bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ORTHOGONAL POLYNOMIALS FOR A LINEAR SUM OF A FREE FAMILY OF PROJECTIONS
Authors: AKIYAMA MAI , YOSHIDA HIROAKI
Published: February 2003

We calculate the probability measures for some linear combinations of a free family of projections by using Voiculescu's R-transform for free additive convolution in the free probability theory. The measures we give in this paper include many examples that have been calculated, for instance, the spectral measure for the adjacency operators of the infinite distance regular graphs, and the Plancherel measures associated with free product groups. Furthermore, we find the recursive relations for the orthogonal polynomials associated with them.
MARKOVIAN KMS-STATES FOR ONE-DIMENSIONAL SPIN CHAINS
Authors: ACCARDI LUIGI , LIEBSCHER VOLKMAR
Published: February 2003

We characterize a class of quantum Markov states in terms of a locality property of their modular automorphism group or, equivalently, of their φ-conditional expectations and we give an explicit description of the structure of these states. This study is meant as a starting point for the investigation of the structure of Markovian KMS-states of quantum spin chains as well as of multidimensional quantum spin lattices.
Protein Analysis by Hydrogen Exchange Mass Spectrometry
Authors: Hoofnagle Andrew N. , Resing Katheryn A. , Ahn Natalie G.
Published: February 2003

▪ Abstract  Mass spectrometry has provided a powerful method for monitoring hydrogen exchange of protein backbone amides with deuterium from solvent. In comparison to popular NMR approaches, mass spectrometry has the advantages of higher sensitivity, wider coverage of sequence, and the ability to analyze larger proteins. Proteolytic fragmentation of proteins following the exchange reaction provides moderate structural resolution, in some cases enabling measurements from single amides. The technique has provided new insight into protein-protein and protein-ligand interfaces, as well as conformational changes during protein folding or denaturation. In addition, recent studies illustrate the utility of hydrogen exchange mass spectrometry toward detecting protein motions relevant to allostery, covalent modifications, and enzyme function.
Structure and Function of the Calcium Pump
Authors: Stokes David L. , Green N. Michael
Published: February 2003

▪ Abstract  Active transport of cations is achieved by a large family of ATP-dependent ion pumps, known as P-type ATPases. Various members of this family have been targets of structural and functional investigations for over four decades. Recently, atomic structures have been determined for Ca2+-ATPase by X-ray crystallography, which not only reveal the architecture of these molecules but also offer the opportunity to understand the structural mechanisms by which the energy of ATP is coupled to calcium transport across the membrane. This energy coupling is accomplished by large-scale conformational changes. The transmembrane domain undergoes plastic deformations under the influence of calcium binding at the transport site. Cytoplasmic domains undergo dramatic rigid-body movements that deliver substrates to the catalytic site and that establish new domain interfaces. By comparing various structures and correlating functional data, we can now begin to associate the chemical changes constituting the reaction cycle with structural changes in these domains.
Acetylcholine Binding Protein (AChBP): A Secreted Glial Protein That Provides a High-Resolution Model for the Extracellular Domain of Pentameric Ligand-Gated Ion Channels
Authors: Sixma Titia K. , Smit August B.
Published: February 2003

▪ Abstract  Acetylcholine binding protein (AChBP) has recently been identified from molluskan glial cells. Glial cells secrete it into cholinergic synapses, where it plays a role in modulating synaptic transmission. This novel mechanism resembles glia-dependent modulation of glutamate synapses, with several key differences. AChBP is a homolog of the ligand binding domain of the pentameric ligand-gated ion-channels. The crystal structure of AChBP provides the first high-resolution structure for this family of Cys-loop receptors. Nicotinic acetylcholine receptors and related ion-channels such as GABAA, serotonin 5HT3, and glycine can be interpreted in the light of the 2.7 Å AChBP structure. The structural template provides critical details of the binding site and helps create models for toxin binding, mutational effects, and molecular gating.
SELECTIVITY INNEUROTROPHINSIGNALING: Theme and Variations
Authors: Segal Rosalind A.
Published: February 2003

▪ Abstract  Neurotrophins are a family of growth factors critical for the development and functioning of the nervous system. Although originally identified as neuronal survival factors, neurotrophins elicit many biological effects, ranging from proliferation to synaptic modulation to axonal pathfinding. Recent data indicate that the nature of the signaling cascades activated by neurotrophins, and the biological responses that ensue, are specified not only by the ligand itself but also by the temporal pattern and spatial location of stimulation. Studies on neurotrophin signaling have revealed variations in the Ras/MAP kinase, PI3 kinase, and phospholipase C pathways, which transmit spatial and temporal information. The anatomy of neurons makes them particularly appropriate for studying how the location and tempo of stimulation determine the signal cascades that are activated by receptor tyrosine kinases such as the Trk receptors. These signaling variations may represent a general mechanism eliciting specificity in growth factor responses.
NUTRITION AND PREVENTION OF TYPE 2 DIABETES
Authors: Costacou T. , Mayer-Davis E.J.
Published: February 2003

▪ Abstract  In recent years, the prevalence of type 2 diabetes has increased alarmingly worldwide, giving diabetes the dimension of an epidemic. Striking parallel increases in the prevalence of obesity reflect the importance of body fatness as a contributing factor to diabetes incidence. Moreover, it has been estimated that up to 75% of the risk of type 2 diabetes is attributable to obesity. Recent clinical trials and observational epidemiologic studies demonstrate the efficacy of lifestyle changes, including decreased energy intake, decreased fat intake, and weight loss, as well as regular participation in physical activity, in improving insulin sensitivity (SI) and reducing the risk of diabetes. This review evaluates evidence of the effect of diet on insulin resistance, insulin secretion, and glucose tolerance, and reflects on directions for future work toward primary prevention of type 2 diabetes.
DIFFERENT APPROACHES TO DEFINE INDIVIDUAL AMINO ACID REQUIREMENTS
Authors: Pencharz Paul B. , Ball Ronald O.
Published: February 2003

▪ Abstract  A full review of the strengths and limitations of the various methods used to define amino acid requirements is provided. The focus is on the recent development of carbon oxidation techniques such as indicator amino acid oxidation and 24-h amino acid balance to determine dietary indispensable (essential) amino acid needs in adults. All approaches depend on the change in a metabolic parameter in response to graded intake of the test amino acid. In humans, the within-subject variance is less than the between-subject variance, which has led to an appreciation of the need to study each subject across a range of intakes, above and below the mean requirement level. The data can then be analyzed using two-phase linear regression crossover and a precise population mean requirement can be determined. Several approaches have been used to define the variance of the mean requirement. Finally, a minimally invasive indicator amino acid oxidation model has been developed which allows the determination of dietary essential amino acid requirements in children and other vulnerable populations.
In Situ Measurements of Heat Generation in a Li/Mesocarbon Microbead Half-Cell
Authors: Lu W. , Prakash J.
Published: February 2003

The heat generation of mesocarbon microbeads (MCMB) in a MCMB/Li cell was measured in an isothermal microcalorimeter. The heat contributions are discussed in terms of reversible and irreversible heat generation. Endothermic and exothermic events observed during the charge and discharge processes are attributed to the stage changes of graphite during the electrochemical lithium insertion-extraction reactions. The initial endothermic peak is attributed to the insertion of the lithium ion into the graphite layer structure; the graphite structure changes from a dilute stage 1′ to stage 4 with a positive

Δ
S

(due to the order/disorder transition). In addition, the heat generation is estimated on the basis of the cell entropy change and cell polarization at a low discharge rate. The open-circuit voltage and

Δ
S

calculated from the isothermal calorimeter results under low charge/discharge rates have the same range and similar shapes when compared to the experimental results. © 2003 The Electrochemical Society. All rights reserved.
Hydrogen Peroxide, an Endogenous Endothelium-Derived Hyperpolarizing Factor, Plays an Important Role in Coronary Autoregulation In Vivo
Authors: Yada Toyotaka , Shimokawa Hiroaki , Hiramatsu Osamu , Kajita Tatsuya , Shigeto Fumiyuki , Goto Masami , Ogasawara Yasuo , Kajiya Fumihiko
Published: February 2003

Background—

Recent studies in vitro have demonstrated that endothelium-derived hydrogen peroxide (H
2
O
2
) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans. The aim of this study was to evaluate our hypothesis that endothelium-derived H
2
O
2
is an EDHF in vivo and plays an important role in coronary autoregulation.

Methods and Results—

To test this hypothesis, we evaluated vasodilator responses of canine (n=41) subepicardial small coronary arteries (≥100 μm) and arterioles (<100 μm) with an intravital microscope in response to acetylcholine and to a stepwise reduction in coronary perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO synthesis with
N
G
-monomethyl-
l
-arginine (L-NMMA). After L-NMMA, the coronary vasodilator responses were attenuated primarily in small arteries, whereas combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates H
2
O
2
into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large-conductance K
Ca
channels) attenuated the vasodilator responses of coronary arteries of both sizes. Residual arteriolar dilation after L-NMMA plus catalase or TEA was largely attenuated by 8-sulfophenyltheophylline, an adenosine receptor inhibitor.

Conclusions—

These results suggest that H
2
O
2
is an endogenous EDHF in vivo and plays an important role in coronary autoregulation in cooperation with NO and adenosine.
Cost Implications of the Use of Ramipril in High-Risk Patients Based on the Heart Outcomes Prevention Evaluation (HOPE) Study
Authors: Lamy Andre , Yusuf Salim , Pogue Janice , Gafni Amiram
Published: February 2003

Background—

The HOPE study has demonstrated that ramipril is beneficial (ie, prevents cardiovascular death, myocardial infarction, and stroke) for a broad range of patients without evidence of left ventricular dysfunction or heart failure who are at high risk for cardiovascular event. In this study, we report the cost implications, in both the United States and Canada, of the use of ramipril after the HOPE study.

Methods and Results—

A third-party perspective was chosen (Medicare for the United States and Ministry of Health for Canada). We calculated the costs of the management strategies of ramipril and placebo. An annual discount rate of 3% was used over the 4.5 years of follow-up. Sensitivity analyses were performed. Costs are reported in United States dollars and in Canadian dollars, respectively. The total costs per patient (including acquisition costs of ramipril) were not different between the groups in both countries (United States, $13 520 versus $13 631; Canada, $8702 versus $8588). From the distribution of cases in the bootstrap analysis, we found that 90% of cases fall either into a cost-neutral or cost-saving situation (64% in United States and 27% in Canada) or into a cost-effectiveness situation with an incremental cost-effectiveness ratio <$10 000 (in respective currency) per primary event saved.

Conclusions—

On the basis of these results, we suggest that the use of ramipril is likely to represent an efficient use of resources in both countries. These findings support the use of ramipril in populations included in the HOPE study.
Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo
Authors: Robin Jonathan , Kharbanda Rajesh , Mclean Peter , Campbell Richard , Vallance Patrick
Published: February 2003

Background—

Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation.

Methods and Results—

For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human blood vessels in a dose-dependent manner, and the effects were reduced by inhibition of both nitric oxide and prostanoid synthesis

Conclusions—

These findings demonstrate that serine protease activity can cause human vasodilation and provide a possible explanation of why serine protease activation in critical illness is associated with vascular dysfunction.
Role of Risk Factors in the Modulation of Tissue Factor Activity and Blood Thrombogenicity
Authors: Sambola Antonia , Osende Julio , Hathcock James , Degen Michael , Nemerson Yale , Fuster Valentin , Crandall Jill , Badimon Juan Jose
Published: February 2003

Background—

Several studies suggest a role for an increased circulating pool of tissue factor (TF) in atherothrombotic diseases. Furthermore, certain cardiovascular risk factors, such as diabetes, hyperlipemia, and smoking, are associated with a higher incidence of thrombotic complications. We hypothesized that the observed increased blood thrombogenicity (BT) observed in patients with type 2 diabetes mellitus may be mediated via an increased circulating tissue factor activity. We have extended our study to smokers and hyperlipidemic subjects.

Methods and Results—

Poorly controlled patients with type 2 diabetes mellitus (n=36), smokers (n=10), and untreated hyperlipidemic subjects (n=10) were studied. Circulating TF was immunocaptured from plasma, relipidated, and quantified by factor Xa (FXa) generation in the presence of factor VIIa. BT was assessed as thrombus formation on the Badimon perfusion chamber. Patients with improvement in glycemic control showed a reduction in circulating TF (362±135 versus 243±74 pmol/L per min FXa,
P
=0.0001). A similar effect was observed in BT (15 445±1130 versus 12 072±596 μm/mm
2
,
P
=0.01). Two hours after smoking 2 cigarettes, TF was increased (217±72 versus 283±106 pmol/L per min FXa,
P
=0.003). Hyperlipidemic subjects showed higher TF (237±63 versus 195±44 pmol/L per min FXa,
P
=0.035) than healthy volunteers.

Conclusions—

These findings suggest that high levels of circulating TF may be the mechanism of action responsible for the increased thrombotic complications associated with the presence of these cardiovascular risk factors. These observations strongly emphasize the usefulness of the management of the patients based on their global risk assessment.
Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression
Authors: Salonen Riitta M. , Nyyssönen Kristiina , Kaikkonen Jari , Porkkala-Sarataho Elina , Voutilainen Sari , Rissanen Tiina H. , Tuomainen Tomi-Pekka , Valkonen Veli-Pekka , Ristonmaa Ulla , Lakka Hanna-Maaria , Vanharanta Meri , Salonen Jukka T. , Poulsen Henrik E.
Published: February 2003

Background—

Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT).

Methods and Results—

The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46,
P
=0.014), in men by 33% (95% CI, 4 to 62,
P
=0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49,
P
=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69,
P
=0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol.

Conclusions—

These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.
The Antioxidant Acetylcysteine Reduces Cardiovascular Events in Patients With End-Stage Renal Failure
Authors: Tepel Martin , van der Giet Markus , Statz Mario , Jankowski Joachim , Zidek Walter
Published: February 2003

Background—

Patients with end-stage renal failure have increased oxidative stress and show elevated cardiovascular mortality. Whether increased cardiovascular events can be prevented by the administration of antioxidants is unknown.

Methods and Results—

We evaluated the effects of acetylcysteine, a thiol-containing antioxidant, on cardiovascular events in patients undergoing hemodialysis. A prospective, randomized, placebo-controlled trial was conducted between October 1, 1999, and September 30, 2001, in 134 patients (76 male and 58 female) with a mean age of 62±16 years (mean±SD) who had been undergoing maintenance hemodialysis for a minimum of 3 months 3 times weekly in an ambulatory center. Median (range) follow-up was 14.5 (1 to 24) months. Patients were randomly assigned either to receive acetylcysteine (600 mg BID) or placebo. The primary end point was a composite variable consisting of cardiac events including fatal and nonfatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral vascular disease with amputation, or need for angioplasty. Secondary end points included each of the component outcomes, total mortality, and cardiovascular mortality. A total of 18 (28%) of the 64 hemodialysis patients assigned to acetylcysteine group and 33 (47%) of the 70 hemodialysis patients assigned to control group had a primary end point (relative risk, 0.60 [95% CI, 0.38 to 0.95],
P
=0.03). No significant differences in secondary end points or total mortality were detected.

Conclusions—

In hemodialysis patients, treatment with acetylcysteine (600 mg BID) reduces composite cardiovascular end points.
Early and Late Effects of Clopidogrel in Patients With Acute Coronary Syndromes
Authors: Yusuf Salim , Mehta Shamir R. , Zhao Feng , Gersh Bernard J. , Commerford Patrick J. , Blumenthal Mel , Budaj Andrzej , Wittlinger Thomas , Fox Keith A.A.
Published: February 2003

Background—

The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS.

Methods and Results—

A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia.

Conclusions—

Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.
Temporal Response and Localization of Integrins β1 and β3 in the Heart After Myocardial Infarction
Authors: Sun Mei , Opavsky M. Anne , Stewart Duncan J. , Rabinovitch Marlene , Dawood Fayez , Wen Wen-Hu , Liu Peter P.
Published: February 2003

Background—

Integrins are involved in structural remodeling and tissue repair. This study aimed to elucidate the role of the β-integrins in cardiac remodeling after myocardial infarction (MI).

Methods and Results—

The MI model was created by ligation of the left anterior descending coronary artery in rats. We detected cardiac integrins β1 and β3 gene expression (quantitative in situ hybridization) and protein production (Western blot and immunohistochemistry) and potential regulation by tumor necrosis factor (TNF) using neonatal ventricular myocytes and TNF
−/−
knockout mice. Integrins β1 and β3 gene expression and protein production were low in sham-operated hearts. After MI, the β1 and β3 mRNA and proteins were significantly increased at the site of MI at day 3, reached a peak at day 7, and gradually declined thereafter. Integrin β1A localized primarily in fibroblasts and inflammatory cells, β1D localized in myocytes, and integrin β3 was associated primarily with endothelial and smooth muscle cells in peri-infarct vessels. In cultured myocytes, there was isoform transition from the adult β1D to the fetal β1A on exposure to TNF-α. This was confirmed in vivo in the peri-infarct myocytes, but the transition was voided in TNF
−/−
-knockout mice.

Conclusions—

Integrins β1 and β3 are significantly activated in the infarcted myocardium. Integrin β1 is active particularly at sites of inflammation and fibrosis, whereas integrin β3 localizes to vessels in the peri-infarct zone in a temporally coordinated manner. Integrin β1D to β1A isoform transition in myocytes is regulated by TNF-α.
Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Kwak Brenda R. , Veillard Niels , Pelli Graziano , Mulhaupt Flore , James Richard W. , Chanson Marc , Mach François
Published: February 2003

Background—

Gap junctions allow the direct exchange of ions and small molecules between cells in contact, thus coordinating physiological processes such as cell growth and differentiation. We have recently demonstrated increased expression of the gap junction protein connexin43 (Cx43) in specific subsets of cells in atherosclerotic lesions. Because the development of atherosclerosis depends critically on paracrine cell-to-cell interactions, we hypothesized that direct intercellular communication via gap junctions may be another factor controlling atherogenesis.

Methods and Results—

The role of Cx43 in atherogenesis was examined by use of both a genetic and a pharmacological approach. First, atherosclerosis-susceptible LDL receptor–deficient (LDLR
−/−
) mice with normal (Cx43
+/+
) or reduced (Cx43
+/−
) levels of Cx43 were fed a cholesterol-rich diet for 14 weeks. The progression of atherosclerosis was reduced by 50% (
P
<0.01) in the thoracoabdominal aorta and in the aortic roots of Cx43
+/−
LDLR
−/−
mice compared with Cx43
+/+
LDLR
−/−
controls. Atheroma in Cx43
+/−
LDLR
−/−
mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or “statins,” lipid-lowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of LDLR
−/−
mice treated orally with pravastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls. This was associated with reduced Cx43 expression in lesions of statin-treated mice.

Conclusions—

These data indicate a critical role for Cx43-mediated gap junctional communication in atherosclerotic plaque formation.
Efficacy and Safety of Milrinone in Preventing Low Cardiac Output Syndrome in Infants and Children After Corrective Surgery for Congenital Heart Disease
Authors: Hoffman Timothy M. , Wernovsky Gil , Atz Andrew M. , Kulik Thomas J. , Nelson David P. , Chang Anthony C. , Bailey James M. , Akbary Akbar , Kocsis John F. , Kaczmarek Raymond , Spray Thomas L. , Wessel David L.
Published: February 2003

Background—

Low cardiac output syndrome (LCOS), affecting up to 25% of neonates and young children after cardiac surgery, contributes to postoperative morbidity and mortality. This study evaluated the efficacy and safety of prophylactic milrinone in pediatric patients at high risk for developing LCOS.

Methods and Results—

The study was a double-blind, placebo-controlled trial with 3 parallel groups (low dose, 25-μg/kg bolus over 60 minutes followed by a 0.25-μg/kg per min infusion for 35 hours; high dose, 75-μg/kg bolus followed by a 0.75-μg/kg per min infusion for 35 hours; or placebo). The composite end point of death or the development of LCOS was evaluated at 36 hours and up to 30 days after randomization. Among 238 treated patients, 25.9%, 17.5%, and 11.7% in the placebo, low-dose milrinone, and high-dose milrinone groups, respectively, developed LCOS in the first 36 hours after surgery. High-dose milrinone significantly reduced the risk the development of LCOS compared with placebo, with a relative risk reduction of 55% (
P
=0.023) in 238 treated patients and 64% (
P
=0.007) in 227 patients without major protocol violations. There were 2 deaths, both after infusion of study drug. The use of high-dose milrinone reduced the risk of the LCOS through the final visit by 48% (
P
=0.049).

Conclusions—

The use of high-dose milrinone after pediatric congenital heart surgery reduces the risk of LCOS.
Diagnostic Value of Pericardial Biopsy
Authors: Seferović Petar M. , Ristić Arsen D. , Maksimović Ružica , Tatić Vujadin , Ostojić Miodrag , Kanjuh Vladimir
Published: February 2003

Background—

The clinical significance of pericardial biopsy is controversial. The aim of this study was to assess the feasibility and diagnostic value of 3 approaches to pericardial biopsy: fluoroscopic control and standard sampling, pericardioscopy guidance with standard sampling, and pericardioscopy guidance with extensive sampling.

Methods and Results—

Forty-nine subsequent patients with a large pericardial effusion underwent parietal pericardial biopsy. In group 1 (12 patients, 66.7% males, age 46.7±12.2 years), pericardial biopsy was guided by fluoroscopy (3 to 6 samples per patient). Group 2 included 22 patients (50% males, age 50.8±10.4 years) undergoing 4 to 6 pericardial biopsies per patient guided by pericardioscopy (16F flexible endoscope). In group 3, extensive pericardial sampling was performed, guided by pericardioscopy (15 patients, 53.3% males, age 53.7±12.8 years, 18 to 20 samples per patient). Sampling efficiency was better with pericardioscopy (group 2, 84.9%; group 3, 84.2%) compared with fluoroscopic guidance (group 1, 43.7%;
P
<0.01). Diagnostic value was defined as a new diagnosis uncovered, etiology revealed, clinical diagnosis confirmed, and the biopsy false-negative. Pericardial biopsy in group 3 had higher diagnostic value than in group 1 in revealing new diagnosis (40% versus 8.3%,
P
<0.05) and etiology (53.3% versus 8.3%,
P
<0.05). In group 2, pericardial biopsy had a higher yield in establishing etiology than in group 1 (40.9% versus 8.3%;
P
<0.05). Pericardial biopsy was false-negative in 58.3% in group 1 in contrast to 6.7% in group 3 (
P
<0.01). There were no major complications.

Conclusions—

Pericardioscopic guidance enhanced pericardial sampling efficiency. The diagnostic value of pericardial biopsy was significantly improved by extensive sampling made possible by pericardioscopy.
High Glucose Causes Upregulation of Cyclooxygenase-2 and Alters Prostanoid Profile in Human Endothelial Cells
Authors: Cosentino Francesco , Eto Masato , De Paolis Paola , van der Loo Bernd , Bachschmid Markus , Ullrich Volker , Kouroedov Alexei , Delli Gatti Chiara , Joch Hana , Volpe Massimo , Lüscher Thomas F.
Published: February 2003

Background—

Prostaglandins generated by cyclooxygenase (COX) have been implicated in hyperglycemia-induced endothelial dysfunction. However, the role of individual COX isoenzymes as well as the molecular mechanisms linking oxidative stress and endothelial dysfunction in diabetes remains to be clarified.

Methods and Results—

Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2 mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX-2. Its upregulation was associated with an increase of thromboxane A
2
and a reduction of prostacyclin (PGI
2
) release. Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI
2
synthase. NO release was reduced despite 2-fold increase of endothelial NO synthase expression. Phorbol ester caused an increase of COX-2 and endothelial NO synthase expression similar to that elicited by glucose. These effects were prevented by the PKC inhibitor calphostin C. N-acetylcysteine, vitamin C, and calphostin C prevented ROS formation, restored NO release, and reduced colocalization of nitrotyrosine and PGI
2
synthase. Expression of p22

phox

, a subunit of NAD(P)H oxidase, was increased, and diphenyleneiodonium inhibited ROS formation. By contrast, indomethacin did not affect glucose-induced ROS generation.

Conclusions—

Thus, high glucose, via PKC signaling, induces oxidative stress and upregulation of COX-2, resulting in reduced NO availability and altered prostanoid profile.
Endothelin-1 Increases Vascular Superoxide via Endothelin
A
–NADPH Oxidase Pathway in Low-Renin Hypertension
Authors: Li Lixin , Fink Gregory D. , Watts Stephanie W. , Northcott Carrie A. , Galligan James J. , Pagano Patrick J. , Chen Alex F.
Published: February 2003

Background—

Angiotensin II–induced hypertension is associated with NAD(P)H oxidase–dependent superoxide production in the vessel wall. Vascular superoxide level is also increased in deoxycorticosterone acetate (DOCA)–salt hypertension, which is associated with a markedly depressed plasma renin activity because of sodium retention. However, the mechanisms underlying superoxide production in low-renin hypertension are undefined.

Methods and Results—

This study investigated (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt hypertensive rats, contributes to arterial superoxide generation and (2) the effect of gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase. Both superoxide and ET-1 levels were significantly elevated in carotid arteries of DOCA-salt rats compared with that of the sham-operated controls. ET-1 concentration-dependently stimulated superoxide production in vitro in carotid arteries of normotensive rats. The increase in arterial superoxide in both ET-1–treated normotensive and DOCA-salt rats was reversed by a selective ET
A
receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor
N
ω
-
l
-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET
A
receptors significantly reduced arterial superoxide levels, with a concomitant decrease of systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese superoxide dismutase or endothelial nitric oxide synthase also suppressed superoxide levels in carotid arteries of DOCA-salt rats.

Conclusions—

These findings suggest that ET-1 augments vascular superoxide production at least in part via an ET
A
/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
Transdifferentiation of Blood-Derived Human Adult Endothelial Progenitor Cells Into Functionally Active Cardiomyocytes
Authors: Badorff Cornel , Brandes Ralf P. , Popp Rüdiger , Rupp Stefan , Urbich Carmen , Aicher Alexandra , Fleming Ingrid , Busse Rudi , Zeiher Andreas M. , Dimmeler Stefanie
Published: February 2003

Background—

Further to promoting angiogenesis, cell therapy may be an approach for cardiac regeneration. Recent studies suggest that progenitor cells can transdifferentiate into other lineages. However, the transdifferentiation potential of endothelial progenitor cells (EPCs) is unknown.

Methods and Results—

EPCs were obtained from peripheral blood mononuclear cells of healthy adults or coronary artery disease (CAD) patients by cultivating with endothelial cell medium and growth factors. After 3 days, >95% of adherent cells were functionally and phenotypically EPCs. Diacetylated LDL–labeled EPCs were then cocultivated with rat cardiomyocytes for 6 days, resulting in significant increases of EPC cell length and size to a cardiomyocyte-like morphology. Biochemically, 9.94±1.39% and 5.04±1.09% of EPCs from healthy adults (n=15) or CAD patients (n=14,
P
<0.01 versus healthy adults), respectively, expressed α-sarcomeric actinin as measured by flow cytometry. Immunocytochemistry showed that human EPCs expressed α-sarcomeric actinin, cardiac troponin I (both with partial sarcomeric organization), atrial natriuretic peptide, and myocyte enhancer factor 2. Fluo 4 imaging demonstrated calcium transients synchronized with adjacent rat cardiomyocytes in transdifferentiated human EPCs. Single-cell microinjection of Lucifer yellow and calcein-AM labeling of cardiomyocytes demonstrated gap junctional communication between 51±7% of EPCs (16 hours after labeling, n=4) and cardiomyocytes. EPC transdifferentiation into cardiomyocytes was not observed with conditioned medium but in coculture with paraformaldehyde-fixed cardiomyocytes.

Conclusions—

EPCs from healthy volunteers and CAD patients can transdifferentiate in vitro into functionally active cardiomyocytes when cocultivated with rat cardiomyocytes. Cell-to-cell contact but not cellular fusion mediates EPC transdifferentiation. The therapeutic use of autologous EPCs may aid cardiomyocyte regeneration in patients with ischemic heart disease.
His Electrogram Alternans Reveal Dual Atrioventricular Nodal Pathway Conduction During Atrial Fibrillation
Authors: Zhang Youhua , Bharati Saroja , Mowrey Kent A. , Mazgalev Todor N.
Published: February 2003

Background—

Traditional tools to study dual-pathway atrioventricular nodal (AVN) electrophysiology are not applicable in subjects with permanent atrial fibrillation (AF). The presence of fast-pathway (FP) and slow-pathway (SP) wavefronts and their possible modification remain uncertain in this condition. We demonstrated previously that His electrogram (HE) alternans can determine whether the FP or the SP reaches the His bundle on a beat-by-beat basis. We have now applied this novel index to monitor dual-pathway conduction and the effects of SP modification during AF.

Methods and Results—

In 12 rabbit AVN preparations, HE alternans were confirmed during a standard A
1
A
2
pacing protocol. During AF, in 9 of the 12 hearts, HE alternans indicated the presence of dual pathways. Successful SP modification guided by the HE alternans eliminated the SP, resulting in a predominantly FP conduction during AF in all hearts. This increased the average His-His interval (204±14 versus 276±51 ms,
P
<0.001). Morphological studies revealed that SP modification damaged only the posterior extension of the AVN.

Conclusions—

We have demonstrated for the first time in rabbits that HE alternans permit “visualization” of dual-pathway electrophysiology and confirmed the presence of both FP and SP wavefronts during AF. This novel index has been used in a selective SP ablation that resulted in a significant slowing of the ventricular rate. HE alternans provide a new insight into the mechanisms of AVN conduction and could guide AVN modification for ventricular rate control in AF clinically.
Factor V Leiden Protects Against Blood Loss and Transfusion After Cardiac Surgery
Authors: Donahue Brian S. , Gailani David , Higgins Michael S. , Drinkwater Davis C. , George Alfred L.
Published: February 2003

Background—

The outcome of cardiac surgery is influenced by several factors, but the impact of specific genetic variants has not been systematically explored. Because blood conservation is a pressing issue in cardiac surgery, we tested the hypothesis that factor V Leiden (FVL), a common coagulation factor polymorphism, may protect against blood loss and transfusion in patients undergoing cardiac surgery.

Methods and Results—

We enrolled 517 patients undergoing cardiac surgery, including 26 heterozygous FVL carriers, and evaluated the impact of FVL on chest tube output and transfusion by using univariate and multivariate techniques. For patients with FVL, blood loss at 6 (238±131 mL) and 24 hours (522±302 mL) was significantly lower than that for noncarriers (358±259 mL and 730±452 mL;
P
<0.001 and
P
=0.001, respectively). In a multivariate regression analysis, controlling for ethnicity and factors known to affect blood loss, FVL was a significant independent contributor at both time points. Using a similar regression approach, FVL did not have a significant effect on the number of units transfused. However, logistic regression of the risk of receiving any transfusion during hospitalization demonstrated a significant independent protective effect of FVL on overall transfusion risk.

Conclusions—

FVL represents a common genetic trait that may protect against blood loss and transfusion in this population. This study demonstrates that genetic variability can affect the outcome of cardiac surgery.
Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart
Authors: Hein Stefan , Arnon Eyal , Kostin Sawa , Schönburg Markus , Elsässer Albrecht , Polyakova Victoria , Bauer Erwin P. , Klövekorn Wolf-Peter , Schaper Jutta
Published: February 2003

Background—

The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF.

Methods and Results—

Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-β
1
were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ in group 2. Cardiomyocyte mitosis was never observed.

Conclusions—

These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.
Decreased Atherosclerotic Lesion Formation in CX3CR1/Apolipoprotein E Double Knockout Mice
Authors: Combadière Christophe , Potteaux Stéphane , Gao Ji-Liang , Esposito Bruno , Casanova Saveria , Lee Eric J. , Debré Patrice , Tedgui Alain , Murphy Philip M. , Mallat Ziad
Published: February 2003

Background—

Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1 expression and reduced risk of acute coronary disease in humans.

Methods and Results—

We generated CX3CR1-deficient mice (
CX3CR1

−
/
−

) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (

apoE
−/−

). Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared with their

CX3CR1
+/+
/apoE
−/−

littermates. The development of atherosclerosis in the aortic sinus was also markedly altered in the double knockout mice, with 50% reduction in macrophage accumulation. Although lesions of
CX3CR1

−
/
−

mice were smaller in size, they retained a substantial accumulation of smooth muscle cells and collagen, features consistent with a stable plaque phenotype. Finally,

CX3CR1
+/−
/apoE
−/−

mice showed the same reduction in atherosclerosis as the
CX3CR1

−
/
−

/apoE

−
/
−

mice.

Conclusions—

The CX3CR1-CX3CL1 pathway seems to play a direct and critical role in monocyte recruitment and atherosclerotic lesion development in a mouse model of human atherosclerosis.
Family Composition and Remarriage in Alsace, 1750–1850
Authors: McQuillan Kevin
Published: February 2003

Data from a family reconstitution study of five villages in Alsace, France, point to the importance of family composition as a determinant of remarriage. For widows and widowers, the likelihood of remarriage increased with the number of children fourteen years of age or younger in their household, though the result was statistically significant only for men. Moreover, having an older daughter (fifteen to twenty-one years of age) was associated with a much lower likelihood of remarriage for widowers, and, surprisingly, for widows as well.
How Italian Was the Renaissance?
Authors: Rabb Theodore K.
Published: February 2003

The traditional account of the Renaissance holds that intellectual and artistic influence moved overwhelmingly in one direction—from Italy to the rest of Europe, and especially toward the North. A remarkable exhibition in Bruges, however, has made the case that traffic did not go just one way, at least so far as innovation in painting was concerned, because the vibrant cultural center of the Low Countries had a powerful and significant impact on southern Europe. That this case is made through art is an indication of how important it is to bring different disciplines to bear on our understanding of the past.
The Configurational Matrix
Authors: Neeleman Ad , Koot Hans van de
Published: February 2003

This article presents a theory of grammatical dependencies that is in accordance with basic assumptions of bare phrase structure theory. It explains Koster's (1987) configurational matrix, the observation that such dependencies share five properties: c-command by the antecedent, obligatoriness, uniqueness of the antecedent, nonuniqueness of the dependent, and locality. The theory is based on two primitive syntactic relations (copying and function application) and a nonatomic view of nodes.
Determiner Raising and Scope Shift
Authors: Takahashi Daiko
Published: February 2003

Whether quantifier scope is regulated by movement or not has been debated for more than two decades, and this issue has become especially important in the minimalist framework. This article provides a novel argument for the existence of a scope-marking movement operation on the basis of what can be called the split-QP construction in Japanese. It is shown that the construction involves overt movement of quantificational determiners, whereby their scope is visibly marked, and that the movement operation is subject to economy so that it may apply only if it yields scope shift.
A Note on “Restructuring” and Quantifier Climbing in French
Authors: Cinque Guglielmo
Published: February 2003

Although Modern French was originally taken to lack the “restructuring” phenomenon altogether, four different “restructuring” effects have more recently been claimed to exist in the language:en andy climbing, quantifier climbing, adverb climbing, and long movement in ‘easy-to-please’ constructions. Evidence discussed in this article shows that only en andy climbing and long movement in ‘easy-to-please’ constructions are bona fide instances of “restructuring” in French.
Raising to Object out of CP
Authors: Tanaka Hidekazu
Published: February 2003

Kuno (1976) presents arguments for raising to object (RTO) in Japanese. After summarizing his analysis, this article presents additional data supporting RTO. Alternative analyses are also critically examined. The significance of RTO constructions in Japanese is that the RTO complement clause has a complementizer. It is suggested that this is permissible under the theory outlined in Chomsky 2000 if the RTO complement CP may have one A(-adjoined)-position in its edge.