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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

At least 181 records · Page 10Linked to original sources
PubMed1992

Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells in culture, is expressed in vivo in a variety of inflammatory conditions associated with cell proliferation, including atherosclerosis, wound repair, pulmonary fibrosis, and glomerulonephritis. However, it is not known if PDGF mediates the fibroproliferative responses that characterize these inflammatory disorders. We administered neutralizing anti-PDGF IgG or control IgG to rats with mesangial proliferative nephritis. Inhibition of PDGF resulted in a significant reduction in mesangial cell proliferation, and largely prevented the increased deposition of extracellular matrix associated with the disease. This suggests that PDGF may have a central role in proliferative glomerular disease.

Animals↗
PubMed1992

The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors.

Interactions among growth factors, cells, and extracellular matrix are critical to the regulation of directed cell migration and proliferation associated with development, wound healing, and pathologic processes. Here we report the association of PDGF-AB and -BB, but not PDGF-AA, with the extracellular glycoprotein SPARC. Complexes of SPARC and 125I-labeled PDGF-BB or -AB were specifically immunoprecipitated by anti-SPARC immunoglobulins. 125I-PDGF-BB and -AB also bound specifically to SPARC that was immobilized on microtiter wells or bound to nitrocellulose after transfer from SDS/polyacrylamide gels. The binding of PDGF-BB to SPARC was pH-dependent; significant binding was detectable only above pH 6.6. The interaction of SPARC with specific dimeric forms of PDGF affected the activity of this mitogen. SPARC inhibited the binding of PDGF-BB and PDGF-AB, but not PDGF-AA, to human dermal fibroblasts in a dose-dependent manner. The expression of SPARC and PDGF was minimal in most normal adult tissues but was increased after injury. Enhanced expression of both PDGF-B chain and SPARC was seen in advanced lesions of atherosclerosis. We suggest that the coordinate expression of SPARC and PDGF-B-containing dimers following vascular injury may regulate the activity of specific dimeric forms of PDGF in vivo.

Animals↗
PubMed1992

Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) II Study.

Global and regional left ventricular performances were evaluated with equilibrium radionuclide angiocardiography in patients in the Thrombolysis in Myocardial Infarction (TIMI) II trial at the time of hospital discharge. Studies at rest were available in 1,162 (69%) of the invasive and 1,150 (69%) of the conservative strategy patients, and exercise studies in 1,133 (67%) of the invasive and 1,145 (69%) of the conservative patients. Repeat studies were performed at the time of 6-week follow-up. Global and regional ejection fraction at rest were both comparable in patients assigned to each of the treatment strategies. However, at the time of hospital discharge patients in the invasive strategy had normal exercise responses more frequently (29.7 vs 25.8% p = 0.01), greater peak exercise LV ejection fraction (54.8 +/- 13.8% vs 53.1 +/- 14.1%, p = 0.004), greater exercise--rest change in LV ejection fraction (3.7 +/- 6.7% vs 2.7 +/- 7.2%, p less than 0.001) and greater peak exercise infarct zone regional ejection fraction (53.2 +/- 31.1% vs 50.3 +/- 33.0%, p less than 0.001) than patients assigned to the conservative strategy. At 6-week follow-up these differences between treatment strategies were no longer evident. When data were restricted to those collected at comparable work loads, similar differences in hospital discharge exercise performance between invasive vs conservative strategy patients were observed. Thus, there is a small transient difference in exercise global and regional LV performance associated with an invasive as opposed to conservative strategy after thrombolytic therapy. These differences are noted at the time of hospital discharge but not at 6 weeks, and are unlikely to confer clinical benefit.

Chi-Square Distribution↗
PubMed1992

The process of atherogenesis--cellular and molecular interaction: from experimental animal models to humans.

Atherogenesis is a disorder of the artery wall that involves: adhesion of monocytes and lymphocytes to the endothelial cell surface; migration of monocytes into the sub-endothelial space and differentiation into macrophages; ingestion of low density lipoproteins and modified or oxidised low density lipoproteins by macrophages by several pathways, including a scavenger pathway, leading to accumulation of cholesterol esters and formation of "foam cells". These foam cells together with T lymphocytes form the fatty streak. Vascular smooth muscle cells migrate from the media into the intima and proliferate with the formation of atherosclerotic plaques. These processes which involve cell adhesion, migration, differentiation, proliferation and cell interaction with the extracellular matrix are regulated by a complex network/cascade of cytokines and growth regulatory peptides. Thus, atherosclerosis may be the result of a specialised chronic inflammatory fibroproliferative process which has become excessive and in its excess this protective response has become the disease state.

Animals↗
PubMed1992

Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences.

The PDGFs are a family of molecules assembled as disulfide-bonded homo- and heterodimers from two distinct but highly homologous polypeptide chains (PDGF-A and PDGF-B). Two PDGF A-chain transcripts, which arise from alternative usage of the 69-bp exon 6 and exon 7, give rise to two forms of PDGF-A. In spite of the conservation of two PDGF A-chain forms over at least 350 million years, no differences in their biological activities have been identified. We have investigated the activity of the sequence encoded by the alternatively spliced exon 6 of the PDGF A-chain (peptide AL). Addition of peptide AL at 10(-5)-10(-9) M to cultured endothelium and smooth muscle induced a dose-dependent, 3-20-fold increase in PDGF in conditioned media within 30 min. Peptide AL had no detectable effect on A- or B-chain transcript levels, and decrease in culture temperature did not prevent rapid release of PDGF. In human umbilical vein endothelial cells treated with peptide AL, the PDGF release was principally PDGF-BB, while in smooth muscle cells it was primarily PDGF-AA. The capacity to induce release of PDGF is shared by the homologous peptide encoded by exon 6 of the B-chain of PDGF. Binding studies and cross-linking analysis are consistent with a charge-based association of exon 6 sequences with membrane- and matrix-associated heparan-sulfate proteoglycans. We hypothesize that translation of exon 6 of the A- or B-chain of PDGF results in compartmentalization of these forms of PDGF with HS-PG, whereas forms lacking this sequence would be soluble and diffuse.

Amino Acid Sequence↗
PubMed1992

Quantification of adipose tissue by MRI: relationship with anthropometric variables.

This study had two objectives: 1) to establish magnetic resonance imaging (MRI) as a tool for measuring total and regional adipose tissue (AT) distribution in humans and 2) to assess the relationship between selected anthropometric variables and MRI-measured AT. Twenty-seven healthy men varying in age [40.8 +/- 14.5 (SD) yr], body mass index (28.5 +/- 4.8), and waist-to-hip ratio (WHR, 0.96 +/- 0.07) participated in the study. Total AT volume was determined using a linear interpolation of AT areas obtained on consecutive slices (n = 41) taken from head to toe (10-mm thickness, 50-mm centers). The mean change for repeated measures of total AT volume was 2.9% (range 0.9-4.3%). Large interindividual differences were observed for total AT volume (6.9-59.3 liters), subcutaneous AT (6.3-49.8 liters), and visceral AT (0.5-8.5 liters). Visceral AT represented 18.3% of the total AT. The single best predictor of total adiposity was waist circumference (R2 = 0.92). For visceral AT volume, WHR was the strongest anthropometric correlate (r = 0.85, P less than 0.01). When controlled for age and adiposity, however, WHR explained only 12% of the variation in absolute visceral AT and less than 1% of the variation in visceral-to-subcutaneous ratio. Age was a better predictor of visceral-to-subcutaneous ratio than level of adiposity or WHR. The results of this study demonstrate that MRI offers a reliable measure of regional and total AT distribution in humans and, thus, is of value as a research tool.

Adipose Tissue↗
PubMed1992

Ontogeny of integumental calcium in relation to surface area and skin water content in the perinatal rat.

Calcium is an important regulator of epidermal differentiation and skin biomechanics in many vertebrate species. In this study, we measured total epidermal calcium in the perinatal Sprague-Dawley rat. Values ranged from 12 to 15 mg per 100 g of tissue. These levels were elevated compared with dermis and other soft (nonbone) organs, including brain, kidney, heart, and liver. Administration of radioactive calcium to the pregnant rat resulted in high rates of 45Ca2+ localization in the fetal epidermis 24 h later. From gestational day 20 to postnatal day 3, the epidermis showed progressive dehydration with water content decreasing from 79 to 73%. Dermal hydration over the same period decreased from 91 to 81%. In the neonatal rat (age 0-3 days), linear regression analysis of surface area vs. body weight on a log-log plot yielded a slope of 1.04. This finding contrasts with an expected slope of 0.67 based on simple surface area-to-volume relationships and differs from the empirical 0.75-power law observed in adult bioenergetics. In summary, these results show the perinatal rat is encapsulated by a continuous differentially hydrated calcium-rich epidermal envelope that increases in surface area over the early postnatal period directly as the first power of body mass.

Animals↗
PubMed1992

Autoradiographic analysis of the distribution of 125I-tyramine-cellobiose-LDL in atherosclerotic lesions of the WHHL rabbit.

It is well established that plasma lipoproteins enter the artery wall and play a role in the atherogenic process. However, it is still unclear where within developing atherosclerotic lesions lipoproteins accumulate and which arterial cells participate in the metabolism of these lipoproteins. For this reason, light and electron microscopic autoradiograms were prepared from sections of lesioned aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits 44 hours after injection of 125I-tyramine cellobiose-low density lipoprotein (TC-LDL). After uptake of 125I-TC-LDL and intracellular degradation of the LDL protein, the nondegradable TC ligand remains trapped and thus demarcates the cells participating in the degradation of LDL. Results of other studies indicate that 48 hours after injection into WHHL rabbits, about one half of the 125I label present in lesions represents accumulated degradation products while the remaining 125I label is present as intact 125I-TC-LDL. The distribution of autoradiographic silver grains was analyzed at low resolution in fatty streaks, transitional lesions, and advanced atheroma. In all cases, the majority of silver grains were associated with superficially located subendothelial macrophage-derived foam cells. In more advanced lesions, labeling was predominant in foam cells situated within the lateral margins of the lesions. Morphometric quantification of the distribution of silver grains in electron photomicrographs of fatty streaks from two young WHHL rabbits strongly supported the data obtained at the light microscopic level. In early fatty streaks from the aortic arch and the thoracic and abdominal aortas, subendothelial macrophage-derived foam cells contained a high proportion of the silver grains (40-60% of the total) and accounted for between 30% and 40% of the lesion volume. In contrast, smooth muscle cells in the lesions contained only 7-10% of the total silver grains and accounted for approximately 20% of the lesion volume. Endothelial cells contained the most silver grains on a per-unit-volume basis by occupying only 1-2% of the lesion volume. However, the endothelium contained less than 5% of the total grains in lesions. The remaining silver grains (25-45%) were associated with the extracellular matrix, which constituted between 40% and 50% of the lesion volume. These data indicate that in the WHHL rabbit, subendothelial macrophage-derived foam cells avidly accumulate and metabolize LDL despite having few functional LDL receptors.

Animals↗
PubMed1992

One-year results of the Thrombolysis in Myocardial Infarction investigation (TIMI) Phase II Trial.

BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial randomized 3,339 patients to either an invasive (INV, n = 1,681) or a conservative (CON, n = 1,658) strategy after intravenous recombinant tissue-type plasminogen activator (rt-PA) for acute myocardial infarction. METHODS AND RESULTS: The patients assigned to the INV strategy routinely underwent cardiac catheterization, and when anatomically appropriate, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting 18-48 hours after infarction. CON patients had these procedures only in response to the occurrence of spontaneous or provoked ischemia. One-year follow-up data are available in 3,316 patients (99.3%). The primary trial end point, death and nonfatal reinfarction, occurred in 14.7% of INV patients and in 15.2% of CON patients (p = NS). When analyzed individually, there was no difference (p = NS) in death (INV, 6.9%; CON, 7.4%) or recurrent infarction (INV, 9.4%; CON, 9.8%) between the two groups. Anginal status at 1 year was also similar. Cardiac catheterization and PTCA were performed more often in INV (98.0% and 61.2%, respectively) compared with CON (45.2% and 20.5%, respectively) patients. At 1 year, the cumulative number of patients who underwent coronary bypass surgery (INV, 17.5%; CON, 17.3%) was similar in the two groups. CONCLUSIONS: The INV and CON strategies resulted in similar favorable outcomes at 1 year of follow-up. In particular, the rates of mortality and reinfarction were not different and were impressively low in both groups. One possible advantage of the INV strategy was detected in subgroup analyses. In patients with a history of myocardial infarction, the data are suggestive that 1-year mortality was lower in INV patients (10.3%) than in CON patients (17.0%) (p = 0.03).

Angioplasty, Balloon, Coronary↗
PubMed1992

Hypocalcemia and pregnancy-induced hypertension produced by maternal fasting.

During pregnancy, maternal calcium needs increase as a result of increasing calcium requirements for fetal bone development. These needs have to be completely supplied by the mother via placental transfer. Several studies link low serum ionized calcium concentrations with the development of hypertension and pregnancy-induced hypertension. We hypothesized that maternal hypocalcemia would develop concomitantly with the development of hypertension in sheep that were fasted in late gestation. Sixteen instrumented ewes were used in the present study. After a 2-day baseline period, food was withdrawn from 10 animals in the experimental group (group 2) for 3 days, whereas the remaining six were allowed to eat and drink normally (group 1). Blood pressure, uteroplacental blood flow, and heart rate were monitored daily. Fasted animals were given deionized water (calcium free) to drink, whereas control animals were given tap water containing 32.9 mg/l calcium concentration. Based on the analysis of the ionized calcium concentration response to fasting, group 2 animals were placed in one of two groups: hypocalcemia did not develop in group 2a, whereas in group 2b the ionized calcium concentration decreased 27% (from 1.09 +/- 0.07 to 0.80 +/- 0.06 mM, p = 0.01) by the third day of fasting. Group 2b responded with a 16% elevation in maternal blood pressure (p = 0.01) and a 43% reduction in uteroplacental blood flow. Furthermore, a positive correlation was found between maternal and fetal blood ionized calcium concentrations (r = 0.860).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of atrial natriuretic peptide and other vasoactive compounds on the uterine vascular bed of the nonpregnant sheep.

It has been reported that atrial natriuretic peptide (ANP) concentrations are elevated in pregnancy and further elevated in pregnancy-induced hypertension. Atrial stretch and volume expansion appear to be important stimuli for ANP release. During normal pregnancy, a striking change in hemodynamics occurs that may increase plasma ANP concentrations. ANP has potent natriuretic, diuretic, and smooth muscle relaxant activities. The biological effects of ANP during pregnancy may play an important role in the physiology and pathophysiology of pregnancy. Because of possible interactions during pregnancy due to secondary effects of maternal cardiovascular changes and physiological adaptation, the present study sought to evaluate and characterize the local effects of atriopeptin II on the uterine vascular bed of the nonpregnant sheep. Ewes with catheters in the femoral artery, femoral vein, and uterine artery and electromagnetic flow probes on the middle uterine arteries were monitored for blood pressure (BP), heart rate (HR), and uterine blood flow before and after the administration into the uterine artery of bolus injections of 2, 4, 20, and 40 x 10(-9) M (5, 10, 50, and 100 micrograms) of the synthetic ANP (atriopeptin II). For comparison purposes, the effects of prostaglandin I2 in doses of 1.2, 2.5, 12, and 25 x 10(-8) M (5, 10, 50, and 100 micrograms), vasoactive intestinal polypeptide in doses of 3, 9, 30, 90, 300, and 900 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms), and bradykinin in doses of 9.4, 28, 94, 280, 940, and 2800 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms) were also tested. Appropriate vehicles were tested and found to be without effect. All four compounds were found to be vasodilators of the nonpregnant uterine vasculature. ANP administered into the uterine artery decreased BP (87 +/- 4 mm Hg to 79 +/- 4 mm Hg with 50 micrograms [20 x 10(-9) M]), increased HR (90 +/- 5 bpm to 105 +/- 4 bpm), and significantly increased uterine blood flow (from 14 +/- 3 to 37 +/- 4 ml/min with a dose of 100 micrograms [40 x 10(-8) M, P < 0.05]). Prostaglandin I2 failed to alter BP, but caused significant increases on HR (100 +/- 4 to 124 +/- 13 bpm, P < 0.05) and uterine blood flow (17 +/- 4 to 73 +/- 10 ml/min, P < 0.05). Vasoactive intestinal polypeptide caused a significant tachycardia (97 +/- 10 to 158 +/- 9 bpm, P < 0.05) at the highest dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Plaque-associated immune reactivity as a tool for the diagnosis and treatment of atherosclerosis.

In summary, we have confirmed that a specific humoral immune reactivity involves human atherosclerotic plaque. By isolating some of the autoantigens and employing them in prototype immunoassays, we have been able to measure for the presence of plaque-specific antibodies. Extracted plaque antigens have also served as immunogens in monoclonal antibody generation. These have shown early promise as plaque-directed in vivo targeting agents. Further scientific evaluation and reagent development remains before the practical utility of employing such reagents or methods in the care of patients with atherosclerosis-related diseases can be ascertained.

Animals↗
PubMed1992

Human atherosclerosis. III. Immunocytochemical analysis of the cell composition of lesions of young adults.

There have been only limited immunocytochemical studies of the cell composition of the early lesions of human atherosclerosis, and none that incorporate a comprehensive panel of antibodies to various cell types and subsets. The authors thus performed a prospective study of 27 lesions from 16 different individuals ranging in age from 15 to 34 years. These were all lesions that appeared grossly as slightly raised, yellow fatty streaks in the posterior ascending aorta, but on histologic examination had varying degrees of round-cell, spindle-cell, and foam-cell accumulation. Using a panel of antibodies, including monoclonal antibodies specific for smooth muscle cells [HHF35], human macrophages [HAM56], endothelial cells [monoclonal antibodies to F. VIII related antigen], lymphocytes [anti-CD45, anti-CD20, anti-CD45RO, anti-T-cell receptor], it was revealed that the predominant cell type in these early lesions was the smooth muscle cell, including the vast majority of the foam cells, which tended to appear in the deeper regions of the lesions. There were variable numbers of smooth muscle cells and lymphocytes; the latter were exclusively T cells. It is concluded that in atherosclerotic lesions of young adults, which may represent various stages of fatty streak formation and advanced fatty streaks, smooth muscle cell accumulation may be an early event.

Adolescent↗
PubMed1991

Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF.

Approximately 30 to 40 percent of atherosclerotic coronary arteries treated by angioplasty or by bypass surgery occlude as a result of restenosis. This restenosis is due principally to the accumulation of neointimal smooth muscle cells, which is also a prominent feature of the advanced lesions of atherosclerosis. The factors responsible for the accumulation of intimal smooth muscle cells have not been identified. Platelet-derived growth factor (PDGF) is a potent smooth muscle chemoattractant and mitogen. It is present in platelets and can be formed by endothelium, smooth muscle, and monocyte-derived macrophages. The development of an intimal lesion in the carotid artery of athymic nude rats induced by intraarterial balloon catheter deendothelialization was inhibited by a polyclonal antibody to PDGF. These data demonstrate that endogenous PDGF is involved in the accumulation of neointimal smooth muscle cells associated with balloon injury and may be involved in restenosis after angioplasty, and perhaps in atherogenesis as well.

Angioplasty, Balloon↗
PubMed1991

Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat.

We investigated whether platelet-derived growth factor (PDGF), or its receptor (PDGF-R), was upregulated in a rat model of mesangial proliferative glomerulonephritis. A marked increase in both PDGF A- and B-chain mRNA could be demonstrated in glomerular RNA by Northern blot analysis 3 and 5 days after disease induction, corresponding to the time of mesangial cell proliferation. PDGF-R beta-subunit mRNA and protein were also increased in glomeruli in mesangial proliferative nephritis, being maximal at day 5. The principal cells expressing PDGF B-chain appeared by immunostaining to be a subpopulation of mesangial cells; in contrast, the majority of the mesangial cells expressed the PDGF-R beta-subunit protein. Both complement depletion and platelet depletion significantly reduced cell proliferation and expression of both PDGF and PDGF-R. Thus, in mesangial proliferative nephritis there is a platelet- and complement-mediated induction of PDGF A and B chain and PDGF-R beta-subunit gene transcription and protein synthesis. The finding that the majority of PDGF is produced by the mesangial cell supports the role of PDGF as an autocrine growth factor in glomerulonephritis.

Animals↗
PubMed1991

The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by human monocyte-derived macrophages.

Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.

Antioxidants↗