bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of thin nanocrystalline VN film as a high-performance diffusion barrier between Cu and SiO2
Authors: Takeyama Mayumi B. , Itoi Takaomi , Satoh Kazumi , Sakagami Masakazu , Noya Atsushi
Published: October 2004

Thin nanocrystalline vanadium nitride (VN) films of low resistivity were examined as an extremely thin diffusion barrier to provide thermal stability in Cu∕VN∕SiO2∕Si systems. A 10-nm-thick VN barrier with grains ranging from several to ∼10nm in diameter provided excellent barrier properties. After annealing at 600°C for 1h, the barrier showed scarcely any change in structure and absence of Cu diffusion and/or decisive interfacial reaction in the system. This was interpreted to mean that the present barrier, which is made of a thermochemically stable δ-VN compound phase with a slightly nitrogen-rich composition and a nanocrystalline structure, was preferable to suppress the solid-phase reaction and/or diffusion, as well as the structural change upon annealing. It was revealed that the nanocrystalline VN barrier is an excellent candidate as a barrier in a forthcoming Cu metallization scheme.
Hard and conductive carbon nanodome thin films deposited by rf magnetron sputtering
Authors: Chowdhury S. , Laugier M. T.
Published: October 2004

This Letter reports the synthesis of hard and conductive carbon nanodome thin films over a range of substrate temperature from 50to550°C. The size of the nanodomes increases from 40–80nm at room temperature to 200–400nm at high temperature (550°C). Electrical characterization shows that these films have conductive behavior with a resistivity depending on the size of the nanodomes. Resistivity values of 19mΩcm were found for nanodomes of size 40–80nm, falling to 6mΩcm for nanodomes of size 200–400nm. Nanoindentation results show that the hardness and Young’s modulus of these films are in the range from 9–22GPa and 100–168GPa, respectively, and these values decrease as the size of the nanodomes increases. Glancing angle x-ray diffraction results confirm that a crystalline graphitic carbon nitride structure has formed.
Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium
Authors: da Silva Rafaela , Lucchinetti Eliana , Pasch Thomas , Schaub Marcus C. , Zaugg Michael
Published: October 2004

Pharmacological (PPC) and ischemic preconditioning (IschPC) provide comparable protection against ischemia in the heart. However, the genomic phenotype may depend on the type of preconditioning. Isolated perfused rat hearts were used to evaluate transcriptional responses to PPC and IschPC in the presence (mediator/effector response) or absence (trigger response) of 40 min of test ischemia using oligonucleotide microarrays. IschPC was induced by 3 cycles of 5 min of ischemia, and PPC by 15 min of 2.1 vol% isoflurane. Unsupervised analysis methods were used to identify gene expression patterns. PPC and IschPC were accompanied by marked alterations in gene expression. PPC and IschPC shared only ∼25% of significantly up- and downregulated genes after triggering. The two types of preconditioning induced a more uniform genomic response after ischemia/reperfusion. Numerous genes separated preconditioned from unprotected ischemic hearts. Three stable gene clusters were identified in the trigger response to preconditioning, while eight stable clusters related to cytoprotection, inflammation, remodeling, and long interspersed nucleotide elements (LINEs) were delineated after prolonged ischemia. A single stable sample cluster emerged from cluster analysis for both IschPC and unprotected myocardium, indicating a close molecular relationship between these two treatments. Principal component analysis revealed differences between PPC vs. IschPC, and trigger vs. mediator/effector responses in transcripts predominantly related to biosynthesis and apoptosis. IschPC and PPC similarly but distinctly reprogram the genetic response to ischemic injury. IschPC elicits a postischemic gene expression profile closer to unprotected myocardium than PPC, which may be therefore more advantageous as therapeutic strategy in cardioprotection.
Restrictive metric regularity and generalized differential calculus in Banach spaces
Authors: Mordukhovich Boris S. , Wang Bingwu
Published: October 2004

We consider nonlinear mappings f : X → Y
between Banach
spaces and study the notion of restrictive metric
regularity of f
around some point , that is, metric
regularity of f from X into the metric space E = f(X). Some
sufficient as well as necessary and sufficient conditions for
restrictive metric regularity are obtained, which particularly
include an extension of the classical Lyusternik‐Graves theorem in
the case when f is strictly differentiable at but its
strict derivative is not surjective. We develop
applications of the results obtained and some other techniques in
variational analysis to generalized differential calculus
involving normal cones to nonsmooth and nonconvex sets,
coderivatives of set‐valued mappings, as well as first‐order and
second‐order subdifferentials of extended real‐valued functions.
Left Ventricular Mass in Relation to Genetic Variation in Angiotensin II Receptors, Renin System Genes, and Sodium Excretion
Authors: Kuznetsova Tatiana , Staessen Jan A. , Thijs Lutgarde , Kunath Christiane , Olszanecka Agnieszka , Ryabikov Andrew , Tikhonoff Valérie , Stolarz Katarzyna , Bianchi Giuseppe , Casiglia Edoardo , Fagard Robert , Brand-Herrmann Stefan-Martin , Kawecka-Jaszcz Kalina , Malyutina Sofia , Nikitin Yuri , Brand Eva
Published: October 2004

Background—

In the European Project On Genes in Hypertension (EPOGH), we investigated in 3 populations to what extent left ventricular mass (LVM) was associated with genetic variation in the angiotensin II receptors type 1 (AGTR1
A1166C
) and type 2 (AGTR2
G1675A
) while accounting for possible gene–gene interactions with the angiotensin-converting enzyme (ACE
D/I
) and angiotensinogen (AGT
−532C/T
) polymorphisms.

Methods and Results—

We randomly recruited 221 nuclear families (384 parents, 431 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariates, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. For AGTR1 and AGTR2, there was no heterogeneity in the phenotype–genotype relations across populations. LVM index was unrelated to the AGTR1
A1166C
polymorphism. In men, in the population- and family-based analyses, the allelic effects of the AGTR2 polymorphism on LVM index differed (
P
=0.01) according to sodium excretion. In women, this gene–environment interaction did not reach statistical significance. In untreated men, LVM index (4.2 g/m
2
per 100 mmol) and left ventricular internal diameter (0.73 mm/100 mmol) increased (
P
<0.02) with higher sodium excretion in the presence of the
G
allele with an opposite tendency in
A
allele carriers. The ACE
D/I
polymorphism, together with the ACE genotype-by-sodium interaction term, significantly and independently improved the models relating LVM index to the AGTR2 polymorphism and the AGTR2 genotype-by-sodium interaction.

Conclusions—

The present findings support the hypothesis that in men the AGTR2
G1675A
and the ACE
D/I
polymorphisms independently influence LVM and that salt intake modulates these genetic effects.
Abnormalities of Neurohormonal and Cardiac Autonomic Nervous Activities Relate Poorly to Functional Status in Fontan Patients
Authors: Ohuchi Hideo , Takasugi Hisashi , Ohashi Hiroyuki , Yamada Osamu , Watanabe Ken , Yagihara Toshikatsu , Echigo Shigeyuki
Published: October 2004

Background—

Impaired cardiac autonomic nervous activities and increased neurohumoral activities (CANA, NHA) characterize Fontan patients. However, the clinical significance of these changes is not clearly understood. Our purpose was to clarify the clinical significance of the CANA and NHA in stable Fontan patients.

Methods and Results—

We divided 22 atriopulmonary connection (APC) and 75 total cavopulmonary connection (TCPC) patients into 4 subgroups according to New York Heart Association (NYHA) class (1.8±0.6) and measured various CANA and NHA indices. All NHA indices were elevated in the symptomatic patients (
P
<0.001). Natriuretic peptides were higher in the APC than in the TCPC patients, and the hemodynamics showed no correlation with brain natriuretic peptide in the APC patients. Low arterial oxygen saturation and impaired hemodynamics greatly influenced all elevated NHA indices (
P
<0.01), except for plasma renin activity, in the TCPC patients. Impaired CANA indices did not relate to NYHA class, although surgeries were associated with lower heart rate variability. In addition to poor correlation between NHA and CANA, age and ventricular morphology had no impact on all CANA and NHA indices, except for high norepinephrine in right ventricular Fontan patients.

Conclusions—

Although symptomatic Fontan patients exhibit higher NHA, CANA is not related to either NYHA class or NHA. APC itself is responsible for higher natriuretic peptides, and arterial oxygen desaturation has a great impact on elevated NHA in the TCPC patients. These characteristics of the NHA and CANA differ from those of heart failure patients with biventricular physiology.
Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase (
NOS3
) Attenuates β-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction
Authors: Massion Paul B. , Dessy Chantal , Desjardins Fanny , Pelat Michel , Havaux Xavier , Belge Catharina , Moulin Pierre , Guiot Yves , Feron Olivier , Janssens Stefan , Balligand Jean-Luc
Published: October 2004

Background—

In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by
NOS3
(endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of
NOS3
in the myocardium.

Methods and Results—

We studied the influence of
NOS3
in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing
NOS3
under the α-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold)
NOS3
overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32,
P
<0.001); an attenuation of the β-adrenergic positive inotropic response (isoproterenol, 10
−7
mol/L: 62.1±7.8% versus 90.8±8.0% of maximum Ca
2+
response; n=10 to 17;
P
<0.05); a potentiation of the muscarinic negative chronotropic response (carbamylcholine, 3.10
−8
mol/L: −63.9±14% versus −27.7±5.6% of basal rate; n=8 to 10;
P
<0.05), confirmed by telemetry in vivo; and an attenuation of the accentuated antagonism of β-adrenergically stimulated contraction (−14.6±1.5% versus −3.5±1.5; n=7 to 11;
P
<0.05). Cardiomyocyte NOS inhibition reversed all 4 effects (
P
<0.05).

Conclusions—

Moderate overexpression of
NOS3
, targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte
NOS3
may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.
Differentiation of Bone Marrow Stromal Cells Into the Cardiac Phenotype Requires Intercellular Communication With Myocytes
Authors: Xu Meifeng , Wani Maqsood , Dai Yan-Shan , Wang Jiang , Yan Mei , Ayub Ahmar , Ashraf Muhammad
Published: October 2004

Background—

Bone marrow stromal cells (BMSCs) have the potential to differentiate into various cells and can transdifferentiate into myocytes if an appropriate cellular environment is provided. However, the molecular signals that underlie this process are not fully understood. In this study, we show that BMSC differentiation is dependent on communication with cells in their microenvironment.

Methods and Results—

BMSCs were isolated from green fluorescent protein (GFP)–transgenic mice and cocultured with myocytes in a ratio of 1:40. Myocytes were obtained from neonatal rat ventricles. The differentiation of BMSCs in coculture was confirmed by immunohistochemistry, electron microscopy, and reverse transcription–polymerase chain reaction. Before coculturing, the BMSCs were negative for α-actinin and exhibited a nucleus with many nucleoli. After 7-day coculture with myocytes, some BMSCs became α-actinin–positive and formed gap junctions with native myocytes. However, BMSCs separated from myocytes by a semipermeable membrane were still negative for α-actinin. Transdifferentiated myocytes from BMSCs were microdissected from cocultures by laser captured microdissection to determine the changes in gene expression. BMSCs cocultured with myocytes expressed mouse cardiac transcription factor GATA-4.

Conclusions—

When cocultured with myocytes, BMSCs can transdifferentiate into cells with a cardiac phenotype. Differentiated myocytes express cardiac transcription factors GATA-4 and myocyte enhancer factor-2. The transdifferentiation processes rely on intercellular communication of BMSCs with myocytes.
Prospective Randomized Multicenter Trial of Empirical Antitachycardia Pacing Versus Shocks for Spontaneous Rapid Ventricular Tachycardia in Patients With Implantable Cardioverter-Defibrillators
Authors: Wathen Mark S. , DeGroot Paul J. , Sweeney Michael O. , Stark Alice J. , Otterness Mary F. , Adkisson Wayne O. , Canby Robert C. , Khalighi Koroush , Machado Christian , Rubenstein Donald S. , Volosin Kent J.
Published: October 2004

Background—

Successful antitachycardia pacing (ATP) terminates ventricular tachycardia (VT) up to 250 bpm without the need for painful shocks in implantable cardioverter-defibrillator (ICD) patients. Fast VT (FVT) >200 bpm is often treated by shock because of safety concerns, however. This prospective, randomized, multicenter trial compares the safety and utility of empirical ATP with shocks for FVT in a broad ICD population.

Methods and Results—

We randomized 634 ICD patients to 2 arms—standardized empirical ATP (n=313) or shock (n=321)—for initial therapy of spontaneous FVT. ICDs were programmed to detect FVT when 18 of 24 intervals were 188 to 250 bpm and 0 of the last 8 intervals were >250 bpm. Initial FVT therapy was ATP (8 pulses, 88% of FVT cycle length) or shock at 10 J above the defibrillation threshold. Syncope and arrhythmic symptoms were collected through patient diaries and interviews. In 11±3 months of follow-up, 431 episodes of FVT occurred in 98 patients, representing 32% of ventricular tachyarrhythmias and 76% of those that would be detected as ventricular fibrillation and shocked with traditional ICD programming. ATP was effective in 229 of 284 episodes in the ATP arm (81%, 72% adjusted). Acceleration, episode duration, syncope, and sudden death were similar between arms. Quality of life, measured with the SF-36, improved in patients with FVT in both arms but more so in the ATP arm.

Conclusions—

Compared with shocks, empirical ATP for FVT is highly effective, is equally safe, and improves quality of life. ATP may be the preferred FVT therapy in most ICD patients.
Intravascular Thrombosis After Hypoxia-Induced Pulmonary Hypertension
Authors: Pidgeon Graham P. , Tamosiuniene Rasa , Chen Gang , Leonard Irene , Belton Orina , Bradford Aidan , Fitzgerald Desmond J.
Published: October 2004

Background—

Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia.

Methods and Results—

Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1±3.2 versus 17.2±3.1 mm Hg; n=8,
P
<0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8±5.9 mm Hg; n=8,
P
<0.05), an effect that was attenuated by the thromboxane (TX) A
2
/prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB
2
increased during hypoxia (5.9±0.9 versus 1.2±0.2 ng/mg creatinine; n=6,
P
<0.01) and was further increased by COX-2 inhibition (8.5±0.7 ng/mg creatinine; n=6,
P
< 0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F
1α
decreased with COX-2 inhibition (8.6±3.0 versus 27.0±4.8 ng/mg creatinine; n=6,
P
< 0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the
COX-2
gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of
COX-1
had no effect.

Conclusions—

COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxia-induced pulmonary hypertension.
Serum Triglycerides as a Risk Factor for Cardiovascular Diseases in the Asia-Pacific Region
Authors:   Asia Pacific Cohort Studies Collaboration
Published: October 2004

Background—

The importance of serum triglyceride levels as a risk factor for cardiovascular diseases is uncertain.

Methods and Results—

We performed an individual participant data meta-analysis of prospective studies conducted in the Asia-Pacific region. Cox models were applied to the combined data from 26 studies to estimate the overall and region-, sex-, and age-specific hazard ratios for major cardiovascular diseases by fifths of triglyceride values. During 796 671 person-years of follow-up among 96 224 individuals, 670 and 667 deaths as a result of coronary heart disease (CHD) and stroke, respectively, were recorded. After adjustment for major cardiovascular risk factors, participants grouped in the highest fifth of triglyceride levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80% (95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95% CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared with those belonging to the lowest fifth. The association between triglycerides and CHD death was similar across subgroups defined by ethnicity, age, and sex.

Conclusions—

Serum triglycerides are an important and independent predictor of CHD and stroke risk in the Asia-Pacific region. These results may have clinical implications for cardiovascular risk prediction and the use of lipid-lowering therapy.
Evolution of Spontaneous Atherosclerotic Plaque Rupture With Medical Therapy
Authors: Rioufol Gilles , Gilard Martine , Finet Gérard , Ginon Isabelle , Boschat Jacques , André-Fouët Xavier
Published: October 2004

Background—

Ruptured coronary atheromatous plaque is generally considered to involve a high risk of subsequent clinical events. Few data are available on the natural evolution of non–culprit-lesion ruptured plaque. We therefore used serial intravascular ultrasound (IVUS) to study how such lesions, detected in the context of a first acute coronary syndrome with elevated troponin I levels, develop.

Methods and Results—

Fourteen patients with 28 distinct plaque ruptures (2±1 per patient) without significant associated stenosis (minimal lumen cross-sectional area >4 mm
2
) were included and systematically treated with 40 mg statin and antiplatelet agent (clopidogrel and aspirin for ≥9 months). Mean clinical and IVUS follow-up was 22±13 months (median, 22 months). No clinical event related to the lesion under study occurred. On final IVUS examination, half (14 of 28) of the ruptured plaques had healed, and the degree of stenosis tended to diminish (stenosis, 22±17% versus 29±17% at baseline;
P
=0.056). No healing-prediction criterion could be identified.

Conclusions—

Nearly 2 years of follow-up found that spontaneous coronary atheromatous plaque rupture without significant stenosis detected on first acute coronary syndrome healed without significant plaque modification in 50% of cases with medical therapy.
Correlations Between Fractional Flow Reserve and Intravascular Ultrasound in Patients With an Ambiguous Left Main Coronary Artery Stenosis
Authors: Jasti Venu , Ivan Eugen , Yalamanchili Venkata , Wongpraparut Nattawut , Leesar Massoud A.
Published: October 2004

Background—

Intravascular ultrasound (IVUS) is being used to assess the significance of a left main coronary artery stenosis (LMCS). However, the cutoff values of IVUS parameters at which to predict a fractional flow reserve (FFR) of 0.75 are unknown.

Methods and Results—

In 55 patients with an angiographically ambiguous LMCS, a pressure guidewire was used to calculate FFR, and IVUS parameters were calculated after automatic pullback. FFR averaged 0.86±0.13 (range, 0.55 to 1.0). IVUS minimum lumen diameter (MLD), minimum lumen area (MLA), cross-sectional narrowing (CSN), and area stenosis (AS) were 3.8±0.61 mm, 7.65±2.9 mm
2
, 59±13%, and 47±19%, respectively. Regression analysis demonstrated strong correlations between FFR and MLD (
r
=0.79,
P
<0.0001) as well as between FFR and MLA (
r
=0.74,
P
<0.0001). There were inverse, moderate correlations between FFR and CSN (
r
=0.69,
P
<0.0001), followed by those between FFR and AS (
r
=0.54,
P
<0.0001). Compared with FFR as the “gold standard,” an MLD of 2.8 mm had the highest sensitivity and specificity (93% and 98%, respectively) for determining the significance of an LMCS, followed by an MLA of 5.9 mm
2
(93% and 95%, respectively). Based on an FFR <0.75 and an FFR ≥0.75, the 38-month survival and event-free survival estimates (EFSEs) were both 100% and 100% versus 90%, respectively (
P
=NS).

Conclusions—

We conclude that (1) an IVUS MLD and MLA of 2.8 mm and 5.9 mm
2
, respectively, strongly predict the physiological significance of an LMCS and (2) among patients with an LMCS, an FFR of 0.75 is a strong predictor of survival and EFSE.
Multivariate Assessment of Lipid Parameters as Predictors of Coronary Heart Disease Among Postmenopausal Women
Authors: Shai Iris , Rimm Eric B. , Hankinson Susan E. , Curhan Gary , Manson JoAnn E. , Rifai Nader , Stampfer Meir J. , Ma Jing
Published: October 2004

Background—

Over the past decade, lipid measurements have been significantly improved and standardized. We evaluated the usefulness of multiple plasma lipid parameters in predicting coronary heart diseases (CHD) among women.

Methods and Results—

Among 32 826 women from the Nurses’ Health Study who provided blood samples at baseline, 234 CHD events were documented during 8 years of follow-up. In a nested study, these cases were matched to controls (1:2) for age, smoking, fasting status, and month of blood draw. We estimated the relative risk (RR) for each lipid parameter, adjusted for C-reactive protein, homocysteine, body mass index, family history, hypertension, diabetes, postmenopausal hormone use, physical activity, alcohol intake, and blood draw parameters. The RRs associated with an increase of ≈1 SD (mg/dL) were as follows: HDL cholesterol (HDL-C) (RR=0.6 [0.5 to 0.8], SD=17), apolipoprotein B
100
(apoB
100
) (RR=1.7 [1.4 to 2.1], SD=32), LDL cholesterol (LDL-C) (RR=1.4 [1.1 to 1.7], SD=36), total cholesterol (TC) (RR=1.4 [1.1 to 1.6], SD=40), and triglycerides (RR=1.3 [1.0 to 1.5], SD=80). Among the lipid indexes, the RRs were: apoB
100
/HDL-C (RR=1.7 [1.4 to 2.1], SD=1.0), TC/HDL-C (RR=1.6 [1.3 to 1.9], SD=1.3), LDL-C/HDL-C (RR=1.5 [1.3 to 1.9], SD=1.0), and non–HDL-C (RR=1.6 [1.3 to 1.9], SD=42 mg/dL). After simultaneous control for several lipid biomarkers, HDL-C was the primary contributor of the variation in multivariate models (
P
=0.01), followed by LDL-C (
P
=0.01), whereas triglycerides and apoB
100
did not contribute further information. HDL-C–related ratios were the strongest contributors to predicting CHD (
P
<0.0001).

Conclusions—

Lower levels of HDL-C may be a key discriminator of higher CHD events among postmenopausal women. HDL-C–related ratios (such as TC/HDL-C) provide a powerful predictive tool independently of other known CHD risk factors.
Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria
Authors: Asselbergs Folkert W. , Diercks Gilles F.H. , Hillege Hans L. , van Boven Ad J. , Janssen Wilbert M.T. , Voors Adriaan A. , de Zeeuw Dick , de Jong Paul E. , van Veldhuisen Dirk J. , van Gilst Wiek H.
Published: October 2004

Background—

Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours).

Methods and Results—

From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51±12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8±1.0 mmol/L, mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (
P
<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10],
P
=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57],
P
=0.649, log-rank).

Conclusions—

In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.
Unfavorable Effects of Resistance Training on Central Arterial Compliance
Authors: Miyachi Motohiko , Kawano Hiroshi , Sugawara Jun , Takahashi Kouki , Hayashi Kouichiro , Yamazaki Ken , Tabata Izumi , Tanaka Hirofumi
Published: October 2004

Background—

Reductions in the compliance of central arteries exert a number of adverse effects on cardiovascular function and disease risk. Endurance training is efficacious in increasing arterial compliance in healthy adults. We determined the effects of resistance training on carotid arterial compliance using the intervention study design.

Methods and Results—

Twenty-eight healthy men 20 to 38 years old were randomly assigned to the intervention group (n=14) and the control group (n=14). Control subjects were instructed not to alter their normal activity levels throughout the study period. Intervention subjects underwent 3 supervised resistance training sessions per week for 4 months and detraining for a subsequent 4 months. The resistance training increased maximal strength in all muscle groups tested (
P
<0.001). There were no significant differences in baseline arterial compliance and β-stiffness index between the intervention and control groups. In the intervention group, carotid arterial compliance decreased 19% (
P
<0.05), and β-stiffness index increased 21% (
P
<0.01) after resistance training. These values returned completely to the baseline levels during the detraining period. Arterial compliance did not change in the control group. In both groups, there were no significant changes in brachial and carotid blood pressure, carotid intima-media thickness, lumen diameter, and femoral arterial compliance. Changes in carotid artery compliance were significantly and negatively related to corresponding changes in left ventricular mass index (
r
=−0.56,
P
<0.001) and left ventricular hypertrophy index (
r
=−0.68,
P
<0.001).

Conclusions—

In marked contrast to the beneficial effect of regular aerobic exercise, several months of resistance training “reduces” central arterial compliance in healthy men.
Ascorbic Acid Prevents Contrast-Mediated Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention
Authors: Spargias Konstantinos , Alexopoulos Elias , Kyrzopoulos Stamatis , Iacovis Panayiotis , Greenwood Darren C. , Manginas Athanassios , Voudris Vassilis , Pavlides Gregory , Buller Christopher E. , Kremastinos Dimitrios , Cokkinos Dennis V.
Published: October 2004

Background—

Contrast agents can cause a reduction in renal function that may be due to the generation of reactive oxygen species. Conflicting evidence suggests that administration of the antioxidant acetylcysteine prevents this renal impairment. The action of other antioxidant agents has not been investigated.

Methods and Results—

We conducted a randomized, double-blind, placebo-controlled trial of ascorbic acid in 231 patients with a serum creatinine concentration ≥1.2 mg/dL who underwent coronary angiography and/or intervention. Ascorbic acid, 3 g at least 2 hours before the procedure and 2 g in the night and the morning after the procedure, or placebo was administered orally. Contrast-mediated nephropathy was defined by an absolute increase of serum creatinine ≥0.5 mg/dL or a relative increase of ≥25% measured 2 to 5 days after the procedure. Contrast-mediated nephropathy occurred in 11 of the 118 patients (9%) in the ascorbic acid group and in 23 of the 113 patients (20%) in the placebo group (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17 to 0.85;
P
=0.02). The mean serum creatinine concentration increased significantly in the placebo group (from 1.36±0.50 to 1.50±0.54 mg/dL,
P
<0.001) and nonsignificantly in the ascorbic acid group (from 1.46±0.52 to 1.52±0.64 mg/dL,
P
=0.07). The mean increase in serum creatinine concentration was greater in the placebo group than in the ascorbic acid group (difference of 0.09 mg/dL; 95% CI, 0.00 to 0.17;
P
=0.049).

Conclusions—

Prophylactic oral administration of ascorbic acid may protect against contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure.
Pressure Overload Induces Cardiac Dysfunction and Dilation in Signal Transducer and Activator of Transcription 6–Deficient Mice
Authors: Hikoso Shungo , Yamaguchi Osamu , Higuchi Yoshiharu , Hirotani Shinichi , Takeda Toshihiro , Kashiwase Kazunori , Watanabe Tetsuya , Taniike Masayuki , Tsujimoto Ikuko , Asahi Michio , Matsumura Yasushi , Nishida Kazuhiko , Nakajima Hiroshi , Akira Shizuo , Hori Masatsugu , Otsu Kinya
Published: October 2004

Background—

Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6
−/−
) mice to examine the in vivo role of STAT6.

Methods and Results—

STAT6
−/−
hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6
−/−
mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase–mediated biotin dUTP nick-end labeling–positive myocytes after TAC had increased in STAT6
−/−
compared with wild-type mice. Prolonged induction of tumor necrosis factor-α (TNF-α) mRNA was observed in STAT6
−/−
hearts, whereas TNF-α mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6
−/−
mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6
−/−
cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6
−/−
cardiomyocytes was rescued by forced expression of STAT6.

Conclusions—

STAT6 plays a protective role against hemodynamic stress in hearts.
Extraction of Pulmonary Vascular Compliance, Pulmonary Vascular Resistance, and Right Ventricular Work From Single-Pressure and Doppler Flow Measurements in Children With Pulmonary Hypertension: a New Method for Evaluating Reactivity
Authors: Weinberg Craig E. , Hertzberg Jean R. , Ivy D. Dunbar , Kirby K. Scott , Chan K. Chen , Valdes-Cruz Lilliam , Shandas Robin
Published: October 2004

Background—

Current evaluation of pulmonary hypertension (PH) in children involves measurement of pulmonary vascular resistance (PVR); however, PVR neglects important pulsatile components. Pulmonary artery (PA) input impedance and ventricular power (VP) include mean and pulsatile effects and have shown promise as alternative measures of vascular function. Here we report the utility of pulsed-wave (PW) Doppler-measured instantaneous flow and pressure measurements for estimation of input impedance and VP and use this method to develop a novel parameter: reactivity in compliance.

Methods and Results—

An in vitro model of the general pulmonary vasculature was used to obtain impedance and VP, measured by PW Doppler and a reference flow meter. The method was then tested in a preliminary clinical study in subjects with normal PA hemodynamics (n=4) and patients with PH undergoing reactivity evaluation (8 patients; 23 data points). In vitro results showed good agreement between the impedance spectra computed from both flow-measurement methods. Excellent correlation was seen in vitro between actual resistance and the zero-frequency (Z
o
) impedance value (
r
2
=0.984). Excellent agreement was also found between Z
o
and PVR in the clinical measurements (
y
=1.075
x
+0.73;
r
=0.993). Furthermore, total VP and VP/cardiac output increased significantly with hypertension (128.73 to 365.91 mW and 2.42 to 6.69 mW · mL
−1
· s
−1
, respectively). The first-harmonic value of impedance (Z
1
) was used as a measure of compliance reactivity; older patients exhibited markedly less compliance reactivity than did younger patients.

Conclusions—

Input impedance and VP calculated from Doppler measurements and a single-catheter pressure measurement provide comprehensive characterization of PH and reactivity.
Opposing Effects of C-Reactive Protein Isoforms on Shear-Induced Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Whole Blood
Authors: Khreiss Tarek , József Levente , Potempa Lawrence A. , Filep János G.
Published: October 2004

Background—

Plasma C-reactive protein (CRP) level is a powerful predictor of cardiovascular events. However, it is not known whether CRP could affect neutrophil-platelet adhesion and neutrophil aggregation, key events in acute coronary syndromes. Emerging in vitro evidence suggests that some bioactivities of CRP are expressed on loss of the pentameric symmetry, resulting in formation of modified or monomeric CRP (mCRP).

Methods and Results—

We studied the impact of human native CRP and bioengineered mCRP that cannot rearrange into the pentameric structure on the kinetics of neutrophil-platelet adhesion and neutrophil aggregation in whole blood subjected to shear (≈100 s
−1
) using real-time flow cytometry. Shear resulted in upregulation of platelet P-selectin expression, leading to platelet capture of neutrophils and subsequent neutrophil aggregation, which was dependent on P-selectin, L-selectin, and CD18. Native CRP at clinically relevant concentrations markedly attenuated these changes. The residual amount of neutrophil adhesion was blocked with anti-CD18 or anti-CD11b antibody. By contrast, mCRP concentration-dependently enhanced shear-induced platelet P-selectin expression and increased the rate and extent of formation of both neutrophil-platelet and neutrophil-neutrophil aggregates. Complete abrogation of platelet-neutrophil adhesion and neutrophil aggregation required both anti-P-selectin and anti-CD18 antibodies but not anti-L-selectin antibody. The CRP action was markedly inhibited by an anti-CD32 antibody, whereas the mCRP effects were significantly attenuated by an anti-CD16 antibody.

Conclusions—

These results indicate that native CRP inhibits platelet activation and prevents platelet capture of neutrophils, whereas mCRP displays potent prothrombotic activities under low levels of shear. Thus, mCRP rather than native CRP may precipitate acute coronary syndromes.
Structure-Based Discovery of a Novel Angiotensin-Converting Enzyme 2 Inhibitor
Authors: Huentelman Matthew J. , Zubcevic Jasenka , Hernández Prada Jose A. , Xiao Xiaodong , Dimitrov Dimiter S. , Raizada Mohan K. , Ostrov David A.
Published: October 2004

Angiotensin-converting enzyme 2 (ACE2) is considered an important therapeutic target for controlling cardiovascular diseases and severe acute respiratory syndrome (SARS) outbreaks. Recently solved high-resolution crystal structures of the apo-bound and inhibitor-bound forms of ACE2 have provided the basis for a novel molecular docking approach in an attempt to identify ACE2 inhibitors and compounds that block SARS coronavirus spike protein-mediated cell fusion. In this study, ≈140 000 small molecules were screened by
in silico
molecular docking. In this structure-activity relation study, the molecules with the highest predicted binding scores were identified and assayed for ACE2 enzymatic inhibitory activity and for their ability to inhibit SARS coronavirus spike protein-mediated cell fusion. This approach identified N-(2-aminoethyl)-1 aziridine-ethanamine as a novel ACE2 inhibitor that also is effective in blocking the SARS coronavirus spike protein-mediated cell fusion. Thus, the molecular docking approach resulting in the inhibitory capacity of N-(2-aminoethyl)-1 aziridine-ethanamine provides an attractive small molecule lead compound on which the development of more effective therapeutic agents could be developed to modulate hypertension and for controlling SARS infections.
Inflammation, Abdominal Obesity, and Smoking as Predictors of Hypertension
Authors: Niskanen Leo , Laaksonen David E. , Nyyssönen Kristiina , Punnonen Kari , Valkonen Veli-Pekka , Fuentes Ricardo , Tuomainen Tomi-Pekka , Salonen Riitta , Salonen Jukka T.
Published: October 2004

Development of hypertension has been linked to chronic low-grade inflammation. However, it is not known whether this connection is mediated by features of the metabolic syndrome or smoking, or their changes, which themselves have been linked to inflammation. We studied the predictive value of highly sensitive C-reactive protein (hs-CRP), smoking, and abdominal obesity to the development of hypertension in an 11-year follow-up of a population-based study cohort comprising 379 middle-aged normotensive men. During the follow-up, 124 men (33%) developed hypertension. Men with hs-CRP ≥3.0 mg/L were 2.8× (95% confidence interval, 1.2 to 6.6) more likely to develop hypertension than with hs-CRP <1.0 mg/L even after adjustment for features of the metabolic syndrome, lifestyle factors, and their changes. Cigarette smoking was also associated with development of hypertension independently of inflammation and other confounders. Waist girth increased more in men who quit smoking than in other men. An increase in waist girth during follow-up strongly predicted incident hypertension. The decrease in smoking was not associated with a lower risk of hypertension in age-adjusted analyses. Hypertension is preceded by low-grade chronic inflammation in middle-aged white men independently of smoking or features of the metabolic syndrome. Furthermore, smoking may be a risk factor for hypertension. Although stopping smoking is beneficial with respect to health outcomes, the subsequent increase in weight and waist girth associated with smoking cessation may offset the decrease in the risk of hypertension that one may otherwise expect.
Platelet-Derived Growth Factor Induces Tissue Factor Expression in Vascular Smooth Muscle Cells via Activation of Egr-1
Authors: Kamimura Motohiro , Bea Florian , Akizawa Tadao , Katus Hugo A. , Kreuzer Jörg , Viedt Christiane
Published: October 2004

Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB–stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB–induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.
Birth Weight Is Inversely Correlated to Adult Systolic Blood Pressure and Pulse Pressure in Type 1 Diabetes
Authors: Fagerudd Johan , Forsblom Carol , Pettersson-Fernholm Kim , Saraheimo Markku , Wadén Johan , Rönnback Mats , Rosengård-Bärlund Milla , af Björkesten Clas-Göran , Thorn Lena , Wessman Maija ,   Per-Henrik Groop, on behalf of the Finn Diane Study Group
Published: October 2004

In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age- and sex-adjusted regression coefficients between systolic blood pressure and birth weight was −1.90 mm Hg/kg (95% confidence interval [CI], −3.71 to −0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (−3.34 mm Hg/kg; 95% CI, −6.06 to −0.62) than in males (−0.42 mm Hg/kg; 95% CI, −2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified.
Managing social exclusion
Authors: Yeung Agnes , Chau Ruby C.M. , Yu Sam W.K.
Published: October 2004

This article is based on two studies conducted in Guangzhou and Hong Kong. It argues that many managerial women in these two Chinese cities rely mainly on an individual approach to reduce their social exclusion and simultaneously use implicit actions to challenge structural inadequacies in the family and the work place.
Rural social work practice in the United States and Australia
Authors: Saltman Joan , Gumpert Joanne , Allen-Kelly Kandie , Zubrzycki Joanna
Published: October 2004

A comparison of social work practice in rural areas of the United States and Australia reflects similar characteristics. Findings add support to the assertion that there are particular qualities to practice in the rural context that are embedded in the subtleties of shaping social work roles to fit into rural culture.
Consumerism
Authors: Harris John
Published: October 2004

The European trend away from welfare statism and towards consumerism is usually regarded as a shift from social development to social delimitation. However, consumerism has the potential to promote procedural rights, to be responsive to individual needs and to treat service users as rational agents.
Microballoon Wall Thickness Effects on Properties of Syntactic Foams
Authors: Gupta Nikhil , Woldesenbet Eyassu
Published: October 2004

A novel approach for changing the density of syntactic foams, while keeping the microballoon (hollow particles) volume fraction constant, is adopted in this work. This is achieved by selecting microballoons of the same size but with different wall thickness. Five types of microballoons are selected to fabricate syntactic foams. All the types of microballoons have about 40 mm mean particle sizes, but different wall thicknesses. This approach allows to maintain the same volume fractions of constituents and interfacial area while changing the density of syntactic foams. The fabricated syntactic foams are tested for their compressive properties in accordance to the ASTM D 695-96 standard. The results of the experimental investigation show a strong dependence of the compressive properties and the fracture characteristics of syntactic foams on the microballoon wall thickness. Shear cracking followed by cracking under secondary tensile stresses has been observed as the fracture mode. The present approach is found to be more effective than changing the microballoon volume fraction to change the syntactic foam density as it considerably increases the strength to the weight ratio.
Polycarbonate Microfoams with a Smooth Surface and Higher Notched Impact Strength
Authors: Bledzki Andrzej K. , Kirschling Hendrik , Steinbichler Georg , Egger Peter
Published: October 2004

Polycarbonate microfoams produced by physical blowing agents usually have an unacceptable surface quality. The surface is rough and the visual difference in the surface quality is striking. However, the surface quality can be improved by the gas counterpressure technology.

Polycarbonate has a high elongation at break but a low notched impact strength. Earlier, the microfoams showed higher notched impact strength, but a considerably reduced elongation at break. Foams produced by the gas counter-pressure technology have both these positive mechanical properties.