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Biomedical subjects

W A Thomas

Publications and source records attributed to W A Thomas.

At least 55 records · Page 3Linked to original sources
PubMed1985

Intimal cell masses in the abdominal aortas of swine fed a low-fat, low-cholesterol diet for up to twelve years of age.

The normal subendothelial intima of large arteries in man, swine and most other species is a variegated structure from birth onwards. In some regions it contains only a few scattered cells; in others there may be a continuous single layer of cells; and in still others the cells pile up to form what we have called intimal cell masses (ICM). The cells in the normal ICM are mostly smooth muscle cells although there is also a small resident population of monocyte-like cells. We have been studying the ICM in swine with emphasis on the abdominal aorta. We have found that atherosclerotic lesions in the abdominal aorta of swine induced by high-fat high-cholesterol diets begin by a hyperplastic reaction of the smooth muscle cells in the ICM and progress to form large lesions characterized by extensive regions of lipid-rich calcific necrotic debris similar to advanced lesions in man. Because of the putative key role of the ICM in atherogenesis we think that it is important to learn as much as possible about their natural history under conditions as normal as possible. In this report we present data on ICM in the abdominal aortas of 34 male and female Hormel miniature swine maintained on a low-fat low-cholesterol diet for up to 12 years of age. The ICM grow slowly with aging and in the distal portion of the aorta account for an average of 9% in the male and 15% in the female of the total cells in the aortic wall (intima + media).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1985

Electrical activity of the cerebral cortex during induced hypotension in man. A comparison of sodium nitroprusside and trimetaphan.

During the routine use of controlled hypotension the electroencephalogram (EEG) and mean arterial pressure (MAP) were monitored in 20 normotensive patients (younger than 70 years-of-age) receiving either trimetaphan (TMP) or sodium nitroprusside (SNP). The reduction in MAP was quicker and greater with SNP. Significant differences in EEG voltage between the two agents were seen in the range 55-40 mm Hg, electrical activity being better maintained with SNP. However, all patients showed some decline in EEG voltage with hypotension and half of these showed significant correlations with MAP. These pressure-dependent cerebral effects were not predictable in terms of age, preoperative arterial pressure or hypotensive agent. Our work supports previous experimental evidence that, during more profound hypotension, cerebral electrical activity is better maintained with SNP than with TMP. A simple measure of total EEG power, or filtered EEG voltage envelope (CFM) was shown to be a more useful monitor of cerebral electrical activity during controlled hypotension than measurements of power distribution in different frequency bands.

Adult↗
PubMed1985

Nitrous oxide inhalation does not influence plasma concentrations of beta-endorphin or Met-enkephalin-like immunoreactivity.

The possibility that nitrous oxide releases endogenous opioid peptides into the circulation has been tested in 10 pain-free, unstressed volunteers breathing 30% nitrous oxide in oxygen. Despite achieving plateau concentrations in venous blood, accompanied by subjective effects, there were no significant changes in plasma concentrations of immunoreactive beta-endorphin, methionine-enkephalin or ACTH. These results indicate that, in the absence of nociceptive input, the effects of the inhalation of nitrous oxide are unrelated to alterations in peripheral concentrations of these endogenous opioid peptides.

Adrenocorticotropic Hormone↗
PubMed1985

Cell population kinetics in atherogenesis. Cell births and losses in intimal cell mass-derived lesions in the abdominal aorta of swine.

Atherosclerotic lesions may arise in a number of different ways. The two most notable, perhaps, are by monocyte infiltration of the intima and by hyperplasia of normally occurring intimal cell masses. This report is limited to the ICM-derived lesion type induced by a hyperlipidemic diet in the abdominal aorta of swine. The HL diet results, by 49 days, in accumulation of lipid in about 50% of the ICM cells and increases in cell division activity, as indicated by tritiated thymidine LI fourfold greater than in ICM of control swine. Cell numbers are not significantly increased over controls at 49 days, but by 90 HL diet days, they have increased to eightfold over control values. Throughout the 90 days, about 95% of the cells in the ICM or ICM-lesions are smooth muscle cells. Monocytes appear to constitute no more than 5% of the cells. Calculated lesion cell deaths are small during the 90 days, and foci of necrosis are rarely found. By scanning electron microscopy, the endothelial cell integrity appears to be maintained even over the ICM-lesions at 90 days. Calculations from tritiated thymidine LI indicate endothelial cell losses equivalent to 50% of the LI, but they are not significantly greater for the HL swine than for controls. We suggest, then, that the lipid in the ICM (or something associated with it) is the most likely candidate for the SMC growth stimulatory agent accounting for the increased tritiated thymidine LI and the great increase in ICM-lesion cell numbers between HL diet days 49 and 90. Platelet- and/or monocyte-derived growth factors may also be involved in some subtle fashion, but this study provides no positive evidence to support this hypothesis. Progression of the ICM-derived lesions to the advanced atheromatous phase by 300 days on HL diet appears to be a much more complex process. By 300 days in the specific experiment cited, approximately 65% of the atherosclerotic lesion volume consisted of lipid-rich calcific necrotic debris; calculated death rates of lesion cells were very high compared to that at 90 days; calculated endothelial cell loss rates were considerably higher than in controls; and, large numbers of monocyte-macrophages were present in many areas generally associated with necrotic foci. These changes in the aggregate suggest a much more complex mode of pathogenesis for progression to advanced stages than for initiation and early development.

Animals↗
PubMed1984

New potent inhibitors of angiotensin converting enzyme.

Using an earlier model of the favoured orientation of binding functions of angiotensin converting enzyme (ACE) inhibitors, it has been possible to postulate a new, 7,6-bicyclic system, based on hexahydropyridazine, which might be expected to have high potency. Some members of this system which have been synthesised have been shown to be very active ACE inhibitors, in vitro and in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Mosaicism in female hybrid hares heterozygous for glucose-6-phosphate dehydrogenase. V. The recovery of DNA synthesis of hare fibroblasts after ultraviolet irradiation.

The effect of uv irradiation on the recovery of DNA synthesis is examined in a population of hare fibroblasts exhibiting heterozygosity with reference to the X-linked enzyme, glucose-6-phosphate-dehydrogenase (G-6-PD). These cells have been grown from skin explants of a hybrid female cross between Lepus timidus (female) and L. europaeus (male), the former carrying the G-6-PD gene for the slow-moving "T" variant and the latter with the fast-moving "E" variant gene. The hybrid, therefore, exhibits genetic mosaicism due to random inactivation in each cell, of one of the two X chromosomes in the embryonic stage. Exponentially growing cells from 13 fibroblast strains, comprising a wide range of E to T ratios, were exposed to moderately low dose of uv irradiation (6 J/m2). The recovery in DNA synthesis during the 2- to 8-h postirradiation period was calculated as the mean percentage rates of [3H]thymidine incorporated during the time as compared to the unirradiated zero-time controls. The results show a statistically significant positive correlation as determined by linear regression analysis between the levels of E and the rate of recovery in DNA synthesis. This is valid also at the higher dose of uv (21 J/m2). These results strengthen our earlier observations with 25-hydroxycholesterol that in the in vitro system the cell expressing the E variant is perhaps more resistant to cytotoxic agents. This also indicates that various factors contribute to the development of monotypism which include cell growth, cell death, mutation, and selection, to name a few.

Animals↗
PubMed1984

Mosaicism in female hybrid hares heterozygous for glucose-6-phosphate dehydrogenase. VI. Production of monotypism in the aortas of 4 of 10 mosaic hares fed cholesterol oxidation products.

The normal aortic tissue of black women heterozygous for glucose-6-phosphate dehydrogenase (G-6-PD) usually consists of two cell phenotypes (mosaicism). By electrophoresis two G-6-PD types are demonstrated (ditypism). Advanced atherosclerotic lesions from such women not infrequently yield samples displaying only one G-6-PD type (monotypism). Possible causes for the monotypism include (1) monoclonal origin of the lesion and (2) selective growth and/or survival advantage of one phenotype over the other. We have been attempting to produce monotypism in the aortas of a hybrid hare model that displays G-6-PD mosaicism in the normal state. In the current study 14 G-6-PD mosaic hares were fed a high-cholesterol diet for 6 to 17 months. All developed extensive moderately severe (as compared to humans) atherosclerotic lesions. No monotypic samples were found. Ten hares were fed (in addition to the standard high-cholesterol diet) small doses of one of two cholesterol oxidation products (25-hydroxycholesterol or triol) for 6 to 21 months. Four of the ten developed monotypic foci in either atherosclerotic lesions or normal aortic tissue or both. The reason for giving the oxidation products was because they are cytotoxic for cells in vitro and one (25-hydroxycholesterol) had been shown to be more toxic for one phenotype than the other with cultured fibroblasts from the mosaic hares (not infrequently resulting in the culture becoming monotypic). We suggest that the monotypism observed in vivo was probably produced by a mechanism similar to that operating in vitro.

Animals↗
PubMed1984

Population dynamics of arterial cells. XIV. Evidence for no significant G2 arrest of intimal and medial cells in young nonatherosclerotic swine.

In an earlier study of swine results from analysis of tritiated thymidine data by an "ancestor table" method suggested a substantial arrest of arterial cells in the G2 phase of the cell cycle. A later study with a cytofluorometric method gave contradictory results with no evidence for significant G2 arrest. On reexamination of the earlier data with the ancestor table method in the light of current knowledge, it was found that the fact that nuclei in the S and G2 phases prior to division are larger than those in G1 after division had not been taken into account. The main purpose of the current study was to find out whether the evidence for G2 arrest would entirely disappear if adjustments were made for differences in nuclear sizes before and after division. A baseline group sacrificed 2 hr after tritiated thymidine injection and two experimental groups (one fed hyperlipidemic diet and the other given cholesterol-free mash) sacrificed 47 hr after injection were studied. Using the ancestor table method it was found that virtually all labeled arterial cells divided in both groups; thus there is no evidence for G2 arrest. The data was also analyzed with a form of the "mean grain count halving" method and this also showed all labeled cells dividing.

Animals↗
PubMed1984

Hypo-atherogenic effect of dietary corn oil exceeds hypo-cholesterolemic effect in swine.

Three groups of young swine were fed semi-purified diets enriched in fat and cholesterol for 90 days. In one group 40% of calories were from butter; in another 40% were from corn oil; in a third group 20% were from corn oil. Mean serum cholesterol values were respectively 530, 458 and 400 mg/dl. Amounts of atherosclerosis in the abdominal aortas expressed as mean number of nuclear profiles per cross-section were respectively 1611, 734 and 585; expressed as mean lesion area per cross section 46.7, 21.4 and 19.4 mm2 X 10(2). All differences between the butter group and either of the two corn oil groups were statistically significant. We found that intimal response to the butter containing diet was significantly greater than to the corn oil containing diet for equivalent hypercholesterolemic response. We present detailed statistical validation of the disproportionately larger intimal response to butter containing diet. Furthermore, we suggest that estimates of comparative atherogenic risk of food fats based on response of serum cholesterol may mask important atherogenic differences.

Animals↗
PubMed1984

Quantification of intimal cell masses and atherosclerotic lesions in coronary arteries of control and hyperlipidemic swine.

In the current study of swine coronary arteries, we have attempted to quantify the coronary intimal cell masses (ICM) with regard to two aspects: (1) percentage of total arterial wall cells (intimal plus medial) that are in the intima, and (2) percentage of arterial wall area occupied by intima. We have studied 4 coronary sites: left main stem (LMS), proximal right (RCA), proximal left circumflex (LCX), and proximal left anterial descending (LAD). In mash-fed ('normal') swine we carried out the study at 3 ages: 2, 5 and 12 months. In addition, we have carried out a similar study in swine fed hyperlipidemic (HL) diets for 3 or approximately 10 months starting at 2 months of age. In the control swine we found approximately 6% of the arterial wall occupied by intima at 2 months of age with no significant increases by 12 months. There were no consistent significant differences among the 4 coronary artery sites with regard to percentage of wall occupied by intima. When the HL diet was fed, there were significant increases in the percentage of the arterial wall occupied by intima (now atherosclerotic lesion) by 3 months on diet and much larger increases by 10 months (up to 87% of wall occupied by intimal lesion) with extensive regions of lipid-rich, calcific, necrotic debris. After 3 months on HL diet the RCA lesions occupied significantly greater percentages of areas than the other 3 sites but this difference had disappeared by 10 months on the HL diet.

Animals↗
PubMed1983

Population dynamics of arterial cells during atherogenesis. XIII. Mitogenic and cytotoxic effects of a hyperlipidemic (HL) diet on cells in advanced lesions in the abdominal aortas of swine fed an HL diet for 270-345 days.

The abdominal aortas of five groups of young male Yorkshire swine were studied: (1) 0-day baseline group; (2) hyperlipidemic (HL) group with ballooning; (3) mash group with ballooning; (4) mash group without ballooning; and (5) HL group without ballooning. The last four groups were injected with [3H]thymidine at 270 days and sacrificed subsequently in subsets at intervals up to 75 days in order to study births and deaths (or loss by migration) among cells over the period 270-345 days. However, only in the HL-ballooned group were there enough swine for the isotopic data to be useful for most purposes. In the 0-day baseline group there were 6 +/- 2 X 10(6) cells in intimal cell masses (ICM); in the 270- to 345-day mash group without ballooning the number was 10 +/- 2 X 10(6), which is not a statistically significant increase over 0-day. This supports the hypothesis that in the normal state births and deaths (or loss by migration) among cells in ICM are nearly balanced at least up to 1 year of age. In the 270- to 345-day mash group with ballooning there were 61 +/- 12 X 10(6) cells in the ICM. Thus a single episode of deendothelialization results in tremendous hyperplasia of ICM. However, even the largest ICM (atherosclerotic lesion) in this group showed essentially no necrosis. In the 270- to 345-day HL group with ballooning there were 108 +/- 17 X 10(6) cells in the ICM turned atherosclerotic lesions. In addition an average of one-third of the lesion volume was occupied by lipid-rich, calcific necrotic debris. Thus the HL diet appears to have associated with it both mitogenic and cytotoxic influences on ICM cells. In the 270- to 345-day HL group not ballooned there were 130 +/- 30 X 10(6) lesion cells and lesions were somewhat more extensive and necrotic than in the HL-ballooned group, probably because the former group included by chance more hyperresponders (as regards serum cholesterol values) to the HL diet than the latter. Regardless of this, the data suggest that in this particular model of advanced atherosclerosis the balloon-injury stimulus to proliferation and the HL-diet stimulus are neither additive nor synergistic.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1983

Anti-proliferative effect of pyridinolcarbamate and of aspirin in the early stages of atherogenesis in swine.

When young swine are fed a suitable hyperlipidemic (HL) diet the number of cells in intimal cell masses (ICM) of large and medium-sized arteries begins to increase in number; by 90 days on the diet the cell increase is several-fold compared to no significant increase in cell numbers in ICM of mash-fed controls. The objective of the current study was to see if the cell increase associated with the HL diet could be reduced by pyridinolcarbamate or aspirin. Arteries studied were the abdominal aorta and the coronaries; time on HL diet was 90 days. Both drugs resulted in significant reductions in the increases in cells in ICM associated with the HL diet in both of the arterial beds that were studied. The reduction was most prominent in the abdominal aorta where the increase in ICM cells in the untreated HL diet-fed swine was from an average of 242 +/- 50 cells per cross-section in the mash-fed controls to 1925 +/- 556; in the pyridinolcarbamate-treated swine the increase was only to 641 +/- 214 and in the aspirin-treated group to 770 +/- 146.

Animals↗
PubMed1982

The design of a new group of angiotensin-converting enzyme inhibitors.

Using X-ray and NMR data relating to the conformation of the antihypertensive, angiotensin-converting enzyme inhibitor, captopril, and structure--activity relationships of analogues, it has been possible to postulate with the aid of computer graphics, the orientation of the three functions, the thiol, the terminal carboxyl and the carbonyl group which are involved in binding to the enzyme. Bicyclic mimetics of captopril, with related arrays of these functions, have been designed and synthesized. Compounds with the closest approximation to the array in captopril are the most active inhibitors of angiotensin converting enzyme, in vitro.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Evans blue dye: its accumulation in extracellular space in relation to endothelial cell basement membrane in normal an atherosclerotic areas of abdominal aorta.

Intravenously (IV) injected Evans blue dye consistently accumulates at particular areas in aortas of normal swine. Theses areas are also where IV injected tracer cholesterol accumulates. We studied the ultrastructural characteristics of blue vs nonblue areas in the abdominal aortas of both control and atherosclerotic swine. In blue areas, the basement membrane was largely missing beneath the endothelial cells in both normal swine and swine with raised atherosclerotic lesions; the basement membrane that was present was often discontinuous. If the basement membrane helps regulate the transport of Evans blue dye across the arterial wall, its absence may play a part in the accumulation of the dye. In raised atherosclerotic lesions, those portions that accumulated Evans blue dye had a larger amount of amorphous extracellular matrix than did nonblue areas. No consistent difference between blue and nonblue areas were seen in the endothelial cell junctions of abdominal aortas in either control or atherosclerotic swine. Similarly, no differences were demonstrable in the number of Golgi complexes, mitochondria, or profiles of smooth or rough endoplasmic reticulum per cell.

Animals↗