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Biomedical subjects

A E Broadus

Publications and source records attributed to A E Broadus.

At least 91 records · Page 5Linked to original sources
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

Impaired phosphorus conservation and 1,25 dihydroxyvitamin D generation during phosphorus deprivation in familial hypophosphatemic rickets.

The pathogenesis of familial hypophosphatemic rickets (FHR) is incompletely understood. We therefore examined the effects of acute dietary phosphorus deprivation to see whether renal phosphate conservation and increased 1,25 dihydroxyvitamin D [1,25(OH)2D] plasma levels, which normally follow restriction of phosphorus intake, could be induced in patients with FHR. Six healthy male volunteers (age 26 +/- 3 yr) and seven male patients with FHR (age 24 +/- 3 yr) were placed on a low phosphorus diet supplemented with aluminum hydroxide and studied over a 4-d period. The patients with FHR excreted more than five times as much phosphorus per day at the conclusion of the study than did the controls (176 +/- 61 mg/24 h vs. 33 +/- 11 mg/h). In the normal subjects, maximum tubular reabsorptive capacity for phosphorus/glomerular filtration rate (TmP/GFR) rose progressively during phosphorus deprivation, and the rise from base line was more than two times greater than that seen in patients with FHR. Immunoreactive parathyroid hormone levels and nephrogenous cyclic AMP were initially normal in both groups and no change was seen in either group with phosphorus deprivation. In the normal subjects, 1,25(OH)2D levels rose progressively over the 96 h of the study (49 +/- 3 to 63 +/- 6 pg/ml, P less than 0.05), while mean circulating 1,25(OH)2D in the patients with FHR did not change (34 +/- 3 to 29 +/- 3 pg/ml). The changes in individual plasma 1,25(OH)2D levels correlated strongly with the change in individual nephrogenous cyclic AMP measurements in the patients with FHR (r = +0.93), while no such correlation was observed in the normal subjects. These data demonstrate a defective renal response to phosphorus deprivation in patients with FHR including a qualitatively abnormal response in 1,25(OH)2D generation.

Absorption↗
PubMed1983

Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells.

The culture media of three cell lines, a human prostate carcinoma (PC3), a rat Leydig cell tumor (Rice-500), and a rat carcinosarcoma (WRC-256), that were derived from tumors associated with humoral hypercalcemia of malignancy (HHM), were examined for stimulation of adenylate cyclase in ROS 17/2.8 osteoblastic cells and for bone resorptive activity in culture. Cells from a nonhypercalcemic variant of the WRC256 tumor served as control. Extracts from three solid human tumors, a lung adenocarcinoma from a patient with HHM and two adenocarcinoma from normocalcemic patients (lung and colon), were also examined for adenylate cyclase stimulation. We found excellent correlation between stimulation of cyclic AMP accumulation in ROS 17/2.8 cells and bone resorbing activity in culture, or production of HHM in vivo. Stimulation of adenylate cyclase by HHM factors was inhibited by the parathyroid hormone competitive inhibitor, [8norleucyl, 18norleucyl, 34tyrosinyl] bovine parathyroid hormone (3-34) amide.

Adenylyl Cyclases↗
PubMed1983

A detailed evaluation of oral phosphate therapy in selected patients with primary hyperparathyroidism.

Recent studies have emphasized the pathophysiological importance of circulating 1,25-dihydroxyvitamin D ((1,25-(OH)2D] in the pathogenesis of hypercalciuria and renal stone formation in primary hyperparathyroidism. Reasoning that phosphate administration might be capable of reducing the plasma concentration of 1,25-(OH)2D in patients with a prominent 1,25-(OH)2D-mediated absorptive component to their disease, 10 carefully selected patients were treated with oral phosphate (1500 mg elemental phosphorus daily) for 1 yr. Phosphate treatment significantly reduced circulating 1,25-(OH)2D levels (84 to 56 pg/ml), the calciuric response to an oral calcium tolerance test (0.30 to 0.21 delta mg calcium/dl GF), and calcium excretion on an unrestricted calcium diet (438-269 mg/day), in essence reversing the absorptive pattern of abnormalities observed before treatment. This response, however, was accompanied by an increase in biochemical hyperparathyroidism, as assessed by circulating immunoreactive PTH and nephrogenous cAMP excretion. In patients with biochemical evidence of an increase in bone resorption before therapy, histomorphometric, radiographic, and biochemical data revealed a trend toward a reduction in bone turnover during phosphorus therapy, with an apparent maintenance of coupled bone resorption and bone formation. This trend, however, was of marginal statistical significance in the patient group as a whole. It is concluded 1) that phosphate therapy represents a viable medical alternative in selected patients with primary hyperparathyroidism, 2) that the net response in treated patients is multifaceted and complex, and 3) that the efficacy of phosphate therapy will ultimately depend upon its long term effects on skeletal homeostasis.

Bone and Bones↗
PubMed1982

Hypercalcemia associated with gynecologic malignancies: biochemical characterization.

Fasting calcium excretion, renal phosphorus threshold, plasma 1,25 dihydroxyvitamin D, immunoreactive PTH, nephrogenous cyclic AMP excretion, and tumor burden were assessed in nine patients with gynecologic neoplasms and hypercalcemia. Gynecologic neoplasms were responsible for hypercalcemia in seven of 34 (20.5%) consecutive patients with malignancy-associated hypercalcemia. The tumor burden in each patient was large. Three of four endometrial carcinomas contained squamous elements. All patients displayed biochemical evidence of nonparathyroid humorally mediated hypercalcemia (bone resorption). Treatment of hypercalcemia did not appear to diminish production of the humoral calcemic factor but eradication of tumor eliminated biochemical evidence of the humoral syndrome. It can be concluded that (1) gynecologic neoplasms are a frequent cause of malignancy-associated hypercalcemia, (2) humoral mechanisms appeared to be responsible for the hypercalcemia in 100% of the patients in this series, (3) squamous features occur with unexpected frequency in hypercalcemic endometrial carcinoma, (4) the presence of hypercalcemia connotes a large tumor burden, and (5) treatment directed at the neoplasm (but not treatment directed at hypercalcemia) may eliminate evidence of ectopic calcemic hormone production.

Adolescent↗
PubMed1982

Calcium homeostasis in immobilization: an example of resorptive hypercalciuria.

Prolonged immobilization may result in hypercalcemia, hypercalciuria, and osteoporosis. Although bone resorption is central to this syndrome, the mechanism of resorption is uncertain. In particular, the role of systemic calcium-regulating hormones remains unclear. In 14 immobilized subjects we measured fasting calcium excretion, 24-hour urinary calcium excretion during restricted calcium intake, the renal phosphorus threshold, plasma 1,25-dihydroxyvitamin D, nephrogenous cyclic AMP, and immunoreactive parathyroid hormone. Mean serum calcium levels were normal, but fasting and 24-hour calcium excretion were markedly elevated (0.28 mg per deciliter of glomerular filtrate and 314 mg per 24 hours, respectively). The mean levels of serum phosphorus (4.8 mg per deciliter) and the renal phosphorus threshold (4.3 mg per deciliter) were elevated. Mean plasma 1,25-dihydroxyvitamin D was strikingly reduced (9.9 pg per milliliter), as were nephrogenous cyclic (0.64 nmol per deciliter of glomerular filtrate) and immunoreactive parathyroid hormone in both assays. These findings indicate that the parathyroid--1,25-dihydroxyvitamin D axis is suppressed in patients with immobilization-induced hypercalciuria, as would be predicted by a model of resorptive hypercalciuria.

25-Hydroxyvitamin D 2↗
PubMed1982

Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity.

Humoral hypercalcemia of malignancy (HHM) results from elaboration by tumors of a circulating bone-resorbing factor(s). THe specific mechanism responsible for this bone resorption is poorly understood, and no comprehensive study employing quantitative histomorphometric analyses of bone biopsies obtained from living patients with HHM has been reported. We describe bone histology and quantitative bone histomorphometry in bone biopsies obtained from seven patients defined biochemically (elevated nephrogenous cAMP excretion) and histologically (no tumor in biopsy sample) as having HHM. These biopsies are compared to biopsies from nine patients with primary hyperparathyroidism (HPT). Compared to patients with HPT, those with HHM displayed (mean +/- SD) greater osteoclastic activity (osteoclast surface, 8.6 +/- 6.1% vs. 2.7 +/- 1.5%; P less than 0.001) and more frequent empty lacunae (9.2 +/- 4.0% vs. 5.8 +/- 3.0%; P less than 0.01), but markedly reduced osteoblastic surface (2.5 +/- 3.1% vs. 13.8 +/- 7.0%; P less than 0.001), osteoid surface (12.9 +/- 11.9% vs. 42.0 +/- 15.0%; P less than 0.001), and osteoid volume (0.3 +/- 0.3% vs. 1.3 +/- 1.0%; P less than 0.01). These findings directly confirm the presence of humorally mediated bone resorption and indicate a striking uncoupling of osteoclast and osteoblast activities in bone from patients with HHM. These findings are in sharp contrast to those in HPT patients, where osteoclast and osteoblast activities are tightly coupled, and net skeletal calcium loss is minimal. This uncoupling provides a mechanism for the marked skeletal calcium losses observed in patients with HHM.

Adult↗
PubMed1981

Long-term treatment of familial hypophosphatemic rickets with oral phosphate and 1 alpha-hydroxyvitamin D3.

Combined treatment with oral phosphate and 1 alpha (OH)D3 was carried out in nine children with familial hypophosphatemic rickets. All nine had positive responses over a four- to six-year period as judged by healing of rickets, change in growth rate, decrease in alkaline phosphatase activity, and symptomatic improvement. In two patients therapy was stopped for a short time because of hypercalcemia. In one patient in whom therapy was effective there was a significant reduction in creatinine clearance which necessitated cessation of treatment. The results of this study suggest that combined treatment with 1 alpha(OH)D3 and oral phosphate is an effective form of therapy for this condition, but that the balancing of these two modalities of therapy in each patient is essential if hypercalcemia and hypercalciuria, on the one hand, and secondary hyperparathyroidism, on the other, are to be avoided. A simple means of balancing these therapeutic modalities is suggested.

Administration, Oral↗
PubMed1981

The influence of calcium intake and the status of intestinal calcium absorption on the diagnostic utility of measurements of 24-hour cyclic adenosine 3',5'-monophosphate excretion.

Twenty-five normal subjects, 45 patients with idiopathic hypercalciuria, and 50 patients with primary hyperparathyroidism were studied with an oral calcium tolerance test and with measurements of 24-h calcium and total cAMP excretion on defined 400-mg and 1000-mg calcium diets. There was a strong positive correlation (r = 0.62; P less than 0.001) between the calciuric response to the tolerance test and the increase in calcium excretion on the 100-mg relative to the 400-mg calcium diet. The increase in daily calcium intake was associated with a significant (P less than 0.001) suppression in total cAMP excretion in each patient group. The suppression in cAMP excretion was sufficient to completely segregate patients with absorptive hypercalciuria from those with renal hypercalciuria on the 1000-mg calcium diet (ranges, 1.24-3.50 and 3.97-4.87 nmol/100 ml glomerular filtrate, respectively). In patients with primary hyperparathyroidism, results for total cAMP excretion were elevated in 48 (96%) patients on the restricted calcium diet but were within the normal range in 14 (28%) patients on the high-normal calcium diet. Net intestinal calcium absorption has a prominent influence on results for 24-h total cAMP excretion, which may be used to diagnostic advantage or seriously impair diagnostic accuracy, depending upon the patient population and the conditions of study.

Adult↗
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

Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups.

In 50 consecutive patients with cancer-associated hypercalcemia, we measured nephrogenous cyclic AMP, tubular phosphorus threshold, fasting calcium excretion, plasma 1,25-dihydroxyvitamin D, and immunoreactive parathyroid hormone as determined by four region-specific antiserums. Nephrogenous cyclic AMP excretion was elevated in 41 patients and suppressed in nine (means, 5.85 vs. 0.51 nmol per 100 ml of glomerular filtrate). There was no overlap between these groups. When compared with 15 patients with primary hyperparathyroidism, the group with increased cyclic AMP excretion had similar reductions in tubular phosphorus threshold; higher fasting calcium excretion (means, 0.66 vs. 0.25 mg per 100 ml of glomerular filtrate, P < 0.01); marked reductions in 1,25-dihydroxyvitamin D (means, 20 vs. 83 pg per milliliter, P < 0.001); and lower levels of immunoreactive parathyroid hormone in all four assays. The data suggest that elevated excretion of nephrogenous cyclic AMP may be a useful marker of humorally mediated cancer-associated hypercalcemia, that this type of hypercalcemia is common, that the humoral factor responsible for this syndrome is not native 1-84 parathyroid hormone, and that the various subtypes of cancer-associated hypercalcemia are biochemically distinguishable from primary hyperparathyroidism.

Animals↗
PubMed1980

The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism.

Fifty patients with primary hyperparathyroidism were studied with an oral calcium-tolerance test, measurements of plasma levels of vitamin D metabolites, and determination of calcium excretion on both a low-normal (400 mg) and high-normal (1000 mg) calcium intake. There were strong positive correlations between plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) and both the calciuric response to the calcium-tolerance test (r = +0.75, P less than 0.001) and calcium excretion on the 1000-mg calcium diet (r = +0.65, P less than 0.001). The patients were classified into two subpopulations: 30 patients showed hyperabsorption with the calcium-tolerance test, striking hypercalciuria, marked elevations in plasma 1,25(OH)2D, and a high incidence (19 of 30 patients) of renal stones; 20 patients had a normal response to the tolerance test, normocalciuria, normal or high-normal plasma 1,25(OH)2D, and a low incidence of stones (three of 20 patients). The findings emphasize the importance of circulating 1,25(OH)2D in the pathogenesis of hypercalciuria and stone formation in primary hyperparathyroidism.

Calcium↗
PubMed1980

Primary hyperparathyroidism with intermittent hypercalcaemia: serial observations and simple diagnosis by means of an oral calcium tolerance test.

Ten patients with subtle primary hyperparathyroidism and intermittent hypercalcaemia were followed serially for periods of 2--18 months (mean 10 months). Fasting serum calcium was elevated (greater than 10.6 mg/dl) in only 20% of determinations and fluctuated widely (9.1--11.2 mg/dl), yet the patients displayed a continuous, rather than episodic, basic disease process as defined by increases in nephrogenous cyclic AMP and serum iPTH. Identical findings were noted in short-term (2--3 successive days) studies in twelve patients. In response to a 1000 mg oral calcium tolerance test, twelve patients with primary hyperparathyroidism and intermittent hypercalcaemia (basal serum calcium 10.2 +/- 0.2 mg/dl, mean +/- SD) displayed: (1) hyperabsorption of calcium (mean calciuric response twice normal); (2) induced-hypercalcaemia (mean serum calcium 11.4 mg/dl, with a mean increase of 1.2 mg/dl versus 0.2 mg/cl in normal subjects); and (3) abnormal parathyroid suppressibility (nephrogenous cyclic AMP 2.66 +/- 0.57 nmol/100 ml GF versus 0.95 +/- 0.40 nmol/100 ml GF in normal subjects, mean +/- SD). The patients demonstrated striking hypercalciuria (452 +/- 123 mg/24 h) on a 1000 mg metabolic calcium diet. Serum levels of 1,25(OH)2D3, measured in ten patients, were markedly elevated at 90 +/- 20 pg/ml (mean +/- SD), and there was a strong positive correlation between the values for 1,25(OH)2D3 and the calciuric response to the calcium tolerance test (r = 0.75, P less than 0.001). These results (1) indicate that the calcium tolerance test is a simple and reliable technique for diagnosis of patients with primary hyperparathyroidism and intermittent hypercalcaemia, and (2) emphasize the important pathophysiologic features of this subtle clinical variant of primary hyperparathyroidism.

Calcium↗