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Biomedical subjects

D Goltzman

Publications and source records attributed to D Goltzman.

At least 163 records · Page 9Linked to original sources
PubMed1984

Total parathyroidectomy: parathyroid hormone levels and supernumerary glands in hemodialysis patients.

Determination of PTH levels by radioimmunoassay can be employed for the accurate monitoring of the completeness of parathyroidectomy and the functioning of transplanted parathyroid tissue in chronic renal failure but the successful use of the approach requires accurate knowledge of the specificity of the assay and appropriate timing of postparathyroidectomy PTH measurements. In our series, 33% of grafts functioned within 9 days of implantation. The incidence of five, or more, glands in 25% of patients and the persistence of detectable PTH levels, postoperatively, in four patients after removal of four or more glands suggest that hypocalcemic stimulation in uremia may cause parathyroid rests ( parathyromatosis ) to enlarge. These findings also suggest that particular attention should be paid to finding a possible 5th or 6th parathyroid gland in uremic patients requiring surgical treatment of hyperparathyroidism.

Adult↗
PubMed1984

Value of high-resolution computerized tomography in localizing diseased parathyroid glands.

Eighteen patients with hyperparathyroidism underwent high-resolution computerized tomography of the neck and superior mediastinum to assess the accuracy of the method in localizing diseased parathyroid glands preoperatively. The tomograms were correlated with surgical and pathological findings. Four scans were technically unsatisfactory. Of the remaining 14 scans, 8 showed an enlarged parathyroid gland; in 7 cases, the scan correctly identified the location of the diseased gland while in 1 case, the side of the lesion was incorrect. The other six scans did not show an abnormal parathyroid. These glands varied in size from 0.05 to 5.0 cm3 at the time of pathological examination. Three patients were undergoing re-exploration for persistent disease; technically acceptable scans were obtained in two and, in both, the location of the adenoma was correctly identified. Excluding patients with technically unsatisfactory scans, this technique has a sensitivity of 50% (7/14) and a false-negative rate of 43% (6/14) independent of gland size. However, in the eight scans interpreted as positive, the correct side of the lesion was localized in 7 (88%). This technique is not recommended for routine preoperative localization but may be of value in re-exploration for persistent disease.

Adenoma↗
PubMed1983

Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy (HHM) most commonly results from secretion by tumors of an unidentified circulating calcemic factor that appears in clinical studies to stimulate both a parathyroid hormone (PTH)-sensitive proximal tubular adenylate cyclase and a distinct PTH-sensitive renal tubular glucose-6-phosphate dehydrogenase complex. In the present study, 8 M urea extracts of tumors from patients with HHM have been shown to contain both in vitro adenylate cyclase-stimulating activity and glucose-6-phosphate dehydrogenase-stimulating activity as detected in a sensitive cytochemical bioassay. Both the adenylate cyclase-stimulating activity and cytochemical bioactivity are due to specific binding of a substance in the tumor extracts to renal PTH receptors, as demonstrated by competitive inhibition studies using the bovine PTH fragment analogue [Nle8,18, Tyr34]bPTH-(3-34) amide. Preincubation with an antiserum to PTH results in no loss of activity in the tumor extract, and the activity appears both on gel filtration and ultrafiltration to be far larger than PTH (estimated Mr 70,000). These studies demonstrate that extracts of tumors from patients with HHM contain a substance that binds to the PTH receptors in the nephron responsible for activation of both the PTH-sensitive glucose-6-phosphate dehydrogenase and the PTH-sensitive adenylate cyclase. This substance is chromatographically and immunologically distinct from PTH. Its role in the genesis of HHM requires further study.

Adenylyl Cyclases↗
PubMed1983

Regulation of vitamin D metabolism in normal human pregnancy.

The increasing serum concentrations of various hormones (PTH, PRL, estrogens, and human placental lactogen) are hypothesized to regulate 1,25-dihydroxyvitamin D [1,25(OH)2D] and possibly 24,25-dihydroxyvitamin D [24,25(OH)2D] production during pregnancy. We examined the correlation between the serum levels of 1,25(OH)2D and the pregnancy-related hormones in 25 normal pregnant women, followed throughout gestation and postpartum. Maternal serum levels of 1,25(OH)2D were high during the first trimester (mean +/- SE, 74 +/- 8 pg/ml), remained high until the time of delivery (95 +/- 14 pg/ml), and then fell to almost normal levels (50 +/- 9 pg/ml) on the third postpartum day. The serum levels of 1,25(OH)2D do not correlate with the serum levels of any of the aforementioned hormones. The increase in serum 1,25(OH)2D in pregnancy has been postulated to be related to the stressed calcium homeostatic mechanisms known to occur in the mother. In twin pregnancy, this maternal calcium homeostatic mechanism(s) conceivably may be stressed to a greater extent. However, serum 1,25(OH)2D levels, measured in 27 women with a twin pregnancy in both the second and third trimesters as well as at delivery, did not differ from the levels observed in women with a singleton pregnancy. There were no significant changes in the serum levels of 24,24(OH)2D or 25-hydroxyvitamin D as pregnancy progressed. However, serum 24,25(OH)2D correlated significantly with both serum 1,25(OH)2D (r - 0.51; p less than 0.001, n = 83) and serum 25-hydroxyvitamin D (r = 0.37; P less than 0.001, n = 94). In conclusion, serum levels of 1,25(OH)2D rise early in the first trimester of pregnancy, fall acutely to normal levels soon after delivery, and are similar in singleton and twin pregnancies. The changes in the serum levels of 1,25(OH)2D do not relate to the changes in the serum levels of any of the pregnancy-related hormones.

24,25-Dihydroxyvitamin D 3↗
PubMed1982

Characterization of the rabbit renal receptor for native parathyroid hormone employing a radioligand purified by reversed-phase liquid chromatography.

Iodinated native bovine parathyroid hormone (bPTH(1-84)) was separated from uniodinated hormone by reversed-phase liquid chromatography techniques after lactoperoxidase labeling. Analysis of iodinated residues after enzymatic digestion indicated that the major labeled product was largely monoiodinated on the sole tyrosine residue. This material retained full bioactivity in an in vitro renal adenylate cyclase assay. Binding of 125I-bPTH(1-84) to rabbit renal membranes at 4 degrees C was proportional to membrane protein concentration and was saturable and dissociable. Radioligand binding was inhibited by concentrations of unlabeled bPTH(1-84) required to stimulate adenylate cyclase in the same membrane preparation but was not inhibited by non-PTH peptides other than adrenocorticotropin at high concentrations (greater than 10 microM). Synthetic NH2-terminal analogues of bPTH(1-84) all elicited approximately equivalent inhibition of radioligand binding which was, however, less potent than unlabeled bPTH(1-84), suggesting a role for the carboxyl region of the molecule in the interaction of bPTH(1-84) with its receptor. Activity of the NH2-terminal agonists was similar to bPTH(1-84) in stimulating adenylate cyclase. Although substitution in sequence position one, of serine in human PTH(1-34) for alanine in bPTH(1-34), reduced activity in the adenylate cyclase assay, inhibition of 125I-bPTH(1-84) binding by both peptides and by an analogue of bPTH(3-34) was equivalent, consistent with a minimal contribution of the first 2 residues for receptor binding of the NH2-terminal region of PTH. The results illustrate the utility of the radiolabeled preparation of native bPTH we have developed and emphasize the importance of probing the PTH receptor with an intact hormone to maximize information concerning the mechanism of PTH action.

Animals↗
PubMed1982

Parathyroid hormone stimulates mammalian renal 25-hydroxyvitamin D3-1 alpha-hydroxylase in vitro.

We have shown that parathyroid hormone (PTH) stimulates 25-hydroxyvitamin D2-1 alpha-hydroxylase activity in mitochondrial preparations of guinea pig kidney in vitro.1,25-[3H]dihydroxyvitamin D3 produced from 25-[3H]hydroxyvitamin D3 was identified by both normal phase and reversed-phase high pressure liquid chromatography. Enzyme stimulation by PTH was dose-dependent, peaked after 15 minutes of incubation with hormone and was maximal at concentrations of approximately 10(-10) M PTH-(1-84) and PTH-(1-34). This guinea pig renal model therefore permits direct examination of hormonal regulation of the mammalian enzyme in vitro.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1982

Brain receptors for blood-borne calcitonin in rats: circumventricular localization and vasopressin-resistant deficiency in hereditary diabetes insipidus.

Specific binding sites for blood-borne calcitonin were localized by means of quantitative radioautography to the circumventricular organs of the rat brain. By this method, using normal Long-Evans rats as controls, specific binding of blood-borne calcitonin in the median eminence region of the hypothalamus was reduced by one-third in homozygous Brattleboro rats, which are genetically deficient in vasopressin. Competitive binding analysis in vitro of the hypothalami from these animals confirmed the binding deficit in homozygous rats, and Scatchard analysis suggested a reduction in the number of binding sites. In homozygous rats daily vasopressin replacement therapy restored normal water balance but did not normalize the hypothalamic calcitonin binding deficit. These studies delineate for the first time specific sites within the central nervous system which could serve to mediate direct actions of blood-borne calcitonin on brain function. The deficit in the Brattleboro rat may provide a model for further investigation of the role of calcitonin within selective regions of the central nervous system.

Animals↗
PubMed1982

Absence of detectable calcitonin synthesis in the pituitary using cloned complementary deoxyribonucleic acid probes.

Recently, several investigators have detected calcitonin (CT)-like material in pituitary tissues by immunochemical techniques. In the present study we examined CT biosynthesis in rat pituitaries using specific and sensitive hybridization assays which used a cloned CT complementary DNA (cDNA) to detect CT mRNAs. Rat CT cDNA encoding the entire CT precursor, was radiolabeled to a high specific activity with 32P-labeled nucleotide and hybridized with mRNA extracted from pituitaries of both normal and genetically obese Zucker rats, in which elevated levels of immunoreactive CT-like material have been detected. Using these assays, we failed to detect mRNA with size and hybridization characteristics similar to those of thryoidal CT mRNA in either normal or Zucker rat pituitaries. We conclude that a mRNA homologous in sequence to that encoding rat thyroidal CT is not synthesized in the pituitary gland. In previous immunochemical studies a CT-like peptide may have been detected which is synthesized in the pituitary but lacks sufficient structural homology for the mRNA to react with our cDNA probe to thyroidal CT mRNA. Alternatively, in these prior studies thyroidal CT bound to pituitary receptors may have been detected.

Animals↗
PubMed1981

Isolation and analysis of human parathyrin in parathyroid tissue and plasma. Use of reversed-phase liquid chromatography.

Reversed-phase liquid chromatography techniques have been used to extract and purify human parathyrin from parathyroid adenomas and to analyse the circulating forms of human parathyrin in plasma. Both the supernatant from tissue homogenates, and plasma were extracted with octadecylsilyl-silica (ODS-silica) in a batch procedure. Extracts were subjected to reversed-phase high-pressure liquid chromatography (h.p.l.c.) employing solvent systems composed of aqueous acetonitrile containing trifluoroacetic acid or heptafluorobutyric acid as hydrophobic ion-pairing reagents. The volatile solvents facilitated the radioimmunoassay, bioassay in vitro and amino acid analysis of column fractions and permitted monitoring for u.v. absorbance at 210nm. Isolated glandular parathyrin was found to be homogeneous by sodium dodecyl sulphate/urea/polyacrylamide-gel electrophoresis, to have an amino acid composition conforming to that of human parathyrin-(1--84)-tetraoctacontapeptide and to be bioactive in both renal adenylate cyclase and cytochemical bioassays. ODS-silica extraction permitted examination of large plasms samples by reversed-phase h.p.l.c., facilitating the resolution of the various circulating molecular forms of parathyrin according to their hydrophobic character. Because of its rapidity, excellent recovery and high resolving power, the methodology utilized is uniquely suited to the purification and analysis of parathyrin in tissues and body fluids.

Adenoma↗
PubMed1981

In vivo demonstration of receptors in rat liver to the amino-terminal region of parathyroid hormone.

The specific binding of the amino-terminal region of parathyroid hormone (PTH) to liver has been assessed by in vivo radioautography employing a biological active 125I-labeled synthetic bPTH analog ([Nle-8,18, Tyr-34]bPTH-(1-34) amide) as a probe. Two minutes after intrajugular injection of the labeled analog into rats, free hormone was separated from that bound to cells by intracardiac perfusion with buffer (30 sec), followed by perfusion-fixation with glutaraldehyde. By light and electron microscope radioautography, the distribution of silver grains over the liver sections revealed localization over the periphery of hepatocytes as well as over endothelial cells. In simultaneous control experiments, the unlabeled synthetic active fragment bPTH-(1-34) and unlabeled intact native bPTH-(1-84) significantly inhibited binding of the labeled analog to liver hepatocytes but not to endothelial cells. Greater uptake of the 125I-labeled bPTH analog was found in rat liver (28% of the injected dose) than in kidney, bone, or other organs examined. In parallel experiments using purified plasmalemma fractions from hepatocytes, both bPTH-(1-34) and intact bPTH-(1-84) demonstrated a dose-dependent activation of adenylate cyclase which was less than that of glucagon but greater than that of epinephrine. The combined results support the concept of the liver as a target organ for the amino-terminal biologically active region of PTH.

Adenylyl Cyclases↗
PubMed1981

Malignancy-associated hypercalcemia: evaluation with a cytochemical bioassay for parathyroid hormone.

Employing a cytochemical assay initially developed for measuring parathyroid hormone (PTH), bioactivity was assessed in 33 patients with malignancies. Initial studies in vitro were consistent with a role for cAMP as a second messenger in the bioassay. Cytochemical bioactivity was increased in the peripheral plasma of 10 of 16 hypercalcemic patients with elevated nephrogenous cAMP excretion, and mean levels were 10-fold higher in these patients than in 17 normocalcemic or hypercalcemic patients with normal or suppressed nephrogenous cAmP excretion, respectively. Plasma bioactivity, serum calcium, and nephrogenous cAMP excretion all fell to normal in 1 patient after tumor resection, and cytochemical bioactivity was demonstrable in the tissue culture medium in which the neoplasm was maintained. Gel chromatographic analysis revealed that a major component of plasma bioactivity eluted before rather than with PTH-(1-84) in patients with malignancy in contrast with that in patients with primary hyperparathyroidism. The studies, therefore, demonstrate the capacity of the cytochemical bioassay to measure increased activity in patients with malignancy, hypercalcemia, and elevated nephrogenous cAMP excretion; suggest that the material responsible for the activity differs from PTH-(1-84); and provide a sensitive detector system for further analysis of this material and its role in the pathogenesis of this disease.

Animals↗
PubMed1980

Direct in vivo demonstration by radioautography of specific binding sites for calcitonin in skeletal and renal tissues of the rat.

An in vivo binding assay using radioautography was employed to visualize calcitonin receptors in rat tissues. At 2 min after intravenous injection of biologically active 125I-salmon calcitonin, free hormone was separated from bound hormone by intracardiac perfusion with lactated Ringer's followed by fixation with 2.5% glutaraldehyde. Various tissues were removed and processed for light and electron microscope radioautography. These were compared to tissues removed from animals that received identical amounts of labeled hormone with a large excess of unlabeled calcitonin. Among the tissues investigated, kidney and bone demonstrated labeling. In kidney, most silver grains were located over vesicles below the brush border of cells of theproximal convoluted tubules. These grains were still present after simultaneous injection of excess unlabeled hormone and most likely represented binding to sites involved with ingestion and degradation of hormone from the urinary filtrate. In contrast, grains localized to the basal surfaces of distal convoluted tubule cells were significantly reduced in number in control animals and represented sites of saturable, specific hormone binding. In bone, specific binding sites were found only at the periphery of osteoclasts. These labeled cells were located at resorption sites examined in tibia, humerus, and alveolar bone. This demonstration of the localization of 124I-calcitonin in situ provides a new approach for study the interaction of calcium-regulating hormones with their target cells.

Animals↗
PubMed1980

Cytochemical bioassay of parathyroid hormone: characteristics of the assay and analysis of circulating hormonal forms.

A cytochemical bioassay for parathyroid hormone (PTH) was used for the characterization of the biological activity of circulating forms of the hormone. PTH-stimulated glucose-6-phosphate dehydrogenase activity in distal convoluted tubule cells was quantitated by integrating microdensitometry and the response to native bovine (b)PTH(1-84) was found to be linear between graded doses of hormone from 5 fg/ml to 5 pg/ml. Synthetic bPTH(1-34) and human (h)PTH(1-34) elicited a parallel and equimolar response; however calcitonin, ACTH, glucagon, epinephrine, vasopressin, and insulin failed to significantly stimulate the enzyme in doses up to 100,000 times greater than the lowest concentration of bPTH used. The assay was capable of distinguishing hormonal activity in normal, hypoparathyroid, and hyperparathyroid human plasma. After gel chromatography, bioactivity in plasma of hyperparathyroid patients with skeletal disease but normal kidney function coeluted mainly with bPTH(1-84), whereas bioactivity in plasma of hyperparathyroid patients with skeletal disease but severe uremia coeluted in approximately equivalent amounts with bPTH(1-84) and hPTH(1-34). Despite the abundance of small molecular-weight bioactivity in the peripheral circulation in uremia, approximately 85% of the bioactivity in the parathyroid venous effluent coeluted with bPTH(1-84). The results therefore demonstrate the sensitivity and specificity of the assay for PTH and its utility in measuring the hormone in human parathyroid disorders. The results furthermore demonstrate the importance of entities cochromatographing with bPTH(1-84) in comprising the circulating bioactive hormone in hyperparathyroidism, and support the concept of a biological role for smaller forms of PTH, at least in chronic renal failure.

Animals↗