bluuebunny/crossref_metadata_2025 huggingface dataset:
Aortic reflection coefficients and their association with global indexes of wave reflection in healthy controls and patients with Marfan's syndrome
Authors: Segers P. , De Backer J. , Devos D. , Rabben S. I. , Gillebert T. C. , Van Bortel L. M. , De Sutter J , De Paepe A. , Verdonck P. R.
Published: January 2006

Early return of reflected pressure waves increases the load on central arteries and may increase the risk of aortic rupture in patients with Marfan's syndrome (MFS). To assess whether wave reflection is elevated in MFS, we used ultrasound and MRI to measure central pressure and flow waveforms in 26 patients (13–54 yr of age) and 26 age- and gender-matched controls. Aortic systolic and diastolic cross-sectional areas were measured at the ascending and descending aorta (AA and DA), diaphragm (DIA), and lower abdominal aorta (AB). From these measurements, local characteristic impedance ( Z0- xx) and local reflection coefficients (Γ xx-yy) were calculated. Calculated global wave reflection indexes were the augmentation index (AIx) and the ratio of backward to forward pressure wave (Pb/Pf). The aorta was wider in MFS patients at AA ( P < 0.01) and DA ( P < 0.01). Aortic pulse wave velocity was 42 cm/s higher in MFS patients ( P < 0.05). Z0- xx was not different between groups, except at DA, where it was lower in MFS patients. In controls, ΓAA-DA was 0.31 ± 0.08, ΓDA-DIA was 0.00 ± 0.11, and ΓDIA-AB was 0.31 ± 0.16. Mean values of Γ xx-yy were not different between MFS patients and controls. In controls, aging diminished ΓAA-DA but increased ΓDIA-AB. Clear age-related patterns were absent in MFS patients. AIx or Pb/Pf was not higher in MFS patients than in controls. There were indications for enhanced wave reflection in young MFS patients. Our data demonstrated that the major determinants of AIx were pulse wave velocity and the effective length of the arterial system and, to a lesser degree, HR and Pb/Pf.
Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway
Authors: Xiao DaLiao , Buchholz John N. , Zhang Lubo
Published: January 2006

The mechanisms of adaptation of uterine artery vascular tone to pregnancy are not fully understood. The present study tested the hypothesis that pregnancy decreases the PKC-mediated Ca2+sensitivity of the contractile process and attenuates myogenic tone in resistance-sized uterine arteries. In pressurized uterine arteries from nonpregnant (NPUA) and near-term pregnant (PUA) sheep, we measured, simultaneously in the same tissue, vascular diameter and vessel wall intracellular Ca2+concentration ([Ca2+]i) as a function of intraluminal pressure. In both NPUA and PUA, membrane depolarization with KCl caused a rapid increase in [Ca2+]iand a decrease in diameter. A pressure increase from 20 to 100 mmHg resulted in a transient increase in diameter that was associated with an increase in [Ca2+]i, followed by myogenic contractions in the absence of further changes in [Ca2+]i. In addition, activation of PKC by phorbol 12,13-dibutyrate induced a decrease in diameter in the absence of changes in [Ca2+]i. Pressure-dependent myogenic responses were significantly decreased in PUA compared with NPUA. However, pressure-induced increases in [Ca2+]iwere not significantly different between PUA and NPUA. The ratio of changes in diameter to changes in [Ca2+]iwas significantly greater for pressure-induced contraction of NPUA than that of PUA. Inhibition of PKC by calphostin C significantly attenuated the pressure-induced vascular tone and eliminated the difference of myogenic responses between NPUA and PUA. In contrast, the MAPKK (MEK) inhibitor PD-098059 had no effect on NPUA but significantly enhanced myogenic responses of PUA. In the presence of PD-098059, there was no difference in pressure-induced myogenic responses between NPUA and PUA. The results suggest that pregnancy downregulates pressure-dependent myogenic tone of the uterine artery, which is partly due to increased MEK/ERK activity and decreased PKC signal pathway leading to a decrease in Ca2+sensitivity of myogenic mechanism in the uterine artery during pregnancy.
Vascular endothelial growth factor in the lung
Authors: Voelkel Norbert F. , Vandivier R. William , Tuder Rubin M.
Published: January 2006

Vascular endothelial growth factor (VEGF) is a pluripotent growth and permeability factor that has a broad impact on endothelial cell function. The lung tissue is very rich in this protein; many different lung cells produce VEGF and also respond to VEGF. VEGF is critical for the development of the lung and serves as a maintenance factor during adult life. In addition to the physiological functions of this protein, there is increasing evidence that VEGF also plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema. Here we provide a comprehensive overview of the rapidly expanding literature.
Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase
Authors: Takenaka Kaori , Nishimura Yoshihiro , Nishiuma Teruaki , Sakashita Akihiro , Yamashita Tomoya , Kobayashi Kazuyuki , Satouchi Miyako , Ishida Tatsuro , Kawashima Seinosuke , Yokoyama Mitsuhiro
Published: January 2006

Although mechanical ventilation (MV) is an important supportive strategy for patients with acute respiratory distress syndrome, MV itself can cause a type of acute lung damage termed ventilator-induced lung injury (VILI). Because nitric oxide (NO) has been reported to play roles in the pathogenesis of acute lung injury, the present study explores the effects on VILI of NO derived from chronically overexpressed endothelial nitric oxide synthase (eNOS). Anesthetized eNOS-transgenic (Tg) and wild-type (WT) C57BL/6 mice were ventilated at high or low tidal volume (Vt; 20 or 7 ml/kg, respectively) for 4 h. After MV, lung damage, including neutrophil infiltration, water leakage, and cytokine concentration in bronchoalveolar lavage fluid (BALF) and plasma, was evaluated. Some mice were given Nω-nitro-l-arginine methyl ester (l-NAME), a potent NOS inhibitor, via drinking water (1 mg/ml) for 1 wk before MV. Histological analysis revealed that high Vt ventilation caused severe VILI, whereas low Vt ventilation caused minimal VILI. Under high Vt conditions, neutrophil infiltration and lung water content were significantly attenuated in eNOS-Tg mice compared with WT animals. The concentrations of macrophage inflammatory protein-2 in BALF and plasma, as well as plasma tumor necrosis factor-α and monocyte chemoattractant protein-1, also were decreased in eNOS-Tg mice. l-NAME abrogated the beneficial effect of eNOS overexpression. In conclusion, chronic eNOS overexpression may protect the lung from VILI by inhibiting the production of inflammatory chemokines and cytokines that are associated with neutrophil infiltration into the air space.
Diesel exhaust enhances virus- and poly(I:C)-induced Toll-like receptor 3 expression and signaling in respiratory epithelial cells
Authors: Ciencewicki Jonathan , Brighton Luisa , Wu Wei-Dong , Madden Michael , Jaspers Ilona
Published: January 2006

Prior exposure of respiratory epithelial cells to an aqueous-trapped solution of diesel exhaust (DEas) enhances the susceptibility to influenza infections. Here, we examined the effect of DEason the Toll-like receptor 3 (TLR3) pathway, which is responsible for the recognition of and response to viruses and double-stranded RNA. Flow cytometric and confocal microscopy analyses showed that TLR3 is predominantly expressed in the cytoplasm of respiratory epithelial cells. To examine the effect of DE on TLR3 expression and function, differentiated human bronchial or nasal epithelial cells as well as A549 cells were exposed to DEasand then infected with influenza A or treated with polyriboinosinic acid-polyribocytidylic acid [poly(I:C)], a synthetic form of double-stranded RNA. Exposure to DEasbefore infection with influenza or stimulation with poly(I:C) significantly upregulated the expression of TLR3. Additionally, preexposure to DEassignificantly increased the poly(I:C)-induced expression of IL-6. Overexpression of a dominant-negative mutant form of TNF receptor-associated factor 6 reversed the effects of DEason poly(I:C)-induced IL-6 expression, suggesting that the response was TLR3 dependent. Similarly, preexposure to DEassignificantly increased nuclear levels of interferon regulatory factor 3 and the expression of IFN-β in response to poly(I:C). Pretreatment with wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, was able to abate the effect of DEason poly(I:C)-induced IFN-β expression. Together, these results indicate that exposure of respiratory epithelial cells to DEascould potentially alter the response to viral infections by increasing the expression and function of TLR3.
Moraxella catarrhalisinduces inflammatory response of bronchial epithelial cells via MAPK and NF-κB activation and histone deacetylase activity reduction
Authors: Slevogt Hortense , Schmeck Bernd , Jonatat Carola , Zahlten Janine , Beermann Wiebke , van Laak Vincent , Opitz Bastian , Dietel Solveig , N'Guessan Philippe Dje , Hippenstiel Stefan , Suttorp Norbert , Seybold Joachim
Published: January 2006

Moraxella catarrhalis is a major cause of infectious exacerbations of chronic obstructive lung disease (COPD) and may also contribute to the pathogenesis of COPD. Little is known about M. catarrhalis-bronchial epithelium interaction. We investigated activation of M. catarrhalis infected bronchial epithelial cells and characterized the signal transduction pathways. Moreover, we tested the hypothesis that the M. catarrhalis-induced cytokine expression is regulated by acetylation of histone residues and controlled by histone deacetylase activity (HDAC). We demonstrated that M. catarrhalis induced a strong time- and dose-dependent inflammatory response in the bronchial epithelial cell line (BEAS-2B), characterized by the release of IL-8 and GM-CSF. For this cytokine liberation activation of the ERK and p38 mitogen-activated protein (MAP) kinases and transcription factor NF-κB was required. Furthermore, M. catarrhalis-infected bronchial epithelial cells showed an enhanced acetylation of histone H3 and H4 globally and at the promoter of the il8 gene. Preventing histone deacetylation by the histone deacetylase inhibitor trichostatin A augmented the M. catarrhalis-induced IL-8 response. After exposure to M. catarrhalis, we found a decrease in global histone deacetylase expression and activity. Our findings suggest that M. catarrhalis-induced activation of il8 gene transcription was caused by interference with epigenetic mechanisms regulating il8 gene accessibility. Our findings provide insight into important molecular and cellular mechanisms of M. catarrhalis-induced activation of human bronchial epithelium.
Effect of stretch on structural integrity and micromechanics of human alveolar epithelial cell monolayers exposed to thrombin
Authors: Trepat Xavier , Puig Ferranda , Gavara Nuria , Fredberg Jeffrey J. , Farre Ramon , Navajas Daniel
Published: January 2006

Alveolar epithelial cells in patients with acute lung injury subjected to mechanical ventilation are exposed to increased procoagulant activity and mechanical strain. Thrombin induces epithelial cell stiffening, contraction, and cytoskeletal remodeling, potentially compromising the balance of forces at the alveolar epithelium during cell stretching. This balance can be further compromised by the loss of integrity of cell-cell junctions in the injured epithelium. The aim of this work was to study the effect of stretch on the structural integrity and micromechanics of human alveolar epithelial cell monolayers exposed to thrombin. Confluent and subconfluent cells (A549) were cultured on collagen-coated elastic substrates. After exposure to thrombin (0.5 U/ml), a stepwise cell stretch (20%) was applied with a vacuum-driven system mounted on an inverted microscope. The structural integrity of the cell monolayers was assessed by comparing intercellular and intracellular strains within the monolayer. Strain was measured by tracking beads tightly bound to the cell surface. Simultaneously, cell viscoelasticity was measured using optical magnetic twisting cytometry. In confluent cells, thrombin did not induce significant changes in transmission of strain from the substrate to overlying cells. By contrast, thrombin dramatically impaired the ability of subconfluent cells to follow imposed substrate deformation. Upon substrate unstretching, thrombin-treated subconfluent cells exhibited compressive strain (9%). Stretch increased stiffness (56–62%) and decreased cell hysteresivity (13–22%) of vehicle cells. By contrast, stretch did not increase stiffness of thrombin-treated cells, suggesting disruption of cytoskeletal structures. Our findings suggest that thrombin could exacerbate epithelial barrier dysfunction in injured lungs subjected to mechanical ventilation.
Pneumocystis cariniiinfection sensitizes lung to radiation-induced injury after syngeneic marrow transplantation: role of CD4+T cells
Authors: Bruckner Lauren , Gigliotti Francis , Wright Terry , Harmsen Allen , Notter Robert H. , Chess Patricia , Wang Zhengdong , Finkelstein Jack
Published: January 2006

A murine model of bone marrow transplant (BMT)-related lung injury was developed to study how infection sensitizes lung to the damaging effects of total body irradiation (TBI) at infectious and TBI doses that individually do not cause injury. Mice infected with Pneumocystis carinii exhibited an asymptomatic, rapid, and transient influx of eosinophils and T cells in bronchoalveolar lavage fluid (BALF). In contrast, mice infected with P. carinii 7 days before receiving TBI and syngeneic BMT ( P. carinii/TBI mice) exhibited severe pulmonary dysfunction, surfactant aggregate depletion, and surfactant activity reductions at 17 days post-BMT. BALF from P. carinii/TBI mice contained a disproportionate initial influx of CD4+T cells (CD4+:CD8+ratio of 2.7) that correlated with progressive lung injury (from 8 to 17 days post-BMT). Levels of TNF-α in BALF were significantly increased in P. carinii/TBI mice compared with mice given either insult alone, with peak values found at 11 days post-BMT. In vivo depletion of CD4+T cells in P. carinii/TBI mice abrogated pulmonary dysfunction and reduced TNF-α levels in BALF, whereas depletion of CD8+T cells did not affect lung compliance or TNF-α. Lung injury was not attributable to direct P. carinii damage, since CD4-depleted P. carinii/TBI mice that exhibited no injury had higher average lung P. carinii burdens than either mice given P. carinii alone or undepleted P. carinii/TBI mice. Together, these results indicate that P. carinii infection can sensitize the lung to subsequent TBI-mediated lung injury via a process dependent on non-alloreactive CD4+T cells.
Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle
Authors: Yang Xiao-Ru , Lin Mo-Jun , McIntosh Lionel S. , Sham James S. K.
Published: January 2006

Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca2+transients ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 μM) and the TRPV4 agonist 4α-phorbol 12,13-didecanoate (1 μM) evoked significant increases in [Ca2+]iin PASMCs and ASMCs. These Ca2+responses were abolished in the absence of extracellular Ca2+or the presence of 300 μM Ni2+but were unaffected by 1 μM nifedipine, suggesting Ca2+influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca2+entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
Elevated Blood Pressure and Heart Rate in Human Renin Receptor Transgenic Rats
Authors: Burcklé Céline A. , Jan Danser A.H. , Müller Dominik N. , Garrelds Ingrid M. , Gasc Jean-Marie , Popova Elena , Plehm Ralph , Peters Jörg , Bader Michael , Nguyen Geneviève
Published: January 2006

Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8±5 versus 118.9±3.7 mm Hg;
P
=0.008), and an augmentation in heart rate (349.1±7.7 versus 303.1±16.16 bpm;
P
=0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428±64.9 versus 207.3±73.24 pg/mL in control;
P
=0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04±2.2 versus 2.8±0.55 in control;
P
=0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).
Payment for Quality: Guiding Principles and Recommendations
Authors: Bufalino Vincent , Peterson Eric D. , Burke Gregory L. , LaBresh Kenneth A. , Jones Daniel W. , Faxon David P. , Valadez Adolfo M. , Brass Lawrence M. , Fulwider Valere B. , Smith Renee , Krumholz Harlan M.
Published: January 2006

Payment-for-quality programs are emerging in the wake of rising healthcare costs and a demonstrated need for quality improvement in healthcare delivery in the United States. These programs, also known as “pay-for-performance” or “pay-for-value” programs, attempt to realign financial incentives with the quality of care delivered. The American Heart Association’s Reimbursement, Coverage, and Access Policy Development Workgroup provides in this statement a set of principles and recommendations for the development, implementation, and evaluation of these programs. The statement also suggests future areas for research around the realignment of financial incentives to improve both the quality of care delivered and patient outcomes.
Long-Term Adherence to Evidence-Based Secondary Prevention Therapies in Coronary Artery Disease
Authors: Newby L. Kristin , Allen LaPointe Nancy M. , Chen Anita Y. , Kramer Judith M. , Hammill Bradley G. , DeLong Elizabeth R. , Muhlbaier Lawrence H. , Califf Robert M.
Published: January 2006

Background—

Studies have examined the use of evidence-based therapies for coronary artery disease (CAD) in the short term and at hospital discharge, but few have evaluated long-term use.

Methods and Results—

Using the Duke Databank for Cardiovascular Disease for the years 1995 to 2002, we determined the annual prevalence and consistency of self-reported use of aspirin, β-blockers, lipid-lowering agents, and their combinations in all CAD patients and of angiotensin-converting enzyme inhibitors (ACEIs) in those with and without heart failure. Logistic-regression models identified characteristics associated with consistent use (reported on ≥2 consecutive follow-up surveys and then through death, withdrawal, or study end), and Cox proportional-hazards models explored the association of consistent use with mortality. Use of all agents and combinations thereof increased yearly. In 2002, 83% reported aspirin use; 61%, β-blocker use; 63%, lipid-lowering therapy use; 54%, aspirin and β-blocker use; and 39%, use of all 3. Consistent use was as follows: For aspirin, 71%; β-blockers, 46%; lipid-lowering therapy, 44%; aspirin and β-blockers, 36%; and all 3, 21%. Among patients without heart failure, 39% reported ACEI use in 2002; consistent use was 20%. Among heart failure patients, ACEI use was 51% in 2002 and consistent use, 39%. Except for ACEIs among patients without heart failure, consistent use was associated with lower adjusted mortality: Aspirin hazard ratio (HR), 0.58 and 95% confidence interval (CI), 0.54 to 0.62; β-blockers, HR, 0.63 and 95% CI, 0.59 to 0.67; lipid-lowering therapy, HR, 0.52 and 95% CI, 0.42 to 0.65; all 3, HR, 0.67 and 95% CI, 0.59 to 0.77; aspirin and β-blockers, HR, 0.61 and 95% CI, 0.57 to 0.65; and ACEIs among heart failure patients, HR, 0.75 and 95% CI, 0.67 to 0.84.

Conclusions—

Use of evidence-based therapies for CAD has improved but remains suboptimal. Although improved discharge prescription of these agents is needed, considerable attention must also be focused on understanding and improving long-term adherence.
Increased Peripheral Chemoreceptors Sensitivity and Exercise Ventilation in Heart Transplant Recipients
Authors: Ciarka Agnieszka , Cuylits Nicolas , Vachiery Jean-Luc , Lamotte Michel , Degaute Jean-Paul , Naeije Robert , van de Borne Philippe
Published: January 2006

Background—

Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea.

Methods and Results—

We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7±1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60±2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52±4 versus 34±3 bursts/min;
P
<0.01) and heart rates (83±3 versus 68±3 bpm;
P
<0.01) during room air breathing. The ventilatory response to hypoxia was higher in HTRs than in referent subjects (
P
<0.01, ANOVA). The increase in MSNA also was more marked during hypoxia in the HTRs than in the referent group (
P
<0.05, ANOVA). Responses to hyperoxic hypercapnia did not differ between the HTRs and the referent group. The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to CO
2
output, was steeper in HTRs than in referent subjects (38±2 versus 29±1 L/mm Hg;
P
<0.01). Exercise ventilation in HTRs was related to the ventilatory response to isocapnic hypoxia (
r
=0.57; n=16;
P
<0.05) and to the ventilatory response to hyperoxic hypercapnia (
r
=0.50; n=16;
P
<0.05).

Conclusions—

Peripheral chemoreceptor sensitivity is increased in HTRs and is related to exercise hyperpnea after heart transplantation.
MyD88 Signaling Controls Autoimmune Myocarditis Induction
Authors: Marty René R. , Dirnhofer Stephan , Mauermann Nora , Schweikert Sacha , Akira Shizuo , Hunziker Lukas , Penninger Josef M. , Eriksson Urs
Published: January 2006

Background—

Experimental autoimmune myocarditis (EAM) is a CD4
+
T-cell–mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known.

Methods and Results—

In contrast to control littermates, MyD88
−/−
mice were protected from myocarditis after immunization with α-myosin heavy chain–derived peptide (MyHC-α) and complete Freund’s adjuvant. Disease resistance of MyD88
−/−
mice resulted from impaired expansion of heart-specific CD4
+
T cells after immunization. Intrinsic defects of MyD88
−/−
CD4
+
T cells were excluded. In contrast, MyD88
−/−
but not MyD88
+/+
primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4
+
T cells. This defect mainly resulted from the inability of MyD88
−/−
DCs to release tumor necrosis factor-α. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-α–loaded MyD88
+/+
DCs that fully restored T-cell expansion and myocarditis in MyD88
−/−
mice.

Conclusions—

Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.
Integrated Electroanatomic Mapping With Three-Dimensional Computed Tomographic Images for Real-Time Guided Ablations
Authors: Dong Jun , Calkins Hugh , Solomon Stephen B. , Lai Shenghan , Dalal Darshan , Lardo Al , Brem Erez , Preiss Assaf , Berger Ronald D. , Halperin Henry , Dickfeld Timm
Published: January 2006

Background—

New ablation strategies for atrial fibrillation or nonidiopathic ventricular tachycardia are increasingly based on anatomic consideration and require the placement of ablation lesions at the correct anatomic locations. This study sought to evaluate the accuracy of the first clinically available image integration system for catheter ablation on 3-dimensional (3D) computed tomography (CT) images in real time.

Methods and Results—

After midline sternotomy, 2.3-mm CT fiducial markers were attached to the epicardial surface of each cardiac chamber in 9 mongrel dogs. Detailed 3D cardiac anatomy was reconstructed from contrast-enhanced, high-resolution CT images and registered to the electroanatomic maps of each cardiac chamber. To assess accuracy, targeted ablations were performed at each of the fiducial markers guided only by the reconstructed 3D images. At autopsy, the position error was 1.9±0.9 mm for the right atrium, 2.7±1.2 mm for the right ventricle, 1.8±1.0 mm for the left atrium, and 2.3±1.1 mm for the left ventricle. To evaluate the system’s guidance of more complex clinical ablation strategies, ablations of the cavotricuspid isthmus (n=4), fossa ovalis (n=4), and pulmonary veins (n=6) were performed, which resulted in position errors of 1.8±1.5, 2.2±1.3, and 2.1±1.2 mm, respectively. Retrospective analysis revealed that a combination of landmark registration and the target chamber surface registration resulted in <3 mm accuracy in all 4 cardiac chambers.

Conclusions—

Image integration with high-resolution 3D CT allows accurate placement of anatomically guided ablation lesions and can facilitate complex ablation strategies. This may provide significant advantages for anatomically based procedures such as ablation of atrial fibrillation and nonidiopathic ventricular tachycardia.
Balloon Atrial Septostomy Is Associated With Preoperative Stroke in Neonates With Transposition of the Great Arteries
Authors: McQuillen Patrick S. , Hamrick Shannon E.G. , Perez Marta J. , Barkovich A. James , Glidden David V. , Karl Tom R. , Teitel David , Miller Steven P.
Published: January 2006

Background—

Preoperative brain injury is common in neonates with transposition of the great arteries (TGA). The objective of this study is to determine risk factors for preoperative brain injury in neonates with TGA.

Methods and Results—

Twenty-nine term neonates with TGA were studied with MRI before cardiac surgery in a prospective cohort study. Twelve patients (41%) had brain injury on preoperative MRI, and all injuries were focal or multifocal. None of the patients had birth asphyxia. Nineteen patients (66%) required preoperative balloon atrial septostomy (BAS). All patients with brain injury had BAS (12 of 19; risk difference, 63%; 95% confidence interval, 41 to 85;
P
=0.001). As expected on the basis of the need for BAS, these neonates had lower systemic arterial hemoglobin saturation (Sa
o
2
) (
P
=0.05). The risk of injury was not modified by the cannulation site for septostomy (umbilical versus femoral,
P
=0.8) or by the presence of a central venous catheter (
P
=0.4).

Conclusions—

BAS is a major identifiable risk factor for preoperative focal brain injury in neonates with TGA. Imaging characteristics of identified brain injuries were consistent with embolism; however, the mechanism is more complex than site of vascular access for BAS or exposure to central venous catheters. These findings have implications for the indications for BAS, timing of surgical repair, and use of anticoagulation in TGA.
Altered Expression of Disintegrin Metalloproteinases and Their Inhibitor in Human Dilated Cardiomyopathy
Authors: Fedak Paul W.M. , Moravec Christine S. , McCarthy Patrick M. , Altamentova Svetlana M. , Wong Amy P. , Skrtic Marko , Verma Subodh , Weisel Richard D. , Li Ren-Ke
Published: January 2006

Background—

Disintegrin metalloproteinases (ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors (integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling.

Methods and Results—

Myocardium was obtained from patients with dilated cardiomyopathy (n=20), hypertrophic obstructive cardiomyopathy (n=5), and nonfailing donor hearts (n=7). Paired samples (n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors β1D and β3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin β1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin β1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin β1D expression. ADAM12 and integrin β1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy.

Conclusions—

Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.
Relation Between Hospital Specialization With Primary Percutaneous Coronary Intervention and Clinical Outcomes in ST-Segment Elevation Myocardial Infarction
Authors: Nallamothu Brahmajee K. , Wang Yongfei , Magid David J. , McNamara Robert L. , Herrin Jeph , Bradley Elizabeth H. , Bates Eric R. , Pollack Charles V. , Krumholz Harlan M.
Published: January 2006

Background—

Hospitals with primary percutaneous coronary intervention (PPCI) capability may choose to predominately offer PPCI to their patients with ST-segment elevation myocardial infarction (STEMI), or they may selectively offer PPCI or fibrinolytic therapy based on patient and hospital-level factors. Whether a greater level of hospital specialization with PPCI is associated with better quality of care is unknown.

Methods and Results—

We analyzed data from the National Registry of Myocardial Infarction-4 to compare in-hospital mortality and times to treatment in STEMI across different levels of hospital specialization with PPCI. We divided 463 hospitals into quartiles of PPCI specialization based on the relative proportion of reperfusion-treated patients who underwent PPCI (≤34.0%, >34.0 to 62.5%, >62.5 to 88.5%, >88.5%). Hierarchical multivariable regression assessed whether PPCI specialization was associated with better outcomes, after adjusting for patient and hospital characteristics, including PPCI volume. We found that greater PPCI specialization was associated with a lower relative risk of in-hospital mortality in patients treated with PPCI (adjusted relative risk comparing the highest and lowest quartiles, 0.64;
P
=0.006) but not in those treated with fibrinolytic therapy. Compared with patients at hospitals in the lowest quartile of PPCI specialization, adjusted door-to-balloon times in the highest quartile were significantly shorter (99.6 versus 118.3 minutes;
P
<0.001), and the likelihood of door-to-balloon times exceeding 90 minutes was significantly lower (relative risk, 0.78;
P
<0.001). Adjusting for PPCI specialization diminished the association between PPCI volume and clinical outcomes.

Conclusions—

Greater specialization with PPCI is associated with lower in-hospital mortality and shorter door-to-balloon times in STEMI patients treated with PPCI.
Impact of Prosthesis-Patient Mismatch on Cardiac Events and Midterm Mortality After Aortic Valve Replacement in Patients With Pure Aortic Stenosis
Authors: Tasca Giordano , Mhagna Zen , Perotti Silvano , Centurini Pietro Berra , Sabatini Tony , Amaducci Andrea , Brunelli Federico , Cirillo Marco , Tomba Margherita Dalla , Quiani Eugenio , Troise Giovanni , Pibarot Philippe
Published: January 2006

Background—

Prosthesis-patient mismatch (PPM) occurs when the effective orifice area (EOA) of the prosthesis being implanted is too small in relation to body size, thus causing abnormally high transvalvular pressure gradients. The objective of this study was to examine the midterm impact of PPM on overall mortality and cardiac events after aortic valve replacement in patients with pure aortic stenosis.

Methods and Results—

The indexed EOA (EOAi) was estimated for each type and size of prosthesis being implanted in 315 consecutive patients with pure aortic stenosis. PPM was defined as an EOAi ≤0.80 cm
2
/m
2
and was correlated with overall mortality and cardiac events. PPM was present in 47% of patients. The 5-year overall survival and cardiac event-free survival were 82±3% and 75±4%, respectively, in patients with PPM compared with 93±3% and 87±4% in patients with no PPM (
P
≤0.01). In multivariate analysis, PPM was associated with a 4.2-fold (95% CI, 1.6 to 11.3) increase in the risk of overall mortality and 3.2-fold (95% CI, 1.5 to 6.8) increase in the risk of cardiac events. The other independent risk factors were history of heart failure, NHYA class III-IV, severe left ventricular hypertrophy, and absence of normal sinus rhythm before operation.

Conclusions—

PPM is an independent predictor of cardiac events and midterm mortality in patients with pure aortic stenosis undergoing aortic valve replacement. As opposed to other risk factors, PPM may be avoided or its severity may be reduced with the use of a preventive strategy at the time of operation.
Intact Recollection Memory in High-performing Older Adults: ERP and Behavioral Evidence
Authors: Duarte Audrey , Ranganath Charan , Trujillo Celina , Knight Robert T.
Published: January 2006

Numerous behavioral studies have suggested that normal aging has deleterious effects on episodic memory and that recollection is disproportionately impaired relative to familiarity-based recognition. However, there is a wide degree of variability in memory performance within the aging population and this generalization may not apply to all elderly adults. Here we investigated these issues by using event-related potentials (ERPs) to measure the effects of aging on the neural correlates of recollection and familiarity in older adults with recognition memory performance that was equivalent to (old-high) or lower than (old-low) that of young adults. Results showed that, behaviorally, old-high subjects exhibited intact recollection but reduced familiarity, whereas old-low subjects had impairments in both recollection and familiarity, relative to the young. Consistent with behavioral results, old-high subjects exhibited ERP correlates of recollection that were topographically similar to those observed in young subjects. However, unlike the young adults, old-high subjects did not demonstrate any neural correlates of familiarity-based recognition. In contrast to the old-high group, the old-low group exhibited neural correlates of recollection that were topographically distinct from those of the young. Our results suggest that the effects of aging on the underlying brain processes related to recollection and familiarity are dependent on individual memory performance and highlight the importance of examining performance variability in normal aging.
Access to Lexical Information in Language Comprehension: Semantics before Syntax
Authors: Müller Oliver , Hagoort Peter
Published: January 2006

The recognition of a word makes available its semantic and syntactic properties. Using electrophysiological recordings, we investigated whether one set of these properties is available earlier than the other set. Dutch participants saw nouns on a computer screen and performed push-button responses: In one task, grammatical gender determined response hand (left/right) and semantic category determined response execution (go/no-go). In the other task, response hand depended on semantic category, whereas response execution depended on gender. During the latter task, response preparation occurred on no-go trials, as measured by the lateralized readiness potential: Semantic information was used for response preparation before gender information inhibited this process. Furthermore, an inhibition-related N2 effect occurred earlier for inhibition by semantics than for inhibition by gender. In summary, electrophysiological measures of both response preparation and inhibition indicated that the semantic word property was available earlier than the syntactic word property when participants read single words.
The Representation of Polysemy: MEG Evidence
Authors: Pylkkänen Liina , Llinás Rodolfo , Murphy Gregory L.
Published: January 2006

Most words in natural language are polysemous, that is, they can be used in more than one way. For example, paper can be used to refer to a substance made out of wood pulp or to a daily publication printed on that substance. Although virtually every sentence contains polysemy, there is little agreement as to how polysemy is represented in the mental lexicon. Do different uses of polysemous words involve access to a single representation or do our minds store distinct representations for each different sense? Here we investigated priming between senses with a combination of behavioral and magnetoencephalographic measures in order to test whether different senses of the same word involve identity or mere formal and semantic similarity. Our results show that polysemy effects are clearly distinct from similarity effects bilaterally. In the left hemisphere, sense-relatedness elicited shorter latencies of the M350 source, which has been hypothesized to index lexical activation. Concurrent activity in the right hemisphere, on the other hand, peaked later for sense-related than for unrelated target stimuli, suggesting competition between related senses. The obtained pattern of results supports models in which the representation of polysemy involves both representational identity and difference: Related senses connect to same abstract lexical representation, but are distinctly listed within that representation.
Effects of Attention on Neuroelectric Correlates of Auditory Stream Segregation
Authors: Snyder Joel S. , Alain Claude , Picton Terence W.
Published: January 2006

A general assumption underlying auditory scene analysis is that the initial grouping of acoustic elements is independent of attention. The effects of attention on auditory stream segregation were investigated by recording event-related potentials (ERPs) while participants either attended to sound stimuli and indicated whether they heard one or two streams or watched a muted movie. The stimuli were pure-tone ABA-patterns that repeated for 10.8 sec with a stimulus onset asynchrony between A and B tones of 100 msec in which the A tone was fixed at 500 Hz, the B tone could be 500, 625, 750, or 1000 Hz, and was a silence. In both listening conditions, an enhancement of the auditory-evoked response (P1-N1-P2 and N1c) to the B tone varied with f and correlated with perception of streaming. The ERP from 150 to 250 msec after the beginning of the repeating ABA-patterns became more positive during the course of the trial and was diminished when participants ignored the tones, consistent with behavioral studies indicating that streaming takes several seconds to build up. The N1c enhancement and the buildup over time were larger at right than left temporal electrodes, suggesting a right-hemisphere dominance for stream segregation. Sources in Heschl's gyrus accounted for the ERP modulations related to f-based segregation and buildup. These findings provide evidence for two cortical mechanisms of streaming: automatic segregation of sounds and attention-dependent buildup process that integrates successive tones within streams over several seconds.
Effect of Language Switching on Arithmetic: A Bilingual fMRI Study
Authors: Venkatraman Vinod , Siong Soon Chun , Chee Michael W. L. , Ansari Daniel
Published: January 2006

The role of language in performing numerical computations has been a topic of special interest in cognition. The “Triple Code Model” proposes the existence of a language-dependent verbal code involved in retrieving arithmetic facts related to addition and multiplication, and a language-independent analog magnitude code subserving tasks such as number comparison and estimation. Neuroimaging studies have shown dissociation between dependence of arithmetic computations involving exact and approximate processing on language-related circuits. However, a direct manipulation of language using different arithmetic tasks is necessary to assess the role of language in forming arithmetic representations and in solving problems in different languages. In the present study, 20 English-Chinese bilinguals were trained in two unfamiliar arithmetic tasks in one language and scanned using fMRI on the same problems in both languages (English and Chinese). For the exact “base-7 addition” task, language switching effects were found in the left inferior frontal gyrus (LIFG) and left inferior parietal lobule extending to the angular gyrus. In the approximate “percentage estimation” task, language switching effects were found predominantly in the bilateral posterior intraparietal sulcus and LIFG, slightly dorsal to the LIFG activation seen for the base-7 addition task. These results considerably strengthen the notion that exact processing relies on verbal and language-related networks, whereas approximate processing engages parietal circuits typically involved in magnitude-related processing.
Automatic Drive of Limb Motor Plasticity
Authors: Magescas F. , Prablanc C.
Published: January 2006

The ability to perform accurate limb movements may require learning mechanisms that continually tune the motor system. In the current study, we isolate a form of pure limb motor plasticity. Participants reached to targets that were turned off just after the onset of an initial eye movement, reappearing at a new location at the end of the reaching movement. In contrast to classical prism or virtual reality paradigms, our task eliminated sensory adaptation by always maintaining a congruency between the seen and felt limb position. We also minimized awareness and potential adaptation processes on the basis of volitional strategies by progressively increasing the size of the target perturbations. In this manner, our adaptation procedure mimicked conditions used to study saccadic adaptation. The results indicated that adaptation under these conditions led to a robust after-effect that generalized to a large range of movements within the workspace. This fully natural, nonim-posed generalization of adaptation is not expressed in a spatial coordinate system, but more likely in a joint-centered coordinate space.
An Onset Advantage without a Preview Benefit: Neuropsychological Evidence Separating Onset and Preview Effects in Search
Authors: Humphreys Glyn W. , Olivers Christian N. L. , Yoon Eun Young
Published: January 2006

Visual search is facilitated if half the distractors are presented as a preview prior to the presentation of the target and second set of distractors-the preview benefit [Watson, D. G., & Humphreys, G. W. Visual marking: Prioritizing selection for new objects by top-down attentional inhibition of old objects. Psychological Review, 104, 90-122, 1997]. On one account, the preview advantage is due to automatic capture of attention by the onsets in the second, search display [Donk, M., & Theeuwes, J. Visual marking beside the mark: Prioritizing selection by abrupt onsets. Perception & Psychophysics, 93, 891-900, 2001]. We provide a neuropsychological test of this assertion. We examined onset capture and preview benefits in search in a group of neuropsychological patients with unilateral parietal damage. We demonstrate a normal pattern of performance when patients detected targets defined by onsets relative to those defined by offsets, irrespective of whether the onset target fell contra-or ipsilateral to the lesion. In contrast, there was a normal preview benefit in search only for ipsilesional targets, and preview search was impaired in the contralesional field. The data demonstrate that the preview benefit can dissociate from the onset advantage in search, and that onsets remain strongly weighted for attention even in the contralesional field of patients with parietal lesions.