bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient summarization of spatiotemporal events
Authors: Agouris Peggy , Stefanidis Anthony
Published: January 2003

Raster datasets at discrete temporal instances capture a variety of spatiotemporal phenomena. These phenomena and the respective datasets that capture them may span various spatial and temporal scales, like a car's trajectory as it is captured by various cameras at video rates, or the long-term erosion of a river's edge captured by an annual series of aerial imagery.
IT research, innovation, and e-government
Authors: Scherlis William L. , Eisenberg Jon
Published: January 2003

Over the past few years, the basic outline of an e-government vision has emerged, and government has taken promising steps to deploy e-government services. Much remains to be done, however, both in implementing e-government services and in developing new technologies and concepts, if the e-government vision is to be broadly realized. A recent study by the National Research Council's Computer Science and Telecommunications Board [2] examines several aspects of this challenge. It identifies areas where government is a demand leader for IT, explores the roles of IT researchers in risk-managed e-government innovation, and discusses approaches that can help accelerate innovation and foster the transition of innovative technologies from the lab to operational systems.
A personal history of the NSF digital government program
Authors: Ciment Melvyn
Published: January 2003

The NSF Digital Government Program has its roots (circa 1993) in the NSF High-Performance Computing and Communications Program, and NSF's National Center for Supercomputing Applications (NCSA) at the University of Illinois. It was the creation of NCSA's Mosaic software suite of browsers and servers that prompted Larry Brandt, then a Program Manager for the NSF Supercomputer Centers Program, to start promoting a concept of driving innovative IT into government functions and services. At the time, I was Deputy Assistant Director for Computer Information Sciences and Engineering (CISE)
1

and Brandt invited me to look at a demo of Mosaic. I was amazed and felt privileged to gaze into the future of a new software paradigm---the genesis of the Web.
Barriers to effective use of knowledge management systems in software engineering
Authors: Desouza Kevin C.
Published: January 2003

An organization must recognize that information technology is only one means to foster knowledge.
Effects of Chronic Treatment With
l
-Arginine on Atherosclerosis in ApoE Knockout and ApoE/Inducible NO Synthase Double-Knockout Mice
Authors: Chen Jiqiu , Kuhlencordt Peter , Urano Fumi , Ichinose Hiroshi , Astern Joshua , Huang Paul L.
Published: January 2003

Objective—

l
-Arginine serves as a substrate for the formation of NO by the NO synthase (NOS) enzymes. In some studies, dietary supplementation of
l
-arginine reduces atherosclerosis through the restoration of NO release and improvement in endothelial function. In the present study, we investigate the effect of
l
-arginine supplementation on the development of atherosclerosis in a mouse model.

Methods and Results—

Apolipoprotein E (apoE) knockout (ko) and apoE/inducible NOS (iNOS) double-ko mice were fed a western-type diet with or without
l
-arginine supplementation in the drinking water (25 g/L).
l
-Arginine did not affect the lesion area after 16 weeks or 24 weeks in apoE ko mice. However,
l
-arginine negates the protective effect of iNOS gene deficiency. In contrast to apoE/iNOS dko mice without arginine supplementation, lesion areas were increased in apoE/iNOS double-ko mice with arginine supplementation at 24 weeks. This was associated with an increase in thiobarbituric acid-reactive malondialdehyde adducts, nitrotyrosine staining within lesions, and a decrease in the ratio of reduced tetrahydrobiopterin to total biopterins.

Conclusions—

Although
l
-arginine supplementation does not affect lesion formation in the western-type diet-fed apoE ko mice, it negates the protective effect of iNOS gene deficiency in this model. This raises the possibility that
l
-arginine supplementation may paradoxically contribute to, rather than reduce, lesion formation by mechanisms that involve lipid oxidation, peroxynitrite formation, and NOS uncoupling.
Effects of Hyperfibrinogenemia on Vasculature of C57BL/6 Mice With and Without Atherogenic Diet
Authors: Gulledge Alyssa A. , McShea Cynthia , Schwartz Todd , Koch Gary , Lord Susan T.
Published: January 2003

Objective—

Elevated fibrinogen is correlated with severe atherosclerosis, as defined by the occurrence of ischemic events, but the mechanistic basis for this correlation remains unknown. To study this relationship, we examined spontaneous and diet-induced atherosclerosis in transgenic mice with hyperfibrinogenemia (elevated fibrinogen).

Methods and Results—

Normal and transgenic mice were fed either an atherogenic diet or simple breeder chow. We measured plasma fibrinogen levels and identified an age-dependent and diet-dependent increase in fibrinogen. After 8 to 12 months, aortic sections were prepared and stained, and lipid-containing lesions were counted, measured, and assessed for maturity. Lipid-filled deposits appeared spontaneously in a small number of mice on breeder chow; typical fatty streak-type lesions appeared in almost all of the diet-fed animals. Morphometric analysis showed that neither the number nor the size of lesions was influenced by either fibrinogen level or genotype.

Conclusions—

Our data showed that neither fibrinogen concentration nor genotype had a statistically significant effect on the initiation, initial growth, or early progression of atherosclerotic lesions.
Influence of Factor VIIa and Phospholipids on Coagulation in “Acquired” Hemophilia
Authors: Butenas Saulius , Brummel Kathleen E. , Paradis Sara G. , Mann Kenneth G.
Published: January 2003

Objective—

This study was performed to evaluate the influences of phospholipids and recombinant factor VIIa (rFVIIa) on thrombin generation and clot formation in “acquired” hemophilia B.

Methods and Results—

A synthetic mixture corresponding to hemophilia A (SHA) and “acquired” hemophilia B blood (AHBB) manufactured in vitro by an anti-FIX antibody were used in this study. With 10 pmol/L tissue factor (TF), 10 nmol/L rFVIIa, and saturating phospholipid, established thrombin generation in SHA was similar to that observed in the presence of factor VIII and rFVIIa at physiological concentrations. At lower phospholipid concentrations, thrombin generation was delayed and reduced. With 5 pmol/L TF, contact pathway-inhibited AHBB clotted later than normal blood and showed reduced clot stability and thrombin generation. These parameters of effectiveness were increased by the addition of phospholipids to AHBB, which restored clot stability and increased thrombin generation. No correction of clot formation or thrombin generation was observed when rFVIIa and phospholipids were added to AHBB in the absence of TF.

Conclusions—

The influence of rFVIIa is dependent on TF, and phospholipids substantially increase the hemostatic (or thrombotic) potential of rFVIIa/TF.
Cardiac Ankyrin Repeat Protein (CARP) Expression in Human and Murine Atherosclerotic Lesions
Authors: de Waard Vivian , van Achterberg Tanja A.E. , Beauchamp Nicholas J. , Pannekoek Hans , de Vries Carlie J.M.
Published: January 2003

Objective—

Cardiac ankyrin repeat protein (CARP) is a transcription factor-related protein that has been studied most extensively in the heart. In the present study, we investigated the expression and the potential function of CARP in human and murine atherosclerosis.

Methods and Results—

CARP expression was observed by in situ hybridization in endothelial cells lining human atherosclerotic plaques, whereas lesion macrophages were devoid of CARP. Furthermore, we established that CARP mRNA and smooth muscle (SM) α-actin antigen both colocalized in a subset of intimal smooth muscle cells (SMCs), whereas no CARP mRNA was encountered in quiescent SMCs in the media. The CARP mRNA-expressing intimal SMCs were distinct from intimal SMCs that synthesized the activation marker osteopontin or proliferating cell nuclear antigen. In addition, we showed that activin A, a member of the TGFβ superfamily that prevents SMC-rich lesion formation, induced CARP mRNA expression in cultured SMCs.

Conclusions—

Based on our data and the knowledge that CARP reduces the proliferation of cultured SMCs, we propose that CARP is involved in inhibition of vascular lesion formation.
Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice
Authors: Shamir Raanan , Shehadeh Naim , Rosenblat Mira , Eshach-Adiv Orly , Coleman Raymond , Kaplan Marielle , Hamoud Shadi , Lischinsky Sophie , Hayek Tony
Published: January 2003

Objective—

The role of insulin in atherosclerosis progression in diabetes is uncertain. We examined the effects of oral insulin supplementation on atherogenesis in apolipoprotein E-deficient (E
0
) mice.

Methods and Results—

One-month-old male E
0
mice were orally supplemented with human insulin (0.1, 0.5, and 1 U/mL) or placebo for 3 months. At the end of the study, serum and macrophage oxidative stress and atherosclerosis progression were studied. Insulin reduced lesion size by 22% to 37% (
P
<0.05) in all study groups. Lipid peroxides serum levels were 18% lower (
P
<0.01), and serum paraoxonase activity was 30% higher (
P
<0.01) in mice supplemented with 1.0 U/mL insulin compared with controls. Insulin reduced mouse peritoneal macrophage (MPM) lipid peroxides content and superoxide anion release by up to 44% and 62%, respectively (
P
<0.01). In addition, oral insulin reduced MPM cholesterol content and cholesterol biosynthesis by up to 36% and 53%, respectively (
P
<0.01). In vitro incubation of E
0
mice MPM with increasing insulin concentrations (0 to 100 μU/mL) resulted in a dose-dependent reduction of cholesterol synthesis by up to 66% (
P
<0.05).

Conclusions—

In E
0
mice, oral insulin supplementation attenuates the atherosclerotic process. This may be attributable to insulin-mediated reduction of oxidative stress in serum and macrophages as well as reduction in macrophage cholesterol content.
Extrahepatic Synthesis of Factor VII in Human Atherosclerotic Vessels
Authors: Wilcox Josiah N. , Noguchi Sumiko , Casanova Juan
Published: January 2003

Objective—

Coagulation is initiated by the interaction of tissue factor (TF) with plasma coagulation factors VII (FVII) and X (FX). TF is highly expressed in atherosclerotic lesions, but little is known about the synthesis of FX or FVII outside of the liver. Previous studies suggested that macrophages synthesize FVII. We therefore hypothesized that macrophages within atherosclerotic lesions may produce FVII, leading to partial activation of the coagulation cascade.

Methods and Results—

Immunohistochemistry was performed using antibodies against FVII, FX, and TF on normal and atherosclerotic vessels. In atherosclerotic lesions, FVII immunostaining was colocalized with TF in macrophages and spindle-shaped smooth muscle cells. FVII mRNA was also detected in these cells using in situ hybridization, suggesting the local synthesis of FVII in atherosclerosis. Reverse transcriptase–polymerase chain reaction confirmed the presence of FVII mRNA in normal and atherosclerotic vessels as well as smooth muscle cells, fibroblasts, and keratinocytes in vitro.

Conclusions—

The localization of FVII synthesis outside the liver may be indicative of other cellular functions for this coagulation protein. The observed coexpression of TF and FVII may contribute to autocrine signaling via thrombin-independent mechanisms and may represent a novel mechanism contributing to growth in the setting of vascular disease.
HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells
Authors: Dichtl Wolfgang , Dulak Jozef , Frick Matthias , Alber Hannes F. , Schwarzacher Severin P. , Ares Mikko P.S. , Nilsson Jan , Pachinger Otmar , Weidinger Franz
Published: January 2003

Objective—

Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation.

Methods and Results—

Simvastatin, atorvastatin, and lovastatin (0.1 to 10 μmol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-κB or AP-1–dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IκB-α protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1α. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells.

Conclusions—

HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-κB, AP-1, and hypoxia-inducible factor-1α. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.
Nutritionally Induced Obesity Is Attenuated in Transgenic Mice Overexpressing Plasminogen Activator Inhibitor-1
Authors: Lijnen H. Roger , Maquoi Erik , Morange Pierre , Voros Gabor , Van Hoef Berthe , Kopp Francis , Collen Désiré , Juhan-Vague Irène , Alessi Marie-Christine
Published: January 2003

Objective—

The objective of this study was to investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue development in vivo.

Methods and Results—

Transgenic (Tg) mice overexpressing murine PAI-1 under control of the adipocyte promoter aP2 and wild-type (WT) controls were kept on standard food (SFD) or on high-fat diet (HFD) for 15 weeks. The body weight and the weight of the isolated subcutaneous and gonadal fat deposits of the Tg mice kept on the HFD were significantly lower than those of the WT mice. The number of adipocytes in the adipose tissue was similar for Tg and WT mice on the HFD, but adipocyte hypotrophy and a significantly lower ratio of stroma cells/adipocytes were observed in the Tg mice. A significant negative correlation (
P
<0.01) was observed between expression of preadipocyte factor-1, which blocks adipocyte differentiation, and adipose tissue weight. Fasting insulin and total cholesterol levels on the HFD were lower in Tg than in WT mice.

Conclusions—

High circulating PAI-1 levels attenuate nutritionally induced obesity. This may be related to modifications in adipose tissue cellularity affecting weight and plasma metabolic parameters.
Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells
Authors: Calnek David S. , Mazzella Louis , Roser Susanne , Roman Jesse , Hart C. Michael
Published: January 2003

Objective—

Peroxisome proliferator-activated receptor γ (PPARγ) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPARγ ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall.

Methods and Results—

The PPARγ ligands, 15-deoxy-Δ
12,14
-prostaglandin J
2
(15d-PGJ
2
) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPARγ was transcriptionally functional. Treatment with 15d-PGJ
2
or ciglitazone significantly increased release of ·NO from PAECs or human aortic endothelial cells and augmented calcium ionophore–induced ·NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in ·NO release caused by treatment with 15d-PGJ
2
occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor α-amanitin. Overexpression of PPARγ or treatment with 9-cis retinoic acid also enhanced PAEC ·NO release. Neither 15d-PGJ
2
nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ
2
, but not ciglitazone, decreased eNOS protein.

Conclusions—

Taken together, these findings demonstrate that PPARγ ligands stimulate ·NO release from endothelial cells derived from multiple vascular sites, through a transcriptional mechanism unrelated to eNOS expression.
Hormone Replacement Therapy and Risk of Cardiovascular Disease
Authors: Kuller Lewis H.
Published: January 2003

The higher rates of coronary heart disease (CHD), stroke, and venous thrombosis among women taking estrogen and progesterone (E+P) compared with placebo in the Women’s Health Initiative clinical trial have important implications for women’s health. Previous studies in both men and women have shown that estrogen therapy lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol. The changes in these lipoproteins should be associated with at least a 30% decline in CHD risk. Estrogens increased very-low-density lipoprotein (VLDL) triglyceride levels and C-reactive protein. There is evidence that estrogens increase thrombin generation and fibrinolysis. The increase in VLDL triglycerides may enhance thrombotic risk as well as higher levels of atherogenic lipoproteins, such as dense low-density lipoprotein. Genetic variations in estrogen receptors and thrombosis or fibrinolysis may also be important in risks associated with E+P therapy. The increased risk of CHD and stroke with E+P therapy may be attributable to rise in VLDL triglycerides and thrombosis.
Synergistic Activation of Human LDL Receptor Expression by SCAP Ligand and Cytokine Oncostatin M
Authors: Liu Jingwen , Zhang Fang , Li Cong , Lin Meihong , Briggs Michael R.
Published: January 2003

Objective—

A recent study identified a new class of compounds designated as the sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) ligands that putatively bind to SCAP, leading to increased LDL receptor (LDLR) expression. In this study, we examined the effects of SCAP ligand GW707 in comparison with lovastatin and cytokine oncostatin M (OM) on the regulation of LDLR expression in cultured HepG2 cells.

Methods and Results—

Our studies uncovered several new features that distinguish SCAP ligand from lovastatin, a classic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and from OM, which utilize an SREBP-independent regulatory pathway. We show that the induction of LDLR mRNA expression by GW707 is not affected by intracellular cholesterol but is completely abolished by blocking de novo protein synthesis. Moreover, the effects of GW707 but not lovastatin on LDLR promoter activity, mRNA expression, and uptake of 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanin perchlorate–LDL are markedly enhanced by OM. We further demonstrate that the amounts of the mature form of SREBP-2 translocated to the nucleus under GW707 treatment are increased by costimulating cells with OM.

Conclusions—

Our studies provide the first evidence that higher levels of LDLR expression and function can be achieved through simultaneous stimulation of the SREBP-dependent and SREBP-independent pathways, suggesting a strategy to develop an adjunct therapeutic intervention utilizing both pathways.
Functional Interplay Between Angiotensin II and Nitric Oxide
Authors: Yan Chen , Kim Dongsoo , Aizawa Toru , Berk Bradford C.
Published: January 2003

Angiotensin II (Ang II) and nitric oxide (NO) signaling pathways mutually regulate each other by multiple mechanisms. Ang II regulates the expression of NO synthase and NO production, whereas NO downregulates the Ang II type I (AT1) receptor. In addition, downstream effectors of Ang II and NO signaling pathways also interact with each other. A feedback mechanism between Ang II and NO is critical for normal vascular structure and function. Imbalance of Ang II and NO has been implicated in the pathophysiology of many vascular diseases. In this review, we focus on the diverse ways in which Ang II and NO interact and the importance of the balance between the signaling pathways activated by these mediators.
The Dynamics of Thrombin Formation
Authors: Mann Kenneth G. , Butenas Saulius , Brummel Kathleen
Published: January 2003

The central event of the hemostatic process is the generation of thrombin through the tissue factor pathway. This is a highly regulated, dynamic process in which thrombin itself plays many roles, positively and negatively its production and destruction. The hemostatic process is essential to normal physiology and is also the Achilles heel of our aging population. The inappropriate generation of thrombin may lead to vascular occlusion with the consequence of myocardial infarction, stroke, pulmonary embolism, or venous thrombosis. In this review, we summarize our present views regarding the tissue factor pathway by which thrombin is generated and the roles played by extrinsic and intrinsic factor Xa generating complexes in hemostasis and the roles of the stoichiometric and dynamic inhibitors that regulate thrombin generation.
Effect of Peroxisome Proliferator–Activated Receptor-α and -γ Activators on Vascular Remodeling in Endothelin-Dependent Hypertension
Authors: Iglarz Marc , Touyz Rhian M. , Amiri Farhad , Lavoie Marie-France , Diep Quy N. , Schiffrin Ernesto L.
Published: January 2003

Objective—

Peroxisome proliferator–activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)–salt rats that overexpress vascular ET-1.

Methods and Results—

Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (n=6 each): control group, DOCA-salt group, DOCA-salt+PPAR-γ activator (rosiglitazone, 5 mg · kg
−1
· d
−1
), or DOCA-salt+PPAR-α activator (fenofibrate, 100 mg · kg
−1
· d
−1
). Systolic blood pressure was significantly increased in the DOCA-salt group (240±11 vs 121±2 mm Hg in Uni-Nx,
P
<0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172±3 mm Hg vs DOCA-salt,
P
<0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3±0.9% vs 4.9±0.5% in Uni-Nx rats,
P
<0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals.

Conclusions—

PPAR-α and -γ activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension.
Serum Plasma Pregnancy-Associated Protein A
Authors: Beaudeux Jean-Louis , Burc Laurence , Imbert-Bismut Françoise , Giral Philippe , Bernard Maguy , Bruckert Eric , Chapman M. John
Published: January 2003

Objective—

The proteolytic activity of metalloproteinases, proinflammatory enzymes that degrade extracellular matrix, is elevated in lipid-rich atherosclerotic plaques, thereby contributing to plaque fragility and rupture. Pregnancy-associated plasma protein (PAPP-A) is a metalloproteinase, expressed in unstable atherosclerotic plaques, whose circulating levels are elevated in acute coronary syndromes. We evaluated serum PAPP-A levels as a marker of the premature development of atherosclerosis in hyperlipidemic subjects at elevated cardiovascular risk.

Methods and Results—

Serum PAPP-A levels were determined in asymptomatic hyperlipidemic male subjects (n=64; mean±SD age, 51±7 years) in whom intima-media thickness (IMT) and lesion status in the carotid artery were evaluated by noninvasive ultrasonography and compared with those of a normolipidemic control group (n=25). No difference was observed in circulating PAPP-A levels between hyperlipidemic subjects and controls (8.99±2.93 and 8.03±2.75 mIU/L, respectively; mean±SD) nor between hyperlipidemic subjects who presented with a luminal obstruction of the carotid artery (9.26±2.53 mIU/L) and those who did not (8.85±3.29 mIU/L). By contrast, in patients with atheromatous carotid plaques, a positive association between serum levels of PAPP-A and C-reactive protein was observed (
P
<0.05); moreover, subjects exhibiting hyperechoic or isoechoic, echogenic lesions had significantly higher PAPP-A levels compared with those with hypoechoic lesions (10.32±2.72 vs 8.27±2.18 mIU/L,
P
<0.05) and with normolipidemic controls (
P
<0.05).

Conclusions—

Elevated serum PAPP-A levels represent a potential marker of the degree of echogenicity of carotid atherosclerotic plaques in asymptomatic hyperlipidemic patients at high cardiovascular risk and equally of an enhanced local inflammatory state involving remodeling of subendothelial extracellular matrix.
Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (
LMNA
) With Partial Lipodystrophy
Authors: Hegele Robert A. , Kraw Maria E. , Ban Matthew R. , Miskie Brooke A. , Huff Murray W. , Cao Henian
Published: January 2003

Objective—

Dunnigan-type familial partial lipodystrophy (FPLD) due to mutant
LMNA
is a monogenic form of insulin resistance. Affected subjects, especially women, are at increased risk of early coronary heart disease (CHD). Although common insulin resistance is associated with several biochemical perturbations, including elevated C-reactive protein (CRP), the biochemical profile in subjects with mutant
LMNA
is incompletely defined.

Methods and Results—

We studied 35 nondiabetic adult FPLD subjects (of whom 24 were women) with either the
LMNA
R482Q or R482W missense mutations and 51 matched normal first-degree relatives (of whom 27 were women). Compared with normal controls,
LMNA
mutation carriers had significantly higher plasma insulin and more dyslipidemia, higher mean triglycerides and lower HDL cholesterol, significantly higher nonesterified free fatty acids and CRP, and significantly lower leptin and adiponectin than controls. Subgroup analyses showed that these differences were more pronounced in women. Other biomarkers such as resistin, fibrinogen, and plasminogen activator inhibitor-1 were not different between groups.

Conclusions—

LMNA
mutations in nondiabetic patients with FPLD are associated with several metabolic and biochemical changes, particularly in women. The unfavorable profile might contribute to the increased susceptibility to CHD seen in
LMNA
mutation carriers.
In Silico Quantitative Trait Locus Map for Atherosclerosis Susceptibility in Apolipoprotein E–Deficient Mice
Authors: Smith Jonathan D. , James Daylon , Dansky Hayes M. , Wittkowski Knut M. , Moore Karen J. , Breslow Jan L.
Published: January 2003

Objective—

Atherosclerosis susceptibility is a genetic trait that varies between mouse strains. The goal of this study was to use a public mouse single nucleotide polymorphism (SNP) database to define the genetic loci that are associated with this trait, without the need to perform strain intercrosses that are normally required to obtain these loci.

Methods and Results—

Apolipoprotein E (apoE)–deficient mice on 6 inbred genetic backgrounds were compared for atherosclerosis lesion size in the aortic root in 2 independent studies. After normalization to the C57BL/6 strain that was used in both studies, lesion areas were found in the following rank order: DBA/2J>C57BL/6>129/SV-ter>AKR/J≈BALB/cByJ≈C3H/HeJ. The log lesion difference in phenotypes between each of the 15 heterologous strain pairs was determined. A mouse SNP database was then used to calculate the genetic differences between the 15 strain pairs in partially overlapping 30-cM bins across the mouse genome. Correlation analyses were preformed to analyze the genetic and phenotypic differences among the strain pairs for each genetic region. The genetic regions with the highest correlations define the in silico quantitative trait loci (QTL) associated with the atherosclerosis phenotype. Five in silico atherosclerosis QTL were identified on chromosomes 1, 10, 14, 15, and 18. The loci on chromosomes 1, 10, 14, and 18 overlap with suggestive atherosclerosis QTL identified through analyses of an F
2
cohort derived from apoE-deficient mice on the C57BL/6 and FVB/N strains.

Conclusions—

The 5 identified in silico QTL are candidates for further study to confirm the presence and identity of atherosclerosis susceptibility genes within these loci.
The Serpin Protease-Nexin 1 Is Present in Rat Aortic Smooth Muscle Cells and Is Upregulated in
l
-NAME Hypertensive Rats
Authors: Bouton Marie-Christine , Richard Benjamin , Rossignol Patrick , Philippe Monique , Guillin Marie-Claude , Michel Jean-Baptiste , Jandrot-Perrus Martine
Published: January 2003

Objective—

Protease-nexin 1 (PN-1) belongs to the serpin superfamily and behaves as a specific thrombin inhibitor in the pericellular environment. Little is known about PN-1 expression and its regulation in the vascular system. In this study, we examined the expression of functionally active PN-1 in vitro in rat aortic smooth muscle cells and in vivo in rat arterial media and its regulation in hypertensive rats.

Methods and Results—

The vascular PN-1 formed specific covalent complexes with thrombin involving the catalytic site of the protease, and heparin increased the formation of these complexes. We also demonstrated PN-1 in rat arterial media by immunohistochemical staining. Moreover, we examined in vivo vascular expression of PN-1 in a model of chronic hypertension induced by long-term administration of
N
G
-nitro-
l
-arginine methyl ester (
l
-NAME). Marked increases in PN-1 mRNA (3-fold) and protein (2-fold) were observed after 2 months of hypertension. Increased expression of PN-1 in the vascular wall was associated with an increase in the formation of complexes between radiolabeled-thrombin and PN-1, indicating that PN-1 was functional.

Conclusions—

PN-1 may thus participate in the mechanisms that regulate thrombin activity in the vessel wall.
Estrogen Reduces Angiotensin II–Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells
Authors: Gragasin Ferrante S. , Xu Yi , Arenas Ivan A. , Kainth Neelam , Davidge Sandra T.
Published: January 2003

Objective—

Angiotensin II (AII) has been shown to increase endothelial NAD(P)H oxidase activity, which is a source of superoxide anion that in turn may induce the formation of peroxynitrite. Estrogen (E
2
) has been reported to have vascular protective effects. In this study, we hypothesized that E
2
reduces the AII-induced expression of NAD(P)H oxidase and peroxynitrite in endothelial cells.

Methods and Results—

Endothelial cells were cultured and stimulated with AII in the absence or presence of E
2
. Western blots were used to assess nitric oxide synthase (NOS) and NAD(P)H oxidase expression. Immunofluorescence of nitrotyrosine provided evidence of peroxynitrite formation. Our data indicate that AII increased the expression of endothelial NOS, inducible NOS, and NAD(P)H oxidase in a dose-dependent manner, which was attenuated by incubation with either E
2
, superoxide dismutase, or the AII type 1 receptor (AT
1
R) inhibitor candesartan. Estrogen as well as superoxide dismutase also inhibited AII-induced AT
1
R expression and nitrotyrosine staining. The effects of E
2
on the AII responses were not inhibited by the E
2
receptor antagonist ICI-182,780.

Conclusions—

AII stimulation of endothelial cells increases expression of NAD(P)H oxidase and NOS, which may contribute to oxidative stress, as evidenced by peroxynitrite formation. E
2
inhibits these AII effects, possibly through reduced AT
1
R expression.
Constitutive Activation of
rac
1 Results in Mitochondrial Oxidative Stress and Induces Premature Endothelial Cell Senescence
Authors: Deshpande Shailesh S. , Qi Bing , Park Young Chul , Irani Kaikobad
Published: January 2003

Objective—

Oxidative stress has been implicated in cellular senescence and vascular aging. We determined the role and mechanism of the small GTPase rac1 in vascular endothelial cell senescence.

Methods and Results—

Adenoviral-mediated expression of the constitutively active allele of
rac
1 (
rac
1V12) in human umbilical vein endothelial cells resulted in mitochondrial oxidative stress with induction of biochemical, molecular, and morphological features of senescence. Suppression of mitochondrial oxidative stress abrogated
rac
1-induced premature senescence.
Rac
1V12 expression also resulted in an increase in endothelial ceramide levels. Moreover, premature endothelial cell senescence induced by an exogenous cell-permeable ceramide analog was not suppressed by inhibiting endogenous
rac
1 signaling. Finally, in human umbilical vein endothelial cells that had undergone replicative senescence,
rac
1 was not activated, and expression of the dominant-negative
rac
1 allele (
rac
1N17) did not suppress mitochondrial oxidative stress.

Conclusions—

These findings paint a picture in which the constitutive activation of
rac
1, via the generation of ceramide, results in mitochondrial oxidative stress and premature endothelial cell senescence. However, they speak against a role for endogenous rac1 activation in the induction of mitochondrial oxidative stress associated with replicative senescence of endothelial cells.
Hepatocyte Growth Factor/Scatter Factor Can Induce Angiogenesis Independently of Vascular Endothelial Growth Factor
Authors: Sengupta Shiladitya , Gherardi Ermanno , Sellers Lynda A. , Wood Jeanette M. , Sasisekharan Ram , Fan Tai-Ping D.
Published: January 2003

Objective—

Hepatocyte growth factor/scatter factor (HGF/SF) promotes vascular endothelial growth factor (VEGF) expression and induces angiogenesis in multiple pathological conditions. The present study was designed to delineate the HGF/SF and VEGF signaling cascades during angiogenesis by using PTK787, a selective VEGF receptor antagonist.

Methods and Results—

PTK787 produced a concentration-dependent (10
−8
to 10
−6
mol/L) inhibition of VEGF-induced angiogenesis, without altering the basal or HGF/SF-induced response in vitro. In contrast, the nonspecific kinase inhibitor genistein blocked the HGF/SF-induced effect. Both VEGF and HGF/SF induced a rapid phosphorylation of extracellular receptor kinases-1 and -2 (ERKs) and Akt. PTK787 inhibited the VEGF-induced activation of Akt and ERKs, without affecting the HGF/SF-induced phosphorylation. Treatment with VEGF and HGF/SF increased total neovascularization in a murine scaffold granuloma model, but no additive or synergistic interactions were observed. PTK787 (50 mg/kg) blocked the VEGF-induced response without altering the basal or HGF/SF-induced neovascularization.

Conclusions—

We demonstrate that HGF/SF can induce angiogenesis independently of VEGF, possibly through the direct activation of the Akt and ERKs. These results demonstrate the necessity of a multitargeted approach for the rational design of newer therapies to inhibit pathophysiological angiogenesis.
Association of Hypoadiponectinemia With Coronary Artery Disease in Men
Authors: Kumada Masahiro , Kihara Shinji , Sumitsuji Satoru , Kawamoto Toshiharu , Matsumoto Satoru , Ouchi Noriyuki , Arita Yukio , Okamoto Yoshihisa , Shimomura Iichiro , Hiraoka Hisatoyo , Nakamura Tadashi , Funahashi Tohru , Matsuzawa Yuji
Published: January 2003

Background—

Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD).

Methods and Results—

The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (
P
<0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquartile cutoff points were 4.0, 5.5, and 7.0 μg/mL. The multivariate-adjusted odds ratios for CAD in the first, second, and third quartiles were 2.051 (95% confidence interval [CI], 1.288 to 4.951), 1.221 (95% CI, 0.684 to2.186), and 0.749 (95%CI, 0.392 to 1.418), respectively.

Conclusions—

Male patients with hypoadiponectinemia (<4.0 μg/mL) had a significant 2-fold increase in CAD prevalence, independent of well-known CAD risk factors.
Soluble CD40 Ligand Levels Indicate Lipid Accumulation in Carotid Atheroma
Authors: Blake Gavin J. , Ostfeld Robert J. , Yucel E. Kent , Varo Nerea , Schönbeck Uwe , Blake Michael A. , Gerhard Marie , Ridker Paul M. , Libby Peter , Lee Richard T.
Published: January 2003

Objective—

The CD40/CD40 ligand pathway mediates inflammatory processes important in atherogenesis and the formation of the intraplaque lipid pool. We tested the hypothesis that plasma levels of soluble CD40 ligand are elevated in patients with evidence of a lipid pool on high-resolution magnetic resonance imaging (MRI) of carotid stenoses.

Methods and Results—

We recruited 49 patients with evidence of carotid atherosclerosis on ultrasonography; 3 patients could not undergo carotid MRI because of claustrophobia. The remaining 46 patients underwent high-resolution MRI of the carotid arteries. Two radiologists blinded to all other data determined the presence or absence of an intraplaque lipid pool based on the loss of signal between the 20-ms echo time (TE20) and the fat-suppressed TE55 fast spin-echo images. Plasma levels of soluble CD40 ligand were determined by ELISA. Baseline levels of soluble CD40 ligand were higher among patients with evidence of intraplaque lipid (n=14) than among those without it (n=32; median, 2.54 ng/mL; interquartile range [IQR], 1.85 to 3.52 vs median, 1.58 ng/mL; IQR, 1.21 to 2.39;
P
=0.02). In contrast, soluble CD40 ligand levels were not correlated with percent diameter stenosis (
r
=−0.19;
P
=0.21). The relative risk for intraplaque lipid associated with soluble CD40 ligand levels above the median was 6.0 (95% confidence interval, 1.15 to 31.23;
P
=0.03). The magnitude of this predictive effect did not substantially change after adjustment for traditional cardiovascular risk factors (relative risk, 5.12; 95% confidence interval, 0.78 to 33.73;
P
=0.09).

Conclusions—

Plasma levels of soluble CD40 ligand may predict patients with features of high-risk atherosclerotic lesions. These data provide novel insight into the mechanism through which elevated levels of soluble CD40 ligand may reflect cardiovascular risk in humans and illustrate the potential value of interfacing high-resolution MRI with studies of vascular inflammation.
Urinary leukotriene E4in preschool children with acute clinical viral wheeze
Authors: Oommen A. , Grigg J.
Published: January 2003

Cysteinyl leukotrienes (cystLTs) are important mediators of wheeze in atopic asthma, but the role of cystLTs in the pathogenesis of preschool viral wheeze (PVW) is unclear. Therefore, evidence for increased production of cystLTs in PVW was sought.

Urinary leukotriene E4(uLTE4) and serum total immunoglobulin (Ig)E were measured in children (1–5 yrs) with PVW during an acute attack (n=44) and in the convalescent phase (n=19), and compared with normal controls (n=15). The effect of atopic sensitisation was assessed in a separate group of atopic controls (n=6) in whom only uLTE4was measured.

The levels of uLTE4were similar in normal and atopic controls and increased in acute PVW (median (interquartile range) 165 (101–285)versus125 (82–163) ng·mM creatinine−1). Stratification by IgE showed that whereas uLTE4was increased in 23 children with acute PVW and IgE >95th percentile (median 211 (118–312) ng·mM creatinine−1), uLTE4was not increased in the 21 children with acute PVW and IgE ≤95th percentile. In the convalescent phase, uLTE4fell in the subgroup with high IgE but not in the subgroup with low IgE.

It is concluded that increased cysteinyl leukotriene production during acute preschool viral wheeze is associated with high serum immunoglobulin E.
Effect of oxygen on breath markers of oxidative stress
Authors: Phillips M. , Cataneo R.N. , Greenberg J. , Grodman R. , Gunawardena R. , Naidu A.
Published: January 2003

Supplemental oxygen is often administered to induce hyperoxia in nonhypoxic patients for indications such as chest pain, despite lack of evidence of clinical benefit. Induced hyperoxia is potentially toxic, since it may increase oxidative stress and peroxidative damage to deoxyribonucleic acid, lipids and proteins.

The aim of this study was to establish whether supplemental oxygen induces oxidative stress in nonhypoxic subjects.

Breath markers of oxidative stress were measured in 31 healthy subjects before and after breathing 28% oxygen at 2.0 L·min−1vianasal prongs for 30 min while resting. The criterion standard of oxidative stress was the breath methylated alkane contour (BMAC), a three-dimensional plot of the alveolar gradients of C4–C20 alkanes and monomethylated alkanes produced by lipid peroxidation. Volatile organic compounds (VOCs) in breath were assayed by gas chromatography and mass spectroscopy, and the BMACs before and after oxygenation were compared.

Following oxygenation, there was a significant increase in mean volume under the curve of the BMAC and in alveolar gradients of three VOCs: 3‐methyltridecane, 3‐methylundecane and 5-methylnonane.

Breath markers of oxidative stress were significantly increased in normal volunteers breathing supplemental oxygen for 30 min.
Socioeconomical conditions as risk factors for bronchial asthma in children aged 4–5 yrs
Authors: Lindbæk M. , Wefring K.W. , Grangård E.H. , Øvsthus K.
Published: January 2003

A number of factors are associated with the development of childhood asthma. The purpose of this study was to establish the prevalence of childhood asthma and to explore the socioeconomic background factors associated with childhood asthma in a Norwegian cohort of children aged 4–5 yrs.

A questionnaire was given to parents in connection with the ordinary child control of 4–5‐yr-old children in Vestfold county, Norway. In addition to the question “Has the child at present or ever had asthma?”, a number of medical and socioeconomical background factors were registered.

Of the 2,430 parents, 1,913 (79%) responded. Of the 163 (cumulative prevalence 8.7%) children with confirmed asthma, 19 did not use any medication and were regarded as having outgrown their asthma. Several background factors were significantly associated with asthma in a logistic regression analysis: few rooms at home, psychosocial problems, fever more than three times during the last year, hay fever, reaction to food and mother or father with chronic disease.

The findings indicate that socioeconomic background factors are associated with asthma in childhood, in addition to other known risk factors.
Modulatory role of tachykinin NK1receptor in cholinergic contraction of mouse trachea
Authors: Tournoy K.G. , De Swert K.O. , Leclere P.G. , Lefebvre R.A. , Pauwels R.A. , Joos G.F.
Published: January 2003

The role of the NK1receptor in airway contraction induced by electrical field stimulation (EFS) was evaluated by comparing the response in NK1receptor knockout mice (NK1R−/−) with that of NK1receptor wild-type controls (WT).

A frequency/response curve on tracheas from NK1R−/−mice and NK1R WT littermates was constructed. After incubation with [3H]choline, [3H]acetylcholine release upon EFS was measured by high-performance liquid chromatography and liquid scintillation counting. The effects of atropine (1×10−6 M), tetrodotoxin (1×10−6 M) and a specific NK1R antagonist (SR140333, 1×10−8 M) were studied, as well as the effects of substance P (1×10−5 M) on precontracted tracheas.

Upon EFS, NK1R−/−mice had a significant lower trachea contractility than the NK1R WT animals, accompanied with less [3H]acetylcholine release. Pretreatment with atropine or tetrodotoxin abolished the EFS-induced contraction in both strains. Pretreatment with the NK1R antagonist SR140333 significantly reduced the contractility in the NK1R WT but not in the NK1R−/−mice. Substance P caused a small contraction in both NK1R WT and NK1R−/−mice. Substance P induced a relaxation in precontracted tracheas in NK1R WT but not in NK1R−/−mice.

The data presented here provide direct evidence that the NK1receptor augments cholinergic neurotransmission in mouse trachea.
Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations
Authors: Jones P.W. , Willits L.R. , Burge P.S. , Calverley P.M.A.
Published: January 2003

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients showed greatest benefit.

In this study the patients were stratified into mild and moderate‐to‐severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined.

There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate‐to‐severe disease. The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate‐to‐severe disease. FP reduced the overall exacerbation rate in moderate‐to‐severe disease (FP median rate 1.47 yr−1, placebo 1.75 yr−1), but not in mild disease (FP 0.67 yr−1, placebo 0.92 yr−1). FP use was associated with fewer patients with ≥1 exacerbation·yr−1being treated with oral corticosteroids (mild: FP 8%, placebo 16%; moderate‐to‐severe: FP 17%, placebo 30%).

Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second <50% predicted. These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate‐to‐severe chronic obstructive pulmonary disease who experience recurrent exacerbations.