bluuebunny/crossref_metadata_2025 huggingface dataset:
Analytic Study of Stationary Solitons in Deep Nonlinear Bragg Grating
Authors: Alatas H. , Iskandar A. A. , Tjia M. O. , Valkering T. P.
Published: August 2003

A study of nonlinear Bragg grating has been carried out using a modified scheme of approximation originally proposed by Iizuka and de Sterke. A complete classification of the solitonic solutions in the system was given. We further demonstrated in this work the existence of in-gap dark and antidark soliton, in addition to the out-gap solutions reported previously. We also found at the boundaries in the bifurcation diagram, the large-amplitude out-gap antidark soliton and broad in-gap dark soliton.
Nonlinear Optics and Optical Limiting Properties of Multifunctional Fullerenol/Polymer Composite
Authors: Elim Hendry Izaac , Ji Wei , Meng Gwee Chen , Ouyang Jianying , Goh Suat Hong
Published: August 2003

The nonlinear optics and optical limiting properties of materials based on multifunctional fullerenol and poly (styrene-co-4-vinylpyridine) matrix were studied using 7 ns pulses of nanosecond laser operating at 532 nm wavelength. The observed imaginary and real parts of third order susceptibility of the fullerenol/polymer composite are found to be lower than that of its parent C60. The optical limiting performances of fullerenol and fullerenol incorporated with poly(styrene-co-4-vinylpyridine) have been proved to be poorer than that of C60 due to their higher limiting thresholds. Concentration dependence of poly(styrene-co-4-vinylpyridine) containing 32 mol% has been mainly contributed to the optical limiting performance of fullerenol.
Characterization of Vertically Waveguide Coupled Microring Resonators by Means of Quantitative Image Analysis
Authors: Tan F. S. , Klunder D. J. W. , Sengo G. , Kelderman H. , Hollink A. , Hoekstra H. J. W. M. , Driessen A.
Published: August 2003

The standard method of measuring the response of a micro resonator with in- and output waveguides consists of detecting the output power as a function of wavelength. In this paper a complementary method by means of quantitative image analysis is proposed. A vertically coupled waveguide microring resonator has been characterized with this method by projecting the scattered power of the device to an IR camera and analyzing the image as a function of wavelength. The reliability of this method has been confirmed by comparison with the standard measurement.
Collective and Individual Molecular Nonlinear Photonics of Liquid Crystals
Authors: Khoo I. C. , Diaz Andres , Ding J. , Chen K. , Zhang Y.
Published: August 2003

This review will examine the origins of nonlinear light scattering processes in nematic liquid crystals, and explore various nonlinear photonic processes associated with optically induced director axis reorientation effects. Our theoretical prediction shows that the upper limit of nematic liquid crystal reorientation nonlinearity can be as high as 1000 cm2/W. The supra-nonlinear responses of nematic liquid crystals enable various self-action or electro-optical guiding, mixing, switching and modulation of light with unprecedented low power thresholds. Owing to the broadband birefringence of NLC, we expect to realize optical elements/devices capable of similar multi-functional operations throughout the visible — infrared regime. We also discuss the optical limiting action of isotropic-phase liquid crystal filled nonlinear fiber arrays.
The Effects of the Asian Crisis of 1997 on Emergent Markets Through a Critical Phenomena Model
Authors: Figueroa M. G. , Mariani M. C. , Ferraro M. B.
Published: August 2003

In the present work we have analyzed the financial Asian crisis of 1997, and its consequences on emerging markets. We have done so by means of a phase transition model originally presented by A. Johansen and D. Sornette [1].

We have analyzed the crashes on leading indices of Hong Kong (HSI), Turkey (XU100), Mexico (MMX), Brazil (Bovespa) and Argentina (Merval).

With the exception of Argentina's index, we were able to obtain optimum values for the critical date, corresponding to the most probable date of the crash.
Evaluating a scientific collaboratory
Authors: Sonnenwald Diane H. , Whitton Mary C. , Maglaughlin Kelly L.
Published: August 2003

The evaluation of scientific collaboratories has lagged behind their development. Do the capabilities afforded by collaboratories outweigh their disadvantages? To evaluate a scientific collaboratory system, we conducted a repeated-measures controlled experiment that compared the outcomes and process of scientific work completed by 20 pairs of participants (upper level undergraduate science students) working face-to-face and remotely. We collected scientific outcomes (graded lab reports) to investigate the quality of scientific work, post-questionnaire data to measure the adoptability of the system, and post-interviews to understand the participants' views of doing science under both conditions. We hypothesized that study participants would be less effective, report more difficulty, and be less favorably inclined to adopt the system when collaborating remotely. Contrary to expectations, the quantitative data showed no statistically significant differences with respect to effectiveness and adoption.The qualitative data helped explain this null result: participants reported advantages and disadvantages working under both conditions and developed work-arounds to cope with the perceived disadvantages of collaborating remotely. While the data analysis produced null results, considered as a whole, the analysis leads us to conclude there is positive potential for the development and adoption of scientific collaboratory systems.
An
n
! lower bound on formula size
Authors: Adler Micah , Immerman Neil
Published: August 2003

We introduce a new Ehrenfeucht--Fraïssé game for proving lower bounds on the size of first-order formulas. Up until now, such games have only been used to prove bounds on the operator depth of formulas, not their size. We use this game to prove that the CTL
+
formula, Occur

n

≡
E[F
p
1
∧
F
p
2
∧ … ∧
F
p
n
], which says that there is a path along which the predicates
p
1
through
p
n
all occur, requires size
n
! to express in CTL. Our lower bound is optimal. It follows that the succinctness of CTL
+
with respect to CTL is exactly Θ(
n
)!. Wilke had shown that the succinctness was at least exponential [Wilke 1999].We also use our games to prove an optimal Ω(
n
) lower bound on the number of boolean variables needed for forward reachability logic (RL

f

) to polynomially embed the language CTL
+
. The number of booleans needed for full reachability logic RL and the transitive closure logic FO
2
(TC) remain open [Immerman and Vardi 1997; Alechina and Immerman 2000].
JavaScript programming basics
Authors: Brady Alyce , McDowell R. C. , Schultz Kelly
Published: August 2003

The JavaScript Programming Basics lab series presents elementary programming concepts using the JavaScript language. In particular, it introduces variables, functions, and event handlers, conditions, loops, arrays, decision trees, sequential search, and selection sort. Students build three different web pages or programs: a guestbook, an "expert advice system" or decision tree, and a CD order form. These labs would be appropriate in courses on web page development, broad overview ("CS 0") courses, or elementary programming courses.Altogether, the module consists of 3 programming labs and 5 shorter "minilabs" contained in 14 files, totaling less than 600KB.There are two categories of labs in the series.•
Minilabs
are short, directed exercises that concentrate on a single concept, such as variables or conditions. A minilab should immediately follow the instructor's introduction of the associated topic (noted as the "prerequisites" to the lab).•
Programming labs
are longer, and ask students to pull together several concepts in a more complex exercise.Since the purpose of the minilabs is immediate practice of new concepts immediately after they have been introduced, the instructions in the minilabs are more detailed and explicit than those in the full-length labs. The module also includes two supplemental programming projects that extend the decision tree lab and the CD order form labs.The JavaScript Programming Basics labs are meant to supplement instructor presentations, allowing students to apply new concepts through guided exercises. This page describes the pedagogical goals and prerequisites for each programming lab and minilab.
Taxonomy of security considerations and software quality
Authors: Wang Huaiqing , Wang Chen
Published: August 2003

Addressing security threats and risks through software quality design factors.
Rethinking the digital divide
Authors: Payton Fay Cobb
Published: August 2003

African-American students are all too aware that the digital divide is not merely about Internet access. Rather, it involves access to the social networks that ease the path to success in high-tech careers.
Spatial queries in dynamic environments
Authors: Tao Yufei , Papadias Dimitris
Published: August 2003

Conventional spatial queries are usually meaningless in dynamic environments since their results may be invalidated as soon as the query or data objects move. In this paper we formulate two novel query types,
time parameterized
and
continuous queries
, applicable in such environments. A time-parameterized query retrieves the
actual result
at the time when the query is issued, the
expiry time
of the result given the current motion of the query and database objects, and the
change
that causes the expiration. A continuous query retrieves tuples of the form <
result
,
interval
>, where each
result
is accompanied by a future
interval
, during which it is valid. We study time-parameterized and continuous versions of the most common spatial queries (i.e., window queries, nearest neighbors, spatial joins), proposing efficient processing algorithms and accurate cost models.
On the computation of relational view complements
Authors: Lechtenbörger Jens , Vossen Gottfried
Published: August 2003

Views as a means to describe parts of a given data collection play an important role in many database applications. In dynamic environments where data is updated, not only information provided by views, but also information provided by data sources yet
missing
from views turns out to be relevant: Previously, this missing information has been characterized in terms of
view complements
; recently, it has been shown that view complements can be exploited in the context of data warehouses to guarantee desirable warehouse properties such as independence and self-maintainability. As the complete source information is a trivial complement for any view, a natural interest for "small" or even "minimal" complements arises. However, the computation of minimal complements is still not very well understood. In this article, it is shown how to compute reasonably small (and in special cases even minimal) complements for a large class of relational views.
Location, location, location
Authors: Schindler Esther
Published: August 2003

What effect will tracking technologies like RFID and GPS have on connected businesses?
Spam I am?!
Authors: Weiss Aaron
Published: August 2003

Several months ago I sent out an e-mail to a couple of thousand people and nearly lost my broadband access as a result. I maintain a personal Web site of a satirical nature which has attracted a good deal of traffic and consistently positive feedback over the years. Eventually I tried to market a modest product based on the Web site. Far from a major retail launch, this was more akin to custom printing a bunch of t-shirts for friends and family. Because the nature of the site did not invite a high rate of return traffic, I sent an e-mail to the people who had themselves sent e-mail in the past with positive feedback, some two thousand folks in all. The e-mail that I sent described new content added to the site as well as the product that was available.
SuperLU_DIST
Authors: Li Xiaoye S. , Demmel James W.
Published: August 2003

We present the main algorithmic features in the software package SuperLU_DIST, a distributed-memory sparse direct solver for large sets of linear equations. We give in detail our parallelization strategies, with a focus on scalability issues, and demonstrate the software's parallel performance and scalability on current machines. The solver is based on sparse Gaussian elimination, with an innovative static pivoting strategy proposed earlier by the authors. The main advantage of static pivoting over classical partial pivoting is that it permits
a priori
determination of data structures and communication patterns, which lets us exploit techniques used in parallel sparse Cholesky algorithms to better parallelize both
LU
decomposition and triangular solution on large-scale distributed machines.
Congestion reduction during placement with provably good approximation bound
Authors: Yang X. , Wang M. , Kastner R. , Ghiasi S. , Sarrafzadeh M.
Published: August 2003

This paper presents a novel method to reduce routing congestion during placement stage. The proposed approach is used as a post-processing step in placement. Congestion reduction is based on local improvement on the existing layout. However, the approach has a global view of the congestion over the entire design. It uses integer linear programming (ILP) to formulate the problem of conflicts between multiple congested regions, and performs local improvement according to the solution of the ILP problem. The approximation algorithm of the formulated ILP problem is studied and good approximation bounds are given and proved. Experiments show that the proposed approach can effectively alleviate the congestion of global routing results. The low computational complexity of the proposed approach indicates its scalability on large designs.
Address code generation for DSP instruction-set architectures
Authors: Lee J.-Y. , Park I.-C.
Published: August 2003

This paper presents a new DSP-oriented code optimization method to enhance performance by exploiting the specific architectural features of digital signal processors. In the proposed method, a source code is translated into the static single assignment form while preserving the high-level information related to the address computation of array accesses. The information is used in generating auto-modification addressing operations provided by most digital signal processors. In addition to the conventional control-data flow graph, a new graph is employed to find auto-modification addressing modes efficiently. Experimental results on benchmark programs show that the proposed method is effective in improving performance and reducing code size.
Knowledge management with patterns
Authors: May Daniel , Taylor Paul
Published: August 2003

Developing techniques to improve the process of converting information to knowledge.
From terabytes to insights
Authors: Colwell Rita R.
Published: August 2003

For scientists and engineers tapping the NSF's high-performance cyberinfrastructure, the path to wisdom follows a route both miraculous and familiar.
Making a game of system design
Authors: Swartout William , van Lent Michael
Published: August 2003

The pleasures and wonders of gameplay, as well as their deeper lessons, are being applied in fields beyond entertainment as diverse as psychological therapy, experience-based education, and design prototyping.
Full-size projection keyboard for handheld devices
Authors: Tomasi Carlo , Rafii Abbas , Torunoglu Ilhami
Published: August 2003

A keyboard made entirely of light projected onto desktops, airplane tray tables, even kitchen counters functions, feels, and sounds like its mechanical counterpart. Next: perhaps on laps and in the air.
The complex-step derivative approximation
Authors: Martins Joaquim R. R. A. , Sturdza Peter , Alonso Juan J.
Published: August 2003

The complex-step derivative approximation and its application to numerical algorithms are presented. Improvements to the basic method are suggested that further increase its accuracy and robustness and unveil the connection to algorithmic differentiation theory. A general procedure for the implementation of the complex-step method is described in detail and a script is developed that automates its implementation. Automatic implementations of the complex-step method for Fortran and C/C++ are presented and compared to existing algorithmic differentiation tools. The complex-step method is tested in two large multidisciplinary solvers and the resulting sensitivities are compared to results given by finite differences. The resulting sensitivities are shown to be as accurate as the analyses. Accuracy, robustness, ease of implementation and maintainability make these complex-step derivative approximation tools very attractive options for sensitivity analysis.
Remark on Algorithm 769
Authors: Hopkins Tim
Published: August 2003

We present a number of corrections and improvements to Algorithm 769 [Pardalos et al. 1997].
SouthamptonTAC
Authors: He Minghua , Jennings Nicholas R.
Published: August 2003

Software agents are increasingly being used to represent humans in on-line auctions. Such agents have the advantages of being able to systematically monitor a wide variety of auctions and then make rapid decisions about what bids to place in what auctions. They can do this continuously and repetitively without losing concentration. Moreover, in complex multiple auction settings, agents may need to modify their behavior in one auction depending on what is happening in another. To provide a means of evaluating and comparing (benchmarking) research methods in this area, the Trading Agent Competition (TAC) was established. This competition involves a number of agents bidding against one another in a number of related auctions (operating different protocols) to purchase travel packages for customers. Against this background, this artcle describes the design, implementation and evaluation of our adaptive autonomous trading agent, SouthamptonTAC, one of the most successful participants in TAC 2002.
The use of dynamic contexts to improve casual internet searching
Authors: Leroy Gondy , Lally Ann M. , Chen Hsinchun
Published: August 2003

Research has shown that most users' online information searches are suboptimal. Query optimization based on a relevance feedback or genetic algorithm using dynamic query contexts can help casual users search the Internet. These algorithms can draw on implicit user feedback based on the surrounding links and text in a search engine result set to expand user queries with a variable number of keywords in two manners. Positive expansion adds terms to a user's keywords with a Boolean "and," negative expansion adds terms to the user's keywords with a Boolean "not." Each algorithm was examined for three user groups, high, middle, and low achievers, who were classified according to their overall performance. The interactions of users with different levels of expertise with different expansion types or algorithms were evaluated. The genetic algorithm with negative expansion tripled recall and doubled precision for low achievers, but high achievers displayed an opposed trend and seemed to be hindered in this condition. The effect of other conditions was less substantial.
How CIOs manage their superiors' expectations
Authors: Potter Richard E.
Published: August 2003

Survival of the chief information officer isn't easy. It takes a keen sense of what the boss anticipates from IT projects as well as a diplomatic understanding of what the boss really does---and does not---know about IT.
Analyzing the application ASP concept
Authors: Walsh Kenneth R.
Published: August 2003

The application service provider model can realize economies of scale in managing hardware, software, and personnel resources, but this new concept also introduces uncertainty as it redistributes responsibilities among organizations.
Induction of Atherosclerosis by Low-Fat, Semisynthetic Diets in LDL Receptor–Deficient C57BL/6J and FVB/NJ Mice
Authors: Teupser Daniel , Persky Adam D. , Breslow Jan L.
Published: August 2003

Objective—

A semisynthetic diet with varying amounts of cholesterol was used to achieve hypercholesterolemia and atherosclerosis in LDL receptor–deficient (LDLR−/−) mice. Atherosclerotic lesions were measured as cross-sectional area at the aortic root and brachiocephalic artery and by en face analysis of aortic lesion area in 209 male and female animals on the C57BL/6J (B6.LDLR−/−) and FVB/NJ (FVB.LDLR−/−) backgrounds.

Methods and Results—

The semisynthetic diet containing 4.3% fat and 0.00% or 0.02% cholesterol was sufficient to induce hypercholesterolemia (12.6±2.4 mmol/L) and atherosclerosis in B6.LDLR−/− mice at the aortic root (98 980±37 727 μm
2
) and brachiocephalic artery (12 039±12 750 μm
2
) but did not produce significant lesions in the aorta measurable by the en face method. Raising dietary cholesterol to 0.15%, 0.30%, or 0.50% more than doubled plasma cholesterol levels (35.9±8.5 mmol/L) and resulted in significant en face lesions. It also led to a significant increase in atherosclerotic lesion area at the aortic root (547 753±182 151 μm
2
) and brachiocephalic arteries (125 666±59 339 μm
2
). Although FVB.LDLR−/− mice developed comparable cholesterol levels, they were relatively atherosclerosis resistant and had many-fold smaller lesions.

Conclusions—

These results should aid investigations of atherosclerosis in LDLR−/− mice by informing the selection of diet to be used and the location of lesions to be scored.
Cholesterol Dependence of Vascular ERK1/2 Activation and Growth in Response to Stretch
Authors: Zeidan Asad , Broman Jonas , Hellstrand Per , Swärd Karl
Published: August 2003

Objective—

Stretch-induced growth of the vascular wall plays a role in hypertension and neointima formation. Its signal pathways involve integrins, cytoskeleton, membrane receptors, and ion channels, some of which are organized in cholesterol-rich, membrane domains such as lipid rafts or caveolae. This study tested the role of rafts/caveolae in stretch-induced vascular growth by manipulation of membrane cholesterol contents.

Methods and Results—

Growth and protein synthesis were induced by mechanical stretch of rat portal veins in vitro. Sucrose gradient centrifugation showed stretch-induced tyrosine phosphorylation primarily in fractions containing caveolin-1. Disruption of membrane caveolae with use of methyl-β-cyclodextrin (mβcd) reduced weight gain, protein synthesis, and DNA synthesis to levels in unstretched, control veins. These effects were partially reversed by restoration of cellular cholesterol contents. Inhibited growth was associated with abolished activation of extracellular signal–regulated kinase (ERK) 1/2 in response to stretch and endothelin-1 (ET-1) but not to angiotensin II. Inhibition of ET-1 type A (ET
A
) receptors by RF139317 or endothelin-converting enzyme by phosphoramidone abolished stretch-induced ERK1/2 activation, which was, however, unaffected by removal of the endothelium.

Conclusions—

Stretch-induced growth signaling in vascular smooth muscle depends on cholesterol-rich, membrane microdomains by a mechanism involving ET
A
receptors that respond to endogenous ET-1 production.
Thiazolidinediones and Blood Lipids in Type 2 Diabetes
Authors: van Wijk Jeroen P.H. , de Koning Eelco J.P. , Martens Edwin P. , Rabelink Ton J.
Published: August 2003

We evaluated study population characteristics and treatment effects on blood lipids between studies in which either rosiglitazone (RSG) or pioglitazone (PIO) was investigated in patients with type 2 diabetes. We performed a summary analysis of all published double-blind, placebo-controlled studies with RSG (4 and 8 mg/d) and PIO (15, 30, and 45 mg/d). Data were analyzed by the random-effects model. Nineteen trials met our inclusion criteria, yielding 5304 patients, 3236 in studies with RSG and 2068 in studies with PIO. Subjects treated with PIO were more obese and showed more pronounced hyperglycemia and dyslipidemia (increased triglycerides and decreased HDL cholesterol) at baseline than did subjects treated with RSG. By weighted linear-regression analysis, studies with PIO showed greater beneficial effects on triglycerides, total cholesterol, and LDL cholesterol, after adjustment for the respective lipid levels at baseline. RSG 8 mg/d showed greater increases in total cholesterol and LDL cholesterol than did RSG 4 mg/d. PIO 30 mg/d showed greater reductions in triglycerides than did PIO 15 mg/d. Studies conducted with PIO showed more beneficial effects on blood lipids, but also different study population characteristics in comparison with studies conducted with RSG. Differences in both pharmacologic properties between agents and study population characteristics are likely to have influenced the results.
Fish Consumption Is Associated With Lower Heart Rates
Authors: Dallongeville Jean , Yarnell John , Ducimetière Pierre , Arveiler Dominique , Ferrières Jean , Montaye Michèle , Luc Gérald , Evans Aluns , Bingham Annie , Hass Bernadette , Ruidavets Jean-Bernard , Amouyel Philippe
Published: August 2003

Background—

Fish consumption decreases risk of sudden death. The goal of the present study was to assess the relationship between fish consumption and heart rate.

Methods and Results—

A cross-sectional analysis was conducted of 9758 men, age 50 to 59 years, without coronary heart disease (CHD) who were recruited in France and Belfast, Ireland, from 1991 to 1993. Heart rate and CHD risk factors were compared among 4 categories of fish consumption, as follows: (1) less than once per week (n=2662), (2) once per week (n=4576), (3) twice per week (n=1964), and (4) more than twice per week (n=556). Fatty acid profiles of erythrocyte phospholipids were determined in a random subsample of 407 subjects. In erythrocyte phospholipids, eicosapentaenoic acid (
P
<0.0005), docosahexaenoic acid (
P
<0.0001), and total n-3 fatty acid (
P
<0.0008) increased across the categories of fish intake. Triglycerides (
P
<0.0001), systolic blood pressure (
P
<0.006), and diastolic blood pressure (
P
<0.0001) were lower and HDL cholesterol levels (
P
<0.004) were higher in fish consumers than in nonconsumers. Similarly, heart rate decreased across the categories of fish intake (
P
<0.0001). After adjustment for age, center, education level, physical activity, smoking habit, alcohol consumption, body mass index, and antiarrhythmic medications, heart rate remained statistically lower among fish consumers than among nonconsumers (
P
for trend <0.0001). Docosahexaenoic acid content of erythrocyte phospholipids was inversely correlated with heart rate (
P
<0.03).

Conclusions—

Fish consumption is associated with decreased heart rate in men. Because heart rate is positively associated with risk of sudden death, this association may explain, at least in part, the lower risk of sudden death among fish consumers.
Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure
Authors: Horwich Tamara B. , Patel Jignesh , MacLellan W. Robb , Fonarow Gregg C.
Published: August 2003

Background—

Cardiac troponin I (cTnI), a sensitive and specific marker of myocardial cell injury, is useful in diagnosing and assessing prognosis in acute coronary syndromes. Small studies report that cTnI is elevated in severe heart failure (HF) and may predict adverse outcomes.

Methods and Results—

The present study evaluated 238 patients with advanced HF referred for cardiac transplantation evaluation who had cTnI assay drawn at the time of initial presentation. Patients with acute myocardial infarction or myocarditis were excluded from analysis. cTnI was detectable (cTnI ≥0.04 ng/mL) in serum of 117 patients (49.1%). Patients with detectable cTnI levels had significantly higher B-type natriuretic peptide (BNP) levels (
P
<0.001) and more impaired hemodynamic profiles, including higher pulmonary wedge pressures (
P
=0.002) and lower cardiac indexes (
P
<0.0001). A significant correlation was found between detectable cTnI and progressive decline in ejection fraction over time. Furthermore, detectable cTnI was associated with increased mortality risk (RR, 2.05; 95% CI, 1.22 to 3.43). After adjustment for other factors associated with adverse prognosis including age, sex, ejection fraction, and coronary artery disease, cTnI remained a significant predictor of death. cTnI used in conjunction with BNP further improved prognostic value.

Conclusions—

cTnI is associated with impaired hemodynamics, elevated BNP levels, and progressive left ventricular dysfunction in patients with HF. cTnI may be a novel, useful tool in identifying patients with HF who are at increased risk for progressive ventricular dysfunction and death.
Plasma Carotenoids and Tocopherols and Risk of Myocardial Infarction in a Low-Risk Population of US Male Physicians
Authors: Hak A. Elisabeth , Stampfer Meir J. , Campos Hannia , Sesso Howard D. , Gaziano J. Michael , Willett Walter , Ma Jing
Published: August 2003

Background—

Increased intake of carotenoids and vitamin E may protect against myocardial infarction (MI). However, prospective data on blood levels of carotenoids other than β-carotene and vitamin E (tocopherol) and risk of MI are sparse.

Methods and Results—

We conducted a prospective, nested case-control analysis among male physicians without prior history of cardiovascular disease who were followed for up to 13 years in the Physicians’ Health Study. Samples from 531 physicians diagnosed with MI were analyzed together with samples from paired control subjects, matched for age and smoking, for 5 major carotenoids (α- and β-carotene, β-cryptoxanthin, lutein, and lycopene), retinol, and α- and γ-tocopherol. Overall, we found no evidence for a protective effect against MI for higher baseline plasma levels of retinol or any of the carotenoids measured. Among current and former smokers but not among never-smokers, higher baseline plasma levels of β-carotene tended to be associated with lower risk (
P
for interaction=0.02). Men with higher plasma levels of γ-tocopherol tended to have an increased risk of MI (
P
for trend=0.01).

Conclusions—

These prospective data do not support an overall protective relation between plasma carotenoids or tocopherols and future MI risk among men without a history of prior cardiovascular disease.
Comparative Effects of Carvedilol and Metoprolol on Regional Vascular Responses to Adrenergic Stimuli in Normal Subjects and Patients With Chronic Heart Failure
Authors: Hryniewicz Katarzyna , Androne Ana Silvia , Hudaihed Alhakam , Katz Stuart D.
Published: August 2003

Background—

Adrenergic receptor blockers used in the treatment of heart failure have distinct receptor affinity profiles. We hypothesized that α-adrenergic–blocking effects of carvedilol would limit vasoconstriction in response to adrenergic stimuli when compared with metoprolol.

Methods and Results—

Forearm vascular resistance responses to isometric handgrip and cold pressor test were determined by plethysmography before and during adrenergic receptor blockade in prospective randomized trials. Acute effects were assessed in a crossover trial in normal subjects (single dose of 25 mg carvedilol, 100 mg metoprolol tartrate, and placebo). Chronic effects (25 mg carvedilol BID versus 200 mg extended-release metoprolol succinate daily for 6 months) were assessed in a parallel group trial of chronic heart failure subjects. In normal subjects, carvedilol decreased forearm vascular resistance responses to adrenergic stimuli when compared with metoprolol and placebo (isometric handgrip −3.5 U for carvedilol versus −1.2 U for metoprolol and −2.2 U for placebo,
P
=0.15; cold pressor test 3.1±8.9 U for carvedilol versus 9.0±2.7 U for metoprolol and 8.2±5.8 U for placebo,
P
<0.05). In heart failure subjects, vasomotor responses to isometric handgrip and cold pressor test did not differ between treatment groups.

Conclusions—

Acute administration of carvedilol attenuates the vasoconstriction response to adrenergic stimuli when compared with placebo and metoprolol in normal subjects, whereas chronic administration of carvedilol does not attenuate the vasoconstrictor response to adrenergic stimuli when compared with metoprolol in heart failure subjects. These data suggest that long-term benefits of carvedilol in heart failure are not mediated by α-adrenergic blockade.
Adenosine Diphosphate–Induced Platelet Aggregation Is Associated With

P2Y
12

Gene Sequence Variations in Healthy Subjects
Authors: Fontana Pierre , Dupont Annabelle , Gandrille Sophie , Bachelot-Loza Christilla , Reny Jean-Luc , Aiach Martine , Gaussem Pascale
Published: August 2003

Background—

The adenosine diphosphate (ADP) receptor P2Y
12
plays a pivotal role in platelet aggregation, as demonstrated by the benefit conferred by its blockade in patients with cardiovascular disease. Some studies have shown interindividual differences in ADP-induced platelet aggregation responses ex vivo, but the mechanisms underlying this variability are unknown.

Methods and Results—

We examined ADP-induced platelet aggregation responses in 98 healthy volunteers, and we identified 2 phenotypic groups of subjects with high and low responsiveness to 2 μmol/L ADP. This prompted us to screen the recently identified G
i
-coupled ADP receptor gene

P2Y
12

for sequence variations. Among the 5 frequent polymorphisms thus identified, 4 were in total linkage disequilibrium, determining haplotypes H1 and H2, with respective allelic frequencies of 0.86 and 0.14. The number of H2 alleles was associated with the maximal aggregation response to ADP in the overall study population (
P
=0.007). Downregulation of the platelet cAMP concentration by ADP was more marked in 10 selected H2 carriers than in 10 noncarriers.

Conclusions—

In healthy subjects, ADP-induced platelet aggregation is associated with a haplotype of the P2Y
12
receptor gene. Given the crucial role of the P2Y
12
receptor in platelet functions, carriers of the H2 haplotype may have an increased risk of atherothrombosis and/or a lesser clinical response to drugs inhibiting platelet function.
Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype
Authors: Dibbs Ziad I. , Diwan Abhinav , Nemoto Shintaro , DeFreitas Gilberto , Abdellatif Maha , Carabello Blase A. , Spinale Francis G. , Feuerstein Giora , Sivasubramanian Natarajan , Mann Douglas L.
Published: August 2003

Background—

Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF-α converting enzyme (TACE) to generate a 17-kDa form of “secreted” TNF. Whereas the effects of secreted TNF in the heart have been characterized extensively, the effects of transmembrane TNF in the heart are unknown.

Methods and Results—

We generated lines of transgenic mice with cardiac-restricted overexpression of a noncleavable, transmembrane form of TNF. We next treated a previously generated transgenic line of mice with cardiac-restricted expression of cleavable TNF (referred to as MHCsTNF mice) with a TACE inhibitor (DPC-IDR1) to determine whether TACE inhibition would prevent the transition from concentric hypertrophy to left ventricular (LV) dilation that occurs in this line of transgenic mice. Two of the founder lines did not have a demonstrable phenotype (M-41 and M-45), whereas a third line developed a concentric hypertrophic cardiac phenotype (M-48). Characterization of the M-48 line at 6 weeks of age showed that this line developed concentric hypertrophy, with an increase in myocyte cross-sectional area and reexpression of the fetal gene program. Four weeks of TACE inhibition abrogated the LV dilation in the MHCsTNF mice and resulted in an increase in LV wall thickness and increased myocyte cross-sectional area, thus mimicking the effects observed in the mice with noncleavable, transmembrane TNF.

Conclusions—

These studies show that transmembrane TNF is biologically active and provokes a concentric hypertrophic cardiac phenotype, thus suggesting that posttranslational processing (ie, secretion) of TNF is responsible for the dilated cardiomyopathic phenotype in mice with targeted, cardiac-restricted overexpression of TNF.
A20 Is Dynamically Regulated in the Heart and Inhibits the Hypertrophic Response
Authors: Cook Stuart A. , Novikov Mikhail S. , Ahn Youngkeun , Matsui Takashi , Rosenzweig Anthony
Published: August 2003

Background—

Nuclear factor (NF)–κB signaling has been implicated in cardiomyocyte hypertrophy. Here, we determine the cardiac regulation and biological activity of A20, an inhibitor of NF-κB signaling.

Methods and Results—

Mice were subjected to aortic banding, and A20 expression was examined. A20 mRNA upregulation (4.3±1.5-fold;
P
<0.05) was detected 3 hours after banding, coinciding with peak NF-κB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (2.8±0.6- and 4±1.1-fold, respectively;
P
<0.05), again paralleling NF-κB activation. Infection of cardiomyocytes with an adenoviral vector (Ad) encoding A20 inhibited tumor necrosis factor-α–stimulated NF-κB signaling with an efficacy comparable to dominant negative inhibitor of κ-B kinase β (dnIKKβ). Ad.dnIKKβ-infected cardiomyocytes exhibited increased apoptosis when they were serum starved or subjected to hypoxia-reoxygenation, whereas Ad.A20-infected cardiomyocytes did not. Expression of Ad.A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1.

Conclusions—

A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NF-κB signaling without sensitizing cardiomyocytes to apoptotic cell death.
Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E–Knockout Mice
Authors: Mallat Ziad , Gojova Andrea , Brun Valérie , Esposito Bruno , Fournier Nathalie , Cottrez Françoise , Tedgui Alain , Groux Hervé
Published: August 2003

Background—

T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.

Methods and Results—

Clones of ovalbumin (OVA)–specific Tr1 cells expanded in vitro were administered intraperitoneally (10
6
cells per mouse) with their cognate antigen (50 μg of OVA subcutaneously in complete Freund’s adjuvant [CFA]) to female apolipoprotein E–knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (
P
<0.0001), a decrease in the production of interferon-γ (
P
<0.001), and an increase in interleukin-10 production (
P
<0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A–stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls (
P
=0.002 to
P
<0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice.

Conclusions—

Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.
Gene Transfer of eNOS to the Thick Ascending Limb of eNOS-KO Mice Restores the Effects of
l
-Arginine on NaCl Absorption
Authors: Ortiz Pablo A. , Hong Nancy J. , Wang Ding , Garvin Jeffrey L.
Published: August 2003

The thick ascending limb of the loop of Henle (THAL) plays an essential role in the regulation of sodium and water homeostasis by the kidney.
l
-Arginine, the substrate for nitric oxide synthase (NOS), decreases NaCl absorption by THALs. We hypothesized that eNOS produces the NO that regulates THAL NaCl transport and that selective expression of eNOS in the THAL of eNOS knockout(−/−) mice would restore the effects of
l
-arginine on NaCl absorption. eNOS−/− mice were anesthetized, the left kidney was exposed, and the renal interstitium was injected with recombinant adenoviral vectors that expressed green fluorescent protein (GFP) or eNOS driven by the promoter of the Na/K/2Cl cotransporter Ad-NKCC2GFP and Ad-NKCC2eNOS, respectively. In Ad-NKCC2eNOS–transduced kidneys, eNOS expression was detected 7 days after injection but was absent in Ad-NKCC2GFP–transduced kidneys. In THALs from eNOS−/− mice transduced with Ad-NKCC2eNOS, adding
l
-arginine increased DAF-2DA fluorescence, a measure of NO production, by 9.1±1.1% (
P
<0.05; n=5), but not in THALs transduced with Ad-NKCC2GFP. In THALs from eNOS−/− mice transduced with Ad-NKCC2eNOS, Cl absorption averaged 85.9±11.8 pmol/min per millimeter. Adding
l
-arginine (1 mmol/L) to the bath decreased Cl absorption to 59.7±11.0 pmol/min per millimeter (
P
<0.05; n=6). In THALs transduced with Ad-NKCC2GFP, Cl absorption averaged 96.0±21.0 pmol/min per millimeter. Adding
l
-arginine to the bath did not significantly affect Cl absorption (100.6±20.6 pmol/min per millimeter; n=4). We concluded that gene transfer of eNOS to the THAL of eNOS−/− mice restores
l
-arginine–induced inhibition of NaCl transport and NO production. These data indicate that eNOS is essential for the regulation of THAL NaCl transport by NO.
Role of Endogenous Angiotensin II on Glutamatergic Actions in the Rostral Ventrolateral Medulla in Goldblatt Hypertensive Rats
Authors: Carvalho Taís Helena F. , Bergamaschi Cássia T. , Lopes Oswaldo U. , Campos Ruy R.
Published: August 2003

In this study, we investigated the cardiovascular responses mediated by rostral ventrolateral medulla neurons (RVLM) in the Goldblatt hypertension model (2K-1C) treated or not treated with captopril. The actions of glutamate into the RVLM were tested, injecting glutamate (0.1 mol/L, 100 nL) and its antagonist kynurenic acid (0.02 mol/L, 100 nL). Glycine (0.5 mol/L, 100 nL) was also microinjected. Experiments were performed in male Wistar rats (weight, 250 to 300 g); 5 groups were studied: (1) 2K-1C nontreated (H, n=6); (2) 2K-1C treated with captopril, 10 mg/kg per day (Ht10, n=10); (3) 2K-1C treated with captopril, 50 mg/kg per day (Ht50, n=7); (4) control normotensive rats (N, n=7); and (5) normotensive rats treated with captopril, 50 mg/kg per day (Nt50, n=8). All experiments in 2K-1C were performed 6 weeks after renal surgery; captopril treatment lasted for the last 2 weeks. In urethane-anesthetized rats (1.2 g/kg IV), bilateral microinjection of glycine into the RVLM caused a depressor response; there was no difference between groups in relation to the change of variation (N: 54±2; H: 46±12; Ht10: 50±3, and Ht50: 42±7 mm Hg). Only in the H group, kynurenic acid microinjection into the RVLM caused a depressor response (H: 158±8 to 132±8 mm Hg). Glutamate response was larger in hypertensive than in normotensive rats (N: 38±2.6 and H: 55±6); no difference was observed between hypertensive groups. The data suggest that glutamate acts tonically to drive the RVLM in 2K-1C rats, and this action is modulated by endogenous angiotensin II. The increase in the glutamate actions within the RVLM may contribute to the pathogenesis of renovascular hypertension.
ET
A
Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension
Authors: Callera Glaucia E. , Touyz Rhian M. , Teixeira Simone A. , Muscara Marcelo N. , Carvalho Maria Helena C. , Fortes Zuleica B. , Nigro Dorothy , Schiffrin Ernesto L. , Tostes Rita C.
Published: August 2003

Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET
A
receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210±9 mm Hg;
P
<0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9±10.3% of ethidium bromide–positive nuclei;
P
<0.05) versus control uninephrectomized (UniNx) rats (118±3 mm Hg; 18.5±3%, respectively). In DOCA-salt rats, the ET
A
antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170±4 versus UniNx, 120±3 mm Hg) and normalized superoxide production (21.7±6 versus UniNx, 11.9±7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8±7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8±4.2% versus UniNx, 95.4±1.9%,
P
<0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5±4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ET
A
receptors in DOCA-salt hypertension, in apparently blood pressure–independent fashion.
Cardiac Memory Is Associated With Decreased Levels of the Transcriptional Factor CREB Modulated by Angiotensin II and Calcium
Authors: Patberg Kornelis W. , Plotnikov Alexei N. , Quamina Aaron , Gainullin Ravil Z. , Rybin Andrew , Danilo Peter , Sun Lena S. , Rosen Michael R.
Published: August 2003

Cardiac memory (CM) has short- (STCM) and long-term (LTCM) components modulated by calcium and angiotensin II. LTCM is associated with reduced
I
to
and Kv4.3 mRNA levels. Because the cAMP response element binding protein, CREB, contributes to CNS memory transcription, we hypothesized that it might be a transcriptional factor in CM, influenced by calcium and angiotensin II. We studied STCM in dogs that were AV sequentially paced (AVP) for 2 hours or sham-operated. STCM was evaluated with ECG and vectorcardiogram (VCG), and subepicardial biopsies were taken at 5 to 120 minutes and investigated for CREB. LTCM was studied in dogs paced for 3 weeks and in sham controls. At 3 weeks the heart was excised, biopsies obtained, and CRE binding tested. STCM induction occurred in AVP dogs but not in sham or AVP dogs treated with saralasin or nifedipine. Nuclear CREB was significantly decreased at 2 hours in the AVP no-drug group only. LTCM dogs manifested reduced binding of nuclear proteins to CRE, and CRE binding activity in the promoter region of Kv4.3. In conclusion, there is an association between STCM induction and decreased nuclear CREB that is angiotensin-modulated and calcium-dependent. Moreover, the decreased CRE binding after 3 weeks of AVP combined with CRE binding activity in the Kv4.3 promoter can explain the Kv4.3 mRNA and
I
to
downregulation that characterize LTCM.