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Biomedical subjects

K D O'Brien

Publications and source records attributed to K D O'Brien.

At least 37 records · Page 2Linked to original sources
PubMed1999

Glycosylphosphatidylinositol-specific phospholipase D is expressed by macrophages in human atherosclerosis and colocalizes with oxidation epitopes.

BACKGROUND: Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may play an important role in inflammation, because it can hydrolyze the GPI anchors of several inflammatory membrane proteins (eg, CD106, CD55, and CD59) and its hydrolytic products upregulate macrophage cytokine expression (eg, interleukin-1 and tumor necrosis factor-alpha). Because of its potential regulatory role in inflammatory reactions, we hypothesized that GPI-PLD might be expressed in atherosclerosis. METHODS AND RESULTS: Immunohistochemistry using human GPI-PLD-specific rabbit polyclonal antiserum was performed on a total of 83 nonatherosclerotic and atherosclerotic human coronary arteries from 23 patients. Macrophages, smooth muscle cells, apoA-I, and oxidation epitopes also were identified immunohistochemically. Cell-associated GPI-PLD was detected in 95% of atherosclerotic segments, primarily on a subset of macrophages. Extracellular GPI-PLD was present in only 30% of atherosclerotic segments and localized to regions with extracellular apoA-I. In contrast, GPI-PLD was not detected in nonatherosclerotic segments. Expression of GPI-PLD mRNA by human macrophages was confirmed in vitro by reverse transcription/polymerase chain reaction. Further studies demonstrated that GPI-PLD-positive plaque macrophages contained oxidation epitopes, suggesting a link between oxidant stress and GPI-PLD expression. This possibility was supported by studies in which exposure of a macrophage cell line to H2O2 led to a 50+/-3% increase in steady-state GPI-PLD mRNA levels. CONCLUSIONS: Collectively, these results suggest that oxidative processes may regulate GPI-PLD expression and suggest a role for GPI-PLD in inflammation and in the pathogenesis of atherosclerosis.

Adult↗
PubMed1999

Murine phospholipid hydroperoxide glutathione peroxidase: cDNA sequence, tissue expression, and mapping.

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), also known as glutathione peroxidase 4 (GPX4), is a 19-kDa, monomeric enzyme that protects cells from lipid peroxide-mediated damage by catalyzing the reduction of lipid peroxides. PHGPx is synthesized in two forms, as a 194-amino acid peptide that predominates in gonadal tissue and localizes to mitochondria, and as a 170-amino acid protein that predominates in most somatic tissues and localizes to the cytoplasm. With the rapid amplification of cDNA ends (RACE) procedure, an 876-bp PHGPx cDNA was amplified from mouse testis, and a 767-bp PHGPx cDNA was amplified from mouse heart. The cDNA sequences were identical except that the testis cDNA contained an additional 109 bp at its 5' end. With a partial cDNA with complete homology to both the testis and myocardial PHGPx cDNAs, the murine tissue distribution of PHGPx mRNA expression was determined by Northern blotting. Highest level of PHGPx expression was found in the testis, followed by the kidney, heart and skeletal muscle, liver, brain, lung, and spleen. Northern blotting performed with a cDNA specific for the longer PHGPx transcript demonstrated that this longer PHGPx transcript was present only in the testis. A 1.4-kb PHGPx genomic fragment was amplified from murine kidney DNA and used to map the PHGPx gene by linkage analysis of restriction fragment length variants (RFLVs). The murine PHGPx gene (Gpx4) was mapped to a region of murine Chromosome (Chr) 10, located 43 cM from the centromere, that is syntenic with the human locus, which is located at the terminus of the short arm of human Chr 19. This information may be valuable in characterizing the role of PHGPx in modulating susceptibility to lipid peroxide-mediated injury in inbred murine strains and for targeted disruption of the gene.

Amino Acid Sequence↗
PubMed1999

Radiation reduction using a modified collimated lateral skull radiograph during orthodontic treatment.

The aim of the study was to investigate whether routine 'during-treatment' clinical cephalometric measurements could be obtained from a lateral skull radiograph collimated to show the maxilla and mandible. The sample consisted of 30 lateral skull radiographs, taken during treatment, of patients with upper and lower fixed appliances. These conventional cephalograms (CC) were copied to give a radiograph with modified collimation (MC) showing the maxilla and mandible and the dentition only. Both types of radiographs were digitised and the readings compared to determine whether the same during-treatment cephalometric values were obtained from both types of radiographs. The limits of agreement obtained, when comparing cephalometric values obtained from the CC and MC lateral skull radiographs, were only marginally larger than those for CC alone. Therefore, the use of an MC lateral skull radiograph to show the maxilla and mandible is a viable alternative for cephalometric measurements for patients wearing two arch fixed appliances.

Cephalometry↗
PubMed1998

Does the ethnicity of teenage children influence oral self perception and prevalence of dental disease?

AIM: The primary aim was to evaluate the effect of ethnicity, social deprivation and oral health on oral self perceptions of 14-15-year-old Asians and Whites. A secondary aim was to assess the influence of ethnicity and social deprivation on oral treatment need in the same sample. DESIGN: A cross-sectional epidemiological study. DATA SOURCE: A stratified, random sample of 408 14-15-year-old Asian and White children from schools in Manchester. METHOD: Information was collected on oral self perceptions using a questionnaire and on oral treatment need with a clinical examination. RESULTS: Multivariate data analysis revealed that oral treatment need, but not ethnicity or social deprivation, was an important predictive variable with respect to oral self perceptions. Ethnicity was the only variable to influence periodontal treatment need. Social deprivation influenced the level of untreated caries. CONCLUSIONS: 1. Socially deprived children have higher caries levels than their more affluent counterparts and this is evident regardless of ethnic background. 2. Although Asian 14-15-year-old children have a higher periodontal treatment need than Whites, there was no ethnic influence on how they perceive their oral health. 3. Oral treatment need is an important factor with respect to oral self perceptions.

Adolescent↗
PubMed1998

Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: colocalization of biglycan with apolipoproteins.

BACKGROUND: Because the content of specific proteoglycans and apolipoproteins is increased in atherosclerotic plaques and in vitro studies have suggested a role for proteoglycans in mediating plaque apolipoprotein (apo) retention, immunohistochemistry was performed to systematically examine the relative locations of proteoglycans and apolipoproteins in human atherosclerosis. METHODS AND RESULTS: The spatial relationships of versican, biglycan, and apoE were compared on 68 human coronary artery segments; apoA-I and apoB also were evaluated on an additional 20 segments. Nonatherosclerotic intima contained extensive deposits of versican, whereas deposits of apoE, apoB, and apoA-I were much less prevalent. In contrast, nearly all atherosclerotic segments contained substantial deposits of biglycan, apoE, apoA-I, and apoB. There was a high degree of colocalization of apoE and biglycan deposits. ApoA-I, the major apolipoprotein of HDL, and apoB also were detected in regions with apoE and biglycan deposition. Exceptions to the localization of biglycan with apolipoproteins were found in regions that lacked intact extracellular matrix because of necrosis or dense macrophage accumulation. In vitro studies demonstrated that biglycan binds apoE-containing but not apoE-free HDL and that biglycan also binds LDL. CONCLUSIONS: These results suggest that biglycan may bind apoE and apoB in atherosclerotic intima. They also raise the possibility that apoE may act as a "bridging" molecule that traps apoA-I-containing HDL in atherosclerotic intima. Taken together, these findings are consistent with the hypothesis that biglycan may contribute to the pathogenesis of atherosclerosis by trapping lipoproteins in the artery wall.

Apolipoprotein A-I↗
PubMed1997

Clinical guidelines for dentistry: will they be useful?

OBJECTIVE: To review the literature on the development and effectiveness of clinical guidelines. DESIGN: Literature review of relevant publications following a Medline search. Publications that reported studies investigating effectiveness of guidelines were confined to randomised controlled trials. CONCLUSIONS: If guidelines are to be effective they should be (i) based on high levels of scientific evidence, (ii) developed with input from the dentists who will be using them and (iii) presented in a satisfactory manner. Importantly, the effectiveness of the guidelines should be rigorously evaluated.

Decision Making↗
PubMed1997

A survey of the opinions of orthodontic specialist trainees in the U.K.

A questionnaire survey was carried out to ascertain a profile of orthodontic postgraduates in training in the United Kingdom during 1993. Information about the postgraduates, their programmes and their career plans was collected. Eighty-nine questionnaires were distributed to those enrolled in 13 of the training programmes in the U.K. at that time from which the response rate was 64 per cent. The results can be compared with a similar survey carried out in the United States of America in 1992 (Keith and Proffit, 1994).

Adult↗
PubMed1997

High-density lipoprotein-binding protein (HBP)/vigilin is expressed in human atherosclerotic lesions and colocalizes with apolipoprotein E.

Accumulation of cholesteryl esters within cells of the arterial intima is a hallmark of atherosclerosis. A small number of proteins have been shown in vitro to be upregulated by cellular cholesterol loading, including apolipoprotein E (apoE) and the recently cloned HDL-binding protein (HBP), but only apoE has been shown to be upregulated in cholesterol-loaded cells in atherosclerosis. To determine whether HBP (also called vigilin) might be expressed in human atherosclerosis, immunohistochemistry and in situ hybridization were performed on coronary arteries of 18 patients. HBP/vigilin was detected on all endothelial cells. HBP/vigilin mRNA and protein also were detected on a subset of macrophages and occasionally on smooth muscle cells (SMC) in atherosclerotic plaques but were not detected on these cell types in nondiseased coronary intima. The majority of HBP/vigilin-expressing macrophages were foam cells, but HBP/vigilin expression also was detected rarely in nonfoam cell macrophages. Foam cell macrophage HBP/vigilin expression was present in 100% of atherosclerotic quadrants, and nonfoam cell macrophage HBP/vigilin expression was present in 6% of atherosclerotic quadrants. HBP/vigilin-expressing human plaque cells also expressed apoE. However, HBP/vigilin was detected in cardiac myocyte foam cells of an apoE-deficient mouse, demonstrating that HBP/vigilin expression can occur independently of apoE. These results suggest that in vivo HBP/vigilin expression is upregulated by intracellular cholesterol loading but also that other factors present in atherosclerotic plaques may upregulate HBP/vigilin. Although the exact function of HBP/vigilin is unknown, its expression in plaque macrophages suggests a role for this molecule in atherogenesis.

Amino Acid Sequence↗
PubMed1997

In vitro and in situ magnetic resonance imaging signal features of atherosclerotic plaque-associated lipids.

The goal of this study was to evaluate magnetic resonance imaging (MRI) signal features of the different types of lipids found in human atherosclerotic plaques. A 1.5-T SIGNA scanner was used to acquire T1-, T2-, and proton density-weighted data at four different temperatures for individual lipids and lipid mixtures designed to replicate the proportions of lipids found in plaques. Individual lipids and lipid mixtures were scanned both in a test tube and after implantation in the media of normal porcine aortas. Each of the three broad classes of lipids (triglycerides, unesterified and esterified cholesterol, and phospholipids) had different and distinct MR signal patterns, which allowed discrimination of these classes of lipids in vitro. Further, lipid implantation studies demonstrated that these distinct MR signal patterns could be used to readily distinguish each lipid type from surrounding porcine aortic media. MR signals from lipid mixtures demonstrated marked regional heterogeneity, similar to the heterogeneous lipid distribution characteristic of human atherosclerotic plaques. In summary, MR signals from lipid mixtures that mimic plaque lipid proportions can be detected at body temperature, especially in those mixtures with an increased percentage of cholesteryl esters. These studies raise the possibility that with further advances in technology, MRI may become a useful tool for determining the lipid content and composition of human atherosclerotic plaques in vivo.

Anhydrides↗
PubMed1996

Oxidation-specific epitopes in human coronary atherosclerosis are not limited to oxidized low-density lipoprotein.

BACKGROUND: Previous small studies have demonstrated positive immunohistochemical staining in rabbit and human atherosclerotic plaques by antibodies that recognize oxidized low-density lipoprotein (OxLDL), but none have examined a large number of human coronary arteries or evaluated whether epitopes recognized by these antibodies might be present on plaque proteins other than OxLDL. METHODS AND RESULTS: Immunohistochemistry was performed on atherosclerotic (n = 87) and nonatherosclerotic (n = 51) coronary arterial segments from 20 patients by use of monoclonal antibodies that recognize epitopes on macrophages, smooth muscle cells, apolipoprotein (apo) B, and OxLDL. Staining with the OxLDL antibody (Ox5) was much more prevalent in atherosclerotic than in control segments. Extracellular Ox5 staining colocalized with apo B, but cell-associated Ox5 staining occurred in the absence of cell-associated apo B staining, which suggests that cell-associated epitopes for Ox5 were on proteins other than LDL. Epitopes for Ox5 formed in vitro on two readily available non-apo B proteins, human serum albumin and apo A-I, when these proteins were incubated under conditions of oxidant stress with polyunsaturated but not monounsaturated fatty acids; furthermore, an antioxidant inhibited Ox5 epitope formation. Thus, epitopes for Ox5 can form on proteins other than apo B. Also, phorbol ester-treated macrophages cultured in apo B-free medium developed epitopes for Ox5. CONCLUSIONS: These findings are consistent with the hypothesis that atherosclerosis is associated with oxidative modification of proteins in addition to LDL, particularly cell-associated proteins, and that the antiatherosclerotic effects of antioxidants seen in some studies may not be solely due to prevention of LDL oxidation.

Adult↗
PubMed1996

Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content.

BACKGROUND: Leukocyte recruitment is an early event in atherogenesis, and the leukocyte adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) recently have been detected in human atherosclerosis. However, no previous study has evaluated either the distribution of these three molecules at different sites within the arterial intima or their relation to plaque leukocyte content. METHODS AND RESULTS: Immunohistochemistry was performed on 99 coronary artery segments (34 controls and 65 with atherosclerotic plaque) to identify E-selectin, ICAM-1, VCAM-1, macrophages, smooth muscle cells, and T lymphocytes. For each segment, the presence or absence of adhesion molecule was determined at the arterial lumen, on intimal neovasculature, and on intimal nonendothelial cells. Each segment was scored for intimal macrophage and T-lymphocyte densities on a semiquantitative scale of 0 to 3. In atherosclerotic plaques, the prevalences of E-selectin, ICAM-1, and VCAM-1 on plaque neovasculature were twofold higher than their prevalences on arterial luminal endothelium. E-selectin was the only adhesion molecule for which expression on arterial luminal endothelial cells was more prevalent in plaques than in control segments. Increased plaque intimal macrophage density was associated with expression of VCAM-1 on neovasculature (P < .01) and on nonendothelial cells (P < .01). Increased plaque intimal T-lymphocyte density was associated with the presence of both ICAM-1 and VCAM-1 on neovasculature (both P < .01) and on nonendothelial cells (both P < .01). CONCLUSIONS: In atherosclerotic plaques, the expression of all three leukocyte adhesion molecules was more prevalent on intimal neovasculature than on arterial luminal endothelium. Further, the presence on neovasculature and nonendothelial cells of VCAM-1 and ICAM-1 was strongly associated with increased intimal leukocyte accumulation. These findings suggest that leukocyte recruitment through and/or activation of intimal neovasculature may play important roles in the pathogenesis of human atherosclerosis.

Adult↗
PubMed1996

Improvement in the organ donation rate at a large urban trauma center.

OBJECTIVE: To implement and then determine the efficacy of a "hospital development" (HD) plan designed to increase organ donation rates at an urban trauma center. DESIGN/SETTING: Retrospective reviews of all deaths at an urban, level I trauma center for 1991 to 1994. SUBJECTS: Potential organ donors were identified by standardized criteria, and the reasons why potential donors did not become actual organ donors ("nonproductive donors") were categorized. Actual donors were defined as individuals in whom one transplantable organ was recovered. Results also were expressed as percentages of potential donors for each year. Changes in actual donor numbers and in nonproductive donor categories were compared for the "pre-HD" (1991-1992) and "post-HD" (1993-1994) periods. INTERVENTION: The HD plan had six components: identification of key contact individuals, development and modification of relevant hospital policies, improvement in procurement agency visibility in hospital units, education of hospital staff regarding organ donation, institution of early on-site donor evaluations, and provision of feedback to hospital staff about the disposition of potential organ donors. RESULTS: Institution of the HD plan was associated with a highly significantly increase in actual donors for the post-HD period as compared with the pre-HD period (P < .001), and pre-HD and post-HD donor rates were 26.1% and 49.5%, respectively. This increase was due primarily to a marked improvement in hospital staff identification and referral of potential donors (P < .001). CONCLUSIONS: A coordinated plan incorporating continuing staff education, organ donation policy refinement, and increased visibility and availability of organ procurement agency personnel can substantially increase organ donation at an urban trauma center.

Feedback↗
PubMed1996

Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis.

Nonrheumatic aortic stenosis of trileaflet aortic valves has been considered to be a "degenerative" process, but the early lesion of aortic stenosis contains the chronic inflammatory cells, macrophages and T lymphocytes. Because lipoprotein deposition is prominent in atherosclerosis, another chronic inflammatory process, this study examined whether lipoproteins accumulate in aortic valve lesions. Immunohistochemical studies were performed to detect apolipoprotein (apo) B, apo(a), apoE, macrophages, and alpha-actin-expressing cells on 18 trileaflet aortic valves that ranged from normal to stenotic. All three apolipoproteins were detected in early through end-stage lesions of aortic stenosis but not in histologically normal regions. Comparison with oil red O staining suggested that most of the extracellular neutral lipid in these valves was associated with either plasma-derived or locally produced apolipoproteins. Thus, in early through end-stage aortic valve lesions, apolipoproteins accumulate and are associated with the majority of extracellular valve lipid. These results are consistent with the hypothesis that lipoprotein accumulation in the aortic valve contributes to pathogenesis of aortic stenosis.

Aortic Valve↗
PubMed1996

Perceptions of the risks and benefits of orthodontic treatment.

Recent National Health Service changes have brought about a greater involvement of the consumers of medical and dental care in decision making regarding their treatment. The aim of this study was to investigate the level of awareness of the risks and benefits of orthodontic treatment among potential consumers and their referring dentists. Parents of patients referred for orthodontic treatment were issued with a questionnaire about the risks and benefits of treatment and the reason the child had been referred. Study models were also made of the child's teeth. The patients' dentists were issued with a similar questionnaire. The results revealed that most of the parents were aware of the benefits of treatment in general and the reason that their own child required it. This awareness was greater where the orthodontic need on aesthetic grounds was greater. There was less awareness of the risks of treatment though again this was greater among those with a greater need for treatment. When the perceptions of the dentists were evaluated, they were more aware of the risks but were not communicating this to the parents. Since for some patients the risks of treatment may outweigh the benefits, it would be helpful if dentists could provide this information for patients before referral.

Adolescent↗
PubMed1995

Osteopontin is expressed in human aortic valvular lesions.

BACKGROUND: Nonrheumatic stenosis of trileaflet aortic valves, in which calcification is a prominent feature, has been termed a "degenerative" condition, but it has been demonstrated recently that chronic inflammation is a characteristic feature of the developing lesion of aortic stenosis. This observation raised the possibility that calcification in the aortic valve might be actively regulated. Thus, the present study investigated whether osteopontin, a protein implicated in the regulation of both normal and dystrophic calcification, could be detected in lesions of valvular aortic stenosis. METHODS AND RESULTS: Morphological and immunohistochemical studies were performed on 14 human aortic valves, representing a range of pathology from normal to clinically stenotic. The extent of calcification and macrophage accumulation and their relation to the presence of osteopontin protein were characterized. Highly statistically significant associations were found between the degree of osteopontin expression and the degrees of both calcification and macrophage accumulation in early through late lesions of aortic stenosis. Further, in situ hybridization localized osteopontin mRNA to a subset of lesion macrophages. CONCLUSIONS: These results suggest that, rather than representing a degenerative and unmodifiable process, calcification in aortic stenosis may be, in part, an actively regulated process with the potential for control either through modification of inflammation or synthesis of proteins such as osteopontin, which may modulate calcification in this tissue.

Aortic Valve↗
PubMed1995

Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis.

BACKGROUND: In human atherosclerosis, most clinical events occur when plaque integrity is compromised and hemorrhage and thrombosis result. One mechanism for this might be the release by plaque cells of matrix-degrading proteases, such as interstitial collagenase (matrix metalloproteinase-1, MMP-1), which degrades two major plaque structural proteins, types I and III collagen. This study was undertaken to determine whether MMP-1 is expressed in human atherosclerotic plaques. METHODS AND RESULTS: To determine the cellular source and location of MMP-1 in human carotid atherosclerotic lesions, in situ hybridization and immunohistochemistry were performed on 20 endarterectomy specimens. Six nonatherosclerotic carotid arteries also were studied. Intense MMP-1 expression (mRNA and protein) was detected in a subset of plaque macrophages located at the borders of the lipid cores adjacent to fibrous caps and shoulder regions. Subsets of plaque smooth muscle cells and endothelial cells also expressed MMP-1. There was a strong correlation between the percentage of the lipid core occupied by hemorrhage and the percentage of the lipid core perimeter positive for MMP-1 (r = .823, P = .0001). MMP-1 was not detected in any cell type in nonatherosclerotic carotid arteries. CONCLUSIONS: This study demonstrates that MMP-1 is expressed by several cell types in human carotid atherosclerosis and that there is a correlation between the expression of the protease and histopathological evidence of plaque instability. Since MMP-1 may degrade the major structural collagens of the plaque, expression of the protease by macrophages in regions critical to plaque integrity could contribute to plaque expansion, rupture, and hemorrhage.

Aged↗