bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrovirus-Induced Synthesis of Nitric Oxide Contributes to Virus Control during Infection
Authors: Koci Matthew D. , Kelley Laura A. , Larsen Diane , Schultz-Cherry Stacey
Published: January 2004

Astrovirus is one of the major causes of infant and childhood diarrhea worldwide. Our understanding of astrovirus pathogenesis trails behind our knowledge of its molecular and epidemiologic properties. Using a recently developed small-animal model, we investigated the mechanisms by which astrovirus induces diarrhea and the role of both the adaptive and innate immune responses to turkey astrovirus type-2 (TAstV-2) infection. Astrovirus-infected animals were analyzed for changes in total lymphocyte populations, alterations in CD4+/CD8+ratios, production of virus-specific antibodies (Abs), and macrophage activation. There were no changes in the numbers of circulating or splenic lymphocytes or in CD4+/CD8+ratios compared to controls. Additionally, there was only a modest production of virus-specific Abs. However, adherent spleen cells from infected animals produced more nitric oxide (NO) in response to ex vivo stimulation with lipopolysaccharide. In vitro analysis demonstrated that TAstV-2 induced macrophage production of inducible nitric oxide synthase. Studies using NO donors and inhibitors in vivo demonstrated, for the first time, that NO inhibited astrovirus replication. These studies suggest that NO is important in limiting astrovirus replication and are the first, to our knowledge, to describe the potential role of innate immunity in astrovirus infection.
Influence of the Route of Infection on Development of T-Cell Receptor β-Chain Repertoires of Reovirus-Specific Cytotoxic T Lymphocytes
Authors: Fulton Jonathan R. , Smith Jeremy , Cunningham Cynthia , Cuff Christopher F.
Published: January 2004

It is well established that the route of infection affects the nature of the adaptive immune response. However, little is known about the effects of the route of exposure on development of cytotoxic T-lymphocyte (CTL) responses. Alternative antigen-presenting cell populations, tissue-restricted expression of class I major histocompatibility complex-encoded molecules, and unique T-cell receptor (TCR)-bearing cells in mucosal tissues could influence the selection and expansion of responder T cells. This study addresses the question of whether the route of virus infection affects the selection and expansion of subpopulations of virus-specific CTLs. Mice were infected orally or in the hind footpads with reovirus, and the repertoires of TCR β-chains expressed on virus-specific CD8+T cells in Peyer's patches or lymph nodes and spleens were examined. CD8+cells expressing the variable gene segment of the TCR β-chain 6 (Vβ6) expanded in the spleens of mice infected by either route and in CTL lines established from the spleens and draining lymphoid tissues. Adoptively transferred Vβ6+CD8+T cells from orally or parenterally infected donors expanded in reovirus-infected severe combined immunodeficient recipient mice and mediated cytotoxicity ex vivo. Furthermore, recovered Vβ6+cells were enriched for clones utilizing uniform complementarity-determining region 3 (CDR3) lengths. However, sequencing of CDR3β regions from Vβ6+CD8+cells indicated that Jβ gene segment usage is significantly more restricted in CTLs from orally infected mice, suggesting that the route of infection affects selection and/or subsequent expansion of virus-specific CTLs.
COIDEAL SUBALGEBRAS IN QUANTUM AFFINE ALGEBRAS
Authors: MOLEV A. I. , RAGOUCY E. , SORBA P.
Published: January 2004

We introduce two subalgebras in the type A quantum affine algebra which are coideals with respect to the Hopf algebra structure. In the classical limit q→1 each subalgebra specializes to the enveloping algebra [Formula: see text], where [Formula: see text] is a fixed point subalgebra of the loop algebra [Formula: see text] with respect to a natural involution corresponding to the embedding of the orthogonal or symplectic Lie algebra into [Formula: see text]. We also give an equivalent presentation of these coideal subalgebras in terms of generators and defining relations which have the form of reflection-type equations. We provide evaluation homomorphisms from these algebras to the twisted quantized enveloping algebras introduced earlier by Gavrilik and Klimyk and by Noumi. We also construct an analog of the quantum determinant for each of the algebras and show that its coefficients belong to the center of the algebra. Their images under the evaluation homomorphism provide a family of central elements of the corresponding twisted quantized enveloping algebra.
DIRICHLET FORMS AND SYMMETRIC MARKOVIAN SEMIGROUPS ON ℤ2-GRADED VON NEUMANN ALGEBRAS
Authors: BAHN CHANGSOO , KO CHUL KI , PARK YONG MOON
Published: January 2004

We extend the construction of Dirichlet forms and symmetric Markovian semigroups on standard forms of von Neumann algebras given in [1] to the case of ℤ2-graded von Neumann algebras. As an application of the extension, we construct symmetric Markovian semigroups on CAR algebras with respect to gauge invariant quasi-free states and also investigate detailed properties such as ergodicity of the semigroups.
CLASSICAL LIMIT OF QUANTUM DYNAMICAL ENTROPIES
Authors: BENATTI F. , CAPPELLINI V. , DE COCK M. , FANNES M. , VANPETEGHEM D.
Published: January 2004

Two non-commutative dynamical entropies are studied in connection with the classical limit. For systems with a strongly chaotic classical limit, the Kolmogorov–Sinai invariant is recovered on time scales that are logarithmic in the quantization parameter. The model of the quantized hyperbolic automorphisms of the 2-torus is examined in detail.
ON ASYMPTOTIC STABILITY OF GROUND STATES OF NLS
Authors: CUCCAGNA SCIPIO
Published: January 2004

We prove in dimension n = 3 an asymptotic stability result for ground states of the Nonlinear Schrödinger Equation which contain one internal mode.
A MATHEMATICAL VERIFICATION OF THE EXISTENCE OF STRINGS OF CIRCULATION IN SUPERFLUID FILMS ON POROUS MEDIA
Authors: BLACK CHRIS PETERSEN
Published: January 2004

A superfluid film flowing along the walls of a porous material can be modeled by a harmonic differential on a punctured Riemann surface satisfying integrality conditions on its periods and residues. In this paper, we use classical Riemann surface theory to mathematically investigate the observed physical phenomenon of the appearance of pairs of vortices in the fluid and the resulting patterns of circulation. We show that the existence of strings of circulation in the superfluid depends on a quantized divisibility condition between the number of vortex–antivortex pairs and the circulation of the fluid.
DEHN FUNCTION AND LENGTH OF PROOFS
Authors: KRAJÍČEK JAN
Published: January 2004

We link the Dehn function of finitely presented groups to the length-of-proofs function in propositional proof complexity.
IDENTITIES AND A BOUNDED HEIGHT CONDITION FOR SEMIGROUPS
Authors: SHNEERSON L. M.
Published: January 2004

We consider two different types of bounded height condition for semigroups. The first one originates from the classical Shirshov's bounded height theorem for associative rings. The second which is weaker, in fact was introduced by Wolf and also used by Bass for calculating the growth of finitely generated (f.g.) nilpotent groups. Both conditions yield polynomial growth. We give the first two examples of f.g. semigroups which have bounded height and do not satisfy any nontrivial identity. One of these semigroups does not have bounded height in the sense of Shirshov and the other satisfies the classical bounded height condition. This develops further one of the main results of the author's paper (J. Algebra, 1993) where the first examples of f.g. semigroups of polynomial growth and without nontrivial identities were given.
REGULARITY OF QUASIGEODESICS IN A HYPERBOLIC GROUP
Authors: HOLT DEREK F. , REES SARAH
Published: January 2004

We prove that for λ≥1 and all sufficiently large ∊, the set of (λ,∊)-quasigeodesics in an infinite word-hyperbolic group G is regular if and only if λ is rational. In fact, this set of quasigeodesics defines an asynchronous automatic structure for G. We also introduce the idea of an exact (λ,∊)-quasigeodesic and show that for rational λ and appropriate ∊ the sets of exact (λ,∊)-quasigeodesics define synchronous automatic structures.
GRADED IDENTITIES FOR THE ALGEBRA OF n×n UPPER TRIANGULAR MATRICES OVER AN INFINITE FIELD
Authors: KOSHLUKOV PLAMEN , VALENTI ANGELA
Published: January 2004

We consider the algebra Un(K) of n×n upper triangular matrices over an infinite field K equipped with its usual ℤn-grading. We describe a basis of the ideal of the graded polynomial identities for this algebra.
IDEMPOTENT DISTRIBUTIVE SEMIRINGS WITH INVOLUTION
Authors: DOLINKA IGOR
Published: January 2004

A semiring with involution is a semiring equipped with an involutorial antiasutomorphism as a fundamental operation. The aim of the present paper is to determine the lattice of all varieties of idempotent and distributive semirings with involution. We start with the description of their structure, which is followed by a complete list of all subdirectly irreducibles. We make a heavy use of general results obtained recently by Dolinka and Vinčić [11] on involutorial Płonka sums. Applying these results and some further structural theorems, we construct the considered lattice. It turns out that it has exactly 64 elements.
WHEN PLANS DISTINGUISH BAYES NETS
Authors: DEKHTYAR ALEX , GOLDSMITH JUDY , PEARCE JANICE L.
Published: January 2004

We consider the complexity of determining whether differing probability distributions for the same Bayes net, result in different, policies, significantly different, policy outcomes or optimal value functions.
INCREMENTAL DEVELOPMENT OF DIAGNOSTIC SET-COVERING MODELS WITH THERAPY EFFECTS
Authors: BAUMEISTER JOACHIM , SEIPEL DIETMAR , PUPPE FRANK
Published: January 2004

Although a lot of work in the field of knowledge acquisition has been done, the manual development of diagnostic knowledge systems by domain experts still is a very complex task. In this paper we will present an incremental approach for building diagnostic systems based on set-covering models. We start with a simple model describing the coarse structure between diagnoses and findings. Subsequently, this simple model can be euhanced by similarities, weights and probabilities to increase the accuracy of the knowledge and the resulting system. We will also show how these static set-covering models can be combined with dynamic set-covering models including higher level knowledge about causation effects. We will motivate how dynamic set-covering models can be used for implementing diagnostic systems including therapy effects. Finally, we report on two practical applications dealing with set-covering models from the geo-ecological and from the medical domain, respectively, that we have implemented.
PROBABILISTIC ASPECTS OF SCORE SYSTEMS
Authors: SCHRAMM MANFRED , FRONHÖFER BERTRAM
Published: January 2004

Due to their simple applicability score systems are in widespread use as a tool for decision making.

Unfortunately, as we all feel, they are somehow not apt to take into account interdependencies among the values which are input to them when trying to decide an actual application case; a drawback which is overcome by the more powerful probabilistic systems. In order to analyze which assumptions are inherent in score systems, we translate them as faithfully as possible into probabilistic systems thus making available the technical machinery of the latter for this analysis task.

Such a translation (as also given in1) reveals indeed some properties of score systems, but leads to an exponential number of probabilistic rules, which rules it out for practical use. For this reason we also developed further translations into probabilistic systems, which keep the simplicity of a score system (i.e. they use the same amount of rules as the score system). Moreover, the resulting probabilistic systems show their structure more explicitly than score systems, and they are also open to the addition of further knowledge.
NONMONOTONIC REASONING BY INHIBITION NETS II
Authors: LEITGEB HANNES
Published: January 2004

This paper is a sequel to Leitgeb7. We show that certain networks called 'inhibition nets' may be regarded as mechanisms drawing nonmonotonic inferences if only an interpretation of net states as states of belief is introduced. We prove that each of the cumulative logical systems studied by Kraus et al.6are sound and complete with respect to certain classes of such interpreted inhibition nets. Thus, there is an adequate cognitive network semantics for the systems C, CL, P, CM, and M of (nonmonotonic) logic.
Genetic Testing for Cardiovascular Disease Susceptibility: A Useful Clinical Management Tool or Possible Misinformation?
Authors: Humphries Steve E. , Ridker Paul M. , Talmud Philippa J.
Published: January 2004

Genetic susceptibility tests are already advertised on the Internet to identify individuals at above average risk for cardiovascular disease (CVD), such as deep vein thrombosis, hyperlipidemia, or atherosclerosis, whereas other tests claim to predict response to a particular drug treatment. Some kits are available to the public directly, bypassing a doctor. Their value, however, must be considered carefully, because although a genotype may be strongly and consistently associated with an intermediate trait, and because the intermediate trait is a strong predictor of CVD risk, there may be little or no association of genotype with risk
over and above
that of the measured trait. This is because multigenic effects and environmental modification (context dependency) of genotype effects determine CVD risk. An individual’s personal characteristics and plasma risk-trait levels (which reflect both genotype
and
exposure) at present are the best predictors of clinical outcome. Only when genetic tests surpass this, possibly by the inclusion of many
functional
common variants, in conjunction with their context-dependent effects on risk, might their usefulness in clinical management be realized. Here we review some of the particular issues and concerns raised by CVD-risk genetic testing, and suggest areas of further research to address these issues.
Membrane Potential-Dependent Inhibition of Platelet Adhesion to Endothelial Cells by Epoxyeicosatrienoic Acids
Authors: Krötz Florian , Riexinger Tobias , Buerkle Martin A. , Nithipatikom Kasem , Gloe Torsten , Sohn Hae-Young , Campbell William B. , Pohl Ulrich
Published: January 2004

Objective—

Epoxyeicosatrienoic acids (EETs) are potent vasodilators produced by endothelial cells. In many vessels, they are an endothelium-derived hyperpolarizing factor (EDHF). However, it is unknown whether they act as an EDHF on platelets and whether this has functional consequences.

Methods and Results—

Flow cytometric measurement of platelet membrane potential using the fluorescent dye DiBac
4
showed a resting potential of −58±9 mV. Different EET regioisomers hyperpolarized platelets down to −69±2 mV, which was prevented by the non-specific potassium channel inhibitor charybdotoxin and by use of a blocker of calcium-activated potassium channels of large conductance (BK
Ca
channels), iberiotoxin. EETs inhibited platelet adhesion to endothelial cells under static and flow conditions. Exposure to EETs inhibited platelet P-selectin expression in response to ADP. Stable overexpression of cytochrome P450 2C9 in EA.hy926 cells (EA.hy2C9 cells) resulted in release of EETs and a factor that hyperpolarized platelets and inhibited their adhesion to endothelial cells. These effects were again inhibited by charybdotoxin and iberiotoxin.

Conclusions—

EETs hyperpolarize platelets and inactivate them by inhibiting adhesion molecule expression and platelet adhesion to cultured endothelial cells in a membrane potential-dependent manner. They act as an EDHF on platelets and might be important mediators of the anti-adhesive properties of vascular endothelium.
Mechanical Stretch Induces Phosphorylation of p38-MAPK and Apoptosis in Human Saphenous Vein
Authors: Cornelissen Jacqueline , Armstrong Johanna , Holt Cathy M.
Published: January 2004

Objective—

Failure of saphenous vein grafts remains a major limitation of coronary bypass surgery. The aims of the present study were to determine whether pressure distension of human saphenous vein induces the activation of p38-MAPK and to determine its role in apoptosis.

Methods and Results—

Phosphorylated p38 was detected at basal levels in human saphenous vein obtained immediately after harvesting. Distended saphenous vein showed significantly higher levels of phosphorylated p38 compared with control vein (
P
<0.01) and nondistended saphenous vein maintained for 3 and 6 hours after harvesting (both
P
<0.01). Apoptosis in distended and nondistended vein was significantly higher at 24 hours compared with control vein, with distended vein showing increased apoptosis compared with nondistended saphenous vein at all time points investigated (
P
<0.001). Immunolocalization showed co-localization of phosphorylated p38 and apoptosis. Inhibition of p38 activity reduced the apoptotic index of cultured vascular smooth muscle cells by 72.1%±1.2% and cultured distended saphenous vein segments by 72.7%±0.9%.

Conclusions—

Pressure distension of intact human saphenous vein induces activation of p38, and this is associated with apoptosis. Inhibition of p38 kinase activity in saphenous vein smooth muscle cells and intact vein reduces apoptosis. These findings contribute to our understanding of the mechanisms of saphenous vein graft failure.
Birth Weight and Lipids in a National Birth Cohort Study
Authors: Skidmore Paula M.L. , Hardy Rebecca J. , Kuh Diana J. , Langenberg Claudia , Wadsworth Michael E. J.
Published: January 2004

Objective—

To investigate the association between birth weight and lipid levels in a 53-year-old birth cohort from England, Scotland, and Wales.

Methods and Results—

Lipid levels were obtained from nonfasting blood samples, collected at the most recent follow-up of the MRC National Survey of Health and Development, for 2559 men and women. Regression models indicated that in men, a 1-kg increase in birth weight was associated with a 0.13-mmol/L decrease (95% CI: −0.23, −0.01) in total cholesterol at age 53 years (
P
=0.03), compared with a 0.02-mmol/L (95% CI: −0.11, 0.15) increase in women and a 0.06-mmol/L (95% CI: −0.15, 0.02) decrease in men and women combined. Adjustment for current height and body mass index (BMI) in men reduced the size of the relationship, with height being responsible for the reduction. Adult height and height at 2 and 4 years were significantly associated with total cholesterol in men and in men and women combined. The negative association between total cholesterol and birth weight was strongest among men with high BMI at age 53 years (
P
=0.03 for test for interaction between birth weight and BMI). There was no significant association between birth weight and LDL or HDL cholesterol in men or women before adjustment, but there was a positive association with HDL in women. When both sexes were analyzed together, an association was seen after adjustment for current body size. No confounding of these findings with social class was observed in this study.

Conclusions—

Our results suggest that the small effect of birth weight on lipid levels at age 53 years has a limited public health impact. The findings suggest that childhood height growth may be more important than prenatal growth.
Role of Magnetic Resonance Angiography in the Diagnosis of Major Aortopulmonary Collateral Arteries and Partial Anomalous Pulmonary Venous Drainage
Authors: Prasad Sanjay K. , Soukias Nikolaos , Hornung Timothy , Khan Mohammed , Pennell Dudley J. , Gatzoulis Michael A. , Mohiaddin Raad H.
Published: January 2004

Background—

Accurate diagnosis of major aortopulmonary collaterals (MAPCAs) and partial anomalous pulmonary venous drainage (PAPVD) in adult patients with congenital heart disease is important but problematic. Three-dimensional contrast-enhanced magnetic resonance angiography (MRA) provides a minimally invasive technique to allow detailed studies in a single breath-hold.

Methods and Results—

We assessed the role of contrast-enhanced 3D MRA in 29 consecutive adult patients with a diagnosis of MAPCAs (n=16) or PAPVD (n=13) made by echocardiogram, cardiac catheterization, or surgical inspection. MRA was performed with a 3D spoiled gradient-echo technique with intravenous gadolinium-DTPA (0.2 mmol/kg). In both types of pathology, there was excellent correlation between MRA and the cardiac catheterization, echocardiogram, or surgical inspection. Additional information was gained for patients with MAPCAs on confluence and size of pulmonary arteries (n=13 had central arteries), pulmonary artery stenosis (n=3), aneurysmal dilatation of pulmonary artery (n=1), and additional anomalous vascular abnormality (n=3). Shunt assessment, where present (9 of 16), showed patency in all cases (100%). For adults with PAPVD, further information was obtained on drainage origin (n=11). There were no complications.

Conclusions—

Contrast-enhanced 3D MRA provides a fast, noninvasive, radiation-free method of accurate and comprehensive diagnosis of MAPCAs and PAPVD in adult patients.
Effects of Adrenomedullin Inhalation on Hemodynamics and Exercise Capacity in Patients With Idiopathic Pulmonary Arterial Hypertension
Authors: Nagaya Noritoshi , Kyotani Shingo , Uematsu Masaaki , Ueno Kazuyuki , Oya Hideo , Nakanishi Norifumi , Shirai Mikiyasu , Mori Hidezo , Miyatake Kunio , Kangawa Kenji
Published: January 2004

Background—

Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

Methods and Results—

Acute hemodynamic responses to inhalation of aerosolized AM (10 μg/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54±3 to 47±3 mm Hg,
P
<0.05) and a 22% decrease in pulmonary vascular resistance (12.6±1.5 to 9.8±1.3 Wood units,
P
<0.05). However, neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly increased peak oxygen consumption during exercise (peak V̇
o
2
, 14.6±0.6 to 15.7±0.6 mL · kg
−1
· min
−1
,
P
<0.05) and the ratio of change in oxygen uptake to that in work rate (ΔV̇
o
2
/ΔW ratio, 6.3±0.4 to 7.0±0.5 mL · min
−1
· W
−1
,
P
<0.05). These parameters remained unchanged during placebo inhalation.

Conclusions—

Inhalation of AM may have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.
Prenatal Exposure to Carbon Monoxide Affects Postnatal Cellular Electrophysiological Maturation of the Rat Heart
Authors: Sartiani Laura , Cerbai Elisabetta , Lonardo Giuseppe , DePaoli Petra , Tattoli Maria , Cagiano Raffaele , Carratù Maria Rosaria , Cuomo Vincenzo , Mugelli Alessandro
Published: January 2004

Background—

Maternal smoking is an independent risk factor for sudden infant death syndrome (SIDS). Carbon monoxide (CO) is a major component of smoke. No information is available about the effect of CO and/or smoking on postnatal maturation of the heart. The aim of this study was to investigate the effect of prenatal exposure to CO on cellular electrophysiological maturation in male Wistar rats.

Methods and Results—

The patch-clamp technique was used to measure action potential (AP) and ionic currents (
I
to
and
I
Ca,L
) from rat ventricular myocytes. During growth, AP duration measured at −20 and −50 mV (APD
−
20
and APD
−
50
) decreased progressively in both groups; the process was significantly delayed in rats exposed prenatally to 150 ppm CO: At 4 weeks, APD
−
20
and APD
−
50
were 89.5±18.2 and 147.7±24.5 ms in CO (n=13) and 35.6±4.5 and 77.8±8.3 ms in control rats (Ctr; n=14;
P
<0.01 and
P
<0.05, respectively) and normalized at 8 weeks. At 4 weeks, the density of
I
Ca,L
was significantly higher (21.3±1.6 pA/pF, n=17, versus 15.9±1.6 pA/pF, n=22;
P
<0.05) and the density of
I
to
significantly lower (9.6±1.5, n=22, versus 15.2±2.2 pA/pF, n=19;
P
<0.01) in CO than in Ctr and normalized thereafter.

Conclusions—

Prenatal CO exposure affects the physiological shortening of APD in neonatal rats. We speculate that a prolonged myocyte repolarization induced by prenatal exposure to smoke may establish a period of vulnerability for life-threatening arrhythmias in infancy.
Dissociation Between Ionic Remodeling and Ability to Sustain Atrial Fibrillation During Recovery From Experimental Congestive Heart Failure
Authors: Cha Tae-Joon , Ehrlich Joachim R. , Zhang Liming , Shi Yan-Fen , Tardif Jean-Claude , Leung Tack Ki , Nattel Stanley
Published: January 2004

Background—

Congestive heart failure (CHF) downregulates atrial transient outward (
I
to
), slow delayed rectifier (
I
Ks
), and L-type Ca
2+
(
I
Ca,L
) currents and upregulates Na
+
-Ca
2+
exchange current (
I
NCX
) (ionic remodeling) and causes atrial fibrosis (structural remodeling). The relative importance of ionic versus structural remodeling in CHF-related atrial fibrillation (AF) is controversial.

Methods and Results—

We measured hemodynamic and echocardiographic parameters, mean duration of burst pacing–induced AF (DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4 weeks (REC), and unpaced controls. Left ventricular ejection fraction averaged 58.6±1.2% (control), 36.2±2.3% (CHF,
P
<0.01), and 57.9±1.6% (REC), indicating full hemodynamic recovery. Similarly, left atrial pressures were 2.2±0.3 (control), 13.1±1.5 (CHF), and 2.4±0.4 (REC) mm Hg. CHF reduced
I
to
density by ≈65% (
P
<0.01), decreased
I
Ca,L
density by ≈50% (
P
<0.01), and diminished
I
Ks
density by ≈40% (
P
<0.01) while increasing
I
NCX
density by ≈110% (
P
<0.05). In REC, all ionic current densities returned to control values. DAF increased in CHF (1132±207 versus 14.3±8.8 seconds, control) and remained increased with REC (1014±252 seconds). Atrial fibrous tissue content also increased in CHF (2.1±0.2% for control versus 10.2±0.7% for CHF,
P
<0.01), with no recovery observed in REC (9.4±0.8%,
P
<0.01 versus control,
P
=NS versus CHF).

Conclusions—

With reversal of CHF, there is complete recovery of ionic remodeling, but the prolonged-AF substrate and structural remodeling remain. This suggests that structural, not ionic, remodeling is the primary contributor to AF maintenance in experimental CHF.
Heterogeneity of Cardiorenal Characteristics in Normotensive Subjects
Authors: Fesler Pierre , du Cailar Guilhem , Ribstein Jean , Mimran Albert
Published: January 2004

Blood pressure is a marker of elevated risk for cardiovascular disease, even within the normotensive range. The present study evaluates cardiorenal modifications observed in normotensive (<140/90 mm Hg) subjects. Using World Health Organization–International Society of Hypertension definitions, 265 normotensive subjects were categorized as having optimal (n=73), normal (n=84), and high-normal (n=108) blood pressure. Renal hemodynamics and function and cardiac morphology were evaluated by isotopic clearance techniques and ultrasonography, respectively. Urinary albumin excretion was measured in 24-hour urine collections. Body mass index and 24-hour urinary sodium (estimate of sodium intake), as well as left ventricular mass index, relative wall thickness, and glomerular filtration rate and filtration fraction, progressively increased in the optimal to high-normal groups. In contrast, effective renal plasma flow remained constant. Albuminuria was similar in all groups. Of interest, the proportion of subjects with concentric pattern of cardiac geometry (relative wall thickness ≥0.44) increased from 7% in optimal to 13% and 20% in normal and high-normal groups, respectively (
P
<0.05). Within this normotensive range of blood pressure, left ventricular mass index and relative wall thickness but not albuminuria were linearly correlated to systolic blood pressure; however, no correlation with diastolic blood pressure was found. In conclusion, changes in cardiac geometry and renal hemodynamics (increase in glomerular filtration rate and filtration fraction, an approximate index of glomerular pressure) that could predispose to cardiovascular morbidity and renal risk are already present in normotensive subjects with blood pressure higher than 120/80 mm Hg.
Role of Platelet Microparticles in the Production of Thromboxane by Rabbit Pulmonary Artery
Authors: Pfister Sandra L.
Published: January 2004

This study examined the role of platelet microparticles in thromboxane A
2
(TXA
2
) production. Incubation of microparticles with [
14
C]arachidonic acid and A23187 produced
14
C-labeled TXB
2
, the stable metabolite of TXA
2
. To investigate the possibility that endothelial cells (ECs) transfer arachidonic acid to platelet microparticles and promote TXB
2
synthesis, ECs with their cellular lipids prelabeled with tritiated arachidonic acid were incubated with microparticles. In the absence of microparticles, there was no production of tritiated TXB
2
by the ECs. However, when microparticles were coincubated with prelabeled ECs, tritiated arachidonic acid was metabolized to tritiated TXB
2
. Aspirin was then used to inhibit cyclooxygenase. ECs coincubated with aspirin-treated platelet microparticles did not produce TXB
2
, as measured by radioimmunoassay. In contrast, aspirin-treated ECs coincubated with microparticles produced TXB
2
, and its production was enhanced by methacholine (10
−4
mol/L), indicating that endothelially derived arachidonic acid, and not endothelially derived prostaglandin endoperoxide, was transferred to the microparticle and further metabolized to TXA
2
. Additional studies with rabbit aorta and pulmonary artery investigated whether microparticles contributed to vascular contractions. Preincubation with microparticles enhanced arachidonic acid–induced contractions in the aorta and methacholine-induced contractions in the pulmonary artery. The thromboxane receptor antagonist SQ29548 and the thromboxane synthase inhibitor dazoxiben blocked these effects. Because TXA
2
is an important mediator in various pathophysiologic states, including hypertension, the ability of platelet microparticles to act as a cellular source of TXA
2
might provide new insight into the role of platelets and platelet microparticles in the control of vascular tone.
Dietary NaCl Regulates Renal Aminopeptidase N: Relevance to Hypertension in the Dahl Rat
Authors: Farjah Mariam , Washington Theressia L. , Roxas Bryan P. , Geenen David L. , Danziger Robert S.
Published: January 2004

Aminopeptidase N (APN) is an abundant metallohydrolase in the brush border of kidney proximal tubule cells that degrades angiotensin III (Ang III) to angiotensin IV (Ang IV) and, along with dipeptidylaminopeptidase, degrades Ang IV. We examined the impact of a high-salt diet on renal APN activity and transcript abundance in the Sprague-Dawley and Dahl salt-sensitive (SS/Jr) rat strains. APN transcript abundance and protein abundance were ≈2-fold greater (
P
<0.05; n=6) in the kidneys of Sprague-Dawley and Lewis rats ingesting 8% versus 0.3% salt diets, suggesting that increased aminopeptidase activity may contribute to decreased renal sodium uptake during adaptation to a high-salt diet. In contrast, renal APN transcript abundance and activity were the same in Dahl SS/Jr rats ingesting 8.0% versus 0.3% salt diets. The APN gene was mapped, using a radiation-hybrid panel, to known quantitative loci on chromosome 1 for blood pressure in the Dahl SS/Jr rat. The results suggest that the APN gene is a good candidate for salt-sensitivity in the Dahl SS/Jr rat.
Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D
1A
Receptor in Obese Zucker Rats
Authors: Trivedi Meghna , Marwaha Aditi , Lokhandwala Mustafa
Published: January 2004

Hypertension related to insulin resistance results from increased sodium retention. Dopamine, by activating D
1A
receptors in renal proximal tubules, increases sodium excretion. Recently, dopamine has been shown to augment its own signaling by recruiting intracellular D
1A
receptors to cell surface in proximal tubules. In this study, we hypothesized that coupling of D
1A
receptors to G proteins and dopamine-induced recruitment of D
1A
receptors to the plasma membrane are impaired in obese Zucker rats, resulting in a diminished natriuretic and diuretic response to D
1A
receptor agonist, SKF-38393. We also examined effects of rosiglitazone (3 mg/kg per day, 15 days) in restoring the defects in D
1A
receptor signaling and function in these animals. In obese rats, D
1A
receptors did not couple to G proteins, as shown by a lack of fenoldopam-sensitive [
35
S] GTPγS binding. In addition, we observed, by using radioligand binding and immunoblotting, that dopamine recruited D
1A
receptors to cell surface in lean Zucker rats but failed to do so in obese rats. Rosiglitazone treatment resulted in restoration of G-protein coupling of D
1A
receptors and their recruitment by dopamine in obese rats similar to that seen in lean rats. Furthermore, SKF-38393 failed to increase natriuresis and diuresis in obese rats compared with lean rats. However, in rosiglitazone-treated obese rats, SKF-38393 elicited a diuretic and natriuretic response similar to that in lean rats. Collectively, these results suggest that insulin resistance may be responsible for impaired renal dopamine D
1A
receptor signaling and function as treatment with an insulin-sensitizer, rosiglitazone, normalizes these parameters in obese Zucker rats.
Role for Thromboxane Receptors in Angiotensin-II–Induced Hypertension
Authors: Francois Helene , Athirakul Krairerk , Mao Lan , Rockman Howard , Coffman Thomas M.
Published: January 2004

To evaluate the role of thromboxane in hypertension and its complications, we studied mice with targeted disruption of the TXA2 receptor gene in an angiotensin-II–dependent model of hypertension. To determine whether genetic background might alter the physiological actions of the TP receptor, we studied two lines of TP knockout (
Tp
−/−
) mice with distinct genetic backgrounds (C57BL/6 and BALB/c). During chronic angiotensin II infusion (1000 ng/kg per minute × 28 days by subcutaneous osmotic pump), TP deficiency prevented mortality in the C57BL/6 background but not in the BALB/c strain. Chronic angiotensin II infusion also caused a rapid and significant increase in blood pressure in wild-type (WT) C57BL/6 and BALB/c animals, which was significantly attenuated in
Tp
−/−
mice on either background. After 28 days of infusion, cardiac hypertrophy only occurred in the C57BL/6 strain: heart/body weight ratio increased by 57%±8% in WT mice compared with 17%±6.5% for the
Tp
−/−
mice (
P
<0.01). Chronic angiotensin II infusion caused albuminuria only in the C57BL/6 strain, and TP deficiency did not alter its development. Cyclooxygenase-1 knockout mice also had attenuated blood pressure increase during chronic angiotensin II infusion, suggesting that cyclooxygenase-1 metabolites are involved in angiotensin-II–dependent hypertension. Thus, on the C57BL/6 background, TP receptors contribute to cardiac hypertrophy but not proteinuria. However, irrespective of genetic background, the TP receptor makes a robust contribution to the pathogenesis of angiotensin II-dependent hypertension.
Heritability of Leukoaraiosis in Hypertensive Sibships
Authors: Turner Stephen T. , Jack Clifford R. , Fornage Myriam , Mosley Thomas H. , Boerwinkle Eric , de Andrade Mariza
Published: January 2004

Ischemic damage to the subcortical white matter of the brain, referred to as leukoaraiosis, is a frequent complication of hypertension-related microvascular disease and contributes to the risk of stroke and vascular dementia. A large genetic contribution to this late-life form of target organ damage was suggested by a study of elderly male twins. As part of the Genetic Epidemiology Network of Arteriopathy (GENOA), 483 non-Hispanic white subjects were recruited to undergo MRI for determination of the brain volume of leukoaraiosis (291 women and 192 men from 210 sibships providing 434 sibling pairs; mean age±SD=65.2±7.3 years). The GENOA–Rochester sibships contain 2 or more siblings with essential hypertension diagnosed before age 60. The frequency distribution of the volume of leukoaraiosis was positively skewed, with a median value of 6.61 cm
3
(interquartile range: 4.77 to 9 0.83 cm
3
). Variance component models were used to estimate the heritability (ie, the proportion of phenotypic variation caused by additive genetic factors). After logarithm transformation of the volume of leukoaraiosis, the estimated heritability (±SE) was 0.802±0.102 (
P
<0.0001). Adjustments for sex, age, systolic blood pressure, and brain volume reduced the heritability estimate to 0.671±0.110 (
P
<0.0001). This evidence of strong genetic influence on the susceptibility to leukoaraiosis justifies efforts to localize the responsible genes and characterize the predisposing genetic polymorphisms.
Production and Role of Extracellular Guanosine Cyclic 3′, 5′ Monophosphate in Sodium Uptake in Human Proximal Tubule Cells
Authors: Sasaki Shota , Siragy Helmy M. , Gildea John J. , Felder Robin A. , Carey Robert M.
Published: January 2004

The present study was designed to determine the capability of human renal proximal tubule (RPT) to generate and export guanosine cyclic 3′, 5′ monophosphate (cGMP) in response to direct stimulation of soluble guanylyl cyclase by nitric oxide (NO) donors. In addition, we investigated whether cGMP extrusion from human RPT cells is required for inhibition of cellular sodium uptake. RPT cells were cultured from fresh human kidneys (normotensive subjects, n=4, mean age 65±4.7 years, 3 men, 1 woman; hypertensive patients, n=6, mean age 64±6.1 years, 4 men, 2 women) after unilateral nephrectomy. The fluorescence dye Sodium Green was employed to determine cytoplasmic Na
+
concentration. In the presence of the Na
+
/K
+
ATPase inhibitor ouabain, fluorescence was monitored at the appropriate wavelength (excitation 485 nm, emission 535 nm). Nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP, 10
−4
M), increased both intracellular and extracellular cGMP (from 1.26±0.21 to 88.7±12.6 pmol/mg protein and from 0.58±0.10 to 9.24±1.9 pmol/mL, respectively,
P
<0.01) and decreased cellular Na
+
uptake by 37.4±6.8% (
P
<0.05) compared with control. The effects of SNAP on cGMP production were similar in normotensive and hypertensive subjects. The increases in intracellular and extracellular cGMP concentration because of SNAP were blocked completely by soluble guanylyl cyclase inhibitor ODQ (1-H-[1,2,4] oxadiazolo [4,2-alpha] quinoxalin-1-one). Probenecid, an organic anion transport inhibitor, augmented the SNAP (10
−6
M)-induced increase in intracellular cGMP accumulation (from 4.9±0.9 to 9.8±1.5 pmol/mg protein,
P
<0.05), abrogated the SNAP-induced increase in extracellular cGMP extrusion (from 1.07±0.4 to 0.37±0.1 pmol/L,
P
<0.05) and blocked the SNAP-induced reduction in cellular Na
+
uptake. Neither intracellular nor extracellular cGMP were influenced by
l
-arginine, the metabolic precursor of NO, or
N
G
-nitro-
l
-arginine methyl ester, an inhibitor of NO synthase. After exogenous administration of cGMP (10
−5
M) or its membrane-permeable analogue 8-Br-cGMP (10
−5
M), only 8-Br-cGMP crossed the cell membrane to increase intracellular cGMP (from 1.36±0.19 to 289.7±29.4 pmol/mg protein,
P
<0.01). However, both cGMP and 8-Br-cGMP were effective in decreasing cellular Na
+
uptake. In conclusion, human RPT cells contain soluble guanylyl cyclase and are able to generate and export cGMP in response to NO. Because human RPT cells do not themselves contain constitutive NO synthase, the NO-generating cGMP must be derived from sources outside the human RPT. The cGMP cellular export system is critical in the regulation of RPT cellular Na
+
absorption in humans.
Epoxy-Keto Derivative of Linoleic Acid Stimulates Aldosterone Secretion
Authors: Goodfriend Theodore L. , Ball Dennis L. , Egan Brent M. , Campbell William B. , Nithipatikom Kasem
Published: January 2004

Plasma levels of aldosterone are not always predictable from the activity of renin and the concentration of potassium. Among the unexplained are elevated levels of aldosterone in some obese humans. Obesity is characterized by increased plasma fatty acids and oxidative stress. We postulated that oxidized fatty acids stimulate aldosteronogenesis. The most readily oxidized fatty acids are the polyunsaturated, and the most abundant of those is linoleic acid. We tested oxidized derivatives of linoleic acid for effects on rat adrenal cells. One derivative, 12,13-epoxy-9-keto-10(
trans
)-octadecenoic acid (EKODE), was particularly potent. EKODE stimulated aldosteronogenesis at concentrations from 0.5 to 5 μmol/L, and inhibited aldosteronogenesis at higher doses. EKODE’s stimulatory effect was most prominent when angiotensin and potassium effects were submaximal. The lipid’s mechanism of action was on the early pathway leading to pregnenolone; its action was inhibited by atrial natriuretic peptide. Plasma EKODE was measured by liquid chromatography/mass spectrometry. All human plasmas tested contained EKODE in concentrations ranging from 10
−9
to 5×10
−7
mol/L. In samples from 24 adults, levels of EKODE correlated directly with aldosterone (
r
=0.53,
P
=0.007). In the 12 blacks in that cohort, EKODE also correlated with body mass index and systolic pressure. Those other correlations were not seen in white subjects. The results suggest that oxidized derivatives of polyunsaturated fatty acids other than arachidonic are biologically active. Compounds like EKODE, derived from linoleic acid, may affect adrenal steroid production in humans and mediate some of the deleterious effects of obesity and oxidative stress, especially in blacks.
Renal Oxidative Stress in Medullary Thick Ascending Limbs Produced by Elevated NaCl and Glucose
Authors: Mori Takefumi , Cowley Allen W.
Published: January 2004

The effects of NaCl, glucose, and thyroid hormone on the production of superoxide (O
2
·−
) within the renal medulla of Sprague-Dawley rats were examined. Responses of intracellular superoxide [O
2
·−
]
i
in isolated medullary thick ascending limbs (mTALs) were studied using real-time fluorescent microscopy with measurement of the dehydroethidium (DHE) to ethidium (Eth) conversion ratio (Eth/DHE ratio unit). The results demonstrated that elevations of extracellular NaCl (from 152 to 252 mmol/L),
d
-glucose (from 5 to 25 mmol/L), and triiodo-thyronine (T3; 10 μmol/L) significantly increased [O
2
·−
]
i
levels. Preincubation with superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid (1 mmol/L) significantly inhibited these responses. Stimulation with equamolar amounts of choline chloride or
l
-glucose failed to increase [O
2
·−
]
i
, indicating that these O
2
·−
responses were not determined by changes in osmolality. The responses to NaCl,
d
-glucose, and T3 were abolished by pretreatment with the Na
+
/K
+
-ATPase pump inhibitor ouabain (4 mmol/L) and with Na
+
/H
+
-exchanger inhibitor dimethylamiloride (100 μmol/L). We conclude that elevations of extracellular NaCl,
d
-glucose, or T3 levels can activate both the Na
+
/K
+
-ATPase pump and Na
+
/H
+
exchanger in mTAL, which, in turn, is associated with increased intracellular concentrations of superoxide.
Indicators of Fetal Growth Do Not Independently Predict Blood Pressure in 8-Year-Old Australians
Authors: Burke Valerie , Beilin Lawrie J. , Blake Kevin V. , Doherty Dorota , Kendall Garth E. , Newnham John P. , Landau Louis I. , Stanley Fiona J.
Published: January 2004

Inverse associations between size at birth and blood pressure (BP) in later life are commonly statistically significant only after adjustment for current size, consistent with change in size as the determinant. Few studies have been prospective or have included a range of potential confounders. Using regression models, including maternal and demographic variables, we examined associations between size at birth and BP in Australian children followed from week 16 of gestation to the age of 8 years. BP measurements were available from 1417 children born after 37 weeks gestation without congenital abnormalities. In models adjusted only for sex, the birthweight (BW), birth length, ponderal index, head circumference, chest circumference, abdominal girth, mid-arm circumference, triceps skinfold, placental weight, or BW/placental weight ratio did not significantly predict SBP in 8-year-olds. With adjustment for current size, associations were inverse but not statistically significant (regression coefficients: BW, −1.11; 95% confidence limits [CL], −2.22, 0.01; birth length, −0.25; 95% CL, −0.52, 0.24) and remained nonsignificant after adjustment for confounders. Current weight, height, or body mass index significantly predicted SBP and DBP (
P
<0.001) with differences of 8/4 mm Hg between upper and lower quartiles; effects were similar in infants with lower and higher BW. These findings are consistent with postnatal change in size as the major determinant of BP in 8-year-olds and are important in the context of the worldwide “epidemic” of obesity in childhood as a likely precursor of increasing rates of hypertension in adults.
Abnormal Calcium Signaling and Sudden Cardiac Death Associated With Mutation of Calsequestrin
Authors: Viatchenko-Karpinski Serge , Terentyev Dmitry , Györke Inna , Terentyeva Radmila , Volpe Pompeo , Priori Silvia G. , Napolitano Carlo , Nori Alessandra , Williams Simon C. , Györke Sandor
Published: January 2004

Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia–linked mutation D307H (CASQ2
D307H
) on Ca
2+
signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated ≈4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2
WT
) or CASQ2
D307H
. Expression of CASQ2
D307H
reduced the Ca
2+
storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic
I
Ca
-induced Ca
2+
transients and of spontaneous Ca
2+
sparks were reduced significantly in myocytes expressing CASQ2
D307H
. Myocytes expressing CASQ2
D307H
also displayed drastic disturbances of rhythmic oscillations in [Ca
2+
]
i
and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca
2+
buffer, citrate. Our data suggest that the arrhythmogenic CASQ2
D307H
mutation impairs SR Ca
2+
storing and release functions and destabilizes the Ca
2+
-induced Ca
2+
release mechanism by reducing the effective Ca
2+
buffering inside the SR and/or by altering the responsiveness of the Ca
2+
release channel complex to luminal Ca
2+
. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.