Subhash Kukreja - Academia.edu (original) (raw)

Papers by Subhash Kukreja

Osteoporosis International, Mar 12, 2009

Among 307 males seen in VA Medical Center, independent determinants (p<0.01 for all) of serum 25h... more Among 307 males seen in VA Medical Center, independent determinants (p<0.01 for all) of serum 25hydroxyvitamin D [25(OH)D] levels included race, vitamin D supplements, BMI, dietary calcium intake and smoking, but not age. Negative association between 25(OH)D and parathyroid hormone (PTH) was similar for Caucasian and African-American men. Introduction In this prospective cohort study, we examined determinants of serum 25-hydroxyvitamin D [25(OH)D] levels and the relationship between 25(OH)D and PTH levels and body mass index (BMI). Methods Male veterans (n=307) were recruited at a VA Medical Center. Serum levels of PTH and 25(OH)D were obtained. Surveys and chart reviews were completed. Vitamin D insufficiency was defined as 25(OH) D <30 ng/ml. Univariate and multivariate regression analyses were performed. Results Among 232 African-American (AA) men (mean ± SD), 25(OH)D level (21.4±10.4 ng/ml) was lower and prevalence of insufficiency (80%) was higher than among 75 Caucasians (C; 28.5±11.1 ng/ml and 53%, respectively, p<0.01 for both). In multivariate regression analysis, independent determinants (p<0.01 for all) of 25(OH)D levels included AA race, vitamin D supplements, BMI, dietary calcium intake, and smoking. Despite lower 25(OH) D levels in African-Americans, PTH levels were similar to those seen in Caucasians. There was a significant (p<0.02) negative linear association between 25(OH)D and PTH in African-American (r 2 =0.05) and Caucasian (r 2 =0.08) men, and there was no difference between the slopes of the relationship. Conclusions 25(OH)D levels are determined by modifiable risk factors such as vitamin D supplementation in both AA and C males. The negative association between 25(OH)D and PTH is similar between the two races.

PubMed, Jul 1, 1996

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible f... more Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. In addition to its hypercalcemic action, PTHrP has been implicated as an autocrine modulator of growth and differentiation, as well as an early response gene in some tissues. Several different types of tumors have been evaluated for the presence of PTHrP immunoreactivity. In the present study, we evaluated the expression of PTHrP by immunohistochemical staining in tissue samples from normal colorectal mucosa, polyps, and colorectal carcinoma removed from the same patients (n = 10 each). We have used a commercially available monoclonal antibody directed against epitopes between amino acids [53-64] which share no homology to parathyroid hormone (PTH). In normal colon, 94.3 per cent of the tissue samples were negative for PTHrP immunoreactivity. In polyps of the colon, only 22.6 per cent of the cells showed positive immunostaining, whereas 91.5 per cent of the samples from colon cancer stained positive for PTHrP. In the case of polyps, the intensity of staining was 1-3+; however, all of the samples from adenocarcinoma stained with 4+ intensity. In the positive samples, the immunoreactivity was present throughout the cytoplasm of the glandular epithelium. Omission of primary antibody, as well as substitution of the primary antibody by a negative control monoclonal antibody or non-immune rabbit serum, resulted in a negative reaction. All analyses were performed in duplicate, and the data have been presented as mean +/- SEM. Differences in normal polyps, carcinoma of the colon, and PTHrP expression were tested for statistical significance by student's t test. Our results show the expression of PTHrP is enhanced in colon cancer tissue as compared to normal colorectal mucosa and polyps. In addition, the expression appears to be greater in polyp than in normal colon. The role of PTHrP in the pathogenesis of colon cancer deserves further study.

Experimental Biology and Medicine, Nov 1, 1978

... GERALD A. WILLIAMS, E. NELSON BOWSER, GARY K. HARGIS, SUBHASH C. KUKREJA, JAYENDRA H. SHAH, N... more ... GERALD A. WILLIAMS, E. NELSON BOWSER, GARY K. HARGIS, SUBHASH C. KUKREJA, JAYENDRA H. SHAH, NILA M. VORA, AND WALTER J. HENDERSON Section of Endocrinology, Departments of Medicine and Nuclear Medicine, VA West Side Hospital and University ...

Metabolism-clinical and Experimental, Feb 1, 1987

Journal of Bone and Mineral Research, Dec 3, 2009

The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female... more The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female rats aged 12 months were divided into three groups: (1) sham-operated controls (SHAM); (2) oophorectomized (OVX); (3) OVX rats treated with progesterone (OVX + PROG). After 20 weeks the dry weight, bone ash, and calcium content of femur, tibia, and fourth lumbar vertebra were significantly lower in OVX than in sham rats. These reductions did not occur in OVX rats treated with PROG. There was no difference in the bone composition between the control and progesterone-treated rats. Vertebral bone histomorphometry showed increased bone resorption as well as increased bone formation parameters in OVX rats. Progesterone treatment inhibited the increased resorption indices, but the bone formation remained elevated. The results indicate that progesterone therapy prevents the postovariectomy bone loss in aged rats. The protective effect of progesterone is mediated by inhibition of bone resorption while maintaining the increased bone formation. These findings suggest that progesterone alone may be a valuable agent for management of postmenopausal osteoporosis.

Archives of internal medicine, Jul 1, 1987

Heiselman and Bennett both suggest that cisplatin-induced hypomagnesemia may be the mechanism for... more Heiselman and Bennett both suggest that cisplatin-induced hypomagnesemia may be the mechanism for the observed reduction in serum calcium levels in our hypercalcemic patients. Cisplatin therapy does induce hypomagnesemia, which, in turn, inhibits parathyroid hormone secretion and action, thus resulting in hypocalcemia.1We had initially considered this possibility and had obtained serum magnesium and parathyroid hormone levels before and after cisplatin administration in six patients (patients 1, 2, 3, 8,10, and 11 in Table 2 of our article).2 Supplemental magnesium was not given. The posttreatment measurements were made either the day serum calcium decreased to a value below 2.87 mmol/L (11.5 mg/dL) or on day 7. The results are shown in the accompanying Table. As expected, serum magnesium levels decreased significantly with cisplatin treatment. There was, however, no relation between hypomagnesemia and decrease in serum calcium levels, eg, serum magnesium drop was the greatest in patient 10, yet there was

American Journal of Physiology-endocrinology and Metabolism, Feb 1, 1989

Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associate... more Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associated hypercalcemia (MAH), whereas murine models of MAH have high circulating 1,25(OH)2D3. To determine the effects of a hypercalcemia-producing tumor on circulating 1,25(OH)2D3, in vitro 25-hydroxyvitamin D1-hydroxylase (1OHase) activity was measured in kidneys from BALB/c athymic mice implanted with a hypercalcemia-producing human lung tumor. Twelve days of low-phosphorus diet (LPD) in control animals lowered serum phosphorus to levels found in tumor-bearing mice fed normal phosphorus diet (NPD; 4.1 +/- 0.3 vs. 4.4 +/- 0.7 mg/dl, P = NS) and increased 1OHase activity (1.6 +/- 0.2 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, NPD vs. LPD, P less than 0.05). 1OHase activity was greater in tumor-bearing animals fed NPD compared with control animals fed LPD (8.4 +/- 0.6 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, P less than 0.01). High-phosphorus intake suppressed 1OHase activity in both control and tumor-bearing animals. Seven days of parathyroid hormone infusion in control animals fed NPD raised serum calcium (9.4 +/- 0.2 vs. 13.3 +/- 1.6 mg/dl, P less than 0.05) and suppressed 1OHase activity (0.25 +/- 0.02 vs. 0.02 +/- 0.002 pmol.mg protein-1.5 min-1, P less than 0.001). The inverse relationship of serum phosphorus and 1OHase activity was much steeper in the tumor-bearing animals, with greater enzyme activity at comparable levels of serum phosphorus. The present study indicates that 1) factors produced by the tumor stimulate 1OHase activity, and 2) hypophosphatemia is required for expression of enhanced enzyme activity.

Hormone and Metabolic Research, Jul 1, 1983

Experimental Biology and Medicine, Feb 1, 1976

In the rat, EDTA and isoproterenol stimulated PTH secretion, whereas high calcium and propranolol... more In the rat, EDTA and isoproterenol stimulated PTH secretion, whereas high calcium and propranolol inhibited it. The stimulatory effects of EDTA and isoproterenol were still evident and unaltered in the presence of blocks induced by propranolol and high calcium, respectively. The findings suggest that: (i) both calcium and beta-adrenergic stimuli affect PTH secretion; and (ii) the two influences affect the PTH secretion by separate initial pathways.

Hormone and Metabolic Research, 1986

This study was undertaken to evaluate the physiological role, if any, of dopamine (DA) in modulat... more This study was undertaken to evaluate the physiological role, if any, of dopamine (DA) in modulating parathyroid hormone (PTH) and calcitonin (CT) secretion in man. Infusion of DA (5 micrograms/kg/min) into 6 normal men, decreased serum immunoreactive prolactin (iPRL) and concomitantly increased serum iPTH to 140 +/- 6.8% of baseline (P less than 0.01) at 30 min, with decline thereafter, despite continuation of the DA infusion. Serum iCT levels did not significantly change. Chlorpromazine (50 mg IM), decreased serum iPTH to 75 +/- 5.4% and 79 +/- 3.7% of baseline (P less than 0.01) at 30 and 60 min, respectively, associated with an increase in iPRL. There was subsequent return of iPTH to baseline even though iPRL remained elevated. iCT levels did not significantly change. These observations would suggest that DA may play a physiological role in iPTH, but not iCT, secretion. However, infusion of more nearly physiological doses of DA (0.02, 0.2, and 2.0 micrograms/kg/min) lowered serum iPRL to levels similar to those after the larger DA dose, but with no concomitant increase in either iPTH or iCT. Also, 1) the DA agonist bromocriptine decreased serum iPRL without modifying iPTH or iCT; 2) the DA precursor, levodopa, and the DA antagonist, metoclopramide, had no effect on serum iPTH or iCT levels. These studies suggest that 1) the transient stimulatory effect of DA on iPTH secretion is pharmacological, and 2) DA does not have a physiological role in secretion of iPTH or iCT in man.

The Journal of Clinical Endocrinology and Metabolism, Mar 1, 1983

Purified secretin infused in an estimated physiological dose caused an increase in serum immunore... more Purified secretin infused in an estimated physiological dose caused an increase in serum immunoreactive PTH (iPTH) and calcitonin (iCT) in man. Ingestion of a gastric acid-stimulating test meal, a procedure known to increase endogenous secretin, caused increases in serum iPTH and plasma iCT in normal subjects. Ingestion of antacid with the test meal blunted the increase in both iPTH and iCT. Ingestion of the test meal by pernicious anemia patients with achlorhydria caused no stimulation of either serum iPTH or plasma iCT. Therefore, based on the observations that 1) exogenous secretin stimulated iPTH and iCT, 2) an acid-stimulating test meal is known to stimulate endogenous secretin release (4), 3) the test meal increased both serum iPTH and iCT in normal man, an effect nullified by simultaneous antacid ingestion, and 4) the test meal caused no increase in either iPTH or iCT in achlorhydric patients, we conclude that endogenous secretin possibly mediates this effect of test meal and, therefore, may play a physiological role in modulating the secretion of PTH and CT.

Journal of Bone and Mineral Research, Dec 3, 2009

Local and systemic insulin‐like growth factors (IGFs) may be involved in the regulation of bone f... more Local and systemic insulin‐like growth factors (IGFs) may be involved in the regulation of bone formation by sex hormones. The present studies describe the in vivo effects of estradiol, progesterone, or both on IGF‐1 mRNA abundance in bone, serum IGF‐1 levels, and bone formation. Rats were sham‐operated (SHAM) or ovariectomized (OVX) at 12 weeks of age and used a week later in three experiments. First, OVX rats were treated with vehicle, estradiol, and/or medroxyprogesterone (MPA) for 3 weeks, and bone formation was assessed in the tibial metaphysis. Second, OVX rats were treated in the same manner and serum IGF‐1 levels measured. Third, OVX rats were treated with an injection of vehicle, estradiol, and/or progesterone, and 24 h later, levels of IGF‐1 mRNA in the femur were analyzed. The mineralized surface, mineral apposition rate, and bone formation rate (BFR) were higher in OVX than in SHAM rats. The BFR was decreased in estrogen‐treated but increased in MPA‐treated rats compared with vehicle‐treated OVX rats. Circulating levels of IGF‐1 were higher in OVX than in SHAM rats but were not affected by sex hormones in a 3‐week experiment, whereas these levels were not different among groups in a 24‐h experiment. Northern analysis detected 7.5 and 0.8 kb IGF‐1 mRNA transcripts. The abundance of IGF‐1 mRNA was higher in OVX than in SHAM rats. IGF‐1 transcripts 7.5 and 0.8 kb were decreased by 72 and 29%, respectively, in estrogen‐treated and increased by 44 and 43%, respectively, in progesterone‐treated rats compared with vehicle‐treated OVX rats. We conclude that in the short term, estrogen lowers and progesterone raises bone IGF‐1 mRNA and these changes are followed by coordinated changes in bone formation rate.

Journal of Bone and Mineral Research, Dec 3, 2009

Exercise may play a role in the prevention of bone fractures in postmenopausal osteoporosis. The ... more Exercise may play a role in the prevention of bone fractures in postmenopausal osteoporosis. The effects of endurance exercise on bone properties were assessed in 9-month-old sham-operated (SH) and ovariectomized (OVX) rats. The rats were either kept sedentary (SED) or were exercised (EX) on a rodent treadmill at 21 m/ minute, 7% grade, 40 minutes/day, 4 days/week for 3 months. Bone mineral (by ash weight), morphometry, and biomechanical properties (by three-point bending) were evaluated after excision of bones at sacrifice. Ovariectomy resulted in a loss of bone mineral in femur, tibia, and fourth lumbar vertebra (U), but biomechanical (force, deformation, stress, strain, and modulus of elasticity) and morphometric (length, cortial and medullary area, and moment of inertia) properties of femur were maintained. The ash weight of femur and tibia, but not L4, as well as femur yield and maximum force and moment of inertia, were improved in OVX-EX rats compared to OVX-SED animals. In SH rats exercise had no influence on ash weight of any of the three bones or femur morphometric properties, yet femur maximum force and plastic deformation were significantly enhanced compared to SH-SED rats. The results of the present study suggest that endurance exercise has beneficial effects on the bone mineral as well as biomechanical properties (femur yield and maximum force) during early stages after ovariectomy and improves the bending strength of the intact femur without an effect on bone mineral in sham-operated rats.

Bone and Mineral, Sep 1, 1990

The Journal of Clinical Endocrinology and Metabolism, Dec 1, 1991

A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against syn... more A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against synthetic PTHrP-(1-40) and recombinant PTHrP-(1-84) as standard. The detection limit is 2 pmol/L, and intra- and interassay coefficients of variation are 4.8% and 13.6%, respectively. This assay does not detect PTH even at concentrations of up to 2000 pmol/L. Cross-reactivity studies using various synthetic PTHrP peptides localize the antibody-binding epitope between residues 20 and 29. Hypercalcemic patients with a range of solid tumors and no evidence of bone metastases on radionuclide scanning (n = 27) all had detectable PTHrP levels (range, 2.8-51.2 pmol/L). Of 17 patients with solid tumors (other than breast) and bone metastases, 11 (64%) also had detectable PTHrP levels (range, 4.9-47.5 pmol/L). Twenty samples from breast cancer patients with hypercalcemia, 19 with evidence of bone metastases, and 1 with a negative bone scan were assayed, and detectable PTHrP levels were found in 13 (65%; range, 3.8-61.6 pmol/L). Patients with squamous cell carcinomata and normal serum calcium levels (n = 11) had no detectable PTHrP or levels close to the detection limit of the assay (range, less than 2 to 3.7 pmol/L). Plasma levels in normal volunteers were below the detection limit of the assay in all but 1 of 38 normal subjects. Patients with chronic renal failure on hemodialysis (n = 18) and patients with primary hyperparathyroidism (n = 14) all had undetectable PTHrP in this assay. This assay allows positive identification of patients with PTHrP-mediated hypercalcemia and, therefore, should be useful in the clinical investigation of the hypercalcemic patient. Furthermore, it has allowed detection of circulating PTHrP in hypercalcemic breast cancer patients with bone metastases, indicating a significant role for PTHrP in this disease.

Hormone and Metabolic Research, 1984

We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic pat... more We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic patients with documented cancer of various organs and cell types. NcAMP levels were elevated in 17 (28%) and decreased in 13 (21%) of the cancer patients. Both high and low NcAMP levels were seen within the various cancer groups. There was a significant correlation (r = 0.383, P less than 0.01) between NcAMP and serum parathyroid hormone (PTH) levels, suggesting that tumor-related factors affecting NcAMP , may be partially related to native PTH. Alternatively, these factors might be altering the effect of endogenous PTH on renal tubules. A significant negative correlation was also observed between NcAMP and tubular maximum for phosphate (r = -0.356, P less than 0.02) suggesting that either cAMP per se or factors affecting NcAMP alter phosphate excretion. Follow up serum calcium data was available on 48 of the 61 patients. Subsequent hypercalcemia developed independent of the initial nephrogenous cAMP levels. It therefore appears that NcAMP elevation and development of hypercalcemia are two separate paraneoplastic phenomena.

Clinical Chemistry, Nov 1, 1982

Samples brought to the laboratory for routine radioassay often have been under suboptimal conditi... more Samples brought to the laboratory for routine radioassay often have been under suboptimal conditions. We compared the effect of some sample-handling conditions on the values for T3, T3 resin uptake (T3RU), T4, thyrotropin, cortisol, and prolactin in serum as determined by radioassays. Blood was collected in three separateplain red-top Vacutainer Tubes from each of six subjects. Serum was separated from one of the three tubes, divided into portions, and frozen within 1 h of collection. Another tube from each patient was allowed to sit at room temperature for 7 h and then the serum was separated, apportioned, and frozen. The third tube from each patient was allowed to sit at room temperature for 7 h, then left overnight in the refrigerator and the serum separated and frozen after a further 17 h. All assays were done with commercially available kits: T4, T3RIA, and thyrotropin kits from Beckman Instruments Inc., Fullerton, CA 92634; T3RU kits from E.R. Squibb and Sons Inc., Princeton, NJ 08540; cortisol kits from Clinical Assays, Cambridge, MA 02139; and prolactin kits from Abbott Laboratories, Diagnostics Division, North Chicago, IL 60064. We could detect no significant detrimental effect of these various samplehandling conditions on the results of routine radioassays.

Clinical Chemistry, Sep 1, 1991

PubMed, Oct 1, 1986

Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and... more Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and progesterone (10(-9) and 3 X 10(-10) M) resulted in stimulation of CT secretion. The effect of the gonadal steroids on CT secretion occurred at near physiological concentrations and persisted for at least 73 h. The studies demonstrate that exposure to gonadal steroids results in direct and prolonged stimulation of CT secretion. Therefore the decrease in bone resorption observed after the administration of gonadal steroids in vivo may at least in part be mediated via stimulation of CT secretion.

American Journal of Physiology-endocrinology and Metabolism, Dec 1, 1990

Parathyroid hormone (PTH)-related protein has been shown to be a factor responsible for hypercalc... more Parathyroid hormone (PTH)-related protein has been shown to be a factor responsible for hypercalcemia of malignancy. Recent studies have shown the presence of mRNA for PTH-related protein in lactating breast tissue, suggesting a physiological role for this peptide during lactation. In the present study, we evaluated the effect of neutralization of PTH-related protein activity in lactating mice (by passive immunization) on various parameters of maternal and neonatal calcium homeostasis. PTH-related protein bioactivity, as tested in the adenylate cyclase assay, was present in mouse milk, and this activity was completely neutralized by the antisera used in the present study. In lactating mice, the effects of injection of PTH-related protein antisera on maternal serum calcium concentrations, milk calcium and phosphorus concentration, pup growth, dam femur calcium content, and pup calcium content were similar to those of the injection of normal rabbit serum. Therefore, maternal PTH-related protein does not appear to have a role in calcium homeostasis during lactation.

Osteoporosis International, Mar 12, 2009

Among 307 males seen in VA Medical Center, independent determinants (p<0.01 for all) of serum 25h... more Among 307 males seen in VA Medical Center, independent determinants (p<0.01 for all) of serum 25hydroxyvitamin D [25(OH)D] levels included race, vitamin D supplements, BMI, dietary calcium intake and smoking, but not age. Negative association between 25(OH)D and parathyroid hormone (PTH) was similar for Caucasian and African-American men. Introduction In this prospective cohort study, we examined determinants of serum 25-hydroxyvitamin D [25(OH)D] levels and the relationship between 25(OH)D and PTH levels and body mass index (BMI). Methods Male veterans (n=307) were recruited at a VA Medical Center. Serum levels of PTH and 25(OH)D were obtained. Surveys and chart reviews were completed. Vitamin D insufficiency was defined as 25(OH) D <30 ng/ml. Univariate and multivariate regression analyses were performed. Results Among 232 African-American (AA) men (mean ± SD), 25(OH)D level (21.4±10.4 ng/ml) was lower and prevalence of insufficiency (80%) was higher than among 75 Caucasians (C; 28.5±11.1 ng/ml and 53%, respectively, p<0.01 for both). In multivariate regression analysis, independent determinants (p<0.01 for all) of 25(OH)D levels included AA race, vitamin D supplements, BMI, dietary calcium intake, and smoking. Despite lower 25(OH) D levels in African-Americans, PTH levels were similar to those seen in Caucasians. There was a significant (p<0.02) negative linear association between 25(OH)D and PTH in African-American (r 2 =0.05) and Caucasian (r 2 =0.08) men, and there was no difference between the slopes of the relationship. Conclusions 25(OH)D levels are determined by modifiable risk factors such as vitamin D supplementation in both AA and C males. The negative association between 25(OH)D and PTH is similar between the two races.

PubMed, Jul 1, 1996

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible f... more Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. In addition to its hypercalcemic action, PTHrP has been implicated as an autocrine modulator of growth and differentiation, as well as an early response gene in some tissues. Several different types of tumors have been evaluated for the presence of PTHrP immunoreactivity. In the present study, we evaluated the expression of PTHrP by immunohistochemical staining in tissue samples from normal colorectal mucosa, polyps, and colorectal carcinoma removed from the same patients (n = 10 each). We have used a commercially available monoclonal antibody directed against epitopes between amino acids [53-64] which share no homology to parathyroid hormone (PTH). In normal colon, 94.3 per cent of the tissue samples were negative for PTHrP immunoreactivity. In polyps of the colon, only 22.6 per cent of the cells showed positive immunostaining, whereas 91.5 per cent of the samples from colon cancer stained positive for PTHrP. In the case of polyps, the intensity of staining was 1-3+; however, all of the samples from adenocarcinoma stained with 4+ intensity. In the positive samples, the immunoreactivity was present throughout the cytoplasm of the glandular epithelium. Omission of primary antibody, as well as substitution of the primary antibody by a negative control monoclonal antibody or non-immune rabbit serum, resulted in a negative reaction. All analyses were performed in duplicate, and the data have been presented as mean +/- SEM. Differences in normal polyps, carcinoma of the colon, and PTHrP expression were tested for statistical significance by student's t test. Our results show the expression of PTHrP is enhanced in colon cancer tissue as compared to normal colorectal mucosa and polyps. In addition, the expression appears to be greater in polyp than in normal colon. The role of PTHrP in the pathogenesis of colon cancer deserves further study.

Experimental Biology and Medicine, Nov 1, 1978

... GERALD A. WILLIAMS, E. NELSON BOWSER, GARY K. HARGIS, SUBHASH C. KUKREJA, JAYENDRA H. SHAH, N... more ... GERALD A. WILLIAMS, E. NELSON BOWSER, GARY K. HARGIS, SUBHASH C. KUKREJA, JAYENDRA H. SHAH, NILA M. VORA, AND WALTER J. HENDERSON Section of Endocrinology, Departments of Medicine and Nuclear Medicine, VA West Side Hospital and University ...

Metabolism-clinical and Experimental, Feb 1, 1987

Journal of Bone and Mineral Research, Dec 3, 2009

The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female... more The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female rats aged 12 months were divided into three groups: (1) sham-operated controls (SHAM); (2) oophorectomized (OVX); (3) OVX rats treated with progesterone (OVX + PROG). After 20 weeks the dry weight, bone ash, and calcium content of femur, tibia, and fourth lumbar vertebra were significantly lower in OVX than in sham rats. These reductions did not occur in OVX rats treated with PROG. There was no difference in the bone composition between the control and progesterone-treated rats. Vertebral bone histomorphometry showed increased bone resorption as well as increased bone formation parameters in OVX rats. Progesterone treatment inhibited the increased resorption indices, but the bone formation remained elevated. The results indicate that progesterone therapy prevents the postovariectomy bone loss in aged rats. The protective effect of progesterone is mediated by inhibition of bone resorption while maintaining the increased bone formation. These findings suggest that progesterone alone may be a valuable agent for management of postmenopausal osteoporosis.

Archives of internal medicine, Jul 1, 1987

Heiselman and Bennett both suggest that cisplatin-induced hypomagnesemia may be the mechanism for... more Heiselman and Bennett both suggest that cisplatin-induced hypomagnesemia may be the mechanism for the observed reduction in serum calcium levels in our hypercalcemic patients. Cisplatin therapy does induce hypomagnesemia, which, in turn, inhibits parathyroid hormone secretion and action, thus resulting in hypocalcemia.1We had initially considered this possibility and had obtained serum magnesium and parathyroid hormone levels before and after cisplatin administration in six patients (patients 1, 2, 3, 8,10, and 11 in Table 2 of our article).2 Supplemental magnesium was not given. The posttreatment measurements were made either the day serum calcium decreased to a value below 2.87 mmol/L (11.5 mg/dL) or on day 7. The results are shown in the accompanying Table. As expected, serum magnesium levels decreased significantly with cisplatin treatment. There was, however, no relation between hypomagnesemia and decrease in serum calcium levels, eg, serum magnesium drop was the greatest in patient 10, yet there was

American Journal of Physiology-endocrinology and Metabolism, Feb 1, 1989

Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associate... more Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associated hypercalcemia (MAH), whereas murine models of MAH have high circulating 1,25(OH)2D3. To determine the effects of a hypercalcemia-producing tumor on circulating 1,25(OH)2D3, in vitro 25-hydroxyvitamin D1-hydroxylase (1OHase) activity was measured in kidneys from BALB/c athymic mice implanted with a hypercalcemia-producing human lung tumor. Twelve days of low-phosphorus diet (LPD) in control animals lowered serum phosphorus to levels found in tumor-bearing mice fed normal phosphorus diet (NPD; 4.1 +/- 0.3 vs. 4.4 +/- 0.7 mg/dl, P = NS) and increased 1OHase activity (1.6 +/- 0.2 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, NPD vs. LPD, P less than 0.05). 1OHase activity was greater in tumor-bearing animals fed NPD compared with control animals fed LPD (8.4 +/- 0.6 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, P less than 0.01). High-phosphorus intake suppressed 1OHase activity in both control and tumor-bearing animals. Seven days of parathyroid hormone infusion in control animals fed NPD raised serum calcium (9.4 +/- 0.2 vs. 13.3 +/- 1.6 mg/dl, P less than 0.05) and suppressed 1OHase activity (0.25 +/- 0.02 vs. 0.02 +/- 0.002 pmol.mg protein-1.5 min-1, P less than 0.001). The inverse relationship of serum phosphorus and 1OHase activity was much steeper in the tumor-bearing animals, with greater enzyme activity at comparable levels of serum phosphorus. The present study indicates that 1) factors produced by the tumor stimulate 1OHase activity, and 2) hypophosphatemia is required for expression of enhanced enzyme activity.

Hormone and Metabolic Research, Jul 1, 1983

Experimental Biology and Medicine, Feb 1, 1976

In the rat, EDTA and isoproterenol stimulated PTH secretion, whereas high calcium and propranolol... more In the rat, EDTA and isoproterenol stimulated PTH secretion, whereas high calcium and propranolol inhibited it. The stimulatory effects of EDTA and isoproterenol were still evident and unaltered in the presence of blocks induced by propranolol and high calcium, respectively. The findings suggest that: (i) both calcium and beta-adrenergic stimuli affect PTH secretion; and (ii) the two influences affect the PTH secretion by separate initial pathways.

Hormone and Metabolic Research, 1986

This study was undertaken to evaluate the physiological role, if any, of dopamine (DA) in modulat... more This study was undertaken to evaluate the physiological role, if any, of dopamine (DA) in modulating parathyroid hormone (PTH) and calcitonin (CT) secretion in man. Infusion of DA (5 micrograms/kg/min) into 6 normal men, decreased serum immunoreactive prolactin (iPRL) and concomitantly increased serum iPTH to 140 +/- 6.8% of baseline (P less than 0.01) at 30 min, with decline thereafter, despite continuation of the DA infusion. Serum iCT levels did not significantly change. Chlorpromazine (50 mg IM), decreased serum iPTH to 75 +/- 5.4% and 79 +/- 3.7% of baseline (P less than 0.01) at 30 and 60 min, respectively, associated with an increase in iPRL. There was subsequent return of iPTH to baseline even though iPRL remained elevated. iCT levels did not significantly change. These observations would suggest that DA may play a physiological role in iPTH, but not iCT, secretion. However, infusion of more nearly physiological doses of DA (0.02, 0.2, and 2.0 micrograms/kg/min) lowered serum iPRL to levels similar to those after the larger DA dose, but with no concomitant increase in either iPTH or iCT. Also, 1) the DA agonist bromocriptine decreased serum iPRL without modifying iPTH or iCT; 2) the DA precursor, levodopa, and the DA antagonist, metoclopramide, had no effect on serum iPTH or iCT levels. These studies suggest that 1) the transient stimulatory effect of DA on iPTH secretion is pharmacological, and 2) DA does not have a physiological role in secretion of iPTH or iCT in man.

The Journal of Clinical Endocrinology and Metabolism, Mar 1, 1983

Purified secretin infused in an estimated physiological dose caused an increase in serum immunore... more Purified secretin infused in an estimated physiological dose caused an increase in serum immunoreactive PTH (iPTH) and calcitonin (iCT) in man. Ingestion of a gastric acid-stimulating test meal, a procedure known to increase endogenous secretin, caused increases in serum iPTH and plasma iCT in normal subjects. Ingestion of antacid with the test meal blunted the increase in both iPTH and iCT. Ingestion of the test meal by pernicious anemia patients with achlorhydria caused no stimulation of either serum iPTH or plasma iCT. Therefore, based on the observations that 1) exogenous secretin stimulated iPTH and iCT, 2) an acid-stimulating test meal is known to stimulate endogenous secretin release (4), 3) the test meal increased both serum iPTH and iCT in normal man, an effect nullified by simultaneous antacid ingestion, and 4) the test meal caused no increase in either iPTH or iCT in achlorhydric patients, we conclude that endogenous secretin possibly mediates this effect of test meal and, therefore, may play a physiological role in modulating the secretion of PTH and CT.

Journal of Bone and Mineral Research, Dec 3, 2009

Local and systemic insulin‐like growth factors (IGFs) may be involved in the regulation of bone f... more Local and systemic insulin‐like growth factors (IGFs) may be involved in the regulation of bone formation by sex hormones. The present studies describe the in vivo effects of estradiol, progesterone, or both on IGF‐1 mRNA abundance in bone, serum IGF‐1 levels, and bone formation. Rats were sham‐operated (SHAM) or ovariectomized (OVX) at 12 weeks of age and used a week later in three experiments. First, OVX rats were treated with vehicle, estradiol, and/or medroxyprogesterone (MPA) for 3 weeks, and bone formation was assessed in the tibial metaphysis. Second, OVX rats were treated in the same manner and serum IGF‐1 levels measured. Third, OVX rats were treated with an injection of vehicle, estradiol, and/or progesterone, and 24 h later, levels of IGF‐1 mRNA in the femur were analyzed. The mineralized surface, mineral apposition rate, and bone formation rate (BFR) were higher in OVX than in SHAM rats. The BFR was decreased in estrogen‐treated but increased in MPA‐treated rats compared with vehicle‐treated OVX rats. Circulating levels of IGF‐1 were higher in OVX than in SHAM rats but were not affected by sex hormones in a 3‐week experiment, whereas these levels were not different among groups in a 24‐h experiment. Northern analysis detected 7.5 and 0.8 kb IGF‐1 mRNA transcripts. The abundance of IGF‐1 mRNA was higher in OVX than in SHAM rats. IGF‐1 transcripts 7.5 and 0.8 kb were decreased by 72 and 29%, respectively, in estrogen‐treated and increased by 44 and 43%, respectively, in progesterone‐treated rats compared with vehicle‐treated OVX rats. We conclude that in the short term, estrogen lowers and progesterone raises bone IGF‐1 mRNA and these changes are followed by coordinated changes in bone formation rate.

Journal of Bone and Mineral Research, Dec 3, 2009

Exercise may play a role in the prevention of bone fractures in postmenopausal osteoporosis. The ... more Exercise may play a role in the prevention of bone fractures in postmenopausal osteoporosis. The effects of endurance exercise on bone properties were assessed in 9-month-old sham-operated (SH) and ovariectomized (OVX) rats. The rats were either kept sedentary (SED) or were exercised (EX) on a rodent treadmill at 21 m/ minute, 7% grade, 40 minutes/day, 4 days/week for 3 months. Bone mineral (by ash weight), morphometry, and biomechanical properties (by three-point bending) were evaluated after excision of bones at sacrifice. Ovariectomy resulted in a loss of bone mineral in femur, tibia, and fourth lumbar vertebra (U), but biomechanical (force, deformation, stress, strain, and modulus of elasticity) and morphometric (length, cortial and medullary area, and moment of inertia) properties of femur were maintained. The ash weight of femur and tibia, but not L4, as well as femur yield and maximum force and moment of inertia, were improved in OVX-EX rats compared to OVX-SED animals. In SH rats exercise had no influence on ash weight of any of the three bones or femur morphometric properties, yet femur maximum force and plastic deformation were significantly enhanced compared to SH-SED rats. The results of the present study suggest that endurance exercise has beneficial effects on the bone mineral as well as biomechanical properties (femur yield and maximum force) during early stages after ovariectomy and improves the bending strength of the intact femur without an effect on bone mineral in sham-operated rats.

Bone and Mineral, Sep 1, 1990

The Journal of Clinical Endocrinology and Metabolism, Dec 1, 1991

A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against syn... more A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against synthetic PTHrP-(1-40) and recombinant PTHrP-(1-84) as standard. The detection limit is 2 pmol/L, and intra- and interassay coefficients of variation are 4.8% and 13.6%, respectively. This assay does not detect PTH even at concentrations of up to 2000 pmol/L. Cross-reactivity studies using various synthetic PTHrP peptides localize the antibody-binding epitope between residues 20 and 29. Hypercalcemic patients with a range of solid tumors and no evidence of bone metastases on radionuclide scanning (n = 27) all had detectable PTHrP levels (range, 2.8-51.2 pmol/L). Of 17 patients with solid tumors (other than breast) and bone metastases, 11 (64%) also had detectable PTHrP levels (range, 4.9-47.5 pmol/L). Twenty samples from breast cancer patients with hypercalcemia, 19 with evidence of bone metastases, and 1 with a negative bone scan were assayed, and detectable PTHrP levels were found in 13 (65%; range, 3.8-61.6 pmol/L). Patients with squamous cell carcinomata and normal serum calcium levels (n = 11) had no detectable PTHrP or levels close to the detection limit of the assay (range, less than 2 to 3.7 pmol/L). Plasma levels in normal volunteers were below the detection limit of the assay in all but 1 of 38 normal subjects. Patients with chronic renal failure on hemodialysis (n = 18) and patients with primary hyperparathyroidism (n = 14) all had undetectable PTHrP in this assay. This assay allows positive identification of patients with PTHrP-mediated hypercalcemia and, therefore, should be useful in the clinical investigation of the hypercalcemic patient. Furthermore, it has allowed detection of circulating PTHrP in hypercalcemic breast cancer patients with bone metastases, indicating a significant role for PTHrP in this disease.

Hormone and Metabolic Research, 1984

We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic pat... more We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic patients with documented cancer of various organs and cell types. NcAMP levels were elevated in 17 (28%) and decreased in 13 (21%) of the cancer patients. Both high and low NcAMP levels were seen within the various cancer groups. There was a significant correlation (r = 0.383, P less than 0.01) between NcAMP and serum parathyroid hormone (PTH) levels, suggesting that tumor-related factors affecting NcAMP , may be partially related to native PTH. Alternatively, these factors might be altering the effect of endogenous PTH on renal tubules. A significant negative correlation was also observed between NcAMP and tubular maximum for phosphate (r = -0.356, P less than 0.02) suggesting that either cAMP per se or factors affecting NcAMP alter phosphate excretion. Follow up serum calcium data was available on 48 of the 61 patients. Subsequent hypercalcemia developed independent of the initial nephrogenous cAMP levels. It therefore appears that NcAMP elevation and development of hypercalcemia are two separate paraneoplastic phenomena.

Clinical Chemistry, Nov 1, 1982

Samples brought to the laboratory for routine radioassay often have been under suboptimal conditi... more Samples brought to the laboratory for routine radioassay often have been under suboptimal conditions. We compared the effect of some sample-handling conditions on the values for T3, T3 resin uptake (T3RU), T4, thyrotropin, cortisol, and prolactin in serum as determined by radioassays. Blood was collected in three separateplain red-top Vacutainer Tubes from each of six subjects. Serum was separated from one of the three tubes, divided into portions, and frozen within 1 h of collection. Another tube from each patient was allowed to sit at room temperature for 7 h and then the serum was separated, apportioned, and frozen. The third tube from each patient was allowed to sit at room temperature for 7 h, then left overnight in the refrigerator and the serum separated and frozen after a further 17 h. All assays were done with commercially available kits: T4, T3RIA, and thyrotropin kits from Beckman Instruments Inc., Fullerton, CA 92634; T3RU kits from E.R. Squibb and Sons Inc., Princeton, NJ 08540; cortisol kits from Clinical Assays, Cambridge, MA 02139; and prolactin kits from Abbott Laboratories, Diagnostics Division, North Chicago, IL 60064. We could detect no significant detrimental effect of these various samplehandling conditions on the results of routine radioassays.

Clinical Chemistry, Sep 1, 1991

PubMed, Oct 1, 1986

Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and... more Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and progesterone (10(-9) and 3 X 10(-10) M) resulted in stimulation of CT secretion. The effect of the gonadal steroids on CT secretion occurred at near physiological concentrations and persisted for at least 73 h. The studies demonstrate that exposure to gonadal steroids results in direct and prolonged stimulation of CT secretion. Therefore the decrease in bone resorption observed after the administration of gonadal steroids in vivo may at least in part be mediated via stimulation of CT secretion.

American Journal of Physiology-endocrinology and Metabolism, Dec 1, 1990

Parathyroid hormone (PTH)-related protein has been shown to be a factor responsible for hypercalc... more Parathyroid hormone (PTH)-related protein has been shown to be a factor responsible for hypercalcemia of malignancy. Recent studies have shown the presence of mRNA for PTH-related protein in lactating breast tissue, suggesting a physiological role for this peptide during lactation. In the present study, we evaluated the effect of neutralization of PTH-related protein activity in lactating mice (by passive immunization) on various parameters of maternal and neonatal calcium homeostasis. PTH-related protein bioactivity, as tested in the adenylate cyclase assay, was present in mouse milk, and this activity was completely neutralized by the antisera used in the present study. In lactating mice, the effects of injection of PTH-related protein antisera on maternal serum calcium concentrations, milk calcium and phosphorus concentration, pup growth, dam femur calcium content, and pup calcium content were similar to those of the injection of normal rabbit serum. Therefore, maternal PTH-related protein does not appear to have a role in calcium homeostasis during lactation.