotide was evaluated in seven patients with progressive disease. All patients had persistently elevated serum calcitonin and carcinoembryonic antigen (CEA) concentrations. Daily doses of 200-1000 micrograms octreotide were administered by means of two or three subcutaneous injections for 3-9 months. In one patient treatment was stopped after 3 days because of aggravation of preexisting diarrhea. No beneficial effect on preexisting diarrhea was observed in three other patients during long-term treatment; in these patients further weight loss occurred. In five of six patients, serum calcitonin concentrations further increased; serum CEA concentrations increased in four of six patients. A therapeutic effect on tumor growth could not be demonstrated; in three patients, metastases continued to grow. We conclude that octreotide does not improve the natural course of advanced stages of medullary thyroid carcinoma.

Adult↗
PubMed1993

[Hypercalcemia].

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Adult↗