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Biomedical subjects

S J Marx

Publications and source records attributed to S J Marx.

At least 109 records · Page 6Linked to original sources
PubMed1989

Inhibitory effects of tumor necrosis factor-alpha and interferon-gamma on deoxyribonucleic acid and collagen synthesis by rat osteosarcoma cells (ROS 17/2.8).

Tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) have potent effects on bone resorption and collagen synthesis in cultured rat long bones. Since the effects of TNF alpha and IFN gamma may result from interaction with multiple cell types, we studied the effects of these cytokines on the synthesis of DNA and collagen in one cell type with osteoblast phenotype, cloned rat osteosarcoma cells (ROS 17/2.8). Recombinant human TNF alpha did not affect DNA synthesis after 48 h with concentrations of 10(-11)-10(-8) M and inhibited DNA synthesis slightly at 10(-6) M. Recombinant rat IFN gamma (5-500 U/ml) caused a dose-dependent inhibition of DNA synthesis. Coincubation with TNF alpha and IFN gamma inhibited DNA synthesis more than maximal doses of either cytokine alone. This enhanced inhibitory effect was due to the induction of a response to TNF alpha by IFN gamma, since preexposure of cells to IFN gamma for 24 h, followed by incubation with TNF alpha alone for an additional 48 h, also resulted in increased inhibition of DNA synthesis. Preexposure to TNF alpha for 24 h, followed by IFN gamma alone, did not increase the inhibition of DNA synthesis. Incubation with either IFN gamma (5-500 U/ml) or TNF alpha (10(-10)-10(-6) M) inhibited the incorporation of [3H]proline into collagen. Coincubation with intermediate concentrations of both cytokines resulted in an inhibitory effect greater than that produced by maximal concentrations of either alone. The results indicate that 1) IFN gamma and TNF alpha have direct actions on osteoblast-like cells in vitro; 2) IFN gamma modulates the DNA response to TNF alpha; and 3) the greater responses to combined cytokines than to high doses of either alone suggest that these cytokines act, at least in part, through different pathways.

Animals↗
PubMed1989

Plasma chromogranin-A in primary hyperparathyroidism.

We sought an explanation for prior findings of high plasma chromogranin-A (Chr-A) in primary hyperparathyroidism. Chr-A was measured in plasma samples from 55 controls and 73 patients with primary hyperparathyroidism caused by adenoma (n = 14), sporadic or familial hyperplasia (n = 10), or familial multiple endocrine neoplasia type 1 (FMEN1; n = 49). Serum or plasma samples were also tested for calcium, PTH, gastrin, pancreatic polypeptide, CG alpha, and PRL. Plasma Chr-A was 34 +/- 10 in parathyroid adenoma, 55 +/- 33 in parathyroid hyperplasia without FMEN1, 63 +/- 88 in FMEN1, and 25 +/- 8 in controls (mean +/- SD; nanograms per ml; FMEN1 or parathyroid hyperplasia vs. control, P less than 0.05). Plasma Chr-A did not correlate with other hormonal variables in controls. Plasma Chr-A correlated with log serum gastrin (r = 0.43; P = 0.003) and plasma PTH (r = 0.52; P less than 0.05) only in FMEN1. In FMEN1, plasma Chr-A was highest in subjects with Zollinger-Ellison syndrome (ZES, 120 +/- 127; no ZES, 30 +/- 33 (P less than 0.0001). Parathyroidectomy did not decrease plasma Chr-A in patients with parathyroid adenoma or parathyroid hyperplasia. For FMEN1 patients with available pre- and postparathyroidectomy samples, Chr-A decreased postoperatively in four of five patients with ZES compared to none of six patients without ZES (P less than 0.05). Elevated plasma Chr-A is not a general feature of primary hyperparathyroidism. Elevated plasma Chr-A in primary hyperparathyroidism was restricted principally to patients who also had ZES. Primary hyperparathyroidism may influence the level of Chr-A by an effect of hypercalcemia or elevated PTH on Chr-A secretion from pancreatic islet tissue.

Adenoma↗
PubMed1989

Differences in mineral metabolism among nonhuman primates receiving diets with only vitamin D3 or only vitamin D2.

We tested for differences in aspects of mineral metabolism during the administration of diets with only vitamin D3 or only vitamin D2 in four nonhuman anthropoid primate species [two catarrhini, Macaca fascicularis (crab-eating macaque) and Macaca mulatta (rhesus macaque), and two platyrrhini, Saimiri sciureus (squirrel monkey) and Aotus vociferans (night monkey)]. All four species maintained approximately 2- to 3-fold higher serum 25-hydroxyvitamin D (25OHD) level while receiving vitamin D3 than while receiving similar amounts of vitamin D2. Serum 25OHD in M. mulatta receiving the standard primate dietary supplement of vitamin D3 was high enough (360 +/- 60 vs. 70 +/- 25 nM in vitamin D-supplemented humans; P less than 0.0001) to suggest that this widely used level of vitamin D3 supplementation is excessive for some M. mulatta. Serum 24,25-dihydroxyvitamin D [24,25-(OH)2D] in A. vociferans was uniquely high [P less than 0.01; species mean, 19 +/- 5, 95 +/- 12, and 27 +/- 5 nM in groups receiving diets with 1.5 IU vitamin D3/g, 6.6 IU vitamin D3/g, and 15 IU vitamin D2/g, respectively; mean 24,25-(OH)2D from the other three species pooled across three diets was 7 +/- 5 nM]. We confirmed relative resistance to 1,25-(OH)2D in S. sciureus, manifested by osteomalacia and moderately high serum 1,25-(OH)2D. Serum 1,25-(OH)2D in S. sciureus increased 4-fold (P less than 0.05) when the precursor in serum was changed from 250HD3 to 250HD2, suggesting that this species shows more severe resistance to 1,25-(OH)2D2 than to 1,25-(OH)2D3. In conclusion, we found many differences in vitamin D metabolism among four nonhuman anthropoid primate species. The striking feature in A. vociferans (high, 24,25-(OH)2D without high 25OHD in serum independent of whether diet contained only vitamin D3 or only vitamin D2) should allow determination of whether 24,25-(OH)2D functions as a unique agonist or an inactive metabolite in this species.

Animals↗
PubMed1988

Ongoing protein synthesis needed for 1,25-(OH)2D3-mediated rapid increase of cyclic GMP in human skin fibroblasts.

Recently we reported that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) through interaction with its specific receptor rapidly (within 1 min) stimulated intracellular cGMP production in cultured human skin fibroblasts. Here we show that this effect of 100 nM 1,25-(OH)2D3 is prevented by brief (30 min) inhibition of RNA synthesis (with actinomycin D or alpha-amanitin) or by brief inhibition of protein synthesis (with cycloheximide or diphtheria toxin). The protein synthesis inhibitors also blocked stimulation of cGMP by other steroids (testosterone or dexamethasone at 100 nM) but did not block cGMP stimulation by sodium nitroprusside. Since the time for the 1,25-(OH)2D3 receptor to increase cGMP seems too short to require de novo protein synthesis, we conclude that the 1,25-(OH)2D3 receptor acts together with rapidly turning over protein(s) to stimulate cGMP synthesis.

Amanitins↗
PubMed1988

Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism.

In a previous report, we described antibodies in autoimmune hypoparathyroidism (AHP) that are cytotoxic for cultured bovine parathyroid cells. In the present study, we show that sera from six AHP patients, but not from 26 patients with other autoimmune diseases or from 7 healthy subjects, react with bovine endothelial cells in culture (by flow cytometry and fluorescence microscopy) and in tissue sections (by immunohistology). We found uniformly that the immunoglobulin class reacting is IgM. Adsorption experiments showed that the antigenic determinants reacting with AHP sera were similar on bovine cultured endothelial cell membranes and in tissue sections of bovine parathyroid glands. The AHP sera also reacted with endothelial cells cultured from bovine adrenal medulla and pulmonary artery. Immunoblot analysis showed antibody binding to two major bands of 200 and 130 kDa solubilized from the membrane fraction of bovine parathyroid endothelial cells. Only one AHP serum consistently recognized endothelium-related structures on frozen sections of three different human parathyroid adenomas; two other sera reacted with one adenoma each; and three did not react with human adenomas. This indicates that human material is less suitable than bovine in detecting endothelium-related immune phenomena in AHP sera. The anti-endothelium IgM antibodies appear to be disease-specific but are not organ- or species-specific. The identification of endothelial cells as the target for antibodies in AHP raises the possibility that the endothelium subserves an important local function for endocrine epithelium.

Animals↗
PubMed1988

Receptor-mediated rapid action of 1 alpha,25-dihydroxycholecalciferol: increase of intracellular cGMP in human skin fibroblasts.

The intracellular cGMP concentration in normal human cultured fibroblasts was increased 2- to 3-fold by 1 alpha,25-dihydroxycholecalciferol [1 alpha,25-(OH)2D3] in a dose-dependent manner between 0.01 nM and 1 microM. The response was detectable within 1 min, reached a maximum (225% +/- 8% of baseline) at 6-8 min, and was no longer detectable at 30 min. The half-maximal effect of 1 alpha,25-(OH)2D3 was at 1.8 nM, and 24,25-dihydroxycholecalciferol showed an estimated EC50 100-fold higher. 1 beta,25-Dihydroxycholecalciferol, 25-hydroxycholecalciferol, and cholecalciferol had no detectable effect. Human skin fibroblasts with three different types of 1 alpha,25-(OH)2D3 receptor defect did not respond to 1 alpha,25-(OH)2D3 exposure with cGMP increase; however, the same cells (like normal cells) responded to testosterone or sodium nitroprusside with a rapid rise of cGMP. We conclude that the rapid rise of cGMP in response to calciferols shows an EC50 for 1 alpha,25-(OH)2D3, a cholecalciferol analog specificity, and a cell line dependency that are all suggestive of mediation through a specific 1 alpha,25-(OH)2D3 receptor.

Calcitriol↗
PubMed1988

Dual effects of calcitonin and calcitonin gene-related peptide on intracellular cyclic 3',5'-monophosphate in a human breast cancer cell line.

The effects of salmon calcitonin (sCT) and human calcitonin (hCT) and of rat (r) and human (h) calcitonin gene-related peptide (CGRP) on intracellular cAMP accumulation were tested in human breast cancer cells (MCF7). In addition to the well known stimulatory effect, each showed a significant inhibitory effect on cAMP accumulation at low doses. cAMP concentrations in response to sCT, hCT, and rCGRP decreased to 47 +/- 2, 45 +/- 4, and 56 +/- 2% (mean +/- 1 SE) of baseline. The potency ratios for the inhibitory action of sCT, hCT, and rCGRP (1:0.25:0.005, respectively) were similar to the potency ratios for stimulatory action (1:0.3:0.005). The inhibition of cAMP accumulation developed at 300-fold lower peptide concentrations than the stimulation. Preincubation with pertussis toxin or with manganese completely abolished the inhibitory effect of the peptides, suggesting that this is mediated by an inhibitory adenylate cyclase regulatory protein. sCT, hCT, and CGRP each showed unique patterns with regard to time course of inhibition of cAMP accumulation. We conclude that 1) CT can activate an inhibitory adenylate cyclase regulatory protein and a stimulatory adenylate cyclase regulatory protein, and 2) CT effect on an inhibitory adenylate cyclase regulatory protein in MCF 7 cells is evident at far lower hormone concentrations than its effect on a stimulatory adenylate cyclase regulatory protein.

Adenylate Cyclase Toxin↗
PubMed1988

Absent intestinal response to calciferols in hereditary resistance to 1,25-dihydroxyvitamin D: documentation and effective therapy with high dose intravenous calcium infusions.

We describe a patient with an absent intestinal response to 1,25-dihydroxyvitamin D [1,25-(OH)2D] and the beneficial effects of treatment with high dose iv calcium infusion. The patient presented with severe rickets despite therapy with extraordinarily high doses of 1 alpha-hydroxyvitamin D3 or 1,25-(OH)2D3. Unidirectional intestinal fractional calcium absorption when he was not treated with any calciferol was 14% (normal, 20-70%), as measured with stable calcium isotopes; no increase in calcium absorption occurred when serum 1,25-(OH)2D levels were more than 50-fold elevated. Cultured skin fibroblasts contained no detectable 25-hydroxyvitamin D3-24-hydroxylase activity in response to 1,25-(OH)2D3 (10(-9)-10(-6) mol/L). High dose iv calcium infusions and oral phosphorus supplementation for 135 days improved or normalized biochemical parameters and resulted in radiographic healing of the rachitic lesions. We conclude that 1) this patient had no response to 1,25-(OH)2D3 in vivo and in vitro; 2) long term parenteral calcium infusions were effective therapy in managing the patient's severe resistance to 1,25-(OH)2D; and 3) stable calcium isotopes are useful for measuring low levels of fractional calcium absorption.

Alkaline Phosphatase↗
PubMed1988

Mitogenic activity on parathyroid cells in plasma from members of a large kindred with multiple endocrine neoplasia type 1.

We tested plasma from 83 members of a large kindred with familial multiple endocrine neoplasia type 1 (FMEN1) for mitogenic activity on cultured bovine parathyroid cells. We evaluated the age dependency of parathyroid mitogenic activity (PMA) in plasma from affected and unaffected members of the kindred, and we analyzed the relation of plasma PMA to indices of activity of parathyroid, pancreatic islet, and anterior pituitary tissue. Plasma PMA was higher in members expressing the FMEN1 gene than in their unaffected first, second, third, or fourth degree relatives (P less than 0.05), and 10 of 20 members expressing the FMEN1 gene had plasma PMA above the 95% limit of the control range. Plasma PMA was not dependent on sex or age; the lack of age dependency and the high values in FMEN1 gene carriers suggested that plasma PMA is elevated in some FMEN1 gene carriers very early in life. Plasma PMA in known gene carriers varied significantly with one index of parathyroid function [plasma PMA was 2.5 times higher in the group with than in the group without prior parathyroidectomy (P less than 0.005), an indicator of more severe prior parathyroid disease] and correlated positively, although not significantly so, with indices of pancreatic islet function (serum gastrin by RIA) and anterior pituitary function (serum PRL by RIA). In summary, (1) plasma PMA levels are high in many known carriers of the FMEN1 gene, (2) the high plasma PMA levels in FMEN1 may precede overt endocrine hyperfunction; and (3) high plasma PMA levels vary with one index of parathyroid function, but do not correlate with indices of pancreatic islet or anterior pituitary function in members expressing the FMEN1 gene. The high plasma PMA levels in FMEN1 may be the direct cause of hyperfunction of the parathyroids, but the relation of high plasma PMA to hyperfunction of the pancreatic islets and anterior pituitary is uncertain.

Aging↗
PubMed1988

Prospective analysis of intraoperative and postoperative urinary cyclic adenosine 3',5'-monophosphate levels to predict outcome of patients undergoing reoperations for primary hyperparathyroidism.

Twenty-five consecutive patients with either persistent or recurrent symptomatic primary hyperparathyroidism after 36 prior operations were prospectively studied to compare the usefulness of intraoperative measurement of urinary cyclic adenosine monophosphate (UcAMP) levels with standard surgical procedures to predict outcome during tedious parathyroid reoperations. The criterion based on UcAMP to predict successful outcome was a 50% decline in intraoperative UcAMP levels from the median baseline level after removal of abnormal parathyroid tissue. Standard surgical criteria were resection of four abnormal glands for hyperplasia and resection of one abnormal gland and biopsy examination of one normal gland for adenoma. In 15 patients (60%) surgery was terminated on the basis of UcAMP criterion. In one patient elevated UcAMP levels never changed and correctly predicted unsuccessful surgery. In nine patients surgery was terminated on the basis of surgical criteria, and each of these patients had a successful outcome. Operative UcAMP levels dropped after the completion of the procedure in six of these latter nine patients. Three patients did not show a significant decrease in UcAMP levels despite successful surgery, and one patient displayed an early false-positive decrease in UcAMP level. The intraoperative UcAMP criterion accurately predicted outcome in 21 of 25 patients (84%). Sensitivity of the UcAMP criterion was 87% and specificity was 50%. The results indicate that by either method a reliable prediction of the outcome of reoperative parathyroid surgery may be made. Intraoperative determination of UcAMP levels will allow successful termination of the reoperation in some patients before operative identification of adequate parathyroid tissue necessary to confidently establish the pathologic diagnosis.

Cyclic AMP↗
PubMed1987

Localization of parathyroid adenomas in patients who have undergone surgery. Part I. Noninvasive imaging methods.

The authors evaluated computed tomography (CT), ultrasound (US), technetium/thallium scintigraphy, and magnetic resonance (MR) imaging as localization procedures in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. CT had the highest overall sensitivity (47%), followed by US (36%) and scintigraphy (27%). There is still too little data to assess MR imaging. Adenoma size affected the sensitivity of CT, scintigraphy, and MR imaging but not US. When all three studies were used, at least one study depicted a lesion in 78% of patients, but definitive localization (two positive studies) was achieved in only 31%.

Adenoma↗
PubMed1987

Localization of parathyroid adenomas in patients who have undergone surgery. Part II. Invasive procedures.

The authors studied intraarterial digital subtraction angiography (DSA), conventional selective angiography, parathyroid venous sampling (PVS), and intraoperative ultrasound (US) as localization procedures for parathyroid adenomas in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. PVS had the highest overall sensitivity as a single study (80%), followed by intraoperative US (78%), angiography (60%), and DSA (49%). Invasive procedures permitted successful localization of adenomas in 41 of 43 patients studied (95%). False-positive studies were uncommon. The optimum sequence of invasive localization procedures is determined by clinical factors and not by the sensitivity of individual tests. The authors recommend DSA be performed first, followed by angiography, PVS, and intraoperative US, in that order.

Adenoma↗
PubMed1987

Angiographic ablation of parathyroid adenomas: lessons from a 10-year experience.

Angiographic ablation of parathyroid adenomas with ionic contrast material was performed in 24 patients with persistent hyperparathyroidism who had undergone at least one prior unsuccessful surgical resection; 23 had mediastinal adenomas. The success rate was 83% at 1 month after ablation and 71% at both 5 and 9 years. Ablation was successful in 85% of the patients in whom the catheter could be wedged into the artery feeding the adenoma. Long-term success was achieved in 89% of the patients in whom contrast enhancement persisted in the adenoma on computed tomographic scans obtained 24 hours later. Acute complications were seen only in patients with glands supplied by the inferior or superior thyroid arteries. Long-term complications were limited to permanent hypocalcemia, present in 8% of patients. Even if unsuccessful for ablation, the procedure may provide localization and does not preclude surgical resection. It is recommended for most patients with persistent hyperparathyroidism and mediastinal adenomas, especially adenomas supplied by the internal thoracic artery.

Adenoma↗