bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice
Authors: Belcher John D. , Mahaseth Hemchandra , Welch Thomas E. , Vilback Asa E. , Sonbol Khalid M. , Kalambur Venkatasubramaniam S. , Bowlin Paul R. , Bischof John C. , Hebbel Robert P. , Vercellotti Gregory M.
Published: January 2005

Activation of vascular endothelium plays an essential role in vasoocclusion in sickle cell disease. The anti-inflammatory agents dexamethasone and adhesion molecule-blocking antibodies were used to inhibit endothelial cell activation and hypoxia-induced vasoocclusion. Transgenic sickle mice, expressing human α-, βS-, and βS-Antilles-globins, had an activated vascular endothelium in their liver, lungs, and skin, as exhibited by increased activation of NF-κB compared with normal mice. NF-κB activation increased further in the liver and skin after sickle mice were exposed to hypoxia. Sickle mice had decreases in red blood cell (RBC) velocities and developed vasoocclusions in subcutaneous venules in response to hypoxia. Dexamethasone pretreatment prevented decreases in RBC velocities and inhibited vasoocclusions and leukocyte-endothelium interactions in venules after hypoxia. Dexamethasone treatment inhibited NF-κB, VCAM-1, and ICAM-1 expression in the liver, lungs, and skin of sickle mice after hypoxia-reoxygenation. VCAM-1 or ICAM-1 blockade with monoclonal antibodies mimicked dexamethasone by inhibiting vasoocclusion and leukocyte adhesion in sickle mice, demonstrating that endothelial cell activation and VCAM-1 and ICAM-1 expression are necessary for hypoxia-induced vasoocclusion in sickle mice. VCAM-1, ICAM-1, and vasoocclusion increased significantly 3 days after dexamethasone discontinuation, possibly explaining rebounds in vasoocclusive crises observed after withdrawal of glucocorticosteroids in sickle patients. We conclude that anti-inflammatory treatments that inhibit endothelial cell activation and adhesion molecule expression can inhibit vasoocclusion in sickle cell disease. Rebounds in vasoocclusive crises after dexamethasone withdrawal are caused by rebounds in endothelial cell activation.
Impaired resting perfusion in viable myocardium distal to chronic coronary stenosis in rats
Authors: Waller Christiane , Engelhorn Tobias , Hiller Karl-Heinz , Heusch Gerd , Ertl Georg , Bauer Wolfgang Rudolf , Schulz Rainer
Published: January 2005

Chronic coronary artery stenosis results in patchy necrosis in the dependent myocardium and impairs global and regional left ventricular (LV) function in rats in vivo. The aim of the present study was to compare regional myocardial blood flow (RMBF) and function (F) in poststenotic myocardium by using magnetic resonance imaging (MRI) and to compare MRI blood flow changes to histological alterations to assess whether RMBF in the viable poststenotic tissue remains normal. MRI was performed in 11 anesthetized Wistar rats with 2-wk stenosis of the left coronary artery. Postmortem, the extent of fibrotic tissue was quantified. Poststenotic RMBF was significantly reduced to 2.21 ± 0.30 ml·g−1·min−1 compared with RMBF in the remote myocardium (4.05 ± 0.50 ml·g−1·min−1). A significant relationship between the poststenotic RMBF (%remote area) and the poststenotic F (%remote myocardium) was calculated ( r = 0.61, P < 0.05). Assuming perfusion in scar tissue to be 32 ± 5% of perfusion of remote myocardium, as measured in five additional rats, and that in remote myocardium to be 114 ± 25% of that in normal myocardium, as assessed in five sham rats, the calculated perfusion in partially fibrotic tissue samples (35.7 ± 5.2% of analyzed area) was 2.88 ± 0.18 ml·g−1·min−1, whereas measured MRI perfusion was only 1.86 ± 0.24 ml·g−1·min−1 ( P < 0.05). These results indicate that resting perfusion in viable poststenotic myocardium is moderately reduced. Alterations in global and regional LV function are therefore secondary to both patchy fibrosis and reduced resting perfusion.
Platelet-activating factor increases endothelial [Ca2+]iand NO production in individually perfused intact microvessels
Authors: Zhu Longkun , He Pingnian
Published: January 2005

We have demonstrated that inhibition of NO synthase (NOS) in endothelial cells by either the NOS inhibitor Nω-monomethyl-l-arginine (l-NMMA) or the internalization of caveolin-1 scaffolding domain attenuated platelet-activating factor (PAF)-induced increases in microvessel permeability ( Am J Physiol Heart Circ Physiol 286: H195–H201, 2004) indicating the involvement of an NO-dependent signaling pathway. To investigate whether an increase in endothelial cytoplasmic Ca2+concentration ([Ca2+]i) is the initiating event and Ca2+-dependent NO production is crucial for permeability increases, PAF (10 nM)-induced changes in endothelial [Ca2+]iand NO production were measured in individually perfused rat mesenteric venular microvessels via fluorescence microscopy. When venular microvessels were exposed to PAF, endothelial [Ca2+]iincreased from 69 ± 8 nM to a peak value of 374 ± 26 nM within 3 min and then declined to a sustained level at 190 ± 12 nM after 15 min. Inhibition of NOS did not modify PAF-induced increases in endothelial [Ca2+]i. PAF-induced NO production was visualized and quantified at cellular levels in individually perfused microvessels using 4,5-diaminofluorescein diacetate and fluorescence imaging. Increased fluorescence intensity (FI), which is an indication of increased NO production, occurred in 75 ± 7% of endothelial cells in each vessel. The mean maximum FI increase was 140 ± 7% of baseline value. This increased FI was abolished by pretreatment of the vessel with l-NMMA and attenuated in the absence of extracellular Ca2+. These results provide direct evidence from intact microvessels that increased endothelial [Ca2+]iis the initial signal that activates endothelial NOS, and the subsequent increased NO production contributes to PAF-induced increases in microvessel permeability.
CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice
Authors: Zhang Chunlian , Xu Zhelong , He Xiao-Rui , Michael Lloyd H. , Patterson Cam
Published: January 2005

Limitation of damage after ischemia and reperfusion injury to the myocardium remains an elusive clinical goal. Previous studies have suggested that molecular chaperones, which include members of the heat shock protein (Hsp) family, may have cardioprotective effects, although the protective role of endogenous chaperones has not been well documented. CHIP (carboxyl terminus of Hsp70-interacting protein) is a cochaperone/ubiquitin ligase that integrates the response to stress at multiple levels. We tested the response of CHIP(−/−) mice to in vivo ischemia and reperfusion injury induced by left anterior descending coronary artery ligation. Compared with wild-type littermates, CHIP(−/−) mice had decreased survival and increased incidence of arrhythmias during reperfusion. The size of myocardial infarction, as assessed by the ratio of infarct area to area at risk, was 50% greater in CHIP(−/−) mice. Increased infarct size was accompanied by impaired upregulation of the chaperone Hsp70 after ischemia-reperfusion injury. In situ analysis also indicated that hearts of CHIP(−/−) mice were more prone to develop apoptosis in cardiomyocytes and especially endothelial cells of intramural vessels. Previous studies have found that CHIP plays a central role in maintaining protein quality control and coordinating the response to stress. The present data indicate that these functions of CHIP provide a critical cardioprotective effect in the setting of ischemia-reperfusion injury due in part to increased apoptosis in cardiac cells. Quality control mechanisms therefore may be underappreciated clinical targets for maximizing myocardial protection after injury.
Chronic nicotine in hearts with healed ventricular myocardial infarction promotes atrial flutter that resembles typical human atrial flutter
Authors: Miyauchi Mizuho , Qu Zhilin , Miyauchi Yasushi , Zhou Sheng-Mei , Pak Hui , Mandel William J. , Fishbein Michael C. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: January 2005

The potential of chronic nicotine exposure for atrial fibrillation (AF) and atrial flutter (AFL) in hearts with and without chronic myocardial infarction (MI) remains poorly explored. MI was created in dogs by permanent occlusion of the left anterior descending coronary artery, and dogs were administered nicotine (5 mg·kg−1·day−1 sc) for 1 mo using osmotic minipumps. High-resolution epicardial (1,792 bipolar electrodes) and endocardial Halo catheters were used to map activation during induced atrial rhythms. Nicotine promoted inducible sustained AFL at a mean cycle length of 134 ± 10 ms in all MI dogs ( n = 6) requiring pacing and electrical shocks for termination. No AFL could be induced in MI dogs ( n = 6), control (non-MI) dogs ( n = 3) not exposed to nicotine, and dogs with no MI and exposed to nicotine ( n = 3). Activation maps during AFL showed a single reentrant wavefront in the right atrium that rotated either clockwise (60%) or counterclockwise (40%) around the crista terminalis and through the isthmus. Ablation of the isthmus prevented the induction of AFL. Nicotine caused a significant ( P < 0.01) but highly heterogeneous increase in atrial interstitial fibrosis (2- to 10-fold increase in left and right atria, respectively) in the MI group but only a 2-fold increase in the right atrium in the non-MI group. Nicotine also flattened ( P < 0.05) the slope of the epicardial monophasic action potential duration (electrical restitution) curve of both atria in the MI but not in non-MI dogs. Two-dimensional simulation in an excitable matrix containing an isthmus and nicotine's restitutional and reduced gap junctional coupling (fibrosis) parameters replicated the experiments. Chronic nicotine in hearts with MI promotes AFL that closely resembles typical human AFL. Increased atrial interstitial fibrosis and flattened electrical restitution are important substrates for the AFL.
α1-Adrenoceptor-mediated phosphorylation of MYPT-1 and CPI-17 in the uterine artery: role of ERK/PKC
Authors: Xiao DaLiao , Longo Lawrence D. , Zhang Lubo
Published: January 2005

We previously demonstrated that ERK/PKC signaling pathways play a key role in regulation of Ca2+sensitivity and contractility of the uterine artery. The present study tested the hypothesis that ERK and PKC differentially regulated myosin light chain phosphatase activity by phosphorylation of myosin phosphatase target protein-1 (MYPT-1) and CPI-17. Agonist-induced contractions and phosphorylation of MYPT-1/Thr696, MYPT-1/Thr850, and CPI-17/Thr38were measured simultaneously in the same tissues of isolated near-term pregnant ovine uterine arteries. Phenylephrine produced time-dependent concurrent increases in the phosphorylation of ERK44/42and MYPT-1/Thr850that preceded contractions. In addition, phenylephrine induced phosphorylation of CPI-17/Thr38that was concurrent with the contractions. In contrast, phenylephrine did not induce phosphorylation of MYPT-1/Thr696in the uterine artery. PD-098059 inhibited phosphorylation of ERK44/42and the initial peak phosphorylation of MYPT-1/Thr850but did not affect CPI-17/Thr38phosphorylation. Activation of PKC by phorbol 12,13-dibutyrate induced a time-dependent phosphorylation of CPI-17/Thr38that preceded contractions of the uterine artery. In addition, phorbol 12,13-dibutyrate activated PKC-α and induced a coimmunoprecipitation of PKC-α with caldesmon. The results suggest that phosphorylation of MYPT-1/Thr850and CPI-17/Thr38play important roles in regulation of agonist-mediated Ca2+sensitivity in the uterine artery, in part by ERK and PKC, respectively. In addition, phosphorylated CPI-17 may regulate Ca2+sensitivity by interacting with caldesmon and reversing its inhibitory effect on myosin ATPase.
Mechanism of potentiation by polyphenols of contraction in human vein-engineered media
Authors: Diebolt M. , Germain L. , Auger F. A. , Andriantsitohaina R.
Published: January 2005

The potential of natural dietary polyphenols in the treatment of vascular diseases originating from veins has been suggested in the literature. However, the mechanisms involved to explain the effects of polyphenols are not yet elucidated. Therefore, the aim of this study was to investigate the mechanisms by which polyphenols from red wine (Provinols) modulated contraction in human veins. We took advantage of a human model previously reported as a new tool for pharmacological research, using tissue-engineered techniques allowing the production of vascular media based exclusively on human smooth muscle cells. Thus human tissue-engineered vascular media (TEVM) were produced with cells originating from umbilical cord vein. TEVM were treated with either vehicle or Provinols. Results showed that treatment of TEVM with Provinols significantly potentiated the contractile responses induced by histamine and bradykinin. The potentiating effect of Provinols was not associated with an enhancement of histamine-induced increase in cytosolic calcium; rather, it implied the presence of a Ca2+-independent signaling pathway. Pharmacological studies indicated that action of Provinols took place at the level of phospholipase A2-Rho-kinase pathway and was associated with an enhancement of myosin light chain kinase activity. These results, obtained using the human TEVM, bring new insights to explain the regulation of venous contraction by polyphenols.
Potential candidates for ischemic preconditioning-associated vascular growth pathways revealed by antibody array
Authors: Mathur Praveer , Kaga Shigeaki , Zhan Lijun , Das Dipak K. , Maulik Nilanjana
Published: January 2005

Our understanding of the phenomenon of myocardial vascular growth is very limited even though various studies have been conducted in several different models, because the focus in each has been on a select very few number of proteins as the possible growth factors. In the present study, we used the ischemic preconditioning (IP) model in the form of four in vivo repetitive cycles of coronary artery occlusion, each followed by reperfusion as the model to stimulate vascular growth, and performed the protein profiling using high-throughput antibody array technology. Rats were divided into two groups: control + left anterior descending coronary artery (LAD) occlusion (CMI), and IP+ LAD occlusion (IPMI). The antibody array experiment performed to compare the expression of 512 proteins between the IPMI and CMI samples revealed significant upregulation of growth proteins like TGF-β, BMX, granulocyte-monocyte colony-stimulating factor, signal transducer and activator of transcription 3, α- and β-catenins, ubiquitin-conjugating enzyme UbcH6, nexilin, and PKC-ε and -λ. JNK1 and c-Src tyrosine kinase were expectedly found to be downregulated. Western blot experiments validated the changes in expression of these proteins. Therefore, this study puts forward the above-mentioned proteins as valid participants in the vascular growth signals that are known to be triggered by ischemic preconditioning of heart.
Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis
Authors: O'Reilly Katherine M. A. , Phipps Richard P. , Thatcher Thomas H. , Graf Beth A. , Van Kirk John , Sime Patricia J.
Published: January 2005

Inhalation of crystalline (CS) and amorphous silica (AS) results in human pulmonary inflammation. However, silicosis develops only following CS exposure, and the pathogenic mechanisms are poorly understood. This report describes the differential abilities of CS and AS to directly upregulate the early inflammatory mediator COX-2, the recently identified prostaglandin E (PGE) synthase and the downstream mediator PGE2in primary human lung fibroblasts. Increased cyclooxygenase (COX)-2 gene transcription and protein production were demonstrated by ribonuclease protection assay, Western blot analysis, and immunocytochemistry. In each case the ability of AS to induce COX-2 exceeded that of CS. Similarly, downstream of COX-2, production of the antifibrotic prostaglandin PGE2was induced in a dose-dependent fashion, but AS was significantly more potent (maximal production: CS = 4,710 pg/ml and AS = 7,651 pg/ml). These increases in COX-2 and PGE2were preceded by induction of the PGE2synthase protein, demonstrating the potential role of this novel molecule in silica-mediated inflammation. There was specificity of induction of prostaglandins, as PGF2α, but not PGD2, was induced. Using specific COX-2 inhibitors, we showed increased PG production to be dependent on the COX-2 enzyme. Furthermore, stimulation of fibroblasts was particle specific, as silica but not carbon black resulted in fibroblast activation. These results demonstrate that silica can directly stimulate human lung fibroblasts to produce key inflammatory enzymes and prostaglandins. Moreover, they suggest a mechanism to explain the differing fibrogenic potential of CS and AS. The molecules COX-2, PGE synthase, and PGE2are identified as effectors in silicosis.
Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL-1β
Authors: Faffe Débora S. , Flynt Lesley , Mellema Matthew , Whitehead Timothy R. , Bourgeois Kerri , Panettieri Reynold A. , Silverman Eric S. , Shore Stephanie A.
Published: January 2005

Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release, and IL-1β enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1β had no effect. IL-1β did not augment the effects of OSM on VEGF promoter activity but did augment OSM-induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM-induced VEGF release and synergy between OSM and IL-1β, without affecting responses to IL-1β alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1β-induced VEGF release. OSM increased type 1 IL-1 receptor (IL-1R1) mRNA expression, as measured by real-time PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1β-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1β also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1β on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airway disease.
Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury
Authors: Jacobson Jeffrey R. , Barnard Joseph W. , Grigoryev Dmitry N. , Ma Shwu-Fan , Tuder Rubin M. , Garcia Joe G. N.
Published: January 2005

Therapies to limit the life-threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 μg/g body wt). Inflammatory indexes [bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 h with histological confirmation] were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/kg; ∼35–60% reduction). Simvastatin also decreased BAL albumin (∼50% reduction) and Evans blue albumin dye extravasation into lung tissue (100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies (e.g., inflammation and immune response, NF-κB regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI.
Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery
Authors: Wang Jian , Weigand Letitia , Wang Wenqian , Sylvester J. T. , Shimoda Larissa A.
Published: January 2005

In pulmonary arterial smooth muscle cells (PASMCs), voltage-gated K+ (Kv) channels play an important role in regulating membrane potential, cytoplasmic free Ca2+ concentration, and pulmonary vasomotor tone. Previous studies demonstrated that exposure of rats to chronic hypoxia decreased Kv channel function in PASMCs from distal pulmonary arteries (dPA). To determine whether this decrease in function was due to decreased expression of Kv channel proteins and which Kv proteins might be involved, we analyzed Kv channel gene expression in intact, endothelium-denuded dPAs obtained from rats exposed to 10% O2 for 3 wk. Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.1, Kv4.3, and Kv9.3 channel α-subunits and Kv1, Kv2, and Kv3 β-subunits were expressed in rat dPAs. Exposure to chronic hypoxia decreased mRNA and protein levels of Kv1.1, Kv1.5, Kv1.6, Kv2.1, and Kv4.3 α-subunits in dPAs but did not alter gene or protein expression of these channels in aorta. Furthermore, chronic hypoxia did not alter the mRNA levels of β-subunits in dPAs. These results suggest that diminished transcription of Kv α-subunits may reduce the number of functional Kv channels in dPAs during prolonged hypoxia, causing the decreased Kv current previously observed in PASMCs and leading to pulmonary artery vasoconstriction.
Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry
Authors: Wang Jian , Shimoda Larissa A. , Weigand Letitia , Wang Wenqian , Sun Dejun , Sylvester J. T.
Published: January 2005

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca2+ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca2+-sensitive dye fura-2 to measure effects of 4% O2 on intracellular [Ca2+] ([Ca2+]i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca2+-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca2+ stores in sarcoplasmic reticulum and nifedipine to prevent Ca2+ entry through L-type voltage-operated Ca2+ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca2+]i caused by restoration of extracellular [Ca2+] and the rate at which extracellular Mn2+ quenched fura-2 fluorescence. These effects, as well as the increased [Ca2+]i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl2, and LaCl3 at concentrations that inhibited CCE >80% but did not alter [Ca2+]i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca2+]i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca2+]i caused by hypoxia was completely reversed by perfusion with Ca2+-free KRBS. LaCl3 increased basal [Ca2+]i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca2+]i. SOCCs and CCE may play important roles in HPV.
Level of β-Adrenergic Receptor Kinase 1 Inhibition Determines Degree of Cardiac Dysfunction After Chronic Pressure Overload–Induced Heart Failure
Authors: Tachibana Hideo , Naga Prasad Sathyamangla V. , Lefkowitz Robert J. , Koch Walter J. , Rockman Howard A.
Published: January 2005

Background—

Heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased level of myocardial βAR kinase 1 (βARK1). Our previous studies have shown that inhibition of βARK1 with the use of the Gβγ sequestering peptide of βARK1 (βARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of βARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of βARK1 inhibition correlates with the degree of heart failure.

Methods and Results—

Transgenic (TG) mice with varying degrees of cardiac-specific expression of βARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial βARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of βARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low βARKct expression developed severe heart failure, whereas mice with high βARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of βARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal βAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in βAR function, similar to the WT mice.

Conclusions—

These data show that the level of βARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when βARK1 inhibition is considered as a molecular target.
Differential Regulation of Vascular Focal Adhesion Kinase by Steady Stretch and Pulsatility
Authors: Lehoux Stéphanie , Esposito Bruno , Merval Régine , Tedgui Alain
Published: January 2005

Background—

In vivo tensile strain in arteries comprises 2 components: steady stretch and pulsatile stretch. However, little attention has been paid to the differential transduction of these stimuli in whole vessels.

Methods and Results—

Using rabbit aortas maintained in organ culture for 24 hours, we found that focal adhesion kinase (FAK) was strongly activated by high intraluminal pressure (150 mm Hg), as evidenced by increased phosphorylation (
P
<0.01) of tyrosine residues Tyr-397 (3.06±0.17-fold), Tyr-407 (3.71±0.65-fold), Tyr-861 (1.92±0.33-fold), and Tyr-925 (2.41±0.39-fold), compared with 80 mm Hg controls. Immunohistochemistry showed positive staining for these phosphotyrosines in the endothelium and innermost smooth muscle cell layers. Total FAK phosphorylation was reduced in vessels at 150 mm Hg by treatment with the Src family kinase inhibitor PP2 or with the integrin–extracellular matrix interaction–blocking RGD peptide, attaining 1.75±0.22-fold and 2.00±0.19-fold, respectively (
P
<0.05), compared with 3.07±0.38-fold (
P
<0.001) in untreated vessels. PP2 prevented phosphorylation of Tyr-407 and Tyr-925, whereas RGD peptide abolished phosphorylation of Tyr-397 and Tyr-407. PP2 and RGD peptide also inhibited high pressure–induced binding of FAK with the effector Grb2 and blocked activation of extracellular regulated kinase (ERK) 1/2 in vessels at 150 mm Hg. In contrast, 10% cyclic stretch in aortas did not induce significant FAK phosphorylation relative to nonpulsatile controls. Furthermore, although ERK1/2 was activated in vessels exposed to pulsatility, it was not blocked by PP2 or RGD peptide treatment.

Conclusions—

Our results demonstrate that (1) steady and cyclic modes of stretch are transduced differently in the aorta, the former implicating FAK, the latter not, and (2) Src and integrins are involved in steady pressure–induced FAK.
Dipyridamole Selectively Inhibits Inflammatory Gene Expression in Platelet–Monocyte Aggregates
Authors: Weyrich Andrew S. , Denis Melvin M. , Kuhlmann-Eyre Jennifer R. , Spencer Eliott D. , Dixon Dan A. , Marathe Gopal K. , McIntyre Tom M. , Zimmerman Guy A. , Prescott Stephen M.
Published: January 2005

Background—

Drugs that simultaneously decrease platelet function and inflammation may improve the treatment of cardiovascular disorders. Here, we determined whether dipyridamole and aspirin, a combination therapy used to prevent recurrent stroke, regulates gene expression in platelet–monocyte inflammatory model systems.

Methods and Results—

Human platelets and monocytes were pretreated with dipyridamole, aspirin, or both inhibitors. The cells were stimulated with thrombin or activated by adhesion to collagen, and gene expression was measured in the target monocytes. Thrombin-stimulated platelets increased monocyte chemotactic protein-1 (MCP-1) expression by monocytes. Dipyridamole but not aspirin attenuated nuclear translocation of NF-κB and blocked the synthesis of MCP-1 at the transcriptional level. Dipyridamole delayed maximal synthesis of interleukin-8 but did not alter cyclooxygenase-2 accumulation. Adherence to collagen and platelets also increased the expression of matrix metalloproteinase-9 (MMP-9) in monocytes, a response that was inhibited by dipyridamole. In this case, however, dipyridamole did not block transcription or distribution of MMP-9 mRNA to actively translating polysomes, indicating that it regulates the expression of MMP-9 protein at a postinitiation stage of translation. Dipyridamole also blocked MCP-1 and MMP-9 generated by lipopolysaccharide-treated monocytes, indicating that at least part of its inhibitory action is unrelated to its antiplatelet properties.

Conclusions—

These results indicate that dipyridamole has selective antiinflammatory properties that may contribute to its actions in the secondary prevention of stroke.
Religious Minorities and Their Rights: A Problem of Approach
Authors: Geoff
Published: January 2005

This article examines the nature of religious minorities and the rights and guarantees accorded to them by public international law generally and, more specifically, international human rights law, particularly since 1945. It is not, though, simply a review of rights pertaining to the group's religious identity, for a difference in religion may reflect the group's sense of national identity. To that end, the rights of religio-nationalist minorities generally are examined: it includes case studies of the ICCPR, the OSCE, the ECHR, the Framework Convention for the Protection of National Minorities, 1995, and the Anglo-Irish Frameworks for the Future. The conclusion, moreover, moves on to consider how international law might best treat religious minorities in order to meet the varied needs of all the parties, that is, the group, the State, the individual members of the minority and majority populations and the international community. It also considers how far law alone can satisfy those varied needs.
One Theme in Two Variations - Self Determination for Minorities And Indigenous Peoples
Authors: Trifunovska
Published: January 2005

During the 20th century self-determination has become one of the most important principles of international law and one of the most prominent rights on the basis of which (all) peoples can decide freely on their political status and their economic, social and cultural development (Article 1 common to the 1966 ICCPR and ICESCR).Whereas the idea of self-determination is envisaged as an advanced concept aimed at the liberation of peoples under foreign domination in the process of de-colonisation, today's situation and reality call for its reconsideration and adequate clarification with respect to the issues of who is entitled to the right of self-determination and in which forms and to which extent it can be exercised if seen from the aspect of the impact which its exercise might have on the integrity of states. This call is strengthened by the fact that all contemporary states have certain complexity with respect to their national/ethnic/religious/linguistic or racial composition. One of the basic problems in the application of the right of self-determination is created by the fact that there are no definitions in international law on the concepts of various groups. There is no clear answer on what are peoples who are entitled to the right of self-determination, nor is there an accepted definition for other groups which are politically relevant, like indigenous peoples and/or minorities. This may cause serious difficulties since such a lack of clarity provides conditions for persistent claims on the part of groups other than peoples on the right of self-determination, which sometimes threatens territorial integrity of states.
'Folk Law and Legal Pluralism: Societies in Transformation' - XIth International Congress of the Commission on Folk Law and Legal Pluralism Held in Moscow, 18-22 August 1997
Authors: Trifunovska
Published: January 2005

No Abstract
Jean-Marie Henckaerts, Mass Expulsion in Modern International Law and Practice, Martinus Nijhoff Publishers, The Hague, 1995
Authors: Zieck
Published: January 2005

No Abstract
Review of: Daniel Warner (ed.), Human Rights and Humanitarian Law. The Quest for Universality, Martinus Nijhoff Publishers, The Hague, (July) 1997
Authors: Zieck
Published: January 2005

No Abstract
Patterns of Surprise
Authors: Hills Matt
Published: January 2005

This article studies one media fan’s consumption patterns, arguing that media fandom has been restrictively defined in cultural studies to date as a matter of faithfulness to singular fan objects. Contra such definitions, the article addresses cyclical fandom, wherein the fan-consumer constantly moves from one fan object to another, experiencing intense affective relationships to a variety of texts. This case study employs psychoanalytic ethnography to analyze such a consumption pattern, where the “surprise” of new fandoms is repeatedly sought. Christopher Bollas’s psychoanalytic concept of the “aleatory object” is used to interpret self-narratives of cyclical fandom.
One-Dimensional Fan
Authors: Sandvoss Cornel
Published: January 2005

Drawing on Marcuse’s analysis of one-dimensional society, this article investigates the relationship between text and fan in its cultural micro and macro framing. The article explores the semiotic conditions through which texts function as objects of fandom and juxtaposes the reflective reading of fan texts based on their immediate concretization and normalization with the reflexive engagement demanded by the textual “blanks” in literary texts Iser described. The aesthetic relevance of fan texts, thus, lies not in any specific meanings but in their lack thereof as manifestation of a social and cultural status quo.
Accidental Activists
Authors: Scardaville Melissa C.
Published: January 2005

This case study explores soap opera fan activism in regard to the decade-long grassroots effort to keep the daytime drama Another World on the air. Using the author’s experience with the campaign and a snowball sample, key participants were interviewed about their involvement. Results show that the majority of respondents were not activists prior to or after their campaign membership and that their perceptions of success were closely correlated to how connected they became to the soap community. Recommendations for future research include examining pending soap cancellations and the link between programming creation and fan feedback management.
Global Television Distribution
Authors: Harrington C. Lee , Bielby Denise D.
Published: January 2005

This article focuses on the sale and purchase of TV programs and formats at international trade fairs and its implications for our understanding of global television audiences, fans, and texts. Through analytic engagement with the core concept of flow, the authors explore three related issues: (a) how viewers and fans are positioned in distribution practices, (b) the ease through which various televisual elements travel through the distribution process, and (c) the limitations of a conceptual reliance on“traveling”discourses to our understanding of global TV trade.
Racial Differences in Death Penalty Support and Opposition
Authors: Baker David N. , Lambert Eric G. , Jenkins Morris
Published: January 2005

Although the death penalty has a long history, it is not without debate and differing views. There appears to be a gap between Whites and Blacks in terms of their support of capital punishment. Students at a Midwestern university were surveyed to determine whether there were differences between the two groups of students in reasons to support or oppose the death penalty. In bivariate tests, there were significant differences between White and Black students on 15 of 16 measures for reasons for supporting or opposing capital punishment. These differences continued for 10 of the 16 measures even after multivariate analysis controlled for the effects of gender, age, and academic level. The results are discussed.
A Mechanical Model of 3D Braided Composites with Internal Transverse Crack
Authors: Zeng Tao , Wu Linzhi , Guo Licheng , Ma Li
Published: January 2005

A laminated mechanical model has been developed that can predict the mechanical properties of 3D braided composites with internal transverse crack. By using the principle of minimum complementary energy, the stress components are obtained in closed-form expressions in terms of a perturbation function, which is governed by two fourth-order inhomogeneous ordinary differential equations. The effective Young’s modulus and Poisson’s ratio of 3D braided composites with internal crack are calculated using the homogenization theorem. To demonstrate the solution, some examples are analyzed. Good agreement is obtained between the presented results and the values predicted by the modified finite element method.
Unambiguous Determination of 3D Fiber Orientation Distribution in Thermoplastic Composites Using SAM Image of Elliptical Mark and Interference Fringe
Authors: Kawamura Munehiro , Ikeda Satoshi , Morita Satoru , Sanomura Yukio
Published: January 2005

The in-plane angle determined using an optical reflection microscope with an image analyzer is ambiguous, because the same elliptical image would be obtained for a fiber. A method of determining the three-dimensional (3D) fiber orientation distribution using the scanning acoustic microscopy (SAM) image of an elliptical mark and interference fringe is proposed. The interference fringe appearing in the composite in the direction of a fiber is observed by SAM. One can easily determine the in-plane angle without ambiguity by adopting this information of interference fringes. It is shown that this technique is effective for the determination of the 3D fiber orientation distribution in plaque and cylindrical composite parts.
A Review of Explicit Finite Element Software for Composite Impact Analysis
Authors: Nguyen Minh Q. , Elder David J. , Bayandor Javid , Thomson Rodney S. , Scott Murray L.
Published: January 2005

As explicit finite element (FE) codes improve and advanced material models become available, such tools will find more widespread application within the aerospace industry, as ‘what-if ’ simulations become more manageable with increasing computing power and greater modeling realism. This paper describes the investigation of three commercial explicit FE analysis packages, LS-Dyna, MSC.Dytran, and Pam-Shock, to determine their capabilities in predicting barely visible impact damage (BVID) in composite structures. The investigation is conducted by first determining the suitability of the codes in constructing an FE model of a stiffened panel, solving for BVID and retrieving results. The results are in turn compared to experimental data in order to gauge the suitability of the codes for composite design and analysis. Comparisons of the FE simulations to experimental data include damage development and degradation, as well as the time-history responses. The Chang-Chang failure theory with brittle degradation was used for both LS-Dyna and MSC.Dytran, while the biphase model was used for Pam-Shock. Results indicated that the general shape of the force-time curves as well as the peak forces were predicted reasonably well. However, all simulations predicted a trough that was much less significant than the test results, as well as a shorter impact duration.
Toward an Integrative Multimodeling Interface: A Human-Computer Interface Approach to Interrelating Model Structures
Authors: Fishwick Paul A.
Published: January 2005

Among the different sorts of challenges for the modeling and simulation community, two types of challenges face us: challenges that optimize space and time for the computer and challenges that improve the human interface to the modeling and simulation process itself. While these types of challenges are important for the future health of simulation, the author presents a grand challenge of the latter variety, based on an area termed integrative multimodeling. The purpose of integrative multimodeling is to provide a human-computer interaction environment that allows components of different model types to be linked to one another. This study specifies current modeling practices in simulation and proceeds to justify a need for the challenge. It then follows this with two areas: aesthetic computing and the RUBE software framework, which supports customized “notations” for dynamic models constructed using the extensible markup language (XML).
Itinerary-Based Segmented Dissemination on a Peer-to-Peer Network
Authors: Zerfiridis Konstantinos G. , Karatza Helen D.
Published: January 2005

Peer-to-peer (P2P) file-sharing networks started out as a way to create a big pool of files to which anyone who participated had access. However, as the Internet evolved, these networks became one of the major enabling technologies. The traditional client-server paradigm does not always come through when great amounts of data need to be disseminated to numerous users. P2P systems became an alternative, relieving the server from becoming the congestion point. The purpose of this article is to show and analyze simulation results of a file being disseminated through two widely used approaches for P2P networks. Emphasis is given to the efficiency of each approach when demand on a highly anticipated file is simulated, as well as the benefits of the mobile agent-based itinerary algorithm proposed in this article.
Computer Simulation of Long-Term Vegetation Status in Landslide-Prone Areas in the Himalayan Region
Authors: Basu S. K. , Roy A.
Published: January 2005

The long-term vegetation pattern in landslide-prone regions is studied using simulation and modeling. A simulator is developed to study the impact of landslides on vegetation status. The first part of the model deals with simulation of the effects of rainfall, earthquakes, and deforestation in the creation of landslides and the concomitant damage to vegetation. The second part is a deterministic model of vegetation regeneration. The authors assume that the interarrival time of earthquakes, the intensity of these earthquakes, and rainfall intensity are stochastic in nature and that the earthquake frequency is independent of earthquake intensity. An estimate is made of the damage to vegetation due to the occurrence of landslides under the combined influence of earthquakes, rainfall, and deforestation. After the ecosystem parameters get modified due to the damage, the vegetation status is recalculated for the annual change according to the vegetation regeneration model.
Forest Fire Spread and Suppression in DEVS
Authors: Ntaimo Lewis , Zeigler Bernard P. , Vasconcelos Maria J. , Khargharia Bithika
Published: January 2005

In this article, the authors discuss modeling and simulation of forest fire spread and suppression using the discrete event system specification (DEVS) cell space approach in DEVSJAVA. The event-based modeling approach enables efficient simulation of cell space and allows one to obtain timely simulation-based predictions of forest fire spread and suppression in uniform and nonuniform environmental conditions. This model represents an advance toward developing a real-time decision support simulation system for predicting forest fire spread and the effects of water-based suppression attempts.
Rave and Straightedge, the Virtual and the Real
Authors: Wilson Brian , Atkinson Michael
Published: January 2005

Over the past 10 years, sociologists have attended to the impacts of the Internet on youth subcultural coalescence, display, identity, and resistance. In this article, the authors develop a critique of this body of work, describing how existing research places undue emphasis on young people’s experiences either online or offline and how a lack of consideration has been given to the ways that subcultural expressions are continuous across the apparent “virtual-real” divide. With the aim of addressing some of these concerns, the authors draw on ethnographic case studies of “Rave” and “Straightedge” to explore the impact of the two realities (i.e., online and offline realities) on understandings of subcultural experience in these youth formations and articulate how the theoretical split between the virtual and real in cyber-subcultural research does not accurately capture the lived experiences or identity negotiations of these youth.
Moving into Motherhood
Authors: Hunt Geoffrey , Joe-Laidler Karen , MacKenzie Kathleen
Published: January 2005

A growing body of research challenges the popular characterization that young mothers are bad mothers. This article focuses on a group of girls and young women who were pregnant or mothers and who were engaged in a risky lifestyle through their heavy involvement in gangs, partying, and drinking. The authors examine the impact of the process of motherhood at its different stages (from pregnancy to parenthood) on both the “homegirls’” involvement and membership in the gang and their alcohol consumption. The authors consider the extent to which different stages of motherhood influence a homegirl’s overall alcohol consumption and drinking practices both within and outside of the gang. The analysis draws from the qualitative and quantitative data of an ongoing comparative study on ethnic youth gangs in the San Francisco Bay Area.
Solution-Focused Approaches in the Practice of UK Educational Psychologists
Authors: Stobie Ingeborg , Boyle James , Woolfson Lisa
Published: January 2005

Solution-focused approaches are increasingly widely used in the practice of the applied educational psychologist (EP) (Ajmal and Rees, 2001; Durrant, 1993; Redpath and Harper, 1999; Rhodes and Ajmal, 1995). Based on a small-scale computer-mediated exploratory survey, this article examines the nature of such practice and investigates whether and how solution-focused practice is evaluated and contributes to EPs’ knowledge and skills base. The exploratory study is integrated into an overview of solution-focused therapy and a literature review of the application of solution-focused practice by EPs. Based on the review and analysis of the survey, the article proposes ways by which solution-focused practice can be evaluated by busy EP practitioners and therefore become potentially evidence-based.
Visibility Management and the School Psychologist
Authors: Lasser Jon
Published: January 2005

Visibility management (VM) refers to a process by which individuals regulate the degree to which they disclose traits or characteristics that would otherwise be inconspicuous. This article defines VM, discusses the importance of VM for the school psychologist, reviews applications of VM in school settings, provides two case studies, considers ethical/legal issues and makes recommendations for future research. As child advocates, school psychologists are encouraged to consider how VM interfaces with the role of promoting the psychological well being of children.