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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

483 records · Page 27Linked to original sources
PubMedDate not supplied

Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.

Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied in chronic, diet-induced hypercholesterolemia in a series of nonhuman primates. Within 12 days of hypercholesterolemia in Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipid-laden macrophages (foam cells). Within a month, a "serofibrinous insudate" formed together with variable numbers of subendothelial lipid-laden macrophages. By the second month, foam cells increased in number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the intima and participate in the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemia, endothelial cell continuity over the lipid-laden macrophages became interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed in whole blood smears, suggesting that many of the lipid-laden macrophages leave the intima and enter the circulation. After 4 months, significant endothelial denudation was found in the iliac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemia centered around the monocyte-macrophage and its interaction with endothelium in the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle interactions, platelet-macrophage interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferative lesions.

Animals↗
PubMedDate not supplied

Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque.

This report presents the second portion of the morphologic studies on chronic, diet-induced hypercholesterolemia in nonhuman primates (Macaca nemestrina) examined sequentially between 5 and 13 months. A direct relationship was observed between the rate of cholesterol increase, the level and duration of hypercholesterolemia, and the changes in the artery wall that led to the formation of fatty streaks and their conversion to fibrous plaques. A loss of endothelial continuity was first observed in the iliac arteries between 3 and 4 months of atherogenic diet and appears to be a critical step in the conversion of many fatty streaks to fibrous plaques. With breaks in endothelial junctions and exposure of some of the macrophages in a fatty streak, many of the lipid-filled macrophages appeared to detach and enter the circulation. The number of circulating foam cells increased precipitously between 3 and 4 months, the time when increased sites of endothelial dysjunction and macrophage egress were observed. Exposure of subendothelial macrophages also permitted adherence of platelets to these macrophages and to exposed connective tissue. Fibrous plaques were found at similar anatomic sites where endothelial denudation had been observed at earlier time points but were more prevalent in the abdominal aorta and iliac arteries. These changes subsequently occurred at every level of the aortic tree and appeared to progress in a cephalad fashion with increasing rate, level, and duration of hypercholesterolemia. The results of these studies stress the importance of following cholesterol levels of each animal throughout the entire period of the study and of sampling the entire arterial tree at every level with time. This helped us to understand the complicated interrelationships between the various cells in atherogenesis, provided further support for the "Response to Injury Hypothesis of Atherosclerosis," and helped to explain how hypercholesterolemia may be involved in the different stages of atherogenesis in nonhuman primates and possibly in humans.

Animals↗
PubMedDate not supplied

Immunocytochemical analysis of cellular components in atherosclerotic lesions. Use of monoclonal antibodies with the Watanabe and fat-fed rabbit.

We have performed immunocytochemical investigations into the distribution of smooth muscle cells and macrophages in the atherosclerotic lesions of the Watanabe heritable hyperlipidemic (WHHL) and fat-fed rabbits. We used monoclonal antibodies specific for muscle cells and macrophages, the latter with a new macrophage-specific monoclonal antibody designated RAM11. Scattered macrophages were observed in the subendothelium in areas of grossly normal aorta. Raised lesions were divided into four major groups, based on qualitative aspects of cell localization: fatty streak, composed predominantly of macrophages; intimal thickening, composed predominantly of smooth muscle cells that displayed considerable morphological heterogeneity with an admixture of macrophages; early fibrous plaques, characterized by approximately equal numbers of smooth muscle cells and macrophages; advanced fibrous plaques, composed of a fibrous cap containing flat smooth muscle cells overlying a macrophage-rich zone of atheromatous debris. These studies demonstrate the nature of the lesions in the two rabbit models and the usefulness of monoclonal antibodies in analyzing the cellular composition of atherosclerotic lesions.

Animals↗
PubMedDate not supplied

Fatty streak expansion and maturation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits.

This study focuses on the expansion and maturation of the fatty streak in the aorta of Watanabe Heritable Hyperlipemic rabbits and comparably hypercholesterolemic fat-fed rabbits between 2 and 6 months duration of hypercholesterolemia. In both groups of animals, the fatty streaks expanded due to: 1) the formation of multiple layers of a mixed population of macrophage-derived foam cells and lipid-containing smooth muscle cells, 2) the hypertrophy of the macrophage-derived foam cells, 3) the continued accumulation of extracellular matrix, 4) the insudation of plasma components. Immunocytochemical studies utilizing macrophage-specific and muscle-actin-specific monoclonal antibodies indicated that the expanding and mature fatty streaks in both the Watanabe and fat-fed rabbits were primarily composed of macrophage-derived foam cells. Hypertrophy of those foam cells situated immediately beneath the endothelium was associated with retraction of the endothelium and exposure of the intimal foam cells to the circulation. Endothelial retraction with exposure of intimal foam cells may facilitate entry of blood cells and lipoproteins into the lesions and formation of mural thrombi on the surfaces of the exposed cells. Biochemical analyses of the cholesterol content of the arteries indicated that both unesterified cholesterol and cholesteryl esters were deposited to a comparable degree in both the Watanabe and fat-fed rabbits. Thus, the absence of the low density lipoprotein receptor in Watanabe rabbits does not appear to directly influence the accumulation of cholesterol in the artery wall.

Animals↗
PubMedDate not supplied

Fatty streak initiation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits.

Morphologic and immunocytochemical studies were conducted to determine the sequence of cellular interactions that occur during the initiation of the fatty streak in the aorta of Watanabe Heritable Hyperlipemic rabbits and comparably hypercholesterolemic fat-fed rabbits. Watanabe rabbits from 3.5 weeks gestation to 2 months of age and fat-fed rabbits from 1 week to 2 months duration of hypercholesterolemia were compared utilizing light microscopic and scanning and transmission microscopic techniques. In both groups of animals, the earliest detectable events were an increase in monocyte adherence and subendothelial migration followed by formation of a single layer of intimal macrophage-derived foam cells. Immunocytochemical studies using macrophage-specific and muscle-actin-specific monoclonal antibodies support the morphologic data which suggests that the early fatty streak in both the Watanabe and fat-fed rabbits is predominantly composed of macrophage-derived foam cells. Thus, the absence of functional low density lipoprotein receptors in the Watanabe rabbit and differences in the distribution of cholesterol among the lipoproteins in the Watanabe and fat-fed rabbits do not appear to alter the initial responses of the cells of the artery wall to chronic hypercholesterolemia.

Animals↗
PubMedDate not supplied

Lipid composition of aorta of Watanabe heritable hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Plasma lipid composition determines aortic lipid composition of hypercholesterolemic rabbits.

Aortic and plasma lipid compositions were compared during a 12-month period in Watanabe heritable hyperlipemic (WHHL), comparably hypercholesterolemic fat-fed, and age-matched control normolipidemic rabbits to determine whether exposure to equivalent degrees of endogenous or exogenous hypercholesterolemia led to differences in the composition and concentration of lipids deposited in the artery wall. Although there were marked differences in the distribution of cholesterol among the lipoproteins in the WHHL versus the fat-fed rabbits, the contents of both free and esterified cholesterol were elevated to an equivalent degree in the aorta and plasma. In contrast, the triglyceride content of both the plasma and aorta were elevated only in the WHHL rabbits. However, aortic total phospholipids were increased in both the WHHL and fat-fed animals as compared to control rabbits. In the control rabbits, there was an age-dependent enrichment in aortic relative to plasma cholesteryl-oleate consistent with low density lipoprotein (LDL) receptor-directed intracellular cholesteryl ester processing. In contrast, enrichment in cholesteryl-oleate in aortae relative to plasma was not detected in either WHHL or fat-fed groups, suggesting that the plasma cholesteryl ester composition was the primary determinant of the aortic cholesterol composition. Thus, during chronic hypercholesterolemia, deposition of lipids in the artery wall appears to be determined by plasma lipoprotein levels and composition if the LDL receptor is either absent on a genetic basis or suppressed due to a high-fat, high-cholesterol diet.

Animals↗
PubMedDate not supplied

Responses of the stenosed and contralateral kidneys to [Sar1, Thr8] AII in human renovascular hypertension.

To better define the intrarenal hemodynamic effects of angiotensin in human renovascular hypertension, 10 patients underwent renal hemodynamic and functional measurements before and during infusion of a competitive angiotensin analog, [Sar1, Thr8] AII. Eight had technically satisfactory split function studies. Despite a fall in mean arterial pressure (132 +/- 6 to 121 +/- 6 mm Hg, p less than 0.05) and humoral changes consistent with angiotensin-mediated hypertension, the intrarenal effects of this analog were commonly those of an angiotensin agonist, producing vasoconstriction and sodium retention. This was quantitatively greatest in the contralateral kidney, whose preinfusion sodium excretion (86 +/- 30 microEq/min vs 25 +/- 9 microEq/min, p less than 0.02) and glomerular filtration rate (76 +/- 7 ml/min vs 41 +/- 7 ml/min, p less than 0.01) were higher than the stenotic kidney. In some cases, an increase in renal blood flow and rise in sodium excretion were evident during angiotensin blockade, suggesting a tonic intrarenal action of angiotensin. Although renin vein renin values differed markedly between the stenotic and contralateral kidney (ratio = 2.05 +/- 0.30), relative changes in effective renal plasma flow were correlated (r = 0.84: p less than 0.01) during infusion of this analog. These results underscore the differences in sensitivities between vascular beds to the effects of angiotensin II and the major role of the contralateral kidney in renal function and sodium homeostasis in human renovascular hypertension.

Adult↗
PubMedDate not supplied

Bioimpedance analysis: potential for measuring lower limb skeletal muscle mass.

BACKGROUND: Ambulation, balance, and lower extremity bone mass and strength are all partially dependent on lower limb skeletal muscle mass. At present, both research and clinical methods of evaluating lower limb skeletal muscle mass as a component of nutrition assessment are limited. One potential simple and inexpensive method is lower extremity bioimpedance analysis (BIA). The present study had two objectives: to examine the determinants of lower limb resistance, with the underlying hypothesis that fluid-containing muscle is the main electrical conductor of the lower limbs; and to establish if a correlation of equivalent magnitude and similar covariates is observed when height squared (H2) is used instead of lower limb length squared (L2) in multiple regression models relating resistance to independent variables. METHODS: Lower limb resistance was measured using a contact-electrode BIA system, and lower limb fat and skeletal muscle were estimated by dual-energy x-ray absorptiometry in healthy adults. A physical BIA model was developed in the form of a regression equation with path-length (as L2 and H2)-adjusted resistance as dependent variables and lower limb skeletal muscle, fat, age, and gender as potential independent variables. RESULTS: There were 94 subjects, 34 men and 60 women, with a mean (-/+SD) age of 41.5+/-17.8 years. Strong associations were observed between L2/resistance and lower limb skeletal muscle, although for both men and women, age entered into the model as a significant covariate (total R2, men = .79 and women = .72; both p < .001). Similar models were observed with H2/resistance as dependent variable. Additional analyses showed a significantly lower resistance in lower limb skeletal muscle and height-matched old vs young subjects. CONCLUSIONS: Strong associations exist between measured lower limb resistance and lower limb muscle mass, adjusting for electrical path length either by L2 or H2. These observations suggest the potential of predicting skeletal muscle using BIA-measured lower limb resistance adjusted for stature. Age is also an independent variable in lower limb resistance-skeletal muscle associations, suggesting the need to establish underlying mechanisms of age-related resistance effects and to consider subject age when developing BIA prediction models.

Absorptiometry, Photon↗
PubMedDate not supplied

The impact of mastectomy on self-concept and social function: a combined cross-sectional and longitudinal study with comparison groups.

Self-concept and social function following radical, modified radical or simple mastectomy for Stage I or II breast cancer, breast biopsy for benign breast disease, cholecystectomy or no operative procedure were measured across a fifteen-month period in a cross-sectional design and across a twelve-month period in a repeated measures design. Women selected for study were without other preexisting mental or physical illness. The degree of disability observed following mastectomy was considerably less than previously reported in uncontrolled studies, with the incidence of actual disturbance extremely small. Women receiving adjuvant therapies following mastectomy, but not women treated by mastectomy alone, reported significantly more body-image dissatisfaction and feminine self-image concerns than the comparison groups. The findings refute previously published impressions of severe psychosocial maladjustments following mastectomy. The study suggests that post-mastectomy women vulnerable to poorer outcome would be those with lower expectations of good quality social support, other present life stressors, other pre-existing chronic diseases, and a disposition to believe in life outcomes as less under their own control.

Adult↗
PubMedDate not supplied

Financial incentives and drug spending in managed care.

This study estimates the impact of patient financial incentives on the use and cost of prescription drugs in the context of differing physician payment mechanisms. A large data set was developed that covers persons in managed care who pay varying levels of cost sharing and whose physicians are compensated under two different models: independent practice association (IPA)-model and network-model health maintenance organizations (HMOs). Our results indicate that higher patient copayments for prescription drugs are associated with lower drug spending in IPA models (in which physicians are not at risk for drug costs) but have little effect in network models (in which physicians bear financial risk for all prescribing behavior).

Adult↗
PubMedDate not supplied

Vascular cell adhesion molecule-1 is induced on endothelium during acute rejection in human cardiac allografts.

An infiltration of mononuclear leukocytes into the myocardium of a cardiac allograft is diagnostic of transplant rejection. The presence of these leukocytes implies their adhesion to, and subsequent migration through, the vascular endothelium. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are endothelial proteins that have been shown to be involved in the binding of mononuclear leukocytes to the endothelium in vitro. We investigated the induction of these proteins in a random series from 99 endomyocardial biopsy specimens obtained from 1 week to 4 years after cardiac allograft transplantation. Intercellular adhesion molecule-1 was found to be expressed constitutively by the myocardial microvasculature in the recipient's original heart and in the posttransplantation biopsy specimens. No correlation was found between the presence or absence of intercellular adhesion molecule-1 expression and cellular rejection. In contrast, no endothelial expression of vascular cell adhesion molecule-1 was observed in the recipient heart or in endomyocardial biopsy specimens lacking cellular rejection. The presence of vascular cell adhesion molecule-1 significantly correlated with the presence of mild or moderate rejection. The de novo induction of vascular cell adhesion molecule-1 on the myocardial vasculature during periods of rejection, in addition to the recruitment of mononuclear leukocytes that are known to bind to this protein, suggests that the expression of this endothelial adhesion protein could be of use in diagnosing rejection.

Antigens, CD↗
PubMedDate not supplied

A comparison of two response-reinforcement methods in pure-tone testing of the retarded.

The purpose of this study was to determine whether a visual reward method or play audiometry is a better motivator in eliciting the lowest possible pure-tone thresholds from a group of Down's syndrome adults. Thresholds were obtained at 250, 500, 2000, 4000, and 6000 Hz for both procedures using a modified ascending method. The method of testing was constructed such that each of the two procedures served as a comparison for validity of the other. The level of significant difference between the play audiometry and the visual reward method was determined using the Sign Test. In each case, there appeared to be a significant difference between the two tests, but the difference was attributed to the order of administration of the tests and practice rather than by the tests themselves. The data obtained suggests that more accurate auditory thresholds may be determined by administering two pure-tone tests and accepting the second as most valid.

Adolescent↗
PubMedDate not supplied

Linking age-related changes in skeletal muscle mass and composition with metabolism and disease.

Skeletal muscle (SM) plays a central role in many biological functions, such as movement and metabolism, and alterations in SM mass and composition can have a marked influence on health and disease. The purpose of this review was to examine and characterize age-related changes in SM mass and composition and to link these changes to corresponding changes in metabolism and disease. It can be concluded from several studies that SM mass decreases with advancing age in both men and women. The age-related reduction in SM, also known as sarcopenia, is related to a corresponding reduction in SM strength, and if left untreated, sarcopenia may lead to functional impairment and physical disability. An emerging body of evidence also suggests that age-related changes in the composition of SM, particularly the accumulation of lipids within SM fibers, may lead to metabolic disorders such as insulin resistance.

Activities of Daily Living↗