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Biomedical subjects

W A Bradley

Publications and source records attributed to W A Bradley.

At least 19 recordsLinked to original sources
PubMed2003

Metaphyseal osteomyelitis in an immature Abyssinian cat.

Metaphyseal osteomyelitis is a rarely described condition in small animals, especially the cat. Infection, most commonly Staphylococcus sp, is considered to occur in the metaphyseal region of the immature animal due to vascular anomalies that predispose to the haematogenous seeding of bacteria in this area. There is also speculation that the characteristics of the bacteria that allow them to adhere to cartilage matrix, rather than vascular linings and erythrocytes, may provide an advantage for colonisation in the metaphysis, resulting in infection. This case describes the successful management of a case of distal radial metaphyseal osteomyelitis in an immature cat using surgical intervention and antibacterial therapy.

Animals↗
PubMed2003

Metaphyseal osteomyelitis in an immature Abyssinian cat.

Metaphyseal osteomyelitis is a rarely described condition in small animals, especially the cat. Infection, most commonly Staphylococcus sp, is considered to occur in the metaphyseal region of the immature animal due to vascular anomalies that predispose to the haematogenous seeding of bacteria in this area. There is also speculation that the characteristics of the bacteria that allow them to adhere to cartilage matrix, rather than vascular linings and erythrocytes, may provide an advantage for colonisation in the metaphysis, resulting in infection. This case describes the successful management of a case of distal radial metaphyseal osteomyelitis in an immature cat using surgical intervention and antibacterial therapy.

Animals↗
PubMed2001

Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo.

We previously showed 1 that a peptide, Ac-hE18A-NH(2), in which the arginine-rich heparin-binding domain of apolipoprotein E (apoE) [residues 141;-150] (LRKLRKRLLR), covalently linked to 18A (DWLKAFYDKVAEKLKEAF; a class A amphipathic helix with high lipid affinity), enhanced LDL uptake and clearance. Because VLDL and remnants contain more cholesterol per particle than LDL, enhanced hepatic clearance of VLDL could lead to an effective lowering of plasma cholesterol. Therefore, in the present article we compared the ability of this peptide to mediate/facilitate the uptake and degradation of LDL and VLDL in HepG2 cells. The peptide Ac-hE18A-NH(2), but not Ac-18A-NH(2), enhanced the uptake of LDL by HepG2 cells 5-fold and its degradation 2-fold. The association of the peptides with VLDL resulted in the displacement of native apoE; however, only Ac-hE18A-NH(2) but not Ac-18A-NH(2) caused markedly enhanced uptake (6-fold) and degradation (3-fold) of VLDL. Ac-hE18A-NH(2) also enhanced the uptake (15-fold) and degradation (2-fold) of trypsinized VLDL Sf 100;-400 (containing no immuno-detectable apoE), indicating that the peptide restored the cellular interaction of VLDL in the absence of its essential native ligand (apoE). Pretreatment of HepG2s with heparinase and heparitinase abrogated all peptide-mediated enhanced cellular activity, implicating a role for cell-surface heparan sulfate proteoglycans (HSPG). Intravenous administration of Ac-hE18A-NH(2) into apoE gene knockout mice reduced plasma cholesterol by 88% at 6 h and 30% at 24 h after injection. We conclude that this dual-domain peptide associates with LDL and VLDL and results in rapid hepatic uptake via a HSPG-facilitated pathway.

Amino Acid Sequence↗
PubMed2000

Safety and efficacy of percutaneous coronary interventions performed immediately after diagnostic catheterization in northern new england and comparison with similar procedures performed later.

"Ad hoc" percutaneous coronary interventions (PCIs)-those performed immediately after diagnostic catheterization-have been reported in earlier studies to be safe with a suggestion of higher risk in certain subgroups. Despite increasing use of this strategy, no data are available in recent years with new device technology. We studied use of an ad hoc strategy in a large regional population to determine its use and outcomes compared with staged procedures. A database from the 6 centers performing PCIs in northern New England and 1 center in Massachusetts was analyzed. During 1997, excluding only patients requiring emergency procedures or those with a prior PCI, 4,136 PCIs were performed, 1,748 (42.3%) of these being ad hoc procedures. Patients having ad hoc procedures were less likely to have peripheral vascular disease, renal failure, prior myocardial infarction, or coronary artery bypass surgery, congestive heart failure, or poor left ventricular function, and more likely to have received preprocedural intravenous heparin or nitroglycerin or to have required an urgent procedure. Narrowings treated during ad hoc procedures were less frequently types B and C or in saphenous vein grafts. Adjusted rates of clinical success were not different between ad hoc and non-ad hoc procedures (93.7% vs 93.6%); there was no difference in the incidence of death (0.6% vs 0.5%), emergency (0. 9% vs 0.8%) or any (1.4% vs 0.8%) coronary artery bypass surgery, or myocardial infarction (2.6% vs 2.0%). As currently practiced in our region, ad hoc intervention is used selectively with outcomes similar for ad hoc and non-ad hoc procedures.

Angina Pectoris↗
PubMed2000

A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis.

We have cloned a human macrophage receptor that binds to apolipoprotein (apo)B48 of dietary triglyceride (TG)-rich lipoproteins. TG-rich lipoprotein uptake by the apoB48R rapidly converts macrophages and apoB48R-transfected Chinese hamster ovary cells in vitro into lipid-filled foam cells, as seen in atherosclerotic lesions. The apoB48R cDNA (3,744 bp) encodes a protein with no known homologs. Its approximately 3.8-kb mRNA is expressed primarily by reticuloendothelial cells: monocytes, macrophages, and endothelial cells. Immunohistochemistry shows the apoB48R is in human atherosclerotic lesion foam cells. Normally, the apoB48R may provide essential lipids to reticuloendothelial cells. If overwhelmed, foam cell formation, endothelial dysfunction, and atherothrombogenesis may ensue, a mechanism for cardiovascular disease risk of elevated TG.

Amino Acid Sequence↗
PubMed2000

The receptor binding domain of apolipoprotein E, linked to a model class A amphipathic helix, enhances internalization and degradation of LDL by fibroblasts.

Human apolipoprotein E (apo E) consists of two distinct domains, the lipid-associating domain (residues 192-299) and the globular domain (residues 1-191) which contains the LDL receptor (LDLR) binding site (residues 129-169). To test the hypothesis that an arginine-rich apo E receptor binding domain (residues 141-150) is sufficient to enhance low-density lipoprotein (LDL) uptake and clearance when covalently linked to a class A amphipathic helix, a peptide in which the receptor binding domain of human apo E, LRKLRKRLLR (hApoE[141-150]), is linked to 18A, a well-characterized high-affinity lipid-associating peptide (DWLKAFYDKVAEKLKEAF), we synthesized the peptide hApoE[141-150]-18A (hE18A) and its end-protected analogue, Ac-hE18A-NH(2). The importance of positively charged residues and the role of the hydrophobic residues in the receptor binding domain were also studied using four analogues. Ac-LRRLRRRLLR-18A-NH(2) [Ac-hE(R)18A-NH(2)] and Ac-LRKMRKRLMR-18A-NH(2) (Ac-mE18A-NH(2)) contained an extended hydrophobic face, including the receptor binding region. Control peptides, Ac-LRLLRKLKRR-18A-NH(2) [Ac-hE(Sc)18A-NH(2)], had the amino acid residues of the apo E receptor binding domain scrambled to disrupt the extended hydrophobic face, and Ac-RRRRRRRRRR-18A-NH(2) (Ac-R(10)18A-NH(2)) had only positively charged Arg residues as the receptor binding domain. The effect of the dual-domain peptides on the uptake and degradation of human LDL by fibroblasts was determined in murine embryonic fibroblasts (MEF1). LDL internalization was enhanced 3-, 5-, and 7-fold by Ac-mE18A-NH(2), Ac-hE18A-NH(2), and Ac-hE(R)18A-NH(2), respectively, whereas the control peptides had no significant biological activity. All three active peptides increased the level of degradation of LDL by 100%. The LDL binding and internalization to MEF1 cells in the presence of these peptides was not saturable over the LDL concentration range that was studied (1-10 microgram/mL). Furthermore, a similar enhancement of LDL internalization was observed independent of the presence of the LDL receptor-related protein (LRP), LDLR, or both. Pretreatment of cells with heparinase and heparitinase abolished more than 80% of the enhanced peptide-mediated LDL uptake and degradation by cells. We conclude that the dual-domain peptides enhanced LDL uptake and degradation by fibroblasts via a heparan sulfate proteoglycan (HSPG)-mediated pathway.

Amino Acid Sequence↗
PubMed1999

The relationship between operator volume and outcomes after percutaneous coronary interventions in high volume hospitals in 1994-1996: the northern New England experience. Northern New England Cardiovascular Disease Study Group.

OBJECTIVES: The purpose of this study was to examine the relationship between annual operator volume and outcomes of percutaneous coronary interventions (PCIs) using contemporaneous data. BACKGROUND: The 1997 American College of Cardiology (ACC)/American Heart Association task force based their recommendation that interventionists perform > or = 75 procedures per year to maintain competency in PCI on data collected largely in the early 1990s. The practice of interventional cardiology has since changed with the availability of new devices and drugs. METHODS: Data were collected from 1994 through 1996 on 15,080 PCIs performed during 14,498 hospitalizations by 47 interventional cardiologists practicing at the five high volume (>600 procedures per hospital per year) hospitals in northern New England and one Massachusetts-based institution that support these procedures. Operators were categorized into terciles based on their annualized volume of procedures. Multivariate regression analysis was used to control for case-mix. In-hospital outcomes included death, emergency coronary artery bypass graft surgery (eCABG), non-emergency CABG (non-eCABG), myocardial infarction (MI), death and clinical success (> or = 1 attempted lesion dilated to < 50% residual stenosis and no death, CABG or MI). RESULTS: Average annual procedure rates varied across terciles from low = 68, middle = 115 and high = 209. After adjusting for case-mix, clinical success rates were comparable across terciles (low, middle and high terciles: 90.9%, 88.8% and 90.7%, Ptrend = 0.237), as were all the adverse outcomes including death (low-risk patients = 0.45%, 0.41%, 0.71%, Ptrend = 0.086; high-risk patients = 5.68%, 5.99%, 7.23%, Ptrend = 0.324), eCABG (1.74%, 2.05%, 1.75%, Ptrend = 0.733) and MI (2.57%, 1.90%, 1.86%, Ptrend = 0.065). CONCLUSIONS: Using current data, there is no significant relationship between operator volumes averaging > or = 68 per year and outcomes at high volume hospitals. Future efforts should be directed at determining the generalizability of these results.

Angioplasty, Balloon, Coronary↗
PubMed1999

Pathophysiology of triglyceride-rich lipoproteins in atherothrombosis: cellular aspects.

Elevated plasma levels of triglyceride-rich lipoproteins (TGRLP), including very low-density lipoproteins (VLDL), chylomicrons, and their remnants, are now acknowledged as risk factors for cardiovascular disease. Interactions of TGRLP with lipoprotein receptors on monocytes, macrophages, and endothelial cells may be mechanistically linked to this risk. Triglyceride-rich lipoproteins from hypertriglyceridemic (HTG) subjects have the abnormal ability to bind to low-denisty lipoprotein receptors via apoE, and plasma chylomicrons from all subjects bind to a new, distinct receptor for apoB48 that is expressed specifically by monocytes, macrophages, and endothelial cells. Receptor binding and uptake of TGRLP by these cells are likely mechanisms involved in the formation of lipid-filled, macrophage-derived "foam cells" of atherosclerotic lesions and for defective fibrinolysis due to endothelial dysfunction. Recognition of the atherothrombogenic potential of TGRLP may lead to improved interventions to lessen or prevent the often fatal sequelae of coronary atherosclerosis and thrombosis associated with elevated plasma triglyceride levels.

Apolipoproteins E↗
PubMed1999

Cause of in-hospital death in 12,232 consecutive patients undergoing percutaneous transluminal coronary angioplasty. The Northern New England Cardiovascular Disease Study Group.

BACKGROUND: Some deaths after percutaneous coronary angioplasty (PTCA) occur in high-risk situations (eg, shock), whereas others are unexpected and related to procedural complications. To better describe the epidemiologic causes of death after PTCA, we undertook a systematic review of all in-hospital PTCA deaths in Northern New England from 1990 to 1993. METHODS: The medical records of 121 patients who died during their acute hospitalization for PTCA were reviewed with a standardized data extraction tool to determine a mode of death (eg, low output failure, arrhythmia, respiratory failure) and a circumstance of death (eg, death attributable to a procedural complication, preexisting acute cardiac disease). Any death not classified as a procedural complication was reviewed by a committee and the circumstance of death assigned by a majority rule. RESULTS: Low-output failure was the most common mode of death occurring in 80 (66.1%) of 121 patients. Other modes of death included ventricular arrhythmias (10.7%), stroke (4.1%), preexisting renal failure (4.1%), bleeding (2.5%), ventricular rupture (2.5%), respiratory failure (2.5%), pulmonary embolism (1.7%), and infection (1.7%). The circumstance of death was a procedural complication in 65 patients (53.7%) and a preexisting acute cardiac condition in 41 patients (33.9%). Women were more likely to die of a procedural complication than were men. CONCLUSION: Procedural complications account for half of all post-PTCA deaths and are a particular problem for women. Other deaths are more directly related to patient acuity or noncardiac, comorbid conditions. Understanding why women face an increased risk of procedural complications may lead to improved outcomes for all patients.

Age Factors↗
PubMed1999

Percutaneous transluminal coronary angioplasty in the elderly: epidemiology, clinical risk factors, and in-hospital outcomes. The Northern New England Cardiovascular Disease Study Group.

OBJECTIVES: To explore the relation between older age and clinical presentation, procedural success, and in-hospital outcomes among a large unselected population undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Although more elderly patients are receiving PTCA, studies of post-PTCA outcomes among the elderly have been limited by small numbers and exclusive selection criteria. METHODS: Data were collected as a part of a prospective registry of all percutaneous coronary interventions performed in Maine, New Hampshire, and from 1 institution in Massachusetts between October 1989 and December 1993. Comparisons across 4 age groups, (<60, 60 to 69, 70 to 79, and 80 years and above) were performed using chi-square tests, the Mantel-Haenzsel test for trend, and logistic regression. RESULTS: Twelve thousand one hundred seventy-two hospitalizations for PTCA were performed with 507 of them (4%) in persons at least 80 years old. Octogenarians were more likely to be women, have multivessel disease, high-grade stenoses, and complex lesions but were less likely to have hypercholesterolemia, a history of smoking, or have undergone a previous PTCA. In the elderly, PTCAs were more often performed urgently and for unstable syndromes compared with younger age groups. Advancing age is strongly associated with in-hospital death, and among the oldest old with an increased risk of postprocedural myocardial infarction. Despite differing presentation and procedural priority, angiographic success and subsequent bypass surgery did not vary by age. CONCLUSIONS: With the increasing age of the population at large as well as that segment at risk for cardiac revascularization, information about age-associated risks of the procedure, especially the substantially higher risk of death in octogenarians, will be critical for both physicians and patients considering PTCA.

Age Factors↗
PubMed1999

Changing outcomes in percutaneous coronary interventions: a study of 34,752 procedures in northern New England, 1990 to 1997. Northern New England Cardiovascular Disease Study Group.

OBJECTIVES: We sought to evaluate the changing outcomes of percutaneous coronary interventions (PCIs) in recent years. BACKGROUND: The field of interventional cardiology has seen considerable growth in recent years, both in the number of patients undergoing procedures and in the development of new technology. In view of recent changes, we evaluated the experience of a large, regional registry of PCIs and outcomes over time. METHODS: Data were collected from 1990 to 1997 on 34,752 consecutive PCIs performed at all hospitals in Maine (two), New Hampshire (two) and Vermont (one) supporting these procedures, and one hospital in Massachusetts. Univariate and multivariate regression analyses were used to control for case mix. Clinical success was defined as at least one lesion dilated to <50% residual stenosis and no adverse outcomes. In-hospital adverse outcomes included coronary artery bypass graft surgery (CABG), myocardial infarction and mortality. RESULTS: Over time, the population undergoing PCIs tended to be older with increasing comorbidity. After adjustment for case mix, clinical success continued to improve from a low of 88.2% in earlier years to a peak of 91.9% in recent years (p trend <0.001). The rate of emergency CABG after PCI fell in recent years from a peak of 2.3% to 1.3% (p trend <0.001). Mortality rates decreased slightly from 1.2% to 1.1% (p trend 0.007). CONCLUSIONS: There has been a significant improvement in clinical outcomes for patients undergoing PCIs in northern New England, including a significant decline in the need for emergency CABG.

Angioplasty, Balloon, Coronary↗
PubMed1999

Multivariate prediction of in-hospital mortality after percutaneous coronary interventions in 1994-1996. Northern New England Cardiovascular Disease Study Group.

OBJECTIVES: Using recent data, we sought to identify risk factors associated with in-hospital mortality among patients undergoing percutaneous coronary interventions. BACKGROUND: The ability to accurately predict the risk of an adverse outcome is important in clinical decision making and for risk adjustment when assessing quality of care. Most clinical prediction rules for percutaneous coronary intervention (PCI) were developed using data collected before the broader use of new interventional devices. METHODS: Data were collected on 15,331 consecutive hospital admissions by six clinical centers. Logistic regression analysis was used to predict the risk of in-hospital mortality. RESULTS: Variables associated with an increased risk of in-hospital mortality included older age, congestive heart failure, peripheral or cerebrovascular disease, increased creatinine levels, lowered ejection fraction, treatment of cardiogenic shock, treatment of an acute myocardial infarction, urgent priority, emergent priority, preprocedure insertion of an intraaortic balloon pump and PCI of a type C lesion. The receiver operating characteristic area for the predicted probability of death was 0.88, indicating a good ability to discriminate. The rule was well calibrated, predicting accurately at all levels of risk. Bootstrapping demonstrated that the estimate was stable and performed well among different patient subsets. CONCLUSIONS: In the current era of interventional cardiology, accurate calculation of the risk of in-hospital mortality after a percutaneous coronary intervention is feasible and may be useful for patient counseling and for quality improvement purposes.

Aged↗
PubMed1999

Antipeptide antibodies reveal interrelationships of MBP 200 and MBP 235: unique apoB-specific receptors for triglyceride-rich lipoproteins on human monocyte-macrophages.

Two human monocyte-macrophage (HMM) membrane binding proteins, (MBP) 200 and 235, are receptor candidates that bind to the apolipoprotein (apo)B-48 domain in triglyceride-rich lipoproteins for uptake independent of apoE. Microsequence analysis of the purified reduced MBP 200R characterized tryptic peptides of MBP 200R. A synthetic peptide mimicking a unique, unambiguous 10-residue sequence (AEGLMVTGGR) induced antipeptide antibodies that specifically recognized MBP 200, 235 and 200R, in 1- and 2-dimensional analyses, indicating 1) the ligand binding protein was sequenced and 2) MBP 200 and 235 yielded MBP 200R upon reduction. These antibodies identified the MBPs in human blood-borne, THP-1, U937 MMs, and endothelial cells (EC) but not in human fibroblasts or Chinese hamster ovary (CHO) cells. Fluorescence activated cell sorting (FACS) analysis located the MBPs on the MM surface as necessary for receptor function. The 10-residue, unambiguous MBP 200-derived sequence is unique, with no matches in extant protein databases. Antipeptide antibodies bind to the MBPs in reticuloendothelial cells that have this receptor activity, but not to proteins in cells that lack this receptor activity. These studies provide the first direct protein sequence and immunochemical data that a new, unique apoB receptor for triglyceride-rich lipoproteins exists in human monocytes, macrophages, and endothelial cells.

Amino Acid Sequence↗
PubMed1998

Operator volume and outcomes in 12,998 percutaneous coronary interventions. Northern New England Cardiovascular Disease Study Group.

OBJECTIVES: We sought to determine whether there is a relation between operator volume and outcomes for percutaneous coronary interventions (PCIs). BACKGROUND: A 1993 American College of Cardiology/American Heart Association task force stated that cardiologists should perform > or = 75 procedures/year to maintain competency in PCIs; however, there were limited data available to support this statement. METHODS: Data were collected from 1990 through 1993 on 12,988 PCIs (12,118 consecutive hospital admissions) performed by 31 cardiologists at two hospitals in New Hampshire and two in Maine and one hospital in Massachusetts supporting these procedures. Operators were categorized into terciles based on annualized volume of procedures. Univariate and multivariate regression analyses were used to control for case-mix. Successful outcomes included angiographic success (all lesions attempted dilated to < 50% residual stenosis) and clinical success (at least one lesion dilated to < 50% residual stenosis and no adverse outcomes). In-hospital adverse outcomes included coronary artery bypass graft surgery (CABG), myocardial infarction (MI) and death. RESULTS: After adjustment for case-mix, higher angiographic (low, middle and high terciles: 84.7%, 86.1% and 90.3%, p-trend 0.006) and clinical success rates (85.8%, 88.0% and 90.7%, p-trend 0.025), with fewer referrals to CABG (4.54%, 3.75% and 2.49%, p-trend <0.001), were seen as operator volume increased. There was a trend toward higher MI rates for high volume operators (2.00%, 1.98% and 2.57%, p-trend 0.06); all terciles had similar in-hospital mortality rates (1.09%, 0.96% and 1.05%, p-trend 0.8). CONCLUSIONS: There is a significant relation between operator volume and outcomes in PCIs. Efforts should be directed toward understanding why high volume operators are more successful and encounter fewer adverse outcomes.

Angioplasty, Balloon, Coronary↗
PubMed1998

Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor.

Studies in animals and humans have demonstrated uptake of plasma chylomicrons (triglyceride-rich lipoprotein [TGRLP] of Sf>400) by accessible macrophages in vivo. One potential mechanism is via a unique receptor pathway we previously identified in human blood and THP-1 monocytes and macrophages for the lipoprotein lipase (LpL)- and apolipoprotein (apo) E-independent, high-affinity, specific binding of plasma chylomicrons and hypertriglyceridemic VLDL (HTG-VLDL) to cell-surface membrane-binding proteins (MBP 200, 235; apparent Mr 200, 235 kD on SDS-PAGE) that leads to lipid accumulation in vitro. Competitive binding studies reported here demonstrate that anti-apoB antibodies specifically block the high-affinity binding of TGRLP to this receptor on THP-1 cells and on ligand blots. LpL, which binds to an N-terminal domain of apoB, also inhibits TGRLP binding both to this site on THP-1s and to MBP 200, 235 by binding to apoB. Chylomicrons of Sf>1100 that contain apoB-48, but not apoB-100, bind specifically to MBP 200, 235, and this binding is blocked by anti-apoB IgG. In contrast, lactoferrin and heparin do not inhibit TGRLP binding. We conclude that the receptor-binding domain is within apoB-48 (or an equivalent in apoB-100) near the LpL-binding domain, but not a heparin-binding domain. Uptake of TGRLP by this mechanism could provide essential nutrients or, in HTG, cause excess lipid accumulation and foam cell formation.

Antibodies↗
PubMed1997

Results of directional coronary atherectomy in Northern New England. Northern New England Cardiovascular Disease Study Group.

The role of directional coronary atherectomy (DCA) in interventional cardiology remains uncertain. We report the Northern New England regional experience with DCA from 1991 to 1994. Data were collected on 11,178 patients having had an intervention on a single lesion in a single vessel (798 DCAs; 10,380 percutaneous transluminal angioplasties [PTCA]). The use of DCA increased from 1.8% of interventions in 1991 to 10% in 1994. Compared with PTCA, DCA patients were younger, more often men, had more 1-vessel disease and more coronary artery bypass surgery (CABG). DCA was more often used in the left anterior descending artery, in vein grafts, for restenoses, for subtotal occlusions, and with type A lesions. Angiographic success (96.7%) and clinical success (93%) were good. Adverse events were rare: mortality 0.9%, emergent CABG 2.2%, nonfatal myocardial infarction 2.8%. After adjusting for case-mix, there was no difference between DCA and PTCA for in-hospital mortality (odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.44 to 2.43, p = 0.95) or need for emergent CABG (OR = 1.27, 95% CI 0.77 to 2.10, p = 0.34). Atherectomy patients were more likely to have a nonfatal myocardial infarction (OR = 2.0, 95% CI 1.26 to 3.20, p <0.01), to sustain an injury to the femoral or brachial artery (OR = 2.89, 95% CI 1.52 to 5.51, p <0.01), and to have a clinically successful procedure (OR = 1.37, 95% CI 1.01 to 1.88, p = 0.05). Our results support the relative safety and effectiveness of DCA as its use disseminated into the region.

Aged↗
PubMed1997

Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells.

The hypothesized relationships between plasminogen activator inhibitor (PAI-1) genotypes, PAI-1 levels, and their potential regulation by hypertriglyceridemic (HTG) very low density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] was examined in a PAI-1 genotyped human umbilical vein endothelial cell (HUVEC) culture model system. Individual human umbilical veins were used to obtain cultured ECs and were genotyped for PAI-1 by using the HindIII restriction fragment length polymorphism (RFLP) as a marker for genetic variation. Digested genomic DNA, examined by Southern blot analysis and probed with an [alpha-32P]dCTP-labeled 2.2-kb PAI-1 cDNA, yielded three RFLPs designated 1/1 (22-kb band only), 1/2 (22-plus 18-kb bands), and 2/2 (18-kb band only). Individual PAI-1 genotyped HUVEC cultures were incubated in the absence or presence of HTG-VLDL (0 to 50 micrograms/mL) or Lp(a) (0 to 50 micrograms/mL) at 37 degrees C for various times (4 to 24 hours), followed by analyses of PAI-1 antigen (by ELISA) and mRNA (by ribonuclease protection assay) levels, EC surface-localized plasmin generation assays, and nuclear run-on transcription assays. Secreted PAI-1 antigen levels were increased approximately 2- to 3-fold by HTG-VLDL and approximately 1.6 to 2-fold by Lp(a); mRNA levels were increased approximately 3- to 4.5-fold by HTG-VLDL and approximately 2.5- to 3.2-fold by Lp(a) compared with medium-incubated controls, primarily in the 2/2 PAI-1 genotype HUVEC cultures. Increases in PAI-1 mRNA induced by HTG-VLDL or Lp(a) could be abolished by coincubation with actinomycin D (2 x 10(-6) mol/mL) or puromycin (1 microgram/mL). In addition, nuclear transcription run-on assays typically demonstrated that HTG-VLDL increased PAI-1 gene transcription rates by approximately 5- to 6-fold and approximately 4- to 5-fold, respectively, primarily in the 2/2 PAI-1 genotype HUVEC cultures compared with 1/1 PAI-1 genotype HUVEC cultures or medium-incubated controls. The positive control interleukin-1 increased both 2/2 and 1/1 PAI-1 mRNA levels by approximately 5- to 6-fold. Increased PAI-1 antigen and mRNA expression were associated with a concomitant 50% to 60% decrease in plasmin generation. These combined results demonstrate the genotype-specific regulation of PAI-1 expression by HTG-VLDL and Lp(a) and further indicate that these risk factor-associated components regulate PAI-1 gene expression at the transcriptional level in cultured HUVECs. Results from these studies further suggest that individuals with this responsive 2/2 PAI-1 genotype may reflect the additional inherent potential for later HTG-VLDL- or Lp(a)-induced fibrinolytic dysfunction, resulting in the early initiation of thrombosis, atherogenesis, and coronary artery disease.

Arteriosclerosis↗