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Biomedical subjects

B Lobaugh

Publications and source records attributed to B Lobaugh.

33 records · Page 2Linked to original sources
PubMed1989

Circadian rhythms for calcium, inorganic phosphorus, and parathyroid hormone in primary hyperparathyroidism: functional and practical considerations.

We obtained serial serum and urine samples from 14 patients with primary hyperparathyroidism both before and 3 to 9 months after excision of their parathyroid adenomas to (1) determine whether the circadian rhythms for calcium, phosphorus, and parathyroid hormone (PTH) previously described in normal human beings are disturbed in this disorder; (2) gauge the effect of surgical treatment on the patterns observed before intervention; and (3) ascertain whether time(s) of blood sampling can be defined for optimal biochemical detection of the disease. Significant rhythms for serum phosphorus, ionized calcium, PTH, urine phosphorus, and urine calcium were observed in many but not all patients before and after surgery. Nonetheless, collective analysis revealed the following: (1) diurnal patterns for serum ionized calcium, phosphorus, urine calcium, and urine phosphorus in patients with primary hyperparathyroidism both before and after surgery, whereas a rhythm for serum PTH was uniquely observed after surgical treatment; and (2) no significant correlation between preoperative serum ionized calcium and PTH but restoration of the expected reciprocal relationship between these variables after surgery. Although variability in individual expression of the rhythm for PTH precludes precise definition of a sampling "window" when hormone levels are likely to be highest, collection of data at points throughout the day helped establish the diagnosis of primary hyperparathyroidism in several patients with borderline serum biochemistries.

Adenoma↗
PubMed1989

Primary hyperparathyroidism: a new experimental animal model.

Although potentially useful in the understanding of hypercalcemic states, a satisfactory animal model of primary hyperparathyroidism has not been developed. Models that use transplants of supernumerary parathyroid (PT) glands or chronic parathyroid hormone (PTH) infusion are not ideal for many reasons. We report a new animal model in which athymic nude mice were used as recipients of human PT tissue heterografts. Three groups received 14, six, or one piece of PT adenoma tissue, and one group received six pieces of normal PT tissue. The significantly higher PTH levels in mice that received adenoma heterografts versus those with similar amounts of normal tissue suggest that adenomatous tissue is functionally distinct. A dose-response relationship between induction of hypercalcemia and the number of pieces implanted was in evidence, although only a small percentage of the mice with high PTH levels developed hypercalcemia. This differential response could be the result of any of several factors: (1) loss of ability to secrete bioactive PTH, (2) differing secretion rates among donor adenomas, (3) variability in host responsiveness to human PTH, and (4) requirement of additional factor(s) to generate consistently the hypercalcemia characteristic of human primary hyperparathyroidism.

Animals↗
PubMed1988

Oral calcitriol and calcium: efficient therapy for uremic hyperparathyroidism.

Therapy with orally administered calcitriol often does not adequately control the biochemical manifestations of secondary hyperparathyroidism in uremic patients. This may be due to inadequate serum concentrations of 1.25(OH)2 vitamin D and/or to insufficient dietary calcium supplementation. In the present study, therefore, we examined the effect on parathyroid function of calcitriol and calcium carbonate, administered orally, in doses sufficient to normalize the serum 1.25(OH)2 vitamin D and calcium concentrations. After nine months of combined therapy, marked suppression of immunoreactive PTH occurred in the absence of hypercalcemia. Furthermore, prolonged therapy resulted in additional suppression of the PTH concentrations comparable in magnitude to that reported following intravenous calcitriol therapy and was associated with a mild degree of hypercalcemia similar to that which occurs with intravenous therapy. Euparathyroidism was achieved in 25% of the patients by 15 months of treatment. In conclusion, secondary hyperparathyroidism can be effectively controlled with combined oral therapy without significant hypercalcemia in selected patients with end-stage renal failure. This salutary effect may result from direct actions of 1.25(OH)2D on the parathyroid gland and/or gastrointestinal tract, or from an overall action of combined treatment to restore calcium homeostasis.

Administration, Oral↗
PubMed1988

Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis.

The inherited metabolic disorder tumoral calcinosis is characterized by elevated serum phosphorus and 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels and paraarticular calcific tumors. The pathogenesis of this disease is obscure, but an elevated renal phosphate reabsorption threshold and increased production of 1,25-(OH)2D are postulated as defects. We studied nine affected patients and found that both serum phosphorus and renal phosphate reabsorption threshold (TmP/GFR) were positively correlated with serum 1,25-(OH)2D levels. Since tumoral calcinosis is a disorder with abnormal renal phosphate transport, we compared the TmP/GFR and serum 1,25-(OH)2D levels to values obtained in patients with two other diseases with renal phosphate transport defects: oncogenic osteomalacia and X-linked hypophosphatemic rickets. We found a significant correlation between TmP/GFR and 1,25-(OH)2D levels in all three diseases, suggesting that in these diseases 1,25-(OH)2D production is regulated in some manner by phosphate transport. Furthermore, previous work indicated that in tumoral calcinosis broad variation exists in serum phosphorus levels. In our patients a negative correlation was found between the serum PTH concentrations and both serum phosphorus levels and TmP/GFR values, respectively. We postulate that although the basic defect in tumoral calcinosis most likely resides in the proximal renal tubular cell, the variation in serum phosphorus levels and possibly disease expression is modulated in part by PTH.

Absorption↗
PubMed1987

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Hypophosphatemia (Hyp) mice have defective regulation of 25(OH)D-1 alpha-hydroxylase activity in response to hypophosphatemia, hypocalcemia, and parathyroid hormone (PTH) administration. However, recent observations support the existence of anatomically distinct, independently regulated renal 1 alpha-hydroxylase systems in mammalian proximal convoluted and straight tubules. To more completely define the extent of the 1 alpha-hydroxylase regulatory defect in Hyp-mice, we compared enzyme maximum velocity in normal and mutants after infusion of calcitonin. Upon stimulation, renal 1 alpha-hydroxylase activity increased to similar levels in normal and Hyp-mouse renal homogenates. Moreover, time-course and dose-dependence studies revealed similar patterns of response in the animal models. Subsequently, we examined whether PTH and calcitonin stimulatory effects on enzyme activity are mediated through different mechanisms. In both animal models administration of PTH and calcitonin increased enzyme activity to levels greater than those obtained after maximal stimulation by either hormone alone, consistent with additive effects. These observations indicate that a calcitonin-sensitive component of 1 alpha-hydroxylase is not compromised in the X-linked hypophosphatemic syndrome.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1986

Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.

Abnormal regulation of vitamin D metabolism is a feature of X-linked hypophosphatemic rickets in man and of the murine homologue of the disease in the hypophosphatemic (Hyp)-mouse. We previously reported that mutant mice have abnormally low renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal 1 alpha-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calcium-deficient (0.02% Ca) diet to raise endogenous PTH; or (b) 24-h continuous infusion of 0.25 IU/h bovine PTH via osmotic minipump. In both cases enzyme activity of identically treated normal mice increased to greater levels than those attained by Hyp-mice. The relative inability of PTH to stimulate 1 alpha-hydroxylase activity is not a function of the hypophosphatemia in the Hyp-mouse since PTH-infused, phosphate-depleted normal mice sustained a level of enzyme activity greater than that of normal and Hyp-mice. In further studies we investigated inhibition of enzyme activity by using: (a) a calcium-loaded (1.2% Ca) diet to suppress endogenous PTH; or (b) 24-h continuous infusion of 0.2 ng/h 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The 1 alpha-hydroxylase activity of normal and Hyp-mice was significantly reduced to similar absolute levels following maintenance on the calcium-loaded diet. Further, infusion of 1,25(OH)2D3 caused a comparable reduction of 1 alpha-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of 1 alpha-hydroxylase by reduced levels of PTH or increased 1,25(OH)2D3 concentrations is intact in the mutants. However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates that a generalized defect of 1 alpha-hydroxylase regulation is manifest in Hyp-mice.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1985

Abnormal parathyroid function in the X-linked hypophosphatemic mouse.

Employing a cytochemical bioassay, we compared parathyroid function in normal and X-linked hypophosphatemic (Hyp) mice. Under basal conditions Hyp mice manifested hypocalcemia and, in accord, had a plasma bioactive parathyroid hormone concentration (3.04 +/- 0.14 pg/ml) significantly greater than that of normals (2.16 +/- 0.14 pg/ml). We confirmed the validity of the bioassay by demonstrating that the plasma collected from both mouse models diluted parallel to the assay standard curve. Moreover, after parathyroidectomy, normal and Hyp mice had plasma bioactive parathyroid hormone levels approximately 90% less than those obtained under basal conditions and indistinguishable from one another. In further studies we observed that dietary calcium and/or vitamin D deprivation in both animal models resulted in a comparable decline of the plasma calcium concentration. However, the concordant increase of the circulating bioactive parathyroid hormone level was greater in the normal mice. Thus, the bioactive parathyroid hormone concentration obtained in response to a low calcium challenge in normals was significantly greater than that in Hyp mice. In contrast, in response to dietary calcium loading, the plasma bioactive parathyroid hormone levels did not decrease significantly from basal values in either animal model. These data illustrate that the bioactive parathyroid hormone concentration in both normal and Hyp mice is inversely correlated with the plasma calcium. However, while the Hyp mice maintain an elevated plasma parathyroid hormone concentration under basal conditions (in response to a decreased plasma calcium), the parathyroid activity of the mutants after a more severe hypocalcemic challenge is attenuated, resulting in a significantly different model of linear correlation. Thus, these data indicate that Hyp mice manifested abnormal regulation of parathyroid function.

Animals↗
PubMed1983

Measurement of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in mammalian kidney.

Until recently measurement of 25-OH-D3-1 alpha-hydroxylase activity in mammalian kidney has not been possible due to the presence of a protein which inhibits the enzyme by reducing available substrate. However, utilization of sufficient unlabeled 25-OH-D3 (80 nmol/ml renal homogenate) to overcome the effect of the inhibitor while maintaining optimal concentration for 1-hydroxylation has made quantitation of enzyme activity possible. We have modified this existing technique in order to increase the sensitivity and to permit detailed study of 1 alpha-hydroxylate regulation in mouse kidney. The modifications that we have incorporated include (i) simplifying the purification scheme for obtaining measurable 1,25-(OH)2D3 by reducing to one the necessary number of high-performance liquid chromatography steps and (ii) quantifying 1,25-(OH)2D3 by radioligand assay. The sensitivity of the assay is 10 pg, which, corrected for fractionation and recovery (50-60%), allows the measurement of 0.5 fmol 1,25-(OH)2D3 produced per milligram kidney per minute. Moreover, reliability and precision of the assay have been confirmed by demonstrating that samples from carefully matched, identically treated mice have reproducible enzyme activity (interassay coefficient of variation = 9.1%, n = 5) and show appropriate dilution characteristics. We have also demonstrated appropriate modulation of enzyme activity by known effectors of 1-hydroxylation. Kidneys from D-deficient mice exhibit significantly higher enzyme activity (15.28 +/- 1.17, n = 21) than do normal mouse kidneys (5.14 +/- 0.26, n = 33). In contrast, enzyme activity is suppressed significantly in kidneys obtained from calcium-loaded (1.20 +/- 0.04, n = 5) and parathyroidectomized animals (2.94 +/- 0.29, n = 5). Our assay now permits the indepth study of 1 alpha-hydroxylase regulation in mammalian (mouse) kidneys.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1983

Abnormal regulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the X-linked hypophosphatemic mouse.

Abnormal vitamin D metabolism has been suspected in patients with X-linked hypophosphatemic rickets (XLH) and X-linked hypophosphatemic mice (Hyp-mice), the murine homologue of the human disease. We compared 25(OH)D-1 alpha-hydroxylase activity in the Hyp-mouse kidney to that in normal and phosphate-depleted mouse kidney. Weanling normal and Hyp-mice were fed a 0.6% phosphorus diet; phosphate-depleted mice received a 0.02% phosphorus diet. At 8-10 wk of age the serum phosphorus values in Hyp (3.35 +/- 0.12 mg/dl) and phosphate-depleted mice (3.83 +/- 0.56) were not significantly different. Despite the similar magnitude of phosphate depletion, however, the maximum levels of 25(OH)D-1 alpha-hydroxylase activity were disparate: phosphate-depleted mouse kidney had profoundly increased activity compared to normal (17.04 +/- .104 vs. 4.96 +/- 0.23 fmol 1,25(OH)2D3 produced/mg kidney per min) while Hyp-mouse kidney had a fourfold lesser increment (8.18 +/- 0.62). These data indicate that phosphate depletion is a potent stimulus of 25(OH)D-1 alpha-hydroxylase activity in the (C57BL6J) mouse. Moreover, the results show that abnormal regulation of 25(OH)D-1 alpha-hydroxylase activity is manifest in the Hyp-mouse.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1983

Blood pressure of chickens selected for leanness or obesity.

Four lines of chickens selected for divergence in body weight followed by selection for obesity or leanness within each body weight line were used as a genetic model to determine the relationship of blood pressure and obesity. Forty females, 10 of each line, and 20 males, 10 from the heavy-weight obese and 10 from the light-weight obese, were used. Direct measurements of blood pressure were obtained from the left brachial artery of seven-month old birds. Systolic, diastolic, and mean blood pressures were recorded in this study. The systolic, diastolic, and mean blood pressure for the light-obese and light-lean females did not differ significantly; likewise, no difference was found for these three parameters in the heavy-obese and heavy-lean females. However, the blood pressures in the light-obese and light-lean lines were significantly higher than the heavy-obese and heavy-lean lines. Also, the blood pressures of the light-obese males were higher than those of the heavy-obese males; both male lines exceeded the females of the two respective lines.

Animals↗
PubMed1981

Regulation of calcium appetite in broiler chickens.

The regulation of the appetite for calcium was studied in broiler chickens which had been trained to meet their calcium requirement by consuming a calcium supplement (10% Ca) provided separately from a calcium-deficient feed (0.12% Ca). Calcium supplement intake was reduced within 150 minutes after intravenous injection of 60 U/kg parathyroid hormone or continuous infusion of 0.077 mg/minute calcium into one common carotid artery. Supplement consumption was also depressed during the first 8 days of continuous infusion of 1 U/kg/hour parathyroid hormone; after 8 days the birds became refractory. Continuous infusion of 0.2 Medical Research Council (MRC) units/kg salmon calcitonin for 10 days or daily intramuscular injections of 1 mg/kg testosterone propionate and 2 mg/kg estradiol dipropionate for 12 days, either alone or in combination, had no effect on calcium appetite. It is concluded that the calcium appetite may be inhibited by increased concentrations of ionic calcium in blood and that the change in behavior is sufficiently rapid to play a role in the calcium homeostasis of birds.

Animals↗
PubMedDate not supplied

Vitamin D and prostate cancer: a prediagnostic study with stored sera.

This study evaluates the risk of prostate cancer in relation to serum levels of the major vitamin D metabolites, 25-hydroxyvitamin D (25-D3) and 1,25-dihydroxyvitamin D (1,25-D). Between 1964 and 1971, more than 250,000 serum samples were collected from members of the Kaiser Permanente Medical Care Plan in Oakland and San Francisco and stored for future use. Levels of 25-D and 1,25-D were measured in samples from 90 black and 91 white men diagnosed with prostate cancer before December 31, 1987 and controls individually matched on age, race, and day of serum storage. Mean serum 1,25-D was 1.81 pg/ml lower in cases than in matched controls (P = 0.002). Risk of prostate cancer decreased with higher levels of 1,25-D especially in men with low levels of 25-D. However, mean 25-D was not significantly different in cases and controls. The association of lower 1,25-D with prostate cancer was found in men above the median age of 57 years at serum storage but not younger men and was similar in black and white men. In men > or = 57 years of age, 1,25-D was an important predictor of risk for palpable and anaplastic tumors but not for tumors incidentally discovered during surgery to treat the symptoms of benign prostatic hyperplasia or well differentiated tumors.

Adult↗
PubMedDate not supplied

Serum androgens: associations with prostate cancer risk and hair patterning.

Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 +/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls (P = 0.03 for DHT/T and P = 0.01 for DHT/free T). Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 +/- 5.5 and 16.2 +/- 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 +/- 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma. In addition, although no differences in hair patterning were detected between cases and controls within this older population, further research (i.e., prospective trials or case-control studies among younger men) may be necessary to determine if hair patterning serves as a viable biomarker for this disease, especially given the strong association between free T levels and baldness.

Aged↗