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R W Downs

Publications and source records attributed to R W Downs.

14 recordsLinked to original sources
PubMed1992

Glucocorticoids decrease vitamin D receptor number and gene expression in human osteosarcoma cells.

The mechanisms by which glucocorticoids (GC) inhibit some actions of vitamin D [1,25-(OH)2D3] are not well understood, but there is growing evidence that GC alter vitamin D receptor (VDR) number. We studied the effects of dexamethasone (DEX) on VDR number and mRNA in the human osteosarcoma cell line, MG-63. The effects of DEX on 1,25-(OH)2D3 binding were examined by incubating confluent cells overnight in media without or with 10(-6) M DEX. DEX decreased VDR number (B max) by approximately 70% (110 versus 32 fmol/mg cellular protein, p less than 0.001) without significantly changing the apparent affinity (K'D) of 1,25-(OH)2D3 for its receptor (3.8 versus 2.2 x 10(-10) M, p greater than 0.05). Overnight incubation of MG-63 cells with DEX produced a time- and dose-responsive decrease in VDR mRNA compared to untreated controls (p less than 0.01). To determine the mechanism of the DEX-mediated decrease in VDR mRNA, the effect of DEX on VDR mRNA stability was studied. We found that the half-life for the VDR mRNA was approximately 5.7 h and was not significantly changed when the cells were incubated with DEX (approximately 6.3 h). We conclude that DEX decreases both VDR number and mRNA in MG-63 osteosarcoma cells. Since the half-life of VDR mRNA was not significantly modified by dexamethasone, glucocorticoids appear to decrease VDR mRNA by inhibiting VDR gene transcription or by affecting the processing of VDR mRNA.

Actins↗
PubMed1992

Mild vitamin D deficiency and secondary hyperparathyroidism in nursing home patients receiving adequate dietary vitamin D.

OBJECTIVE: To compare the vitamin D metabolite and nutritional status of institutionalized elderly males with a noninstitutionalized control group. DESIGN: Case-control study. SETTING: Veterans Administration Medical Center Nursing Home (NH) in Richmond, Virginia. PATIENTS: Fifty-seven consecutive nursing home subjects were screened. After excluding blacks, those receiving anticonvulsants, glucocorticoids, or vitamin supplements, and those with liver or renal failure (creatinine greater than 1.5 mg/dL), 35 subjects were enrolled, and 22 completed the study. The noninstitutionalized control group (n = 18) consisted of consecutive volunteers, meeting the above criteria, from either a senior citizen group or a geriatric clinic. MEASUREMENTS AND MAIN RESULTS: The serum 25-hydroxy-vitamin D level in the NH residents was significantly lower than in community dwellers (17.4 +/- 5.2 ng/mL vs 31.2 pg/mL +/- 8.0 ng/mL, P less than 0.0001). No significant difference was demonstrated in 1,25-dihydroxyvitamin D levels (36.5 pg/mL +/- 10.5 in NH residents vs 42.0 pg/mL +/- 11.1 in controls). In the NH group PTH levels were inversely correlated with 25 OHD levels (P less than 0.008) and positively correlated with length of stay in the NH (P less than 0.016). There was no significant seasonal variation in vitamin D metabolite levels in the NH group. In the NH patients, the mean dietary intake of vitamin D was 232 +/- 378 mg/day and of calories was 1811 +/- 447 kcal/day. CONCLUSION: Despite apparently adequate calories, calcium, and vitamin D intake, hypovitaminosis D with compensatory PTH elevations occurs, regardless of season, in the nursing home population.

25-Hydroxyvitamin D 2↗
PubMed1989

Cyclic nucleotides regulate collagen production by human intestinal smooth muscle cells.

The effect of cyclic nucleotides on collagen production by human intestinal smooth muscle cells was examined in vitro. Cholera toxin and isobutylmethylxanthine, agents that elevate cyclic adenosine monophosphate, caused selective inhibition of collagen production when cells were exposed to these agents for 24-72 h. Exposure for 6 h inhibited noncollagen protein synthesis without effects on collagen production. Forskolin similarly inhibited collagen production, decreasing relative collagen synthesis 40% at 10 microM and 60% at 100 microM. After 48 h of exposure to cholera toxin and isobutylmethylxanthine, levels of cyclic adenosine monophosphate had increased in a concentration-dependent manner. The effect of cyclic nucleotide analogues was also examined. Dibutyryl cyclic adenosine monophosphate inhibited collagen production, whereas dibutyryl cyclic guanosine monophosphate increased collagen production by 65%. This effect was maximal at a concentration of 10 microM. These observations suggest that cyclic adenosine monophosphate has a significant effect on collagen production by human intestinal smooth muscle cells in vitro and may play a role in the modulation of collagen production by these cells in vivo.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Cushing's disease in two sisters.

Hereditary Cushing's syndrome is an uncommon clinical entity, and most reported cases have been described in families with nodular adrenocortical dysplasia. Isolated cases of Cushing's disease (pituitary-dependent bilateral adrenal hyperplasia) have been reported in association with the multiple endocrine neoplasia syndrome, Type I (MEN I), but there are no published reports of pedigrees with more than one affected family member. Within a period of 8 months, two sisters presented with clinical findings suggestive of hypercortisolism, and Cushing's disease was confirmed by appropriate diagnostic studies. There was no evidence of any other endocrine excess syndrome in either patient. Transsphenoidal pituitary surgery confirmed the presence of an ACTH-immunostaining pituitary adenoma in each woman. The authors think this is the first report in the English literature of Cushing's disease in first-degree relatives.

Adenoma↗
PubMed1989

New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase.

Patients with pseudohypoparathyroidism type Ia have resistance to multiple hormones because of deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) that couples membrane receptors to activation of adenylate cyclase. However, in a subset of patients with pseudohypoparathyroidism who have resistance to multiple hormones yet possess normal erythrocyte membrane Gs activity, the biochemical abnormality responsible for hormone resistance has remained undefined. Cultured skin fibroblasts were derived from a patient with this atypical form of pseudohypoparathyroidism. In the patient's fibroblast membranes, adenylate cyclase stimulation mediated by Gs after fluoride ion treatment produced only 52% of normal activity, yet fibroblast membrane Gs activity measured by cyc- complementation was normal. Activation of the catalytic unit of adenylate cyclase with manganese produced 49% of normal activity; manganese plus forskolin produced 54% of normal adenylate cyclase activity. beta-Adrenergic receptor coupling to Gs and phosphodiesterase activity were normal. A defect in the catalytic unit of adenylate cyclase can account for these results and may be a mechanism for clinical resistance to multiple hormones that act through adenylate cyclase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Separation of a guanine nucleotide regulatory unit from the adenylate cyclase complex with GTP affinity chromatography.

We studied the relationship between guanine nucleotide binding proteins and adenylate cyclase activity of solubilized turkey erythrocyte membranes with GTP affinity chromatography. Solubilized adenylate cyclase from untreated membranes or membranes pretreated with GMP only (GMP prep) responded poorly to GTP or Gpp(NH)p but were markedly stimulated by fluoride. The solubilized enzyme from membranes pretreated with isoproterenol+GMP (ISO+GMP prep) did not respond to GTP but was markedly stimulated by Gpp(NH)p. Fluoride-stimulated activity of the ISO+GMP prep was reduced by comparison with the GMP prep but could be increased significantly by addition of GTP. GTP hexane agarose (GTP linked to matrix via morpholine derivative of ribose) failed to interact specifically with either the GMP or ISO+GMP prep. Incubation of ISO+GMP prep with GTP-gamma-agarose (GTP linked to matrix via terminal phosphate) reduced the Gpp(NH)p response and the GTP-dependent fraction of the fluoride response. GTP-gamma-agarose did not reduce the fluoride response of the GMP prep. Following incubation with ISO+GMP prep, GTP-gamma-agarose beads were eluted with buffer containing Gpp(NH)p. The eluate had only slight intrinsic adenylate cyclase activity but was able to increase significantly the activity of GTP-gamma-agarose-treated ISO+GMP prep as well as untreated GMP prep. An eluate from GTP-gamma-agarose beads incubated with GMP prep did not possess activity. Our results suggest that the guanine nucleotide-regulatory unit is reversibly associated with the adenylate cyclase complex of turkey erythrocyte membranes.

Adenylyl Cyclases↗
PubMed1978

Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism.

Three indices of circulating parathyroid hormone (PTH) activity were compared between two groups: the first a group of 23 patients from three large kindreds with autosomal dominant hypercalcemia without hypercalciuria [familial hypocalciuric hypercalcemia (FHH)] and the second a group of 64 patients with typical primary hyperparathyroidism (1HPT) manifesting comparable hypercalcemia. The group with 1HPT differed from normal with respect to plasma PTH 1HPT concentration (normal, less 0.2 ng/ml), urinary cAMP excretion per 100 ml glomerular filtrate (U cAMP/GF) (normal, 2.3 x/divided by 0.6 nmol/100 ml glomerular filtrate; mean, x/divided 1 SD), and renal tubular maximum of phosphate transport corrected for glomerular filtration rate (TMP/GFR; normal, 3.4 +/- 0.4 mg/dl; mean, +/- 1 SD). The group with 1HPT also diverged significantly from the group with FHH for all three indices: for PTH, 0.37 x/divided by .48 vs. 0.25 x/divided .46 (P less than 0.05); for UcAMP/GF, 4.3 x/divided by .53 vs. 2.6 x/divided .60 (P less than 0.0005); and for TMP/GFR, 2.0 +/- 0.6 vs. 2.6 +/- 0.7 (P less than 0.01). The between-group differences for all three indices were also significant after adjustment for their variation with serum calcium. However, only the difference in TMP/GFR remained significant after adjustment for covariance attributable to serum calcium concentration, age, and creatinine clearance. The group with FHH differed from normal for TMP/GFR but not for UcAMP/GF. However, analysis of changes in UcAMP/GF and serum calcium concentration around the time of parathyroidectomy in three patients with FHH suggested that the parathyroid glands contributed to the abnormalities of mineral homeostasis in at least one. It was concluded that higher serum concentrations of PTH do not account for the lower renal clearance of calcium and magnesium in FHH calcium concentration, the group with FHH showed indices suggesting lower circulating PTH activity than the group with 1HPT.

Calcium↗
PubMed1978

A familial syndrome of decrease in sensitivity to 1,25-dihydroxyvitamin D.

Typical features of hereditary vitamin D-dependent (pseudovitamin D-deficient) rickets were observed beginning at ages 20 and 5 months in a brother and sister. Both had calcium malabsorption correctable with high doses of 25-hydroxyvitamin D. During periods of hypocalcemia they both manifested secondary hyperparathyroidism with hypophosphatemia and high serum concentrations of endogenously produced 1,25-dihydroxyvitamin D. In each, normalization of serum calcium concentration and resolution of osteomalacia were obtained with continuous administration of high doses of ergocalciferol or high doses of 1,25-dihydroxycholecalciferol. Chemical features of vitamin D deficiency were corrected in the presence of high circulating concentrations of 1,25-dihydroxyvitamin D2, produced endogenously, or of 1,25-dihydroxyvitamin D3, administered by mouth. Serum concentrations of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal in five first degree relatives. We conclude that in these five first degree relatives. We conclude that in these siblings, rickets and osteomalacia resulted from a hereditary decreased sensitivity to 1,25-dihydroxyvitamin D at the intestine and perhaps other vitamin D target tissues.

Absorption↗
PubMed1975

Management of recurrent melanoma of the extremity.

Two forms of therapy employed for treatment of patients with recurrent melanoma limited to the extremity, and carried out during different intervals of time, are presented. Perfusion of the involved extremity with phenylalanine mustard has resulted in a 5-year survival rate of 28% of 43 patients. A second group of 25 patients has been treated by a four-stage immunotherapy program consisting of sensitization with intradermal BCG, followed in 6 weeks by intra tumor injection of BCG. A third stage involved the activation of the patients's lymphocytes, after removal by a blood cell separator, incubated in vitro with irradiated neuraminidase-treated melanoma cells and reintroduced into the patient either by subcutaneous or intratumor injection. The fourth stage of immunotherapy involves injection of an inoculum of irradiated neuraminidase-treated autochothonous tumor cells plus BCG injected intratumorally or subcutaneously. Sixteen of 24 patients receiving immunotherapy treatment program have experienced arrest of their disease lasting from 5 to 42 months.

Adult↗