bluuebunny/crossref_metadata_2025 huggingface dataset:
Distributed query evaluation on semistructured data
Authors: Suciu Dan
Published: July 2002

Semistructured data
is modeled as a rooted, labeled graph. The simplest kinds of queries on such data are those which traverse paths described by regular path expressions. More complex queries combine several regular path expressions, with complex data restructuring, and with sub-queries. This article addresses the problem of efficient query evaluation on distributed, semistructured databases. In our setting, the nodes of the database are distributed over a fixed number of sites, and the edges are classified into local (with both ends in the same site) and cross edges (with ends in two distinct sites).
Efficient evaluation
in this context means that the number of communication steps is fixed (independent on the data or the query), and that the total amount of data sent depends only on the number of cross links and of the size of the query's result. We give such algorithms in three different settings. First, for the simple case of queries consisting of a single regular expression; second, for all queries in a calculus for graphs based on
structural recursion
which in addition to regular path expressions can perform nontrivial restructuring of the graph; and third, for a class of queries we call
select-where queries
that combine pattern matching and regular path expressions with data restructuring and subqueries. This article also includes a discussion on how these methods can be used to derive efficient view maintenance algorithms.
Probabilistic game semantics
Authors: Danos Vincent , Harmer Russell S.
Published: July 2002

A category of HO/N-style games and probabilistic strategies is developed where the possible choices of a strategy are quantified so as to give a measure of the likelihood of seeing a given play. A two-sided die is shown to be universal in this category, in the sense that any strategy breaks down into a composition between some deterministic strategy and that die. The interpretative power of the category is then demonstrated by delineating a Cartesian closed subcategory that provides a fully abstract model of a probabilistic extension of Idealized Algol.
Classifying digital products
Authors: Hui Kai Lung , Chau Patrick Y. K.
Published: July 2002

A framework for classifying digital products is essential for devising successful e-commerce strategies.
Introduction
Authors: Agha Gul A.
Published: July 2002

Customization, policy management, coordination, and other services are available for distributed, mobile, embedded systems, increasingly assembled on the fly through the Web.
Reducing truncation errors by programming
Authors: Wolfe Jack M.
Published: July 2002

In accumulating a sum such as in a numerical integration with a large number of intervals, the sum itself becomes much larger than the individual addends. This may produce a less accurate sum as the number of intervals is increased.Separate variables can be established as accumulators to hold partial sums within various distinct intervals. Thus, the extensive successive truncations are eliminated.
Virtual humans for validating maintenance procedures
Authors: Badler Norman I. , Erignac Charles A. , Liu Ying
Published: July 2002

They can be sent to check the human aspects of complex physical systems by simulating assembly, repair, and maintenance tasks in a 3D virtual environment.
RICE AS A MODEL FOR COMPARATIVE GENOMICS OF PLANTS
Authors: Shimamoto Ko , Kyozuka Junko
Published: July 2002

▪ Abstract  Rapid progress in rice genomics is making it possible to undertake detailed structural and functional comparisons of genes involved in various biological processes among rice and other plant species, such as Arabidopsis. In this review, we summarize the current status of rice genomics. We then select two important areas of research, reproductive development and defense signaling, and compare the functions of rice and orthologous genes in other species involved in these processes. The analysis revealed that apparently orthologous genes can also display divergent functions. Changes in functions and regulation of orthologous genes may represent a basis for diversity among plant species. Such comparative genomics in other plant species will provide important information for future work on the evolution of higher plants.
Eukaryotic Ribonuclease P: A Plurality of Ribonucleoprotein Enzymes
Authors: Xiao Shaohua , Scott Felicia , Fierke Carol A. , Engelke David R.
Published: July 2002

▪ Abstract  Ribonuclease P (RNase P) is an essential endonuclease that acts early in the tRNA biogenesis pathway. This enzyme catalyzes cleavage of the leader sequence of precursor tRNAs (pre-tRNAs), generating the mature 5′ end of tRNAs. RNase P activities have been identified in Bacteria, Archaea, and Eucarya, as well as organelles. Most forms of RNase P are ribonucleoproteins, i.e., they consist of an essential RNA subunit and protein subunits, although the composition of the enzyme in mitochondria and chloroplasts is still under debate. The recent purification of the eukaryotic nuclear RNase P has demonstrated a significantly larger protein content compared to the bacterial enzyme. Moreover, emerging evidence suggests that the eukaryotic RNase P has evolved into at least two related nuclear enzymes with distinct functions, RNase P and RNase MRP. Here we review current information on RNase P, with emphasis on the composition, structure, and functions of the eukaryotic nuclear holoenzyme, and its relationship with RNase MRP.
Electromagnetic Fields: Human Safety Issues
Authors: Gandhi Om P.
Published: July 2002

▪ Abstract  Most of the recently revised safety standards worldwide are set in terms of internal rates of electromagnetic energy deposition (specific absorption rates or SAR) at radio frequencies (RF) and microwave frequencies, and of induced electric fields or current densities at lower frequencies up to 10 MHz. Numerical methods have been developed that use millimeter resolution anatomically based models of the human body to determine SAR or the induced electric fields and current densities for real-life EM exposure conditions. A popular method for use at RF and microwave frequencies is the finite-difference time-domain method. This method is described and illustrated for SAR distributions due to cellular telephones for head models based on human anatomy. A method often used for calculations of induced electric fields and current densities at low frequencies is the impedance method. Use of this method is illustrated by an example of an electronic article surveillance (EAS) system for anatomic models of an adult and 10- and 5-year-old children. Experimental phantoms using a fluid to simulate the dielectric properties of the brain may be used for determination of peak 1- or 10-g SAR needed for compliance with the various safety standards.
Molecular and Mesoscale Simulation Methods for Polymer Materials
Authors: Glotzer Sharon C. , Paul Wolfgang
Published: July 2002

▪ Abstract  Polymers offer a wide spectrum of possibilities for materials applications, in part because of the chemical complexity and variability of the constituent molecules, and in part because they can be blended together with other organic as well as inorganic components. The majority of applications of polymeric materials is based on their excellent mechanical properties, which arise from the long-chain nature of the constituents. Microscopically, this means that polymeric materials are able to respond to external forces in a broad frequency range, i.e., with a broad range of relaxation processes. Computer simulation methods are ideally suited to help to understand these processes and the structural properties that lead to them and to further our ability to predict materials properties and behavior. However, the broad range of timescales and underlying structure prohibits any one single simulation method from capturing all of these processes.

This manuscript provides an overview of some of the more popular computational models and methods used today in the field of molecular and mesoscale simulation of polymeric materials, ranging from molecular models and methods that treat electronic degrees of freedom to mesoscopic field theoretic methods.
Cellular Automata in Materials Science with Particular Reference to Recrystallization Simulation
Authors: Raabe Dierk
Published: July 2002

▪ Abstract  The paper is about cellular automaton models in materials science. It gives an introduction to the fundamentals of cellular automata and reviews applications, particularly for those that predict recrystallization phenomena. Cellular automata for recrystallization are typically discrete in time, physical space, and orientation space and often use quantities such as dislocation density and crystal orientation as state variables. Cellular automata can be defined on a regular or nonregular two- or three-dimensional lattice considering the first, second, and third neighbor shell for the calculation of the local driving forces. The kinetic transformation rules are usually formulated to map a linearized symmetric rate equation for sharp grain boundary segment motion. While deterministic cellular automata directly perform cell switches by sweeping the corresponding set of neighbor cells in accord with the underlying rate equation, probabilistic cellular automata calculate the switching probability of each lattice point and make the actual decision about a switching event by evaluating the local switching probability using a Monte Carlo step. Switches are in a cellular automaton algorithm generally performed as a function of the previous state of a lattice point and the state of the neighboring lattice points. The transformation rules can be scaled in terms of time and space using, for instance, the ratio of the local and the maximum possible grain boundary mobility, the local crystallographic texture, the ratio of the local and the maximum-occurring driving forces, or appropriate scaling measures derived from a real initial specimen. The cell state update in a cellular automaton is made in synchrony for all cells. The review deals, in particular, with the prediction of the kinetics, microstructure, and texture of recrystallization. Couplings between cellular automata and crystal plasticity finite element models are also discussed.
PHYSICAL CHEMISTRY OF NUCLEIC ACIDS
Authors: Tinoco Ignacio
Published: July 2002

[Figure: see text]

▪ Abstract  The Watson-Crick double helix of DNA was first revealed in 1953. Since then a wide range of physical chemical methods have been applied to DNA and to its more versatile relative RNA to determine their structures and functions. My major goal is to predict the folded structure of any RNA from its sequence. We have used bulk and single-molecule measurements of thermodynamics and kinetics, plus various spectroscopic methods (UV absorption, optical rotation, circular dichroism, circular intensity differential scattering, fluorescence, NMR) to approach this goal.
Long Pentraxin PTX3 Upregulates Tissue Factor Expression in Human Endothelial Cells
Authors: Napoleone Emanuela , Di Santo Angelomaria , Bastone Antonio , Peri Giuseppe , Mantovani Alberto , de Gaetano Giovanni , Donati Maria Benedetta , Lorenzet Roberto
Published: July 2002

Inflammation is a major contributing factor to atherosclerotic plaque development and ischemic heart disease. PTX3 is a long pentraxin that was recently found to be increased in patients with acute myocardial infarction. Because tissue factor (TF), the in vivo trigger of blood coagulation, plays a dominant role in thrombus formation after plaque rupture, we tested the possibility that PTX3 could modulate TF expression. Human umbilical vein endothelial cells, incubated with endotoxin (lipopolysaccharide) or the inflammatory cytokines interleukin-1β and tumor necrosis factor-α, expressed TF. The presence of PTX3 increased TF activity and antigen severalfold in a dose-dependent fashion. PTX3 exerted its effect at the transcription level, inasmuch as the increased levels of TF mRNA, mediated by the stimuli, were enhanced in its presence. The increase in mRNA determined by PTX3 originated from an enhanced nuclear binding activity of the transacting factor c-Rel/p65, which was mediated by the agonists and measured by electrophoretic mobility shift assay. The mechanism underlying the increased c-Rel/p65 activity resided in an enhanced degradation of the c-Rel/p65 inhibitory protein IκBα. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. Our results suggest that PTX3, by increasing TF expression, potentially plays a role in thrombogenesis and ischemic vascular disease.
Oxidative Stress in Human Abdominal Aortic Aneurysms
Authors: Miller Francis J. , Sharp William J. , Fang Xiang , Oberley Larry W. , Oberley Terry D. , Weintraub Neal L.
Published: July 2002

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by localized connective tissue degradation and smooth muscle cell (SMC) apoptosis, leading to aortic dilatation and rupture. Reactive oxygen species are abundantly produced during inflammatory processes and can stimulate connective tissue–degrading proteases and apoptosis of SMCs. We hypothesized that reactive oxygen species are locally increased in AAA and lead to enhanced oxidative stress. In aortas from patients undergoing surgical repair, superoxide levels (measured by lucigenin-enhanced chemiluminescence) were 2.5-fold higher in the AAA segments compared with the adjacent nonaneurysmal aortic (NA) segments (6638±2164 versus 2675±1027 relative light units for 5 minutes per millimeter squared, respectively; n=7). Formation of thiobarbituric acid–reactive substances and conjugated dienes, 2 indices of lipid peroxidation, were increased 3-fold in AAA compared with NA segments. Immunostaining for nitrotyrosine was significantly greater in AAA tissue. Dihydroethidium staining indicated that increased superoxide in AAA segments was localized to infiltrating inflammatory cells and to SMCs. Expression of the NADPH oxidase subunits p47
phox
and p22
phox
and NAD(P)H oxidase activity were increased in AAA segments compared with NA segments. Thus, oxidative stress is markedly increased in AAA, in part through the activation of NAD(P)H oxidase, and may contribute to the disease pathogenesis.
Impact of Alcohol Intake on Measures of Lipid Metabolism Depends on Context Defined by Gender, Body Mass Index, Cigarette Smoking, andApolipoprotein EGenotype
Authors: Lussier-Cacan Suzanne , Bolduc Aline , Xhignesse Marianne , Niyonsenga Théophile , Sing Charles F.
Published: July 2002

Hyperlipidemia, smoking, and obesity are well-known risk factors for cardiovascular disease. Conversely, moderate alcohol intake is associated with lower atherosclerosis risk. However, the influence of taking alcohol on the interrelationships of these factors in a particular context has not been thoroughly investigated. In this study, we asked whether the association between plasma measures of lipid metabolism and alcohol intake is dependent on context defined by gender, age, body mass index (BMI), smoking, andapolipoprotein E(APOE)genotype. Data were obtained in a sample of 869 women and 824 men who participated in the Quebec Heart Health Survey. There was no evidence that variation amongAPOEgenotypes influenced the association between LDL cholesterol (LDL-C) or HDL cholesterol (HDL)-C and alcohol, after adjustment for age and BMI. Further, the positive (LDL-C and BMI) and the negative (HDL-C and BMI) associations that were observed in men and women with theε3/2andε3/3genotypes were not modified by alcohol intake. However, in women with theε4/3genotype only, we found a significant influence of an alcohol by BMI interaction on the prediction of total cholesterol, LDL-C, HDL-C, apoA-I, and apoB, and this interaction was influenced by the status of smoking. Whereas the influence of an alcohol by BMI interaction on total cholesterol and LDL-C was significant in smokers, its influence on HDL-C was significant only in non-smokers. This study emphasizes the context dependency of the influence of alcohol on lipid metabolism and demonstrates how biological, environmental, and genetic factors interact to determine cardiovascular disease risk.
Heritability of Subclinical Atherosclerosis in Latino Families Ascertained Through a Hypertensive Parent
Authors: Xiang Anny H. , Azen Stanley P. , Buchanan Thomas A. , Raffel Leslie J. , Tan Sylvia , Cheng L.S.-C. , Diaz Justo , Toscano Edgar , Quinonnes M. , Liu C.R. , Liu C.H. , Castellani Lawrence W. , Hsueh Willa A. , Rotter Jerome I. , Hodis Howard N.
Published: July 2002

Although clinical coronary heart disease and many cardiovascular risk factors are well known to aggregate within families, the heritability of carotid artery intima-media thickness (IMT) is less well documented. We report IMT heritability estimates in Mexican American, Salvadoran American, or Guatemalan American (all referred to as Latino) families ascertained through a hypertensive proband. IMT and cardiovascular risk factors (age, sex, blood pressure, body mass index, lipids, fasting glucose, and insulin sensitivity) were measured in 204 adult offspring of 69 hypertensive probands, along with 82 parents (54 probands and 28 spouses). In the offspring, variance component analysis revealed a heritability for IMT of 64% (P< 0.0001) after adjustment for significant cardiovascular risk factors. Genetic factors accounted for 50% of the total variation in IMT, whereas significant cardiovascular risk factors explained 22% (14% were due to age). For offspring and parents combined, adjusted IMT heritability was less, 34% (P=0.0005), with genetic factors accounting for 18% of the total IMT variation, whereas significant cardiovascular risk factors explained 46% (38% were due to age). We conclude that variation incommon carotid artery IMT is heritable in Latino families with a hypertensive proband. Heritability is particularly evident in younger family members, suggesting that acquired factors contribute progressively to IMT variability with aging.
The Von Willebrand Factor Propeptide (VWFpp) Traffics an Unrelated Protein to Storage
Authors: Haberichter Sandra L. , Jozwiak Mary A. , Rosenberg Jonathan B. , Christopherson Pamela A. , Montgomery Robert R.
Published: July 2002

The von Willebrand factor (VWF) propeptide (VWFpp) is critical for the targeting of VWF multimers to storage granules. VWFpp alone efficiently navigates the storage pathway in AtT-20 and endothelial cells and chaperones mature VWF multimers to storage granules when the two proteins are expressed
in cis
or
in trans
. To further define the role of VWFpp in granular sorting, we examined its ability to sort an unrelated protein, C3α into the regulated secretory pathway. Chimeric constructs of VWFpp and the α-chain of C3 were developed. The C3α protein expressed alone did not sort to granules in AtT-20 cells. The
trans
expression of C3α and VWFpp resulted in granular storage of VWFpp but no corresponding storage of C3α. When C3α is expressed as a single chain molecule with VWFpp that was rendered uncleavable by furin, C3α is re-routed to storage and is colocalized with VWFpp. The uncleavable protein was expressed in bovine aortic endothelial cells where it sorted to Weibel-Palade bodies, colocalized with bovine VWF, and was released when agonist stimulated. We now demonstrate that VWFpp re-routes a constitutively secreted protein to the regulated storage pathway. Furthermore, our studies suggest that the VWFpp storage signal is contained within amino acids 201 to 741.
Shear Stress Induces Expression of Vascular Endothelial Growth Factor Receptor Flk-1/KDR Through the CT-Rich Sp1 Binding Site
Authors: Abumiya Takeo , Sasaguri Toshiyuki , Taba Yoji , Miwa Yoshikazu , Miyagi Megumi
Published: July 2002

Fluid shear stress is 1 of the major factors that control gene expression in vascular endothelial cells. We investigated the role of shear stress in the regulation of the expression of fetal liver kinase-1/kinase domain region (Flk-1/KDR), a vascular endothelial growth factor receptor, by using human umbilical vein endothelial cells. Laminar shear stress (15 dyne/cm
2
) elevated Flk-1/KDR mRNA levels by ≈3-fold for 8 hours, and the expression was upregulated within the range of 5 to 40 dyne/cm
2
. Deletion analysis of the 5′-flanking region of the Flk-1/KDR gene promoter by use of a luciferase reporter vector revealed that a shear stress–responsive element resided in the sequence between −94 and −31 bp, which contained putative nuclear factor-κB, activator protein-2, and GC-rich Sp1 and CT-rich Sp1 binding sites. Electrophoretic mobility shift assay demonstrated that nuclear extract was bound to the GC-rich Sp1 sites and the CT-rich Sp1 site with a similar pattern. However, shear stress enhanced the DNA-protein interactions only on the CT-rich Sp1 site but not on the GC-rich Sp1 sites. A 3-bp mutation in the CT-rich Sp1 site eliminated the response to shear stress in electrophoretic mobility shift assay and luciferase reporter assay. These results suggest that shear stress induces Flk-1/KDR expression through the CT-rich Sp1 binding site.
Cyclooxygenase-2–Dependent Prostacyclin Formation Is Regulated by Low Density Lipoprotein Cholesterol In Vitro
Authors: Smith Layton Harris , Boutaud Olivier , Breyer Matthew , Morrow Jason D. , Oates John A. , Vaughan Douglas E.
Published: July 2002

Reduction of plasma low density lipoprotein (LDL) levels is associated with a reduced risk of myocardial infarction, stroke, and death. Some of this clinical benefit may be derived from an improvement in endothelium-dependent vasodilation. In the present study, we examined the effects of LDL reduction on cyclooxygenase (COX) activity and prostacyclin (PGI
2
) production. Human umbilical vein endothelial cells exposed to reduced concentrations of LDL demonstrated increased PGI
2
production in a dose-dependent manner (from 0.75±0.2 to 2.6±0.2 ng/mL,
P
<0.0001). This alteration in PGI
2
production did not result from LDL-induced changes in PGI
2
synthase expression. However, selective inhibition of COX-2, but not COX-1, blocked PGI
2
production under low cholesterol conditions. Addition of exogenous cholesterol induces dose-dependent reductions in endothelial COX-2 expression as measured by reverse transcription–polymerase chain reaction and by Western blotting. Pretreatment of cells with actinomycin D, a transcription inhibitor, reduced COX-2–derived PGI
2
production by 45.9% (from 0.55±0.09 to 0.25±0.08 ng/mL). Taken together, these observations indicate that endothelial PGI
2
production is regulated by cholesterol at the transcriptional level and that cholesterol-sensitive transcriptional pathways that regulate COX-2 expression are present in vascular tissue.
Circulating Oxidized LDL Is Associated With Subclinical Atherosclerosis Development and Inflammatory Cytokines (AIR Study)
Authors: Hulthe Johannes , Fagerberg Björn
Published: July 2002

Objective—Circulating oxidized LDL (Ox-LDL) is associated with clinical manifestations of atherosclerosis. However, no previous study has examined the relationship between subclinical atherosclerosis and Ox-LDL. The aims of the present study were to investigate the relationship between clinically silent ultrasound-assessed atherosclerotic changes in the carotid and femoral arteries and Ox-LDL and to explore the relationship between Ox-LDL, C-reactive protein, and the inflammatory cytokines interleukin-6 and tumor necrosis factor-α.

Methods and Results—The study group (n=391) consisted of clinically healthy, 58-year-old men recruited from the general population. Ox-LDL was measured by using a specific monoclonal antibody, mAb-4E6. The results showed that Ox-LDL was related to intima-media thickness and plaque occurrence in the carotid and femoral arteries. In addition, Ox-LDL was associated with tumor necrosis factor-α and C-reactive protein. Circulating Ox-LDL was also associated with LDL cholesterol but not with blood pressure or smoking. When adjusting for other risk factors, both LDL cholesterol and Ox-LDL seemed to be independent predictors of plaque occurrence in the carotid and femoral arteries (odds ratios for quintile 5 versus quintile 1 were 2.17,P=0.049 and 2.25,P=0.050, for LDL cholesterol and Ox-LDL, respectively).

Conclusions—Ox-LDL was associated with both subclinical atherosclerosis and inflammatory variables, supporting the concept that oxidatively modified LDL may play a major role in atherosclerosis development, although no causality can be shown in this cross-sectional study.
Angiotensin II Type 1 and 2 Receptors in Conduit Arteries of Normal Developing Microswine
Authors: Bagby Susan P. , LeBard Linda S. , Luo Zaiming , Speth Robert C. , Ogden Bryan E. , Corless Christopher L.
Published: July 2002

Objective

—

To identify vascular cells capable of responding to angiotensin II (Ang II) generated in conduit arteries, we examined the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) in the thoracic aorta (TA) and abdominal aorta (AA) and branches in 90-day fetal, 3-week postnatal, and 6-month adult microswine.

Methods and Results

—

By autoradiography (
125
I-[Sar
1
Ile
8
]-Ang II with or without AT1R- or AT2R-selective analogues or
125
I
-
CGP 42112), there were striking rostrocaudal differences in (1) AT2R binding at all ages (prominent in AA wall and branches, sparse in TA wall and branches) and (2) a non-AT2R binding site for CGP 42112 (consistently evident in postnatal TA and branches but absent in AA and branches). Furthermore, patterns of AT2R distribution in infradiaphragmatic arteries were developmentally distinct. In fetal AAs, high-density AT2Rs occupied the inner 60% of the medial-endothelial wall. In postnatal AAs, AT2Rs were sparse in the medial-endothelial wall but prominent in a circumferential smooth muscle α-actin–negative cell layer at the medial-adventitial border, occupying ≈20% to 25% of the AA cross-sectional area. AT1R density in the TA and AA medial-endothelial wall increased with age, whereas AT2R density decreased after birth.

Conclusions

—

A novel AT2R-positive cell layer confined to postnatal infradiaphragmatic arteries physically links adventitial and medial layers, appears optimally positioned to transduce AT2R-dependent functions of local Ang II, and suggests that adventitial Ang II may elicit regionally distinct vascular responses.
Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects
Authors: Zheng Haoyi , Dimayuga Clarito , Hudaihed Alhakam , Katz Stuart D.
Published: July 2002

Objective

—

Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects.

Methods and Results

—

Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of
l
-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m
2
) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1±0.4 μmol/L at baseline to 14.2±1.3 μmol/L at 4 hours,
P
<0.001) and decreased FMD (from 3.8±0.7% at baseline to 1.2±0.5% at 4 hours,
P
=0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9±1.1 μmol/L at 4 hours,
P
=0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5±0.5% at baseline to 5.9±1.1% at 4 hours,
P
<0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane.

Conclusions

—

Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects.
Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E–Deficient Mice Unable to Make Ascorbic Acid
Authors: Nakata Yukiko , Maeda Nobuyo
Published: July 2002

Background—

Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals.

Methods and Results—

Gulo
−/−
Apoe
−/−
mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone-γ-oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the
Gulo
−/−
Apoe
−/−
mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 μg/mL in plasma) or high vitamin C (average 10 to 30 μg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red–staining collagen (36.4±2.2% versus 54.8±2.3%,
P
<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia.

Conclusions—

Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.
Metoprolol CR/XL in Female Patients With Heart Failure
Authors: Ghali Jalal K. , Piña Ileana L. , Gottlieb Stephen S. , Deedwania Prakash C. , Wikstrand John C.
Published: July 2002

Background

—

Underrepresentation of women in heart failure clinical trials has limited conclusions regarding the effect of various management strategies on survival in women with heart failure and decreased left ventricular ejection fraction (LVEF).

Methods and Results

—

MERIT-HF (Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure) was a randomized, placebo-controlled study, the purpose of which was to evaluate the effect of metoprolol controlled-release/extended-release (CR/XL) in 3991 patients with New York Heart Association class II to IV heart failure and LVEF ≤0.40. We performed a post hoc analysis to evaluate the effect of metoprolol CR/XL on outcome in women (n=898), including the outcome in 183 women with severe heart failure (New York Heart Association class III/IV and LVEF <0.25). Treatment with metoprolol CR/XL in women resulted in a 21% reduction in the primary combined end point of all-cause mortality/all-cause hospitalizations (164 versus 137 patients;
P
=0.044). The number of cardiovascular hospitalizations was reduced by 29% (164 versus 120;
P
=0.013), and hospitalization for worsening heart failure was reduced by 42% (95 versus 56;
P
=0.021). Similar results were noted in the subgroup of women with severe heart failure, with a 57% reduction in cardiovascular hospitalizations (63 versus 30;
P
=0.005) and a 72% reduction in hospitalization due to worsening heart failure (46 versus 14;
P
=0.0004). A pooling of mortality results from MERIT-HF, the Cardiac Insufficiency Bisoprolol Study (CIBIS II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) showed very similar survival benefits in women and men.

Conclusions

—

The beneficial effects of metoprolol CR/XL extend to women with heart failure, including women with clinically stable severe heart failure.
Relationship of the TIMI Myocardial Perfusion Grades, Flow Grades, Frame Count, and Percutaneous Coronary Intervention to Long-Term Outcomes After Thrombolytic Administration in Acute Myocardial Infarction
Authors: Gibson C. Michael , Cannon Christopher P. , Murphy Sabina A. , Marble Susan J. , Barron Hal V. , Braunwald Eugene
Published: July 2002

Background

—

Although 90-minute TIMI flow grades (TFGs), corrected TIMI frame counts (CTFCs), and TIMI myocardial perfusion grades (TMPGs) have been associated with 30-day outcomes, we hypothesized that these indices would be related to long-term outcomes after thrombolytic administration.

Methods and Results

—

As a substudy of the TIMI 10B trial (tissue plasminogen activator versus tenecteplase), 49 centers carried out 2-year follow-up. TIMI grade 2/3 flow (Cox hazard ratio [HR] 0.41,
P
=0.001), reduced CTFCs (faster flow,
P
=0.02), and an open microvasculature (TMPG 2/3) (HR 0.51,
P
=0.038) were all associated with improved 2-year survival. Rescue percutaneous coronary intervention (PCI) of closed arteries (TFG 0/1) at 90 minutes was associated with reduced mortality (
P
=0.03), and mortality trended lower with adjunctive PCI of open (TFG 2/3) arteries (
P
=0.11). In a multivariate model correcting for previously identified correlates of mortality (age, sex, pulse, left anterior descending coronary artery infarction, and any PCI during initial hospitalization), patency (TFG 2/3) (HR 0.32,
P
<0.001), CTFC (
P
=0.01), and TMPG 2/3 remained associated with reduced mortality (HR 0.46,
P
=0.02).

Conclusions

—

Both improved epicardial flow (TFG 2/3 and low CTFCs) and tissue-level perfusion (TMPG 2/3) at 90 minutes after thrombolytic administration are independently associated with improved 2-year survival, suggesting complementary mechanisms of improved long-term survival. Although rescue PCI reduced long-term mortality, improved microvascular perfusion (TMPG 2/3) before PCI was also related to improved mortality independently of epicardial blood flow and the performance of rescue or adjunctive PCI. Further prospective trials are warranted to re-examine the benefit of early PCI with thrombolysis.
Cyclooxygenase-1 and Bicistronic Cyclooxygenase-1/Prostacyclin Synthase Gene Transfer Protect Against Ischemic Cerebral Infarction
Authors: Lin Heng , Lin Teng-Nan , Cheung Wai-Mui , Nian Gau-Ming , Tseng Ping-Hui , Chen Shu-Fen , Chen Jean-Ju , Shyue Song-Kun , Liou Jun-Yang , Wu Cheng-Wen , Wu Kenneth K.
Published: July 2002

Background

—

We tested the hypothesis that bicistronic cyclooxygenase-1 (COX-1)/prostacyclin synthase (PGIS) and COX-1 gene transfer reduce cerebral infarct volume by augmenting synthesis of protective prostaglandins.

Methods and Results

—

We infused into lateral ventricle of a rat stroke model recombinant adenoviruses (rAd) containing COX-1 (Adv-COX-1), COX-1 and PGIS (Adv-COX-1/PGIS), or Adv-PGK control vector, and we determined COX-1 and PGIS protein and eicosanoid levels and infarct volume. COX-1 and PGIS proteins were increased in a time-dependent manner. Adv-COX-1/PGIS infusion selectively augmented prostacyclin levels, with reduction of other eicosanoids in ischemic cortex and a significant reduction of infarct volume, even when the rAd was administered 5 hours after ischemia. Infusion of Adv-COX-1 also increased prostacyclin, suppressed leukotriene levels, and achieved a similar degree of cerebral protection. Its neuroprotection was abrogated by treatment with a selective COX-1 inhibitor.

Conclusions

—

COX-1/PGIS and COX-1 gene transfer reduce cerebral infarct volume by augmenting prostacyclin and suppressing leukotriene productions. COX-1–based gene transfer has potential for treating ischemic stroke.
Mineralocorticoid Receptor Antagonism in Experimental Atherosclerosis
Authors: Rajagopalan Sanjay , Duquaine Damon , King Steven , Pitt Bertram , Patel Paresh
Published: July 2002

Background

—

Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis.

Methods and Results

—

New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O
2
·−
) generation. SARA normalized O
2
· −
generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31±0.04 and 0.27±0.02 in HL versus 0.16±0.05 and 0.07±0.02 in HL-SARA, respectively;
P
<0.01 by ANOVA). This was associated with improvements in peak relaxations to the endothelial-dependent agonist acetylcholine (82±6% in HL-SARA versus 61±4 in HL;
P
<0.01 by ANOVA; ED
50
6.8×10
−8
mol/L in HL-SARA and 1.2×10
−7
mol/L in HL;
P
=NS) to near-normal levels. Vessels from the HL group demonstrated hyperreactivity to angiotensin II that could not be corrected with SARA. Plasma aldosterone levels by radioimmunoassay demonstrated a 4- to 5-fold increase in response to SARA but no differences with lipid feeding. Real-time reverse transcriptase–polymerase chain reaction studies revealed expression of MR in the aorta of HL rabbits and those of controls.

Conclusions

—

MR antagonism improves endothelial function and reduces O
2
·−
generation in diet-induced atherosclerosis. Targeting aldosterone by blocking its receptor has potential antiatherosclerotic effects.
Pooling in Chronic Orthostatic Intolerance
Authors: Stewart Julian M.
Published: July 2002

Background

—

Orthostatic intolerance is characterized by postural tachycardia syndrome (POTS) with exaggerated tachycardia, orthostatic symptoms, and “pooling” (which comprises acrocyanosis and dependent edema when upright). My colleagues and I tested the hypothesis that pooling results from increased venous compliance in POTS patients.

Methods and Results

—

Fifteen patients aged 13 to 19 years were compared with 11 healthy, age-matched controls. The POTS group was divided into patients with high venous pressure (P
v
>20 mm Hg) and normal P
v
on the basis of resting supine P
v
obtained in previous work. Subjects were studied using strain gauge plethysmography to measure blood flow, P
v
, and the venous compliance volume-pressure relation while supine and during incremental head-up tilt testing at −10°, 0°, 20°, and 35°. Volume-pressure relations of controls and POTS patients with normal P
v
and high P
v
were not different and were unchanged by orthostasis. Supine leg peripheral resistance was greater than control resistance in patients with high P
v
(54±9 versus 30±6 mm Hg · mL
−1
· 100 mL
−1
· min
−1
) and less than control resistance in patients with normal P
v
(17±2 mm Hg · mL
−1
· 100 mL
−1
· min
−1
). On upright tilt, resistance decreased in high P
v
to approximate resistance in normal P
v
. Resistance in controls increased throughout tilt. Leg P
v
increased in patients with normal P
v
and in controls but remained unchanged in the high P
v
group.

Conclusions

—

The findings suggest that pooling in POTS is due to blunted arterial vasoconstriction, which produces passive redistribution of blood within peripheral venous capacitance beds. Venous compliance in POTS is similar to that in control subjects.
First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease
Authors: Dyke Christopher K. , Becker Richard C. , Kleiman Neal S. , Hochman Judith S. , Bovill Edwin G. , Lincoff A. Michael , Gerstenblith Gary , Dzavik Vladimir , Gardner Laura H. , Hasselblad Vic , Zillman Linda A. , Shimoto Yoshimasa , Robertson Thomas L. , Kunitada Satoshi , Armstrong Paul W. , Harrington Robert A.
Published: July 2002

Background

—

Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa.

Methods and Results

—

In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti–factor Xa activity (
r
=0.97), prothrombin time (
r
=0.77), and international normalized ratio (
r
=0.72) but less so with activated partial thromboplastin time (
r
=0.56; all
P
<0.001).

Conclusions

—

This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.
Safety and Tolerability of Pravastatin in Long-Term Clinical Trials
Authors: Pfeffer Marc A. , Keech Anthony , Sacks Frank M. , Cobbe Stuart M. , Tonkin Andrew , Byington Robert P. , Davis Barry R. , Friedman Carola P. , Braunwald Eugene
Published: July 2002

Background

—

Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data.

Methods and Results

—

The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3× the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo.

Conclusions

—

This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.
Essential Role of Monocyte Chemoattractant Protein-1 in Development of Restenotic Changes (Neointimal Hyperplasia and Constrictive Remodeling) After Balloon Angioplasty in Hypercholesterolemic Rabbits
Authors: Mori Emiko , Komori Kimihiro , Yamaoka Terutoshi , Tanii Mitsugu , Kataoka Chu , Takeshita Akira , Usui Makoto , Egashira Kensuke , Sugimachi Keizo
Published: July 2002

Background
—

Renarrowing of dilated arterial sites (restenosis) hampers the clinical benefits of coronary angioplasty. Infiltration and activation of monocytes in the arterial wall mediated by monocyte chemoattractant protein-1 (MCP-1) might be a major cause of restenosis after angioplasty. However, there is no direct evidence to support a definite role of MCP-1 in the development of restenosis.

Methods and Results
—

We recently devised a new strategy for anti–MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We used this strategy to investigate the role of MCP-1 in the development of restenotic changes after balloon injury in the carotid artery in hypercholesterolemic rabbits. Intramuscular transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation in the injured arterial wall and thus attenuated the development of neointimal hyperplasia and negative remodeling.

Conclusions
—

MCP-1–mediated monocyte infiltration is necessary in the development of restenotic changes to balloon injury in hypercholesterolemic rabbits. This strategy may be a useful and practical form of gene therapy against human restenosis.
Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium
Authors: Nakamura Kazufumi , Kusano Kengo , Nakamura Yoichi , Kakishita Mikio , Ohta Keiko , Nagase Satoshi , Yamamoto Mika , Miyaji Katsumasa , Saito Hironori , Morita Hiroshi , Emori Tetsuro , Matsubara Hiromi , Toyokuni Shinya , Ohe Tohru
Published: July 2002

Background
—

Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating β-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level.

Methods and Results
—

Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (
P
<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9±4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22±8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (
P
<0.005) along with amelioration of heart failure.

Conclusions
—

Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.