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Biomedical subjects

G V Segre

Publications and source records attributed to G V Segre.

At least 109 records · Page 6Linked to original sources
PubMed1988

Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure.

It has been postulated that hyperparathyroidism in chronic renal failure results from hypocalcemia, occurring, in part, from phosphate retention and/or deficient 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] synthesis. However, many studies have failed to demonstrate hyperphosphatemia or low 1,25-(OH)2D levels in patients with mild renal failure. We measured creatinine clearance (CCr), fractional excretion of phosphorus (FEP), and serum phosphorus, ionized calcium, and plasma N-terminal PTH, and 1,25-(OH)2D concentrations in 21 normal subjects and 51 patients with renal failure. Patients with mild renal failure (Ccr, greater than 40 mL/min.1.73 m2) had normal mean serum phosphorus and ionized calcium and decreased mean 1,25-(OH)2D levels compared with those in normal subjects. In patients with moderate renal failure (CCr, 20-40), the mean ionized calcium level was normal, plasma PTH levels and FEP were elevated, and the decrement in 1,25-(OH)2D was more pronounced. The mean ionized calcium level was decreased only in the group of patients with severe renal failure (CCr, less than 20). The 1,25-(OH)2D values correlated positively with CCr and negatively with the log of plasma PTH and serum phosphorus concentrations. Log of plasma PTH correlated negatively with CCr and positively with FEP. The ionized calcium concentration correlated very weakly with CCr and the log of the plasma PTH level. These data demonstrate the presence of hyperparathyroidism, normocalcemia, and 1,25-(OH)2D deficiency in renal failure and are consistent with a role for 1,25-(OH)2D in the suppression of parathyroid activity through as yet unidentified mechanisms.

Adult↗
PubMed1987

Age-related rise in parathyroid hormone in man: the use of intact and midmolecule antisera to distinguish hormone secretion from retention.

Circulating levels of parathyroid hormone (PTH) rise with age in normal men and women. To resolve the basis for this observation we measured iPTH in 137 normal men and women, age 23 to 85 years, using two antisera which responded to different portions of the PTH molecule. A midmolecule assay (Mid-PTH) employed antiserum NG-5, which recognizes mid- and carboxy-terminal portions of hPTH, whereas antiserum CK-67, which recognizes determinants in the 1-34 hPTH sequence, was used to measure intact PTH (NH2-PTH). Two-hour fasting urine was collected for measurement of creatinine clearance and excretion indices of phosphorus and cyclic AMP. Serum was analyzed for 25-hydroxyvitamin D (25-OHD) in addition to iPTH. Mid-PTH rose significantly with age in the 72 women (r = 0.38, p less than 0.001) and in the 65 men (r = 0.40, p less than 0.001). NH2-PTH rose with age in women (r = 0.23, p less than 0.05), but a change in men was not significant (r = 0.19, n.s.). Cyclic AMP excretion rose significantly with age in both women (r = 0.42) and men (r = 0.41), whereas phosphorus excretion rose significantly in women only (r = 0.32, p less than 0.01). 25-OHD levels were 27.5 +/- 1.3 ng/ml for women and 26.1 +/- 1.2 ng/ml for men. No change in 25-OHD was observed with age in women, and a significant decrease in men was due entirely to extremely high values in three young subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Tumor-induced osteomalacia. Kinetics of calcium, phosphorus, and vitamin D metabolism and characteristics of bone histomorphometry.

A patient with a mesenchymal tumor and hypophosphatemic osteomalacia was studied before and after tumor excision. Initial laboratory values included normal serum calcium, decreased serum phosphorus and tubular reabsorption of phosphate, undetectable 1,25-dihydroxyvitamin D, and normal parathyroid hormone. Histomorphometry of a bone biopsy specimen showed evidence of increased osteoclastic bone resorption. By 16 hours after tumor removal, 1,25-dihydroxyvitamin D level had normalized, but serum phosphorus level was unchanged; at 28 hours, both serum phosphorus value and tubular reabsorption of phosphate were within normal limits. It is concluded that tumor removal is associated with rapid correction both of 1,25-dihydroxyvitamin D production and of renal phosphate wasting. Increased bone resorption suggests the production of an osteoclast activator by the tumor and may explain the typically normal serum calcium value in this disorder.

Adult↗
PubMed1987

Parathyroid hormone directly inhibits tubular reabsorption of bicarbonate in normocalcaemic rats with chronic hyperparathyroidism.

The hypothesis that chronic metabolic acidosis encountered in some patients with primary hyperparathyroidism is due to inhibition of proximal HCO3 reabsorption has recently been challenged. Indeed, this action of parathyroid hormone (PTH) has only been observed in acute studies, whereas in animal models of chronic hyperparathyroidism a metabolic alkalosis has been induced, probably owing to the release of alkaline salts from bone tissue, and to the stimulation of tubular acid secretion by hypercalcaemia. Studies were, therefore, performed to determine the effect of PTH on the renal handling of HCO3 in an animal model in which changes in plasma calcium and phosphate, and nephrocalcinosis, all known to affect tubular acidification, did not occur. Thyroparathyroidectomized (TPTX) rats were infused with synthetic bovine hormone fragment bPTH 1-34 via Alzet minipumps at the rate of 0.7 U h-1 to simulate normal endogenous production of PTH (group I) and at the three-fold higher rate of 2.1 U h-1 (group II). In order to prevent changes in serum calcium and phosphate, and nephrocalcinosis, animals of group II were fed a Ca- and P-free diet prior to TPTX (compared with a regular diet for group I) and both groups were treated with dichloromethylene-diphosphonate (Cl2MDP, 10 mg kg-1 day-1) and a Ca-free diet during PTH infusion. During the course of PTH infusion both groups of animals had stable and normal levels of plasma calcium and phosphate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1987

Animal model of primary hyperparathyroidism.

An experimental model of hyperparathyroidism was developed in the rat to simulate primary hyperparathyroidism in humans. In this model thyroparathyroidectomized (TPTX) or parathyroidectomized (PTX) animals were infused for 6 days with an amount of bovine synthetic parathyroid hormone (PTH)-(1-34) fragment to restore plasma calcium levels to normal (0.7 U X h-1) or with PTH at twofold (1.4 U X h-1) or threefold (2.1 U X h-1) this basal level. Animals infused with 2.1 U X h-1 of bovine PTH-(1-34) exhibited hypercalcemia, hypophosphatemia, a reduction in theoretical renal threshold for phosphate and an increase in 1,25-dihydroxyvitamin D plasma levels that were approximately threefold the control value. In addition, these animals demonstrated nephrocalcinosis and changes of bone histology that were typical of the findings in patients with primary hyperparathyroidism. In contrast, in animals infused at 1.4 U X h-1, plasma calcium, phosphate, and theoretical renal threshold for phosphate remained within normal limits, but plasma 1,25-dihydroxyvitamin D was increased above control, suggesting that increased activity of 1 alpha-hydroxylase may be the most sensitive index of increased PTH levels. This animal model permits sustained elevation of PTH plasma levels at basal or pathologically elevated levels and should provide an effective means by which to evaluate the consequences of chronic hyperparathyroidism on epithelial function, bone, and other organ systems.

Acid-Base Equilibrium↗
PubMed1987

Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia.

We have developed a highly sensitive, two-site immunoradiometric assay (IRMA) for human parathyrin (PTH) that is specific for the intact, secreted, biologically active 84-amino-acid peptide. This assay has several technical advantages: it does not detect even high concentrations of inactive carboxyl-terminal fragments, results are available within 24 h, and the detection limit for intact hormone is low (1 ng/L). The assay readily measures concentrations of PTH in all healthy subjects and distinguishes these values from low or undetectable PTH values observed in clinical situations in which PTH secretion is expected to be suppressed. We found complete separation of results from 37 patients with surgically proven hyperparathyroidism and those from 23 patients with hypercalcemia associated with malignancy, the latter having PTH values at or below the lower limits of normal for this assay. The sensitivity, specificity, and rapid turnaround time of this two-site IRMA should advance the laboratory evaluation of patients with disorders of calcium metabolism.

Humans↗
PubMed1986

The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects.

The effect of brief periods of phosphate administration on indices of human skeletal metabolism was investigated. Thirteen subjects (8 women, 5 men; 19-36 years old) received 2 g of oral phosphate daily for 5 days. Serum phosphorus rose 26% (3.8 +/- 0.1 mg/dl to 4.8 +/- 0.1 mg/dl; p less than .01) while total calcium fell (9.3 +/- 0.1 mg/dl to 8.9 +/- 0.1 mg/dl; p less than .01). Parathyroid hormone levels increased by 50% (14.1 +/- 2.0 pg/ml to 21.5 +/- 1.7 pg/ml; p less than .05) although values remained within the normal range. A persistent phosphaturia (0.64 +/- 0.10 g/g Cr to 1.8 +/- 0.4 g/g Cr; p less than .05) and a 69% fall in urinary calcium (80.8 +/- 10.0 mg/g Cr to 24.6 +/- 6.0 mg/g Cr; p less than .001) were observed. 1,25-dihydroxyvitamin D3 and urinary hydroxyproline concentrations did not change significantly but the bone gamma-carboxyglutamic acid protein (BGP) concentration rose 41% by day 2 (9.6 +/- 1.3 mg/ml to 13.5 +/- 2.2 mg/ml; p less than .005) and remained elevated throughout the study period. These results support the possibility that brief periods of phosphate administration may be useful in the therapy of disorders associated with low bone turnover, such as osteoporosis.

Administration, Oral↗
PubMed1986

Spontaneous hypercalcemia in patients undergoing dialysis. Etiologic and therapeutic considerations.

Ten dialysis-treated patients with hypercalcemia (11.5 +/- 0.3 mg/dl, mean +/- SE) due to renal osteodystrophy were compared with 30 control dialysis-treated patients who were not hypercalcemic (9.5 +/- 0.1 mg/dl). The hypercalcemic patients were more disabled than the control patients. Fifty percent of the hypercalcemic patients and 37 percent of the control patients had a mineralization defect (p greater than 0.6). In the control group, intact parathyroid hormone level was significantly higher in patients with osteitis fibrosa than in those with osteomalacia (247 +/- 39 pg/ml versus 60 +/- 20 pg/ml, respectively, p less than 0.005) whereas in the hypercalcemic patients, parathyroid hormone measurements did not discriminate between these two types of bone disease. Osteomalacia was more severe and bone aluminum staining was stronger in the hypercalcemic patients than in the control patients (2.02 +/- 0.47 versus 0.35 +/- 0.11 mm/mm2 tissue area, p less than 0.001). The mean serum calcium level fell from 11.2 +/- 0.2 mg/dl to 10.5 +/- 0.3 mg/dl (p less than 0.01) in eight hypercalcemic patients treated with 24,25-dihydroxyvitamin D. It is concluded that hypercalcemia in patients undergoing dialysis is associated with an increase in bone aluminum level, and with more severe osteomalacia. Intact parathyroid hormone levels are useful for predicting bone histomorphometric parameters but only when hypercalcemia is not present. The drug, 24,25-dihydroxyvitamin D, was effective in lowering the serum calcium level.

Adolescent↗
PubMed1986

Humoral hypercalcemia of malignancy. Release of a prostaglandin-stimulating bone-resorbing factor in vitro by human transitional-cell carcinoma cells.

Secretion by tumor cells of circulating bone-resorbing factors may frequently underlie the hypercalcemia that occurs in patients with malignancy. Efforts to identify the responsible mediators have been hampered by a lack of available human tumor cell systems suitable for study of the pathogenesis of the humoral hypercalcemia syndrome. We have established a transitional-cell carcinoma (TCC) line in vitro from a patient with humoral hypercalcemia. These cells are tumorigenic and cause hypercalcemia in athymic nude mice. Culture medium conditioned by TCC cells contains potent bone-resorbing activity in vitro, the physical and biological properties of which are similar to those of bone-resorbing activity present in the original patient's urine. The bone-resorbing activity of the TCC factor is accompanied by increased prostaglandin release from bone and is blocked by indomethacin and calcitonin. The TCC-derived bone-resorbing activity coelutes with prostaglandin-stimulating activity during gel filtration with an approximate molecular weight of 15,000. This activity is nondialyzable, stable to concentrated urea and reducing agents, and destroyed by boiling. The TCC factor does not increase cyclic AMP production in bone or kidney bioassays and does not exhibit transforming growth factor activity. We conclude that a unique macromolecular factor released by TCC cells causes bone resorption by a mechanism dependent upon stimulation of bone cell cyclooxygenase, and that this factor is the probable cause of the hypercalcemia in vivo. The TCC cell line provides a new model for study of the human humoral hypercalcemia syndrome.

Animals↗
PubMed1985

Effect of heavy exercise on mineral metabolism and calcium regulating hormones in humans.

The relationship between acid base status and mineral metabolism after heavy exercise has been examined in 12 healthy subjects. Following burst exercise (duration 60-130 sec) to the point of exhaustion, blood pH had decreased (7.42 +/- 0.01 vs. 7.18 +/- 0.02, P less than 0.001) and plasma ionized calcium had increased (1.09 +/- 0.01 vs. 1.22 +/- 0.02 mmol/liter, P less than 0.001). Log ionized calcium concentration showed a significant negative correlation with pH (r = -0.90). Although plasma total calcium increased after exercise (2.47 +/- 0.05 vs. 2.67 +/- 0.04 mmol/liter, P less than 0.001), this change was not seen if the observed values were corrected for the accompanying increase in plasma protein concentration, suggesting that hemoconcentration accounted for these increments. Significant increases were also seen in plasma inorganic phosphate concentration, though not in plasma magnesium. Radioimmunoassay of parathyroid hormone using two different region-specific assays, one directed at the mid-region/carboxy-terminal and the other at the amino-terminal portion of the molecule, and of calcitonin, showed no change during exercise-induced hypercalcemia. The results do not suggest significant skeletal buffering of this type of acidosis and indicate that the changes in ionized calcium associated with short bursts of intense exercise are directly related to acidosis and that those in total calcium are a consequence of hemoconcentration.

Acidosis↗
PubMed1985

Evaluation of an in vitro parathyroid hormone antagonist in vivo in dogs.

A potent competitive inhibitor of PTH-stimulated biological responses in vitro, [Nle8,Nle18,Tyr34] bovine PTH (bPTH)-(3-34)amide, was evaluated in vivo in dogs. These studies confirm observations in vitro, suggesting that positions 1 and 2 of the peptide are critical to its biological activity. However, unlike the results from studies in vitro, this PTH analog is a weak agonist with effects on parathyroid target tissues that produce hypercalcemia and phosphaturia and increase urinary cAMP excretion. Assessed by these three parameters of hormonal action in vivo, the estimated potency of this analog is less than 1% of that of the intact hormone. In addition, PTH-induced biological responses were not inhibited by relatively large doses of the bPTH-(3-34) analog. These results emphasize the need for a systemic, integrated approach, combining chemical with biological studies, to design effective inhibitors of hormonal action in vivo. Although the rationale for introducing particular modifications into the peptide structure is most frequently based on bioassays performed in vitro, the success of the strategy chosen must rely, ultimately, upon the demonstration of specific biological properties in vivo.

Animals↗
PubMed1985

Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism.

A child with a pheochromocytoma had hypercalcemia but no evidence for excessive parathyroid hormone secretion from the parathyroid glands or the pheochromocytoma. Therapy with the catecholamine synthesis inhibitor metyrosine (alpha-methyltyrosine) reversed the catecholamine excess but had no effect on the hypercalcemia. Adrenalectomy promptly reversed the hypercalcemia. Extracts of the tumor contained a substance(s) that produced both potent in-vitro bone resorption and striking adenylate-cyclase-stimulating activity in renal cortical membranes. This stimulating activity was due to activation of the parathyroid hormone receptor/adenylate cyclase complex but was not due to parathyroid hormone. Our findings document hypercalcemia in association with pheochromocytoma and show that hypercalcemia occurred in the absence of previously proposed mechanisms. We also provide preliminary characterization of the presumed responsible substance(s) and suggest that this substance(s) may be related to that associated with the humoral hypercalcemia of malignancy.

Adenylyl Cyclases↗
PubMed1984

The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects.

We measured serum concentrations of calcium and parathyroid hormone in seven pregnant women who were receiving intravenous magnesium sulfate for the suppression of premature labor. After administration of magnesium sulfate, the mean (+/- S.E.M.) serum magnesium level rose rapidly from the normal base-line level of 2.0 +/- 0.2 mg per deciliter to 6.1 +/- 0.4 mg per deciliter (0.8 +/- 0.1 to 2.5 +/- 0.2 mmol per liter) (P less than 0.001) at 30 minutes and remained markedly elevated. Concentrations of total and ionized calcium fell gradually in all subjects from normal base-line concentrations, 8.6 +/- 0.2 and 4.4 +/- 0.1 mg per deciliter (2.2 +/- 0.1 and 1.1 +/- 0.03 mmol per liter), respectively, into the hypocalcemic range, reaching a nadir of 7.6 +/- 0.2 and 3.9 +/- 0.1 mg per deciliter (1.9 +/- 0.1 and 0.98 +/- 0.03 mmol per liter), respectively, at three hours (P less than 0.001). Parathyroid hormone levels fell rapidly in response to magnesium infusion, from 13.1 +/- 2.5 to 7.8 +/- 0.7 pg per milliliter at 30 minutes, and were significantly below base-line levels for two hours despite frank hypocalcemia. These results suggest that hypermagnesemia rapidly decreases the secretion of parathyroid hormone in vivo in human subjects and that parathyroid hormone levels remain depressed despite concomitant hypocalcemia. The results also suggest that the hypocalcemia associated with hypermagnesemia may be due in part to the suppressive effects of hypermagnesemia on parathyroid hormone secretion.

Adult↗
PubMed1984

Effect of histamine H2-receptor blockade on parathyroid status in normal and uraemic man.

Reports of parathyroid suppression during cimetidine therapy suggest that prolonged therapy with H2 antagonists may, by inducing relative hypoparathyroidism, compromise skeletal homeostasis and that under appropriate circumstances, these drugs may serve as a new modality in treating hyperparathyroidism. Using three different region-specific immunoassays, we have been unable to show an effect of cimetidine (1,800 mg/day) on parathyroid hormone concentration, or on urinary cyclic adenosine monophosphate and renal threshold phosphate concentration in 4 normal subjects. Ranitidine given for 8 weeks to 4 haemodialysed patients likewise failed to decrease parathyroid hormone concentration. H2 antagonists appear not to alter parathyroid status in either normal subjects or in uraemics and therefore are unlikely to influence skeletal metabolism in either instance.

Adult↗
PubMed1984

Primary hyperparathyroidism in German shepherd dogs: a disorder of probable genetic origin.

Primary hyperparathyroidism was diagnosed in two German shepherd pups from a litter of four females. Clinical signs were apparent by two weeks of age and included stunted growth, muscular weakness, and polydipsia/polyuria. Radiography revealed diffuse reduction in bone density. Both pups had marked hypercalcemia, hypophosphatemia, increased plasma immunoreactive parathyroid hormone concentrations and increased fractional clearance of inorganic phosphate in the urine. Intravenous infusion of one affected pup with calcium gluconate failed to suppress the plasma concentration of immunoreactive parathyroid hormone, suggesting autonomous secretion of parathyroid hormone. Necropsy of the other pup at eight weeks of age revealed diffuse hyperplasia of parathyroid chief cells, nodular hyperplasia of thyroid C-cells, skeletal alterations consistent with fibrous osteodystrophy, hypercalcemic nephropathy, and extensive mineralization of the lungs and gastric mucosa. The dam and sire were half sibs. One male pup from a previous litter of six had developed similar clinical signs and radiographic lesions, suggesting autosomal recessive inheritance. This is the first report of hereditary primary hyperparathyroidism in domestic animals, a disease which may be analogous to hereditary neonatal primary hyperparathyroidism in children.

Animals↗
PubMed1984

Syncytial cells in canine parathyroid glands.

Multinucleated syncytial cells consisting of clusters of closely apposed, darkly staining nuclei and densely eosinophilic cytoplasm were present in parathyroid glands from 25 of 36 dogs (69%). They were most often located either peripherally in the parathyroid gland or adjacent to blood vessels. The numbers of nuclei per syncytial cell ranged from two to greater than 30. Syncytial cells had degenerative changes as suggested by vacuolated mitochondria, dilated rough endoplasmic reticulum, irregular nuclear outlines, and condensed nuclear chromatin. These ultrastructural changes contrasted sharply with adjacent chief cells that had well-preserved organelles. The presence of desmosomes and fragments of cell membranes between nuclei suggested that syncytial cells were derived from fusion of adjacent chief cells rather than nuclear division without cytokinesis. Syncytial cells were present in normal, hyperplastic, and inactive parathyroid glands from dogs. There were no significant correlations between the presence of multinucleated cells and age of dog, parathyroid histology, and changes in the concentrations of serum calcium, phosphorus, creatinine, or plasma parathyroid hormone. Syncytial cells occurred frequently in canine parathyroid glands regardless of the state of activity of the gland or the concentration of plasma parathyroid hormone or serum calcium.

Animals↗
PubMed1983

Circulating bovine lymphocytes contain receptors for parathyroid hormone.

No cell type practicably obtainable in vivo, such as blood cells, is known to contain parathyroid hormone (PTH) receptors; this deficiency has hampered investigation of receptor regulation. Second, PTH in vivo is among the potent stimulators of osteoclastic activity, although no direct hormonal effects on these cells have been identified. Several lines of evidence suggest that cells of the immune system may mediate PTH effects on osteoclasts. We, therefore, studied bovine blood cells for the presence of PTH receptors and PTH-stimulated adenylate cyclase. Using an analogue of bovine PTH, (125)I-labeled [Nle(8),Nle(18),Tyr(34)]bPTH-(1--34)amide, we found PTH-specific binding to intact, nonadherent mononuclear cells (lymphocytes) and PTH-stimulated adenylate cyclase in plasma membranes prepared from these cells, and not with cells or membranes from other blood cells. Lymphocytes may serve to study the effects of physiologic and pathologic perturbations on PTH-receptor function in vivo. Exploration of PTH-related lymphocyte responses may help define the relation between cells of the immune system and osteoclastic bone resorption.

Adenylyl Cyclases↗