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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

At least 289 records · Page 16Linked to original sources
PubMed1985

Serum and lymphocyte, aluminum and nickel in chronic renal failure.

In the past decade, aluminum has been recognized as a toxic metal in patients with chronic renal failure. It is, however, possible that other trace metals, such as nickel, may also have toxic actions in these patients. The plasma concentration of a metal, such as aluminum or nickel, may not provide a valid index of either tissue content or total body burden. In the study reported here, the aluminum and nickel content of lymphocytes was measured and compared with plasma concentrations in normal controls and patients with chronic renal failure. The findings suggest that lymphocytes may be of value as a nucleated 'tissue' for the assessment of trace metal status.

Adult↗
PubMed1985

Platelet-derived growth factor: its potential roles in wound healing, atherosclerosis, neoplasia, and growth and development.

Platelet-derived growth factor (PDGF) has been found to be derived not only from platelets that have been induced to release their contents, but also from a number of transformed cells (including cells transformed by both DNA and RNA viruses, spontaneous transformation, and cells from various human tumours), from activated macrophages, from embryonic rat aortic smooth muscle cells, and from rat aortic smooth muscle cells derived from experimentally induced intimal proliferative lesions. The studies discussed demonstrate the potential role of platelets and macrophages in atherosclerosis and in wound repair, and indicate the ability of anti-PDGF IgG to inhibit proliferative responses in vitro. With the demonstration that the transforming protein derived from the oncogene from the simian sarcoma virus is highly homologous with PDGF, it was possible to show that a number of transformed cells secrete PDGF and show markedly decreased binding of PDGF. The same is true for embryonic rat aortic smooth muscle cells and for cells from experimentally induced proliferative lesions in the rat carotid artery. All these findings point to the role of PDGF in the formation of these lesions and can be correlated with the capacity of the cells noted above, as well as injured endothelial cells, to secrete PDGF or PDGF-like molecules. The biological significance of these observations is discussed and a model for atherogenesis is proposed.

Animals↗
PubMed1985

Analysis of the mitogenic effect of fetuin preparations on arterial smooth muscle cells: the role of contaminant platelet-derived growth factor.

Fetuin, a major protein of fetal calf serum, partially purified by the method of Pedersen, stimulated growth of aortic smooth muscle cells. More highly purified fetuin preparations stimulated growth less than Pedersen fetuin, as previously described for other cell types, suggesting that this activity is due to a contaminant. Recently bovine alpha 2-macroglobulin or "Embryonin" has been proposed as the mitogenic component of crude fetuin preparations. We found that active fetuin preparations did contain alpha 2-macroglobulin that stimulated smooth muscle cell growth. However, alpha 2-macroglobulin purified directly from platelet-poor bovine plasma or fetuin purified from Pedersen fetuin by gel filtration lacked appreciable mitogenic effect on smooth muscle cells. Since alpha 2-macroglobulin can bind platelet-derived growth factor (PDGF), and since highly acidic fetuin might bind the very basic PDGF molecule non-specifically, we measured the PDGF content of various fetuin preparations and found a good correlation between the PDGF content and mitogenic activity. Gel filtration experiments demonstrated that in Pedersen fetuin PDGF occurred both free, and in association with alpha 2-macroglobulin. We conclude that the principal mitogenic component for smooth muscle cells in crude fetuin preparations is PDGF, since purified bovine alpha 2-macroglobulin or fetuin do not appreciably affect growth of these cells. These results help to resolve a long-standing controversy regarding the nutrition of cultured cells. In addition, we suggest that before alpha 2-macroglobulin or "Embryonin" is accepted as a bona fide growth factor for a given cell type, the role of contamination with PDGF should be assessed.

Animals↗
PubMed1985

A significant part of macrophage-derived growth factor consists of at least two forms of PDGF.

The macrophage has been suggested to be responsible for the connective tissue cell proliferation that accompanies most chronic inflammatory responses. One of the secretory products of activated macrophages is MDGF, a growth factor (or factors) for fibroblasts, 3T3 cells, smooth muscle, and vascular endothelium. This report demonstrates that a significant portion of the mitogenic activity for 3T3 cells secreted by cultured human alveolar and peritoneal macrophages is due to a molecule (or molecules) similar to platelet-derived growth factor (PDGF). Two size classes (approximately 37,000-39,000 and 12,000-17,000 daltons) of mitogenically active PDGF-like molecules are detected by two criteria--antigenic similarity with PDGF and ability to compete with 125I-PDGF for high-affinity binding to the PDGF receptor. The presence of mRNA for the B chain of PDGF is demonstrated by Northern analysis, and de novo synthesis of these molecules by activated macrophages is shown by immunoprecipitation of 35S-labeled proteins with anti-PDGF IgG.

Animals↗
PubMed1985

Responsiveness of the in vitro hematopoietic microenvironment to platelet-derived growth factor.

The adherent or stromal cells in human long-term marrow cultures, a possible in vitro counterpart of the in vivo microenvironment, were investigated for responsiveness to platelet-derived growth factor (PDGF). Many stromal cells from cultures derived from normal donors as well as from patients with chronic myelogenous leukemia, bore receptors to PDGF and were stimulated to incorporate [3H]-thymidine by highly purified PDGF and to a lesser extent by epidermal growth factor (EGF). These data suggest that PDGF and perhaps EGF may be involved in the regulation of the in vitro microenvironment and, therefore, of normal and possibly neoplastic hematopoiesis.

Autoradiography↗
PubMed1985

Effects of acute and chronic treatment with glucocorticoids on the intestinal absorption of calcium and phosphate and on plasma 1,25-dihydroxyvitamin D levels in pigs.

We have used young pigs, each prepared surgically with a Thiry-Vella loop of proximal small intestine, to study the time course of changes in the intestinal absorption of calcium, phosphate, sodium, glucose and water and on the plasma levels of 1,25-dihydroxyvitamin D after treatment of the animals with glucocorticoids. Perfusion of the intestinal loop for 6 h with a solution containing hydrocortisone or beta-methasone was without effect on the absorption of calcium or phosphate. The oral administration of betamethasone stimulated the absorption of calcium and phosphate by 15-20% for 2-3 days before the trend was reversed and absorption was progressively reduced. Chronic treatment with betamethasone inhibited only the active component of calcium and phosphate absorption. Treatment with betamethasone was associated with a sustained 25-50% increase, to a maximum by 2 days, in the absorption of sodium, glucose and water. Plasma levels of 1,25-dihydroxyvitamin D were reduced within 2 days of the start of treatment and reached a minimum (40-50% decrease) in 4-6 days. We conclude that the initial stimulation of calcium and phosphate absorption is caused by the increased absorption of water. The long-term decrease in absorption may not be caused solely by the decreased circulating levels of 1,25-dihydroxyvitamin D since absorption continued to fall for several weeks after 1,25-dihydroxyvitamin D levels had reached a minimum.

Animals↗
PubMed1985

Effect of dietary calcium and phosphorus depletion on vitamin D metabolism and calcium binding protein in the growing pig.

Twenty-four young pigs were divided into three groups and each fed a replete, low calcium (Ca) or low phosphorus (P) diet. It was found that the deficient diets induced rises in renal 25 hydroxy-vitamin D 1,hydroxylase (1-hydroxylase) activity, circulating 1,25 dihydroxy-vitamin D3 (1,25 (OH)2-D3) and Ca binding protein (CaBP) and intestinal 1,25(OH)2D3 and CaBP. All these rises were statistically significant in the low Ca group but only the rises in the 1-hydroxylase activity and intestinal 1,25(OH)2D3 were significant in the low P group. A high degree of correlation existed between the parameters. There was no enhancement of intestinal 1,25(OH)2D3 or CaBP concentration relative to the 1-hydroxylase activity in the low P pigs as occurs in the chick. The low-P-induced rise in 1-hydroxylase activity was independent of parathyroid hormone.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1985

Platelets, platelet-derived growth factor, growth control, and their interactions with the vascular wall.

The response-to-injury hypothesis of atherosclerosis describes how risk factors associated with atherogenesis may alter endothelial function, creating opportunities for endothelial cell separation and interactions with blood monocyte/macrophages and platelets that result in the intimal proliferative smooth-muscle lesions of atherosclerosis. Growth factors derived from platelets (platelet-derived growth factor) and macrophages (macrophage-derived growth factor) are described and their possible role in atherogenesis is presented. Possible approaches for the prevention of atherosclerosis include the development of means of interfering with the activity of these growth factors.

Animals↗
PubMed1985

The effect of dopamine agonist therapy on large functionless pituitary tumours.

Fifteen patients (12 male) with large pituitary tumours and serum prolactin levels below 1000 mU/l were given dopamine agonist therapy (bromocriptine, mesulergine or pergolide) for a mean of 9 months (range 3-36 months). Serum prolactin became undetectable in all. Despite this, significant suprasellar extensions and any associated neurological defect remained in 14 patients, who therefore were referred for surgery. In one patient there was evidence of spontaneous pituitary infarction unrelated to dopamine agonist therapy. At operation 12 patients had apparently functionless pituitary adenomas which failed to immunostain for prolactin, one had an epidermoid cyst and one a Rathke's pouch cyst. We conclude that patients with large pituitary tumours and only a mildly elevated serum prolactin are unlikely to have prolactinomas, and that such tumours are not likely to show significant tumour shrinkage with medical treatment with dopamine agonists.

Adenoma, Chromophobe↗
PubMed1985

Locally acting growth factors for vascular smooth muscle cells: endogenous synthesis and release from platelets.

Release of platelet-derived growth factor (PDGF) from platelets has been postulated to stimulate at least some of the cell proliferation seen at sites of tissue damage, both beneficially (wound healing) and perniciously (during formation of atherosclerotic lesions). Two other growth factors have been localized to the platelet: epidermal growth factor and transforming growth factor. These factors may function synergistically with PDGF in promoting smooth muscle cell proliferation in the injured vessel wall. PDGF-like molecules (PDGF-c) that bind to the PDGF receptor and are at least partially recognized by antiserum against PDGF may also be synthesized by vessel wall cells themselves under certain circumstances. Arterial endothelial cells secrete several mitogens, one of which is a PDGF-c. Release is greatly stimulated by exposure of the cells to physiologic concentrations of thrombin. Also, aortic smooth muscle cells from 2-week-old rats secrete mitogenic levels of PDGF-c. In this case, PDGF-c accounts for all the mitogenic activity in conditioned medium (when assayed on 3T3 cells). Smooth muscle cells obtained from adult rat aortae secrete 150-fold less PDGF-c. In a third example, when adult rat carotid arteries are damaged with a balloon catheter, smooth muscle cells migrate into the intima of the artery and proliferate. By 2 weeks, the number of smooth muscle cells in the artery has doubled. When these intimal smooth muscle cells are cultured, they are found to secrete PDGF-c. These findings suggest that activation of endogenous synthesis of PDGF-c may contribute to the smooth muscle cell proliferation seen in response to vascular injury.

Animals↗
PubMed1985

Human platelet-derived growth factor stimulates prostaglandin synthesis by activation and by rapid de novo synthesis of cyclooxygenase.

Human platelet-derived growth factor (PDGF) stimulated prostaglandin (PG) E2 synthesis in the cell cycle of Swiss 3T3 cells at two distinct time intervals, with a first plateau within 10 min and a second plateau within 2-4 h after addition of PDGF. At 4 h, the concentration of PGE2 in PDGF-stimulated cultures exceeded the quiescent control cells by a factor of 10-15. Quiescent cells incubated with up to 16 microM exogenous arachidonic acid (AA) synthesized only small amounts of PGE2. In contrast, 4 h after addition of PDGF, the concentration of PGE2 synthesized from exogenous AA exceeded that in quiescent cultures by a factor of 28. The effect of PDGF stimulation on PG synthesis from exogenous AA could not be explained by growth factor-mediated increase in the cellular free AA pool as shown in experiments using [14C]AA. PDGF also stimulated synthesis of PGI2 (prostacyclin), thromboxane, and PGF2 alpha from exogenous AA. While inhibition of protein synthesis by 10 micrograms/ml cycloheximide had no effect on the early increase in PGE2 synthesis, the second increase was completely prevented. Additionally, cycloheximide treatment at 6 h after PDGF stimulation resulted in rapid decline of PGE2 synthesis from exogenous AA. Quiescent cultures pretreated with 100 microM aspirin and stimulated by PDGF thereafter recovered from cyclooxygenase inhibition within 180 min. Our results suggest that phospholipase activation and resultant AA release is not sufficient to induce the burst of PG synthesis observed in PDGF-stimulated cells. Instead, PDGF stimulates PG synthesis by direct effects on the PG-synthesizing enzyme system, one involving a protein synthesis-independent mechanism and another that requires rapid translation of cyclooxygenase.

Arachidonic Acid↗
PubMed1985

Platelet-derived growth factor enhances in vitro erythropoiesis via stimulation of mesenchymal cells.

The growth of erythroid colonies (from erythroid colony-forming cells) and erythroid bursts (from burst-forming cells [BFU-E]) is enhanced in the presence of serum as compared with plasma. A significant proportion of the enhanced growth is due to the platelet release product, platelet-derived growth factor (PDGF). Colony growth in cultures of whole marrow cells in platelet-poor plasma-derived serum (PDS) and erythropoietin was enhanced in a dose-dependent fashion by increasing concentrations of purified human PDGF with optimal enhancement at 12.5 ng/ml. However, no effect of platelet-release products or PDGF was observed on nonadherent human marrow cells or peripheral blood BFU-E, suggesting that an accessory cell population was required for the effect of PDGF on hematopoietic progenitors. In a two-layer culture system, pure populations of fibroblasts or smooth muscle cells, known to be present in the marrow microenvironment, restored the response of nonadherent marrow cells in the overlayer to PDGF and also conferred responsiveness to peripheral blood BFU-E. Endothelial cells in the two-layer culture system and macrophages, in contrast, lacked the ability to restore the enhancing effect of PDGF. Because other platelet-release mitogenic products are also found in serum, a monospecific anti-PDGF IgG preparation was added to cultures grown in platelet rich plasma-derived serum. Only partial reduction in colony and burst growth was seen, suggesting that other platelet-release products were acting in this system. These results demonstrate that PDGF enhancement of human hematopoietic progenitor cell growth requires mesenchymal cells, and provide an example and mechanism by which growth factors may influence hematopoietic progenitors via cells of the marrow microenvironment.

Bone Marrow↗
PubMed1985

Effects of low phosphorus and low calcium diets on the production and metabolic clearance rates of 1,25-dihydroxycholecalciferol in pigs.

Severe dietary calcium (Ca) or phosphorus (P) deficiency leads to a similar degree of stimulation of plasma and intestinal 1,25-dihydroxycholecalciferol (calcitriol) levels and intestinal Ca absorption. In contrast, P depletion causes a much smaller increase in the renal 25-hydroxycholecalciferol-1-hydroxylase enzyme activity than does Ca depletion. To test the hypothesis that a reduced metabolic clearance rate (MCR) during P depletion might, in part, account for the observed increase in calcitriol levels, we have developed a simple primed-infusion technique to determine the MCR and production rate (PR) of calcitriol, in vivo, in pigs fed low Ca and low P diets. The MCR of calcitriol was unchanged (0.92 ml/min per kg metabolic body size (MBS)) when low P diets were fed, but showed a significant 15% increase (1.06 ml/min per kg MBS) during the feeding of low Ca diets. The PR of calcitriol increased by 2.3-fold when low P diets were fed and by fourfold during Ca depletion. Thus the increase in plasma calcitriol levels during P depletion of pigs is caused by an increase in production rather than a decrease in clearance. In contrast, Ca depletion is associated with a slightly higher PR than indicated by measurement of plasma calcitriol levels because of the increased MCR.

Animals↗