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Biomedical subjects

E Blind

Publications and source records attributed to E Blind.

At least 19 recordsLinked to original sources
PubMed1992

Tumor necrosis factor alpha inhibits the stimulatory effect of the parathyroid hormone-related protein on cyclic AMP formation in osteoblast-like cells via protein kinase C+.

Tumor necrosis factor alpha (TNF alpha) and parathyroid hormone-related protein (PTHrP) are both factors that have been implicated in the mechanism of hypercalcemia of malignancy. In this study we investigated the effect of TNF alpha on the PTHrP-stimulated accumulation of intracellular cyclic AMP in osteoblast-like cells. In the clonal cell line Saos-2 and in primary cell cultures from fetal rat calvaria, PTHrP-stimulated accumulation of cAMP was time- and dose-dependently inhibited by exposure to TNF alpha. Significant inhibition occurred at concentrations as low as 2 x 10(-12) M and was maximal at 1 x 10(-9) M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF alpha was probably mediated by protein kinase C, since the phorbol ester PMA mimicked the effect of TNF alpha, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF alpha. In conclusion, these observations suggest a possible mechanism by which TNF alpha may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy.

Animals↗
PubMed1992

Evaluation of sensitive PDN-21 (katacalcin) determination as tumor marker in medullary thyroid carcinoma.

PDN-21 (katacalcin), a peptide from the calcitonin (CT) gene, was measured in plasma from healthy persons and patients with medullary thyroid carcinoma (MTC). PDN-21 was detectable (greater than or equal to 10 ng/l) in 73% of normal persons (n = 40). In 17 normal persons with undetectable basal plasma levels, PDN-21 became detectable (greater than or equal to 10 ng/l) by stimulation with iv pentagastrin in 7 cases. Basal levels were more often detectable in men than in women. In 65 patients with MTC, PDN-21 levels were highly correlated with CT levels as determined by an "in house" RIA (r = 0.99); the mean ratio of CT/PDN-21, on a molar base, was 0.96 +/- 0.33 over the entire range. In iv stimulation tests with pentagastrin, PDN-21 and CT showed good parallelism (mean ratio of CT/PDN-21: 1.1 +/- 0.62); in MTC patients with normal basal levels, however, peak to basal ratios during iv pentagastrin testing were higher for PDN-21 than for CT, due to the more sensitive PDN-21 assay. In a selective venous catheter study of a patient with MTC, the mean CT/PDN-21 ratio for all samples was 1.04 +/- 0.12, but the peak to peripheral levels were higher for PDN-21 (4.1-fold) than for CT (2.8-fold). In conclusion, determination of PDN-21 by RIA is equivalent to determination of CT in diagnosing MTC patients. In few patients, it might be even slightly more sensitive. PDN-21 should be determined in all cases with borderline CT results.

Biomarkers, Tumor↗
PubMed1992

Characterization of antibodies against human N-terminal parathyroid hormone by epitope mapping.

Two polyclonal antisera from goat and mouse and two monoclonal antibodies against human parathyroid hormone (1-34) were characterised by epitope mapping. Hexapeptides were synthesized on polystyrene pins, the sequences of which overlapped and represented the entire sequence of hPTH(1-34). Binding of antibodies to these hexapeptides was determined and antigenic determinants thus characterized. At least one predominant binding sequence was detected in the region of hPTH(7-14).

Amino Acid Sequence↗
PubMed1992

Chromogranin A as tumor marker in medullary thyroid carcinoma.

We measured plasma levels of chromogranin A (CgA) and calcitonin (CT) in 61 patients with surgically confirmed medullary thyroid carcinoma (MTC). CT was elevated in 46 patients, whereas CgA was elevated in 14 patients. Plasma levels of CgA and CT were moderately correlated (r = 0.87), but CgA became elevated in most patients only in advanced disease. Patients with high plasma CT values (greater than 10 micrograms/L) also had elevated CgA in 83% of cases. An elevated plasma CgA level despite normal CT levels was found in only 1 patient. In 8 MTC patients with moderately elevated basal CT levels, pentagastrin as a secretagogue usually was not able to release detectable amounts of CgA from MTC tissue. In 2 MTC patients, i.v. catheter sampling gave sharp gradients for CT concentrations (greater than 2.7-fold peak to peripheral ratios) and, therefore, precise MTC tissue localization, whereas no gradients were demonstrable for CgA (less than 1.2-fold). One patient with MTC and elevated CgA reached normal CgA plasma levels within 8 days after thyroidectomy. In metastatic tissue from 8 patients with MTC, CgA and CT were detectable immunohistologically in all cases, but plasma CgA was elevated only in 2 and CT in 7 of them. Plasma CgA levels in patients with MTC usually became elevated only in advanced disease and were not able to detect early disease stages, were correlated with CT levels, were not useful in stimulation tests or venous localization studies, and probably resulted from the release from MTC tissue as the major tissue source, as shown in the sporadic cases.

Biomarkers, Tumor↗
PubMed1992

Circulating levels of midregional parathyroid hormone-related protein in hypercalcaemia of malignancy.

OBJECTIVE: We have developed and evaluated a sensitive radioimmunoassay directed against the midregional part of parathyroid hormone-related protein (PTHrP), which is involved in the syndrome of humoral hypercalcaemia of malignancy. PATIENTS: Midregional PTHrP levels were studied in 41 consecutive inpatients with malignancy and hypercalcaemia, 32 normocalcaemic patients with malignancy, 21 patients with primary hyperparathyroidism, 34 patients with renal failure, and 87 normals. MEASUREMENTS: The assay used an antiserum against the midregional amino acid residues 53-84 of PTHrP and PTHrP(1-86) as label and standard. Midregional PTHrP was stable in serum and plasma and could be measured directly without sample extraction. RESULTS: Normal plasma concentrations ranged from undetectable (< 5 pmol/l) to 21 pmol/l. In renal failure, PTHrP was positively correlated with serum creatinine, but PTHrP elevations of up to 30 pmol/l were found only in severe renal dysfunction with creatinine > 850 mumol/l. In hypercalcaemia caused by solid tumours, midregional PTHrP was elevated in 81% (22 of 27) of patients, ranging from undetectable to 203 pmol/l (median: 40 pmol/l). In these patients serum calcium correlated positively with PTHrP (P < 0.01). Mean PTHrP levels were indistinguishable in subgroups with and without metastatic skeletal disease. The mechanism of hypercalcaemia in 14 patients with haematological malignancy was apparently different, since all but one had normal or only marginally elevated PTHrP levels. In 21 patients with primary hyperparathyroidism midregional PTHrP was normal in 20. The assay was therefore especially useful in distinguishing the latter condition from humoral hypercalcaemia of malignancy as the second major cause of hypercalcaemia. PTHrP was normal in all 32 patients with normocalcaemic malignancy. CONCLUSION: This radioimmunoassay of midregional PTHrP provides high diagnostic sensitivity in the identification of humoral hypercalcaemia of malignancy caused by solid tumours. The assay should therefore be useful in the differential diagnosis of hypercalcaemia.

Diagnosis, Differential↗
PubMed1992

Determination of serum calcitonin by immunometric two-site assays in normal subjects and patients with medullary thyroid carcinoma.

We evaluated the clinical usefulness of a commercial two-site immunoassay for calcitonin, which is based on two monoclonal antibodies against distinct epitopes of calcitonin. The potential lower detection limit of the assay was 2 ng/l. Inter-assay and intra-assay variation were both < 11%. No cross reaction with calcitonins from different species (salmon and eel calcitonin) was found. Of the various fragments of human calcitonin, only the 11-32 fragment could be detected. Basal calcitonin concentrations in normals (n = 69) ranged from < 2 ng/l to 50 ng/l. Basal calcitonin concentrations in 30% of the men (< 2-48 ng/l) and 51% of the women (< 2-10 ng/l) were undetectable. Stimulation of calcitonin with pentagastrin (0.5 microgram/kg body weight) in normal subjects was followed by an increase in calcitonin in all men (n = 17) and in 60% of the women (n = 12). The upper reference value for pentagastrin-stimulated calcitonin concentrations for all 29 normals was 78 ng/l (defined as the 95th percentile): 79 ng/l for men, and 50 ng/l for women. Using a different immunoradiometric two-site assay, a similar percentage of "positive" responses to pentagastrin in normals was obtained (20 out of 29). Four previously thyroidectomized patients with medullary thyroid carcinoma had normal basal, but pathological stimulated calcitonin values at follow-up. At reoperation, cervical lymph nodes with tumour tissue were removed. Postoperatively, the patients had basal and stimulated calcitonin concentrations within the limits of the established reference range. In conclusion, reference ranges for basal and pentagastrin-stimulated calcitonin concentrations have been established for an immunometric two-site assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Serum levels of intact parathyroid hormone and alkaline phosphatase correlate with cortical and trabecular bone loss in primary hyperparathyroidism.

We examined the relationship between bone loss and several biochemical indices in 38 patients with primary hyperparathyroidism. Bone mineral density was reduced by 12 +/- 4.0% in the lumbar spine, 18 +/- 4.2% at the distal radius and 21 +/- 2.8% at the proximal radius (mean +/- SEM). There were significant negative correlations between the serum concentrations of intact parathyroid hormone (PTH) and the Z-scores of the bone mineral content at the proximal and distal radius. In the lumbar spine, bone mineral density was greater in patients with mildly elevated PTH and less in patients whose PTH levels exceeded 8.6 pmol/l. We also observed a strong association between increased levels of serum alkaline phosphatase and low bone mineral Z-scores. Our data thus indicate that cortical and, with the exception of mild primary hyperparathyroidism, trabecular bone loss is proportional to the concentration of circulating PTH and the severity of PTH-induced bone turnover. For the individual patient, however, the usefulness of intact PTH and alkaline phosphatase measurements for assessing bone loss associated with primary hyperparathyroidism seems to be only limited.

Aged↗
PubMed1992

PDN-21 (katacalcin) and chromogranin A: tumor markers for medullary thyroid carcinoma.

The malignant C-cell releases several markers of potential clinical significance into the circulation. To determine the usefulness of these markers for management of medullary thyroid carcinoma (MTC), it is necessary to compare the usefulness of these markers with calcitonin (CT), the classical tumor marker for MTC. Measurement of serum concentrations of the peptide PDN-21 (katacalcin), a carboxyterminal cleavage product of procalcitonin, showed a high correlation with serum CT levels (r = 0.99, P < 0.01, n = 65 patients with MTC). The presence of equimolar concentrations of CT and PDN-21 (CT/PDN-21 molar ratio = 0.95 +/- 0.33) indicates the peptide is cosecreted with CT. Stimulation of CT release by intravenous pentagastrin was associated with a parallel increase of PDN-21, providing further evidence of cosecretion of these two peptides. Finally, measurement of either PDN-21 or CT in selective venous catheterization specimens was useful for localization of MTC. Chromogranin A (CgA) levels were also measured in patients with MTC. Circulating levels were elevated in most patients with advanced disease. There was a moderate correlation between CgA and CT serum levels (r = 0.87, P < 0.01, n = 61 patients with MTC). Pentagastrin did not stimulate CgA, and the long half-life of CgA in the circulation did not make it possible to use this peptide for tumor localization by selective venous catheterization. We conclude that measurement of PDN-21 provides an independent assay system for diagnosis, localization, and postoperative management of MTC, whereas CgA measurement is not useful in early diagnosis of MTC and is of limited value for localization or management of progressive disease.

Biomarkers, Tumor↗
PubMed1990

[Epidemiology of hypercalcemia. Significance of the determination of intact parathyroid hormone for differential diagnosis].

Serum-calcium levels were determined in 9666 hospital inpatients during one year. Hypercalcaemia was present in 101 patients (51 women, 50 men, mean age 57 years). In 46 patients, hypercalcaemia was caused by malignancy. The second commonest cause was primary hyperparathyroidism (pHPT) in 35 cases. In the other 20 patients, hypercalcaemia was related to thiazid medication (8 patients), elevated 25-hydroxy-vitamin-D3-levels (six patients) or immobilisation (two patients). In four patients, no cause was found. Intact parathyroid hormone levels reliably distinguished patients with pHPT (values greater than 60 ng/l) from patients with hypercalcaemia of other causes (values less than 40 ng/l). Other laboratory tests were less useful. Serum-calcium levels greater than 2.9 mmol/l were found only in pHPT and hypercalcaemia of malignancy. In pHPT, the medical history frequently revealed nephrolithiasis (12 patients) and gastrointestinal ulcers (8 patients), whereas weight loss was far more common in hypercalcaemia of malignancy (28 patients).

Adult↗
PubMed1990

Intact parathyroid hormone in primary hyperparathyroidism.

In 49 patients with primary hyperparathyroidism, intact parathyroid hormone (PTH) was measured with a recently developed immunoradiometric assay, and midregional PTH fragments (sequence 44-68) were measured with an established radioimmunoassay technique. In 47 normal subjects, the concentration of intact PTH ranged from 2.0 to 6.8 pmol/l, and in 49 patients with primary hyperparathyroidism it ranged from 6.4 to 80.0 pmol/l. In contrast, midregional PTH fragments were normal in seven of 49 patients with primary hyperparathyroidism. In five healthy controls and in 12 patients with surgically confirmed primary hyperparathyroidism and serum calcium levels below 3.0 mmol/l, a rapid calcium loading test was performed. In healthy controls, intact PTH was in the low normal to subnormal range within 2.5-5.0 min, and had recovered within 15 min of calcium infusion. In patients with primary hyperparathyroidism, the calcium infusion also led to a 30-50 per cent decrease in intact PTH levels within 5.0-7.5 min after injection, with a slow recovery after 10-15 min. In six of the patients with only slightly elevated basal intact PTH, a suppression to the normal range was observed. In 24 patients (16 patients with a solitary adenoma and eight patients with four-gland hyperplasia) the intact PTH levels were followed intraoperatively during parathyroidectomy, revealing a significantly different rate of decline for single adenomas compared with hyperplasia during the first 15 min after removal of the primary enlarged gland. Intact PTH values remained constantly elevated in one patient with primary hyperparathyroidism and an unsuccessful neck exploration. These results confirm that (a) the measurement of intact PTH in patients with primary hyperparathyroidism is superior to the measurement of midregional fragments; (b) PTH secretion in primary hyperparathyroidism is not totally autonomous; and (c) intraoperative monitoring of intact PTH values could be used to monitor the success of surgery.

Adenoma↗
PubMed1989

Two-site immunochemiluminometric assay of intact human parathyrin in serum with use of a tracer peptide purified by reversed-phase high-performance liquid chromatography.

For this two-site immunochemiluminometric assay of intact human parathyrin (hPTH), the luminescent tracer was synthetic hPTH(53-84), conjugated via succinimide linkage to (aminobutyl)ethyl-isoluminol hemisuccinimide (abei-h). Purification of the labeled hPTH(53-84) by reversed-phase high-performance liquid chromatography allowed isolation of the conjugate having the highest incorporation of abei-h, 1.6 mol per mole of hPTH(53-84). The solid-phase antibody directed against the N-terminal part of hPTH was immobilized by adsorption onto the polystyrene surface of the assay tube and extracted the intact hPTH and N-terminal fragments. Another antibody against synthetic hPTH(53-84), which bound to the C-terminal part of intact hPTH, was indirectly labeled at its second free binding site with the abei-h-labeled hPTH(53-84). The assay has a detection limit of 0.5 pmol/L; it is accurate, precise, and reliable; and it shows a linear response for samples containing up to 100 pmol of hPTH per liter. The normal reference interval ranged from 1.8 to 5.9 pmol/L; 56 patients with primary hyperparathyroidism had concentrations ranging from 5.9 to 113 pmol/L. The concentrations detected in patients with idiopathic hypoparathyroidism were below the normal reference interval.

Chromatography, High Pressure Liquid↗
PubMed1988

Two-site assay of intact parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a midregion assay.

We compared the utility of measurements of serum intact human PTH-(1-84) and midregion human PTH-(44-68) in patients with disorders of extracellular calcium metabolism. Serum midregion PTH was determined by RIA, and serum intact PTH was measured by a sensitive and specific immunoradiometric two-site assay. The serum intact PTH concentrations in 70 patients with primary hyperparathyroidism were above the normal range in 69, and thus widely separated from the levels in 40 patients with hypercalcemia of malignancy, in whom serum intact PTH values were usually below normal. In contrast, both groups had overlapping serum midregion PTH values. In patients after renal transplantation and those with chronic renal failure, serum intact PTH levels were in the normal range twice as often as were serum midregion PTH values. The intact PTH assay was also superior in detecting venous gradients of the hormone and changes in PTH secretion caused by altered serum calcium concentrations, and serum intact PTH was remarkably low in hepatic venous effluent. We conclude that this new assay for serum intact PTH is superior to the midregion RIA in investigating parathyroid function in several different clinical conditions.

Adult↗
PubMed1987

[Treatment of tumor hypercalcemia with clodronate. Effect on parathormone and calcitriol].

Clodronate (dichlormethylene diphosphonate) was administered to 21 patients with hypercalcemia due to malignant tumor. The drug was initially given intravenously, then orally. In 20 patients the serum calcium level had been reduced to the normal range within one week of the start of treatment (from 3.3 +/- 0.5 mmol/l to 2.4 +/- 0.3 mmol/l). With oral administration there was a renewed rise in calcium levels in some patients, which had to be treated with higher oral doses or intravenous administration. Parallel with the reduction in calcium levels there was an improvement in the originally impaired renal function. The serum level of intact parathormone(1-84) and 1.25-dihydroxy-vitamin-D3 (calcitriol) rose significantly from usually lowered initial levels. There was a non-linear inverse correlation between parathormone and calcium. No side effects were noted, even after long-term administration.

Adult↗