bluuebunny/crossref_metadata_2025 huggingface dataset:
The Study of Boundaries in the Social Sciences
Authors: Lamont Michèle , Molnár Virág
Published: July 2002

▪ Abstract  In recent years, the concept of boundaries has been at the center of influential research agendas in anthropology, history, political science, social psychology, and sociology. This article surveys some of these developments while describing the value added provided by the concept, particularly concerning the study of relational processes. It discusses literatures on (a) social and collective identity; (b) class, ethnic/racial, and gender/sex inequality; (c) professions, knowledge, and science; and (d) communities, national identities, and spatial boundaries. It points to similar processes at work across a range of institutions and social locations. It also suggests paths for further developments, focusing on the relationship between social and symbolic boundaries, cultural mechanisms for the production of boundaries, difference and hybridity, and cultural membership and group classifications.
Ideas, Politics, and Public Policy
Authors: Campbell John L.
Published: July 2002

▪ Abstract  Scholars have become acutely interested in how behavior driven by ideas rather than self-interest determines policy-making outcomes. This review examines the literature on this subject. It differentiates among the types of ideas that may affect policy making (i.e., cognitive paradigms, world views, norms, frames, and policy programs) and identifies some of the persistent difficulties associated with studying how ideas shape policy. In particular, studies often do a poor job pinpointing the causal mechanisms that link ideas to policy-making outcomes. More attention needs to be paid to articulating the causal processes through which ideas exert effects. Suggestions for future scholarship that might improve this situation are offered. These include identifying the actors who seek to influence policy making with their ideas, ascertaining the institutional conditions under which these actors have more or less influence, and understanding how political discourse affects the degree to which policy ideas are communicated and translated into practice.
Reconsidering the Effects of Sibling Configuration: Recent Advances and Challenges
Authors: Steelman Lala Carr , Powell Brian , Werum Regina , Carter Scott
Published: July 2002

▪ Abstract  Until recently, social scientists were headed to consensus over the impact of the structural parameters of the sibling group, especially size and birth order, on educational and other status outcomes. New developments challenge this conventional wisdom, thus offering an opening for dialogue on this topic. We identify the utility and implications of studying the consequences of sibling configuration within sociology, across disciplines, and for public policy. Revisiting the association between sibship size and educational advancement, we evaluate challenges to long-held beliefs regarding this relationship. We then discuss the effects of birth order, highlighting recent declarations that these effects are more profound than previously believed. We next summarize scholarship on two less-explored components of the sibling matrix: spacing and sex composition. Finally, we consider generalizability of research done mostly in the United States to other countries. We hope examining and critiquing this research will frame future debate and stimulate further empirical analysis.
Electrochemical Behavior of Cobalt Hydroxide Used as Additive in the Nickel Hydroxide Electrode
Authors: Pralong V. , Delahaye‐Vidal A. , Beaudoin B. , Leriche J‐B. , Tarascon J‐M.
Published: July 2002

As an attempt to understand better how cobalt hydroxide additives improve the nickel electrode performance, the

Co
(
OH

)

2

/
CoOOH

redox system has been investigated through electrochemical cycling starting from a commercial

Co
(
OH

)

2

sample. A study of the influence of texture and morphology as well as cycling parameters was performed. For charge rates greater than C/5, relative to the amount of

Co
(
OH

)

2

, the electrochemical oxidation was found to be a solid‐state process. This process led to a nonstoichiometric

Co

x

4
+

Co

1
−
x

3
+

OOH

1
−
x

phase having a mosaic texture with enhanced electronic conductivity due to the presence of

Co

4
+

ions. For lower charge rates (C/100), the reaction rate is slower, and

Co

2
+

can dissolve in the electrolyte, leading to a less conductive phase having a stoichiometric composition (CoOOH) and a monolithic texture. When present, the

Co

4
+

ions are reduced to

Co

3
+

, at 1.05 V while other reductions

Co

3
+

→

Co

2
+

and

Co

2
+

→
Co
°

take place at a lower potential, 0.67 and 0.0 V, respectively. These two reactions are both associated with a dissolution of Co(II) species, followed by a migration of cobalt toward the current collector, with the overall result being an electrode degradation. © 2000 The Electrochemical Society. All rights reserved.
Role of Mitochondrial Oxidant Generation in Endothelial Cell Responses to Hypoxia
Authors: Pearlstein Daryl P. , Ali Mir H. , Mungai Paul T. , Hynes Karen L. , Gewertz Bruce L. , Schumacker Paul T.
Published: July 2002

Endothelial cells increase their secretion of the cytokine interleukin-6 (IL-6) during hypoxia, which then acts in an autocrine fashion to increase the permeability of cell monolayers. These responses are attenuated by antioxidants, suggesting that reactive oxygen species (ROS) participate in signaling in hypoxic endothelium. We tested whether mitochondria are responsible for these ROS in human umbilical vein endothelial cells exposed to hypoxia. Oxidation of the probe 2′, 7′-dichlorodihydrofluorescein to fluorescent dichlorofluorescein or the probe dihydroethidium was used to assess oxidant signaling, whereas permeability was assessed by using transendothelial electrical resistance. Hypoxia elicited increases in dichlorofluorescein and dihydroethidium fluorescence that were abrogated by the mitochondrial electron transport (ET) inhibitors rotenone (2 μmol/L) and diphenyleneiodonium (5 μmol/L). The same ET inhibitors also attenuated hypoxia-induced increases in nuclear factor-κB (NF-κB) activation, although they did not abrogate NF-κB activation in response to endotoxin (lipopolysaccharide). ET inhibition also abolished the hypoxia-induced increases in IL-6 mRNA expression, hypoxia-stimulated IL-6 secretion into the media, and the hypoxia-induced increases in transendothelial electrical resistance of human umbilical vein endothelial cell monolayers. By contrast, the above responses to hypoxia were not significantly affected by treatment with the NAD(P)H oxidase inhibitor apocynin (30 μmol/L), the xanthine oxidase inhibitor allopurinol (100 μmol/L), or the NO synthase inhibitor
N
-nitro-
l
-arginine (100 μmol/L). We conclude that ROS signals originating from the mitochondrial ET chain trigger the increase in NF-κB activation, the transcriptional activation of IL-6, the secretion of IL-6 into the cell culture media, and the increases in endothelial permeability observed during hypoxia.
Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models
Authors: Vincent Loïc , Soria Claudine , Mirshahi Farrokh , Opolon Paule , Mishal Zohair , Vannier Jean-Pierre , Soria Jeannette , Hong Li
Published: July 2002

Cerivastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It inhibits the biosynthesis of cholesterol and its precursors: farnesyl pyrophosphate and geranylgeranyl pyrophosphate (GGPP), which are involved in Ras and RhoA cell signaling, respectively. Statins induce greater protection against vascular risk than that expected by cholesterol reduction. Therefore, cerivastatin could protect plaque against rupture, an important cause of ischemic events. In this study, the effect of cerivastatin was tested on angiogenesis because it participates in plaque progression and plaque destabilization. Cerivastatin inhibits in vitro the microvascular endothelial cell proliferation induced by growth factors, whereas it has no effect on unstimulated cells. This growth arrest occurs at the G
1
/S phase and is related to the increase of the cyclin-dependent kinase inhibitor p21
Waf1/Cip1
. These effects are reversed by GGPP, suggesting that the inhibitory effect of cerivastatin is related to RhoA inactivation. This mechanism was confirmed by RhoA delocalization from cell membrane to cytoplasm and actin fiber depolymerization, which are also prevented by GGPP. It was also shown that RhoA-dependent inhibition of cell proliferation is mediated by the inhibition of focal adhesion kinase and Akt activations. Moreover, cerivastatin inhibits in vivo angiogenesis in matrigel and chick chorioallantoic membrane models. These results demonstrate the antiangiogenic activity of statins and suggest that it may contribute to their therapeutic benefits in the progression and acute manifestations of atherosclerosis.
Association Between the PPARA L162V Polymorphism and Plasma Lipid Levels
Authors: Tai E.S. , Demissie S. , Cupples L.A. , Corella D. , Wilson P.W. , Schaefer E.J. , Ordovas J.M.
Published: July 2002

Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the
PPARA
locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (
P
=0.0012 and
P
=0.0004, respectively) and apolipoprotein B in men (
P
=0.009) and women (
P
=0.03 after adjustment for age, body mass index, smoking, and use of β-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the
APOE
locus and the G allele at the
APOC3
3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase LDL cholesterol observed with the L162V
PPARA
polymorphism.
RANK Ligand and Osteoprotegerin
Authors: Schoppet Michael , Preissner Klaus T. , Hofbauer Lorenz C.
Published: July 2002

In 1997, investigators isolated a secreted glycoprotein that blocked osteoclast differentiation from precursor cells, prevented osteoporosis (decreased bone mass) when administered to ovariectomized rats, and resulted in osteopetrosis (increased bone mass) when overexpressed in transgenic mice. Since then, the isolation and characterization of the protein named osteoprotegerin (OPG) has stimulated much work in the fields of endocrinology, rheumatology, and immunology. OPG functions as a soluble decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL, or OPG ligand) and shares homologies with other members of the tumor necrosis factor receptor superfamily. OPG acts by competing with the receptor activator of nuclear factor-κB, which is expressed on osteoclasts and dendritic cells for specifically binding to RANKL. RANKL is crucially involved in osteoclast functions and bone remodeling as well as immune cell cross-talks, dendritic cell survival, and lymph node organogenesis. More recently, emerging evidence from in vitro studies and mouse genetics attributed OPG an important role in vascular biology. In fact, OPG could represent the long sought-after molecular link between arterial calcification and bone resorption, which underlies the clinical coincidence of vascular disease and osteoporosis, which are most prevalent in postmenopausal women and elderly people.
Age and Sex Distribution of Subclinical Aortic Atherosclerosis
Authors: Jaffer Farouc A. , O’Donnell Christopher J. , Larson Martin G. , Chan Stephen K. , Kissinger Kraig V. , Kupka Michelle J. , Salton Carol , Botnar Rene M. , Levy Daniel , Manning Warren J.
Published: July 2002

Autopsy data demonstrate a correlation between subclinical aortic atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60±9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal aortic CMR scanning. CMR evidence of aortic atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.
Oxidized Cholesteryl Linoleates Stimulate Endothelial Cells to Bind Monocytes via the Extracellular Signal–Regulated Kinase 1/2 Pathway
Authors: Huber Joakim , Boechzelt Herbert , Karten Barbara , Surboeck Michael , Bochkov Valery N. , Binder Bernd R. , Sattler Wolfgang , Leitinger Norbert
Published: July 2002

Oxidation products of cholesteryl esters have been shown to be present in oxidized low density lipoprotein and in atherosclerotic lesions. Monocyte adhesion to the endothelium is an initiating crucial event in atherogenesis. Here, we show that in vitro oxidized cholesteryl linoleate (oxCL) stimulated human umbilical vein endothelial cells (HUVECs) to bind human peripheral blood mononuclear cells as well as monocyte-like U937 cells but not peripheral blood neutrophils or neutrophil-like HL-60 cells. Among the oxidation products contained in oxCLs, 9-oxononanoyl cholesterol (9-ONC) and cholesteryl linoleate hydroperoxides stimulated U937 cell adhesion. OxCL-induced U937 cell adhesion was inhibited by an antibody against the connecting segment-1 region of fibronectin. Neither oxCL nor 9-ONC induced activation of the classical nuclear factor-κB pathway. In contrast, stimulation of HUVECs with oxCL resulted in phosphorylation of the extracellular signal–regulated kinase 1/2. Moreover, U937 cell adhesion induced by 9-ONC and oxCL was blocked by a mitogen-activated protein kinase/extracellular signal–regulated kinase inhibitor and a protein kinase C inhibitor. Taken together, oxCLs stimulate HUVECs to specifically bind monocytes, involving endothelial connecting segment-1 and the activation of a protein kinase C– and mitogen-activated protein kinase–dependent pathway. Thus, oxidized cholesteryl esters may play an important role as novel mediators in the initiation and progression of atherosclerosis.
Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis
Authors: Böhm Felix , Ahlborg Gunvor , Johansson Bo-Lennart , Hansson Lars-Olof , Pernow John
Published: July 2002

Endothelin (ET)-1 causes vasoconstriction via ET
A
and ET
B
receptors located on vascular smooth muscle cells and vasodilatation via ET
B
receptors on endothelial cells. Studies in vitro indicate an upregulation of ET
B
receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ET
B
receptor antagonist BQ788 evoked a significant increase in FBF (31±13%) in the patients, whereas a 20±9% reduction was observed in the control subjects. The ET
A
receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102±25%) in the patients compared with no effect in the control subjects (−3±9%,
P
<0.001 versus patients). The ET
A
receptor antagonist BQ123 increased FBF to a similar degree in patients (39±11%) as in control subjects (41±11%). The increase in FBF evoked by selective ET
A
receptor blockade was significantly (
P
<0.05) less than that evoked by combined ET
A
/ET
B
receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1–mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ET
B
-mediated vasoconstriction.
T-786C Polymorphism in Endothelial NO Synthase Gene Affects Cerebral Circulation in Smokers
Authors: Nasreen Shampa , Nabika Toru , Shibata Hiroshi , Moriyama Hidehiko , Yamashita Kazuya , Masuda Junichi , Kobayashi Shotai
Published: July 2002

Effects of smoking on white matter lesions, such as lacunar infarction and leukoaraiosis, are still controversial. We hypothesized that the endothelial NO synthase (eNOS) genotype was a modulating factor for the effect of smoking on cerebral circulation. We took a cross-sectional population from the participants of a health examination to study the effects of smoking and a single-nucleotide polymorphism in the eNOS gene, T-786C. Smokers and nonsmokers were defined as having a smoking index (cigarettes per day times years) of ≥200 and 0, respectively. One hundred sixty-six male nonsmokers and 344 male smokers were recruited. Cerebral blood flow was measured by the
133
Xe inhalation method. Genotyping of T-786C was performed by using a newly developed allele-specific polymerase chain reaction. Smokers were exposed to greater oxidative stress, as estimated by urinary F
2
-isoprostane excretion. In smokers, CC homozygotes of T-786C showed a significant decrease of cerebral blood flow (56.6±13.3, 57.6±11.5, and 44.0±7.2 mL/min per 100 g tissue for TT, TC, and CC, respectively;
P
=0.03 by ANOVA) and a significant increase of cerebrovascular resistance, whereas the eNOS genotype did not affect these parameters in nonsmokers. This result indicated that the eNOS genotype could modify cerebrovascular circulation in a general population by potentiating the adverse effect of smoking.
Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules
Authors: Broeders Martijn A.W. , Tangelder Geert Jan , Slaaf Dick W. , Reneman Robert S. , oude Egbrink Mirjam G.A.
Published: July 2002

We investigated in vivo the effect of cholesterol diet–induced hypercholesterolemia (HC) on thromboembolism in nonatherosclerotic rabbit mesenteric arterioles and venules (diameter 21 to 45 μm). After mechanical vessel wall injury, the ensuing thromboembolic reaction was studied by intravital videomicroscopy. A dramatic prolongation of embolization duration (median >600 seconds) was observed in the arterioles of the HC group compared with the arterioles of a normal chow–fed (NC) control group (142 seconds,
P
<0.0001); concomitantly, relative thrombus height increased (thrombus height/vessel diameter was 68% for the HC group and 58% for the NC group;
P
<0.05). By contrast, in venules, cholesterol did not affect embolization duration (42 seconds for HC group, 34 seconds for NC group) and thrombus height (66% for HC group, 64% for NC group). Furthermore, the role of endothelial NO synthesis was studied. In arterioles, stimulation of endogenous NO synthesis through mesenteric superfusion of
l
-arginine (1 mmol/L) completely reversed cholesterol-enhanced embolization (152 seconds) but did not influence thrombus height (63%).
l
-Arginine had no effect in venules of the HC group (51 seconds) and nor in the arterioles and venules of the NC group (177 seconds for arterioles, 43 seconds for venules). This study indicates that hypercholesterolemia selectively enhances thrombus formation and embolization in arterioles but not in venules and that stimulation of endogenous NO production antagonizes this enhancement of arteriolar thromboembolism.
Induction of Plasminogen Activator Inhibitor-1 in Endothelial Cells by Basic Fibroblast Growth Factor and Its Modulation by Fibric Acid
Authors: Kaneko Takeaki , Fujii Satoshi , Matsumoto Akio , Goto Daisuke , Ishimori Naoki , Watano Keiko , Furumoto Tomoo , Sugawara Taeko , Sobel Burton E. , Kitabatake Akira
Published: July 2002

Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis and proteolysis. Basic fibroblast growth factor (bFGF) stimulates angiogenesis, which requires regional proteolysis. Because modulation of vasculopathy requires tight control of proteolysis, effects of bFGF on PAI-1 expression in endothelial cells (ECs) were characterized. bFGF increased PAI-1 mRNA and accumulation of PAI-1 protein in conditioned media in human umbilical vein ECs. The bFGF-mediated increase in PAI-1 mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. The rate of decrease in PAI-1 mRNA after actinomycin D treatment was not affected by bFGF. Transient transfection assays of the human PAI-1 promoter-luciferase construct demonstrated that bFGF-induced PAI-1 transcription was dependent on the elements within the −313 to −260 bp relative to the transcription start site. This region contains an E26 transformation specific 1 (Ets-1)-like site. Electrophoretic mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of the Ets-1-like transcription factor to the PAI-1 promoter. Nucleotide substitution to disrupt the Ets-1-like site reduced bFGF-stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator-activated receptor-α, inhibited basal and bFGF-stimulated PAI-1 expression. By inducing PAI-1 expression from ECs, bFGF may control proteolysis and fibrinolysis in vessel walls.
PAR-4 Agonist AYPGKF Stimulates Thromboxane Production by Human Platelets
Authors: Henriksen Ruth Ann , Hanks Vallere K.
Published: July 2002

Previous reports have indicated that thrombin-induced thromboxane production by human platelets occurs through two types of interaction between thrombin and the platelet surface. One of these interactions is with protease activated receptor(PAR)-1, the first identified thrombin receptor. These studies were undertaken to determine whether stimulation of PAR-4 also results in thromboxane production. The results show that treatment of washed human platelets with the PAR-4 agonist AYPGKF stimulates a maximum of 40% to 60% of the thromboxane produced by 100 nmol/L thrombin. Maximal thromboxane production requires approximately 1.0 mmol/L AYPGKF, despite the observation that maximal aggregation is produced by 45 μmol/L AYPGKF. Thromboxane produced by the combined stimulation of PAR-1 and PAR-4 is additive. Pretreatment of platelets with 45 μmol/L AYPGKF partially desensitizes thromboxane production in response to higher concentrations of AYPGKF and thrombin but not to stimulation by SFLLRN. PAR-4–induced stimulation is also significantly inhibited by 60 μmol/L genistein. It is concluded that activation through either PAR-1 or PAR-4 results in thromboxane production, but that stimulation of neither receptor alone produces thromboxane equivalent to that produced by 100 nmol/L thrombin. Thus, these findings demonstrate the presence of two pathways for thrombin-induced thromboxane production by platelets as proposed previously.
Lysophosphatidylcholine Activates Extracellular Signal-Regulated Kinases 1/2 Through Reactive Oxygen Species in Rat Vascular Smooth Muscle Cells
Authors: Yamakawa Tadashi , Tanaka Shun-ichi , Yamakawa Yuko , Kamei Junzo , Numaguchi Kotaro , Motley Evangeline D. , Inagami Tadashi , Eguchi Satoru
Published: July 2002

Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants,
N
-acetyl-
l
-cysteine, glutathione monoester, or α -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of
c-fos
expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.
CCAAT/Enhancer-Binding Protein Decoy Oligodeoxynucleotide Inhibition of Macrophage-Rich Vascular Lesion Formation in Hypercholesterolemic Rabbits
Authors: Kelkenberg Ute , Wagner Andreas H. , Sarhaddar Jasmin , Hecker Markus , von der Leyen Heiko E.
Published: July 2002

Many cytokine genes, including those encoding acute-phase proteins and immunoglobulins, share binding sites for the CCAAT/enhancer-binding protein (C/EBP) in their 5′-flanking regions, and C/EBP-related transcription factors regulate cell proliferation during terminal differentiation. Therefore, C/EBP represents an attractive target for inhibiting restenosis after balloon angioplasty. In a rabbit model of restenosis that combines balloon injury of the carotid artery with cholesterol-mediated chronic inflammation, a decoy oligodeoxynucleotide (ODN) capable of neutralizing C/EBP was administered to the site of injury for 30 minutes. Electrophoretic mobility shift analysis confirmed that C/EBP activity in decoy ODN–treated segments was virtually absent after 2 days. Morphometric analysis after 28 days revealed significant reduction (up to 50%) of neointimal formation and intravascular inflammation in decoy ODN–treated segments compared with mutant control ODN or vehicle-treated segments. In addition, de novo synthesis of endothelin-1 and the number of proliferating cell nuclear antigen–positive smooth muscle cells in the vessel wall were markedly attenuated at day 3. These findings suggest that decoy ODN–based neutralization of C/EBP may be a feasible and effective method to limit restenosis after angioplasty brought about, at least in part, by inhibiting the de novo synthesis of endothelin-1.
Regulation of Endothelial Cell Survival and Apoptosis During Angiogenesis
Authors: Chavakis Emmanouil , Dimmeler Stefanie
Published: July 2002

The process of angiogenesis plays an important role in many physiological and pathological conditions. Inhibition of endothelial cell (EC) apoptosis providing EC survival is thought to be an essential mechanism during angiogenesis. Many of the angiogenic growth factors inhibit EC apoptosis. In addition, the adhesion of ECs to the extracellular matrix or intercellular adhesion promotes EC survival. In contrast, increasing evidence suggests that the induction of EC apoptosis may counteract angiogenesis. In this review, we focus on the regulation of EC survival and apoptosis during angiogenesis and especially on the effects and intracellular signaling promoted by angiogenic growth factors, endogenous angiogenic inhibitors (such as angiostatin, endostatin, and thrombospondin-1), and the adhesion to the extracellular matrix. Furthermore, we discuss the effects of cross talk between adhesion molecules and growth factors. Understanding the molecular mechanisms involved in the regulation of EC survival and apoptosis may provide new targets for the development of new therapies to enhance angiogenesis in the case of tissue-ischemia (eg, the neovascularization of myocardium) or to inhibit angiogenesis in the case of neovascularization-dependent disease (eg, tumor, diabetic retinopathy).
Lp(a) Particles Mold Fibrin-Binding Properties of Apo(a) in Size-Dependent Manner
Authors: Kang Chantal , Dominguez Miguel , Loyau Stéphane , Miyata Toshiyuki , Durlach Vincent , Anglés-Cano Edouard
Published: July 2002

Objective

—

Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes.

Methods and Results

—

Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (
K
d
3.6±0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC
50
16.8±5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (
K
d
2.5 versus 10.5 nmol/L and
K
d
3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC
50
0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10.

Conclusions

—

Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.
Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients
Authors: Sampson M.J. , Davies I.R. , Brown J.C. , Ivory K. , Hughes D.A.
Published: July 2002

Objective—We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive.

Methods and Results—Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P<0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P=0.03).

Conclusions—Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.
Nuclear Magnetic Resonance Spectroscopy of Lipoproteins and Risk of Coronary Heart Disease in the Cardiovascular Health Study
Authors: Kuller Lewis , Arnold Alice , Tracy Russell , Otvos James , Burke Greg , Psaty Bruce , Siscovick David , Freedman David S. , Kronmal Richard
Published: July 2002

Objectives

—

Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.

Methods and Results

—

The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 “healthy” participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between “healthy” participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.

Conclusions

—

Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.
Cholesteryl Ester Transfer Protein

Taq

I B2B2 Genotype Is Associated With Higher HDL Cholesterol Levels and Lower Risk of Coronary Heart Disease End Points in Men With HDL Deficiency
Authors: Brousseau Margaret E. , O’Connor John J. , Ordovas Jose M. , Collins Dorothea , Otvos James D. , Massov Tatyana , McNamara Judith R. , Rubins Hanna B. , Robins Sander J. , Schaefer Ernst J.
Published: July 2002

Objective

—

We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP)
Taq
IB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level.

Methods and Results

—

We tested for associations between the CETP
Taq
IB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (≤40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (−27%,
P
<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%,
P
<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6±4.8 mg/dL), followed by B1B2 men (32.0±5.3 mg/dL), and, last, by B1B1 men (30.9±4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (−34%,
P
=0.006). CETP
Taq
IB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (
P
=0.08).

Conclusions

—

Our data demonstrate that in men with CHD and HDL deficiency, the CETP
Taq
I B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.
Peroxisome Proliferator-Activated Receptor α Gene Variants Influence Progression of Coronary Atherosclerosis and Risk of Coronary Artery Disease
Authors: Flavell David M. , Jamshidi Yalda , Hawe Emma , Pineda Torra Inés , Taskinen Marja-Riitta , Frick M. Heikki , Nieminen Markku S. , Kesäniemi Y. Antero , Pasternack Amos , Staels Bart , Miller George , Humphries Steve E. , Talmud Philippa J. , Syvänne Mikko
Published: July 2002

Background

—

Peroxisome proliferator-activated receptor α (PPARα) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD).

Methods and Results

—

We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARα gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism

Conclusions

—

The PPARα gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARα affects atherosclerotic progression directly in the vessel wall.
Acute Pulmonary Embolectomy
Authors: Aklog Lishan , Williams Christopher S. , Byrne John G. , Goldhaber Samuel Z.
Published: July 2002

Background

—

Acute pulmonary embolism confers a high mortality rate despite advances in diagnosis and therapy. Thrombolysis is often effective but has a high frequency of major bleeding complications, especially intracranial hemorrhage. Therefore, we liberalized our criteria for acute pulmonary embolectomy and considered operating on patients with anatomically extensive pulmonary embolism and concomitant moderate to severe right ventricular dysfunction despite preserved systemic arterial pressure.

Methods and Results

—

We report 29 (17 men and 12 women) consecutive patients who underwent embolectomy from October 1999 through October 2001. Twenty-six patients (89%) survived surgery and were alive more than 1 month postoperatively. Median follow-up is 10 months.

Conclusion

—

The high survival rate of 89% can be attributed to improved surgical technique, rapid diagnosis and triage, and careful patient selection. We hope that other tertiary centers will evaluate pulmonary embolism patients with an algorithm that includes surgical embolectomy as one of several therapeutic options. Our contemporary approach to pulmonary embolectomy no longer confines this operation to a treatment of last resort reserved for clinically desperate circumstances.
Paradoxical Pressor Effects of β-Blockers in Standing Elderly Patients With Mild Hypertension
Authors: Cleophas T.J. , Grabowsky I. , Niemeyer M.G. , Mäkel W.M. , van der Wall E.E.
Published: July 2002

Background—

Baroreflex sensitivity declines with age, creating a fall in systolic blood pressure and pulse pressure when standing. If, in addition, blood pressure is reduced as a result of antihypertensive medication, compensatory mechanisms may be inadequate and orthostatic problems may occur. This may be less true in patients on β-blockers. β-blockers cause pressor effects in standing patients with autonomic neuropathy, but their effects on standing pulse pressures in elderly subjects with mild hypertension have not been systematically studied.

Methods and Results—

We studied 3741 patients with mild hypertension for 6 months who were being treated with the β-blocker nebivolol 5 mg daily. Blood pressures were measured after 10 minutes in the supine position and after 1 minute in the standing position. Overall, systolic and diastolic blood pressures rose slightly while standing, whereas pulse pressures remained unchanged. When previously untreated patients (n=2085) >60 and <60 years of age were assessed separately, supine pulse pressures were consistently higher in the elderly group compared with those of the younger subjects by 6 to 11 mm Hg (
P
<0.001 to 0.0001). However, while standing, pulse pressures rose in the younger subjects, whereas they tended to fall in the elderly group. After 6 months of β-blockade, this pattern was unchanged in the younger subjects but reversed into significant rise of pulse pressures in the elderly group by 4 (SD 1) mm Hg (
P
<0.001). In the patients previously treated with other classes of antihypertensive drugs (n=712), the effects were essentially the same.

Conclusions—

In elderly patients with mild hypertension, a depressor trend of pulse pressure while standing can be turned into a significant pressor response by treatment with a β-blocker.
Expression of Macrophage Migration Inhibitory Factor in Different Stages of Human Atherosclerosis
Authors: Burger-Kentischer Anke , Goebel Heike , Seiler Rüdiger , Fraedrich Gustav , Schaefer Hans E. , Dimmeler Stefanie , Kleemann Robert , Bernhagen Jürgen , Ihling Christian
Published: July 2002

Background

—

Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. Macrophage migration inhibitory factor (MIF), a cytokine with potent inflammatory functions, was thus considered to be important in atherosclerotic lesion evolution.

Methods and Results

—

We studied the presence and distribution of MIF immunoreactivity (MIF-IR) and MIF mRNA in internal mammary arteries with a normal histology and arteries with plaques in different stages of human atherosclerosis. To address a potential role for the coactivator Jab1 as a cellular mediator of MIF effects in vascular tissue, we correlated the expression of MIF to that of Jab1 by using immunohistochemistry and coimmunoprecipitation. We further sought to determine a potential functional role for endothelium-derived MIF in early atherogenesis by studying the effects of oxidized LDL on MIF expression in cultured human umbilical vascular endothelial cells. The results showed that MIF-IR and Jab1-IR are found in all cell types present in atherosclerotic lesions, that MIF-IR is upregulated during progression of atherosclerosis, that MIF is produced locally in the arterial wall, and that all MIF
+
cells are simultaneously Jab1
+
. Coimmunoprecipitation experiments demonstrated in vivo complex formation between MIF and Jab1 in plaques. MIF expression in human umbilical vascular endothelial cells and a macrophage line was upregulated after stimulation with oxidized LDL.

Conclusions

—

MIF is produced abundantly by various cells in all types of human atherosclerotic lesions and thus may play an important role in early plaque development and advanced complicated lesions. MIF-Jab1 complexes could serve critical regulatory functions in atherosclerotic lesion evolution.
Increased Myocardial Gene Expression of Tumor Necrosis Factor-α and Nitric Oxide Synthase-2
Authors: Kalra Dinesh K. , Zhu Xi , Ramchandani Mahesh K. , Lawrie Gerald , Reardon Michael J. , Lee-Jackson Dorellyn , Winters William L. , Sivasubramanian Natarajan , Mann Douglas L. , Zoghbi William A.
Published: July 2002

Background

—

Whether cardioinhibitory cytokines are elevated in regions of hibernating myocardium and account in part for the depression in resting function is currently not known.

Methods and Results

—

Thirteen patients with stable ischemic ventricular dysfunction scheduled for bypass surgery underwent preoperative dobutamine echocardiography (DE) and intraoperative myocardial biopsies. The numbers of copies of mRNA for the negatively inotropic cytokines tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (NOS2) were quantified by reverse transcription–polymerase chain reaction. In normal segments, myocardial TNF-α was barely detectable (1.2±0.4 copies per 10
6
copies of β-actin). A 13.7-fold increase in myocardial TNF-α was observed in dysfunctional segments with a biphasic response to DE (contractile reserve and ischemia) and was highest (45.5-fold) in segments with ischemia and without contractile reserve (
P
<0.001). A similar graded increase was seen for NOS2. Cytokine results were also similar if analysis was performed using recovery of function at 3 months as the index of viability. The change in serum TNF-α and nitrite levels from baseline to 3 months after surgery correlated inversely with both the change in ejection fraction and the number of DE viable segments (
r
=−0.92 to −0.93;
P
<0.001).

Conclusions

—

TNF-α and NOS2 gene expression is regionally upregulated in hibernating myocardium to a level intermediate between that of normal regions and ischemic regions without contractile reserve. This, along with a decline in serum cytokine levels after revascularization proportional to the extent of myocardial viability, suggests a contributing role for cardioinhibitory cytokines in the observed depression of function seen in hibernating myocardium.
Effects of Sustained-Release Moxonidine, an Imidazoline Agonist, on Plasma Norepinephrine in Patients With Chronic Heart Failure
Authors: Swedberg Karl , Bristow Michael R. , Cohn Jay N. , Dargie Henry , Straub Matthias , Wiltse Curtis , Wright Theressa J.
Published: July 2002

Background
—

In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure.

Methods and Results
—

A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events.

Conclusions
—

Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.