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Biomedical subjects

N Woolf

Publications and source records attributed to N Woolf.

At least 19 recordsLinked to original sources
PubMed1999

Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes.

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet beta-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha, whereas both subsets produced macrophage inflammatory protein-1beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing beta-cells are protected or destroyed.

Animals↗
PubMed1996

Synthesis of TNF alpha and TGF beta mRNA in the different micro-environments within atheromatous plaques.

OBJECTIVE: To examine localisation of tumour necrosis factor (TNF alpha) and transforming growth factor beta (TGF beta) mRNA synthesis in human coronary artery atheromatous plaques, to explore how synthesis of these cytokines relates to distribution of macrophages and smooth muscle cells, and to correlate this with plaque micro-environments. METHOD: In situ hybridisation with digoxigenin-labelled sense and anti-sense riboprobes was used, combined with immunohistochemistry to detect TNF alpha protein, macrophage, lymphocyte and smooth muscle cell markers. RESULTS: In the intimal plaque TNF alpha mRNA is synthesised by monocytes/macrophages as well as by smooth muscle cells. Both TNF alpha and TGF beta mRNAs were present at the margins of the lesions and in reactive areas, where there was little lipid and fibrosis. Focal aggregates of macrophages in the adventitia expressed both TNF alpha mRNA and protein and TGF beta mRNA. CONCLUSION: Synthesis of these two cytokines by macrophages as well as smooth muscle cells contributes to the pathobiology of the plaque and that this is part of the 'reaction to injury', rather than a feature of a specific cell, or a specific layer, within the vessel wall.

Coronary Disease↗
PubMed1995

Inaccuracy of self-reported weights and heights among American Indian adolescents.

To determine the accuracy of self-reported weights and heights and of relative weight status in a sample of American Indian adolescents, a survey was conducted in middle and high schools on or near three Indian reservations-Navajo, Choctaw, and Blackfeet. Self-reported weights and heights were compared with measured weights and heights. Participants were 12 through 19 years old. (N = 806, 47.4% male). Overall, both boys and girls underreported weight (mean difference = self-reported - measured mean values)(-3.4 +/- 13.1 and -4.6 +/- 13.0 lb, respectively) and overreported height (0.6 +/- 2.1 and 0.2 +/- 2.6 in, respectively) However, underweight boys and girls overreported weight (normal: -1.6 +/- 7.9 and -1.4 +/- 6.3; overweight: -7.5 +/- 17.9 and -11.6 +/- 19.0 lb, respectively). Although correlations between measured and reported weight, height, and body mass index (BMI) were high, the sensitivity of relative weight categories based on BMI using self-reported weight and height compared with measured weight and height was poor: 66.7% for underweight (BMI < 15th percentile, based on a national reference population), 88.9% for normal weight, and 73.6% for overweight (> 85th percentile). These results call into question the accuracy of self-reported weight and height measurements among American Indian youth and are similar to findings among non-American Indian adolescents. Therefore, their use in prevalence studies should be avoided, and they should be used cautiously in other types of epidemiologic studies.

Adolescent↗
PubMed1994

Lipid and cellular constituents of unstable human aortic plaques.

Unstable plaques are undergoing thrombosis which, in most instances, is due to fissuring and rupture of the plaque cap. This process (deep intimal injury) is a complication of plaques with a lipid-rich core. The cap tear allows blood to enter the core from the lumen, leading initially to intraplaque thrombosis and, subsequently, in some cases intraluminal thrombosis. Cap tears reflect the interplay between the force exerted on the tissue and its inherent mechanical strength. Factors which elevate and concentrate circumferential wall stress on the cap during systole include an increasing proportion of the total plaque volume occupied by the lipid core, thinning of the cap and a loss of internal collagen struts within the core. Factors which lead to an inherent reduction in the mechanical strength of cap tissue include a reduction in collagen and glycosaminoglycan concentrations, an increase in the number and density of macrophages, and a concomitant reduction in smooth muscle cells in the cap tissue. It is therefore possible to define a vulnerable plaque as one in which the lipid core is disproportionately large, the cap thin, and in which monocytes preponderate over smooth muscle cells.

Arteriosclerosis↗
PubMed1993

Reaction of nitric oxide with hydrogen peroxide to produce potentially cytotoxic singlet oxygen as a model for nitric oxide-mediated killing.

Nitric oxide, as well as being a major regulator of vascular reactivity, has been shown to be one of the mediators of cytotoxicity in macrophages. This cytotoxic effect seems to be due to the interaction between nitric oxide and oxygen-related free radicals. This study shows that, in vitro, nitric oxide reacts with hydrogen peroxide to release large amounts of chemiluminescence with the characteristics of the highly cytotoxic species, singlet oxygen. This is supported by the observation that when nitric oxide was added to a superoxide generating system, catalase inhibited the production of singlet oxygen while superoxide dismutase enhanced it.

Cytotoxins↗
PubMed1993

The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis.

The expression of PECAM, ICAM-1, VCAM-1, and E-selectin was studied in 64 samples of human coronary arteries taken from 15 explanted hearts obtained within 5 min of transplantation. Normal artery (n = 12), predominantly fibrous plaques (n = 23), and plaques containing extracellular lipid (n = 26) and three segments showing recanalization channels were studied. All endothelial cells strongly and equally expressed PECAM; positive staining was used to check that artefactual denudation of the endothelial surface had not occurred. PECAM was also present in some lipid-filled macrophages. Normal arteries showed no VCAM-1 staining but focal segments of the endothelium were positive for ICAM-1 and E-selectin. ICAM-1 was strongly and constantly expressed by the endothelium over all types of plaques and in macrophages. E-selectin expression was confined to endothelial cells and occurred on the surface in 35 per cent of fibrous and 22 per cent of lipid-containing plaques. VCAM-1 staining of surface endothelium occurred in 39 per cent of fibrous and 20 per cent of lipid-containing plaques. A population of spindle-shaped cells of macrophage type (positive for EMB11 antigen) expressed VCAM-1 in lipid-containing plaques. Adventitial vessels adjacent to plaques showed endothelial expression of ICAM-1 and E-selectin. VCAM-1 staining of adventitial vessel endothelium was associated with local lymphoid aggregation. In conclusion, the expression of cell adhesion molecules is an important element in the inflammatory component of atherosclerosis and contributes to both monocyte and lymphocyte activation and recruitment from adventitial vessels and the arterial lumen.

Adult↗
PubMed1993

Effects of the synthetic anti-oxidant, probucol, on the U937 monoblastoid cell line.

Probucol is a clinically important drug that decreases plasma cholesterol in humans and has a marked anti-atherogenic effect in hyperlipidaemic Watanabe rabbits. The action of probucol in this animal model has been partly attributed to its anti-oxidant abilities. Probucol can decrease the oxidative modification of low-density lipoprotein and hence diminish its uptake by macrophages. In this paper, we have examined the effect of probucol on the monoblastic cell line U937 and on U937 cells induced to differentiate towards a macrophage phenotype by 1,25-dihydroxycholecalciferol (DHCC), tumour necrosis factor-alpha (TNF-alpha) or phorbol myristate acetate (PMA). We found that probucol enhanced the proliferation of undifferentiated U937 cells. Probucol also enhanced proliferation in cultures that had been pre-treated with DHCC or TNF-alpha, but had no effect on cultures that had been pre-treated with PMA. In contrast, when U937 cells were treated simultaneously with probucol and DHCC or TNF-alpha, there was a more marked decrease in proliferation than was induced by these agents in the absence of probucol. Probucol had little effect on the phenotype of resultant cells. The surface expression of CD13 (aminopeptidase N), CD4, CD35 (C3b receptor), CD64 (Fc gamma RI), CD71 (transferrin receptor) and HLA Class II was not affected by probucol. Probucol treatment led to a small increase in the surface expression of CD16 (Fc gamma RIII) in TNF-alpha treated cells and to a small decrease in the expression of CD14 (a monocyte marker) in PMA-treated cells. The induction of c-fgr mRNA and TNF-alpha mRNA by DHCC or PMA or TNF-alpha was not significantly altered in the presence of probucol. The affect of probucol on U937 cells does not appear to be due to its anti-oxidant abilities because butylated hydroxytoluene (BHT), an equally powerful anti-oxidant, did not have the same effect on the cell proliferation as probucol and because no changes were detected in the levels of lipid peroxidation in U937 cell culture supernatants.

Antigens, Surface↗
PubMed1993

Effect of cigarette smoking on cultured human endothelial cells.

OBJECTIVE: The aim was to investigate whether the morphological changes previously described in endothelium exposed to cigarette smoke are linked with the oxidative burden imposed on the cells. METHODS: Cultured human umbilical vein endothelial cells (HUVEC) were exposed to samples of plasma taken from volunteer smokers and to samples of plasma to which small doses of fresh cigarette smoke derived from a smoking machine had been added. Measurements of the pentose phosphate pathway and the extruded total glutathione (GSSG) were performed to assess the presence and degree of oxidative stress on cells. Angiotensin converting enzyme (ACE) release into the medium and the ATP content of the cells were used to assess early membrane damage and cytotoxicity. RESULTS: Treatment of endothelial cells with plasma exposed to cigarette smoke in vitro resulted in activation of the pentose phosphate pathway of glucose metabolism, increased extrusion of glutathione from the cells into the medium, a decrease in the ATP pool, and release of ACE from the cells into the medium. Plasma taken from volunteers immediately after smoking showed, as might be expected, similar but less marked changes in the release of glutathione and ACE. CONCLUSIONS: Plasma from human volunteer smokers or human plasma exposed to cigarette smoke in vitro produced injury in HUVEC as assessed by changes in the ATP pool and ACE release. The extrusion of glutathione from the cells and the activation of the hexose monophosphate shunt, which is necessary to keep glutathione in the reduced state, is indicative of oxidative stress. These findings support the view that cigarette smoke related endothelial injury is, at least in part, mediated by the oxidative burden imposed by the free radicals present in cigarette smoke.

Adenosine Triphosphate↗
PubMed1993

Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content.

OBJECTIVE: To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. DESIGN: The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. MATERIAL: Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n = 31). Nine aortas showed both intact plaques (group B, n = 79) and plaques that were undergoing thrombosis (group C, n = 45). RESULTS: In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups A + B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells. CONCLUSIONS: In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.

Aged↗
PubMed1992

Atrial myxoma: a tumour in search of its origins.

OBJECTIVE: To determine whether atrial myxomas express antigens suggesting a neural origin. DESIGN: A retrospective analysis based on immunohistochemical examination of myxoma tissue. SETTING: Atrial myxomas excised by two tertiary referral cardiothoracic surgical units. SUBJECTS: 24 excised atrial myxomas. Three were from known cases of familial myxoma syndrome. METHODS: Immunohistochemical identifications of three neuroendocrine markers (protein gene product (PGP) 9.5, neurone specific enolase (NSE), synaptophysin) and S100 antigen; CD34 and von Willebrand factor; and chi smooth muscle actin to identify possible Schwann cell differentiation, endothelial cells, and smooth muscle cells respectively. RESULTS: The myxoma cells were PGP 9.5 positive in 18, S100 positive in 16, and NSE positive in 12. Of the 12 NSE positive myxomas seven were synaptophysin positive. All tumours that were NSE positive were also S100 and PGP 9.5 positive. The tumour surface was partially covered by myxoma cells, partly by endothelial cells. CONCLUSION: The histological appearances of myxomas with stellate cells embedded within a loose connective tissue stroma, abundant basophil cell infiltration, and the presence of pericellular type IV collagen are similar to nerve sheath tumours (neurofibromas) at other sites. A significant proportion of myxomas also express Schwann cell and neuroendocrine differentiation markers. These features cannot prove the origin of myxomas because tumours may develop aberrant phenotype expression but they do accord with the view that myxomas originate from endocardial sensory nerve tissue.

Antigens, Neoplasm↗
PubMed1991

An antioxidant role for calcium antagonists in the prevention of adrenaline mediated myocardial and endothelial damage.

OBJECTIVE: To investigate the mechanism of calcium antagonist mediated cytoprotection against the damaging effects of adrenaline in vivo on cardiac myocytes and human endothelial cells from the umbilical vein. METHODS: Human endothelial cells cultured from the umbilical vein and isolated rat cardiac myocytes were treated with plasma from rats given adrenaline 30 minutes previously with pretreatment with calcium antagonists and without. The effect on indices of cell damage that suggest oxidation stress was determined. RESULTS: Pretreatment of rats with calcium antagonists before adrenaline administration largely inhibited the cytotoxic effects of their plasma on the two target cells used. Plasma taken from animals not pretreated with calcium antagonists caused release of oxidised glutathione from cells, a fall in intra-cellular reduced glutathione concentration, a fall in ATP production, and release of angiotensin converting enzyme from the endothelial cells. CONCLUSION: Calcium antagonists protect against the cardiotoxic effects of catecholamine by preventing the generation of plasma borne cytotoxic compounds, which are probably free radicals.

Animals↗
PubMed1990

Pathology of atherosclerosis.

This communication gives a brief account of the morphology and natural history of atherosclerosis. It defines atherosclerosis, in dynamic terms as the resultant of three interacting sets of processes: accumulation and modification of plasma-derived lipid within the arterial intima, connective tissue proliferation and connective tissue necrosis forming an atheromatous pool at the plaque base. The first of these leads to the accumulation of lipid-filled macrophages within the affected intima and this step is most probably mediated via oxidative modifications of the low density lipoprotein molecule. An alteration of the functional phenotype of the intimal smooth muscle cell as a result of interactions with growth factors (most notably PDGF) constitutes the basis for the connective tissue proliferation. Plaque necrosis, which is extremely important as a risk factor for acute thrombosis, is the least well understood area; the activated macrophage may well play a significant role in this connexion.

Arteries↗
PubMed1990

Nicotine and cigarette smoking: effects on the ultrastructure of aortic endothelium.

The aortic endothelium from rats has been examined by scanning (SEM) and transmission electron microscopy (TEM) following nicotine administration or cigarette smoking. Nicotine was administered to rats by subcutaneous injections at concentrations of 1, 5, 10 and 20 mg/kg or by continuous subcutaneous pumps delivering a solution of 0.54 g/ml of nicotine at the rate of 1 microliter/h for 7 days. Animals were exposed to fresh smoke from eight cigarettes, each yielding 19 mg tar and 1.5 mg nicotine. Twenty minutes after subcutaneous injections, no endothelial abnormalities were evident by SEM, apart from at the high dose where minimal endothelial damage was seen. Limited endothelial damage was discerned following nicotine infusion and this consisted of microvillus formation, platelet adhesion and some cell separation. TEM revealed no endothelial changes in any of the animals. Cigarette smoking, however, resulted in considerable endothelial morphological changes consisting of the formation of blebs, microvillus-like projections, increased numbers of plasmalemmal vesicles and an increase in the numbers of Weibel-Palade bodies. The results suggest that components of cigarette smoke other than nicotine are responsible for the endothelial cell changes associated with smoking.

Animals↗
PubMed1989

Primary prevention of atherosclerosis by lovastatin in a genetically hyperlipidaemic rabbit strain.

Lovastatin, a lipid-lowering drug which inhibits cholesterol synthesis, was administered to genetically hyperlipidaemic rabbits from the age of 2 months. Twenty rabbits were selected with similar plasma cholesterol levels and divided into matched treatment and control groups. The treated animals showed a 60% decrease in plasma cholesterol due to reduced levels of low density lipoprotein (LDL) and intermediate density lipoprotein (IDL). Levels of other lipoproteins remained unchanged. In untreated animals cholesterol levels in plasma, LDL and IDL increased with age. The area of aortic atherosclerosis-like lesions was quantified after 2-10.5 months of treatment. At each time point the extent of arterial disease was profoundly less in treated than in untreated animals. The findings demonstrate that primary prevention of arterial lesions resembling human atherosclerosis (increased amounts of fibrous tissue, smooth muscle cell proliferation, foam cell formation and necrosis at the base of the plaques) results from early effective reduction of elevated plasma lipids by lovastatin in this rabbit strain.

Animals↗
PubMed1989

Vascular endothelial cell function and ultrastructure in thrombotic microangiopathy following allogeneic bone marrow transplantation.

We report studies on vascular endothelial function and ultrastructure in 2 cases of fatal cyclosporin (CS)-associated thrombotic microangiography following allogeneic bone marrow transplantation (BMT). Spontaneous vascular release of prostacyclin (PGI2) from a vein sample ex vivo was absent, and scanning electron microscopy (SEM) showed surface changes indicative of vascular endothelial damage (case 1). PGI2 release from cultured human umbilical vein endothelial cells incubated with patients' serum in vitro was normal in both cases. Plasma von Willebrand factor (vWF) antigen and ristocetin cofactor activity levels were raised in both patients, 5.06 and 7.02 (case 1) and 3.60 and 2.01 (case 2) (normal ranges 0.59-1.57 and 0.42-1.74 U/ml), respectively, but multimer patterns were normal. The SEM appearances coupled with the absent PGI2 release and raised vWF levels suggest that vascular endothelial damage is central to the pathogenic process in thrombotic microangiopathy following allogeneic BMT but the mechanisms appear to be distinct from those in the haemolytic uraemic syndrome and de novo thrombotic thrombocytopenic purpura. The precise role of CS in this process remains to be identified.

Adult↗