bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1-phosphate receptors: Effect of simvastatin
Authors: González-Díez María , Rodríguez Cristina , Badimon Lina , Martínez-González José
Published: June 2008

Prostacyclin (PGI2) is an important regulator of vascular homeostasis. Our goal was to analyze the role of sphingosine 1-phosphate (S1P) and its receptors in the up-regulation of cyclooxygenase-2 (Cox-2) induced by HDL in human vascular smooth muscle cells (VSMC). S1P induces Cox-2 expression in a time-and dose-dependent manner at concentrations (0.02–1 µM) compatible with those present in physiological HDL levels. The effect was mimicked by dihydro-S1P (DhS1P), a S1P derivative that only acts through cell surface S1P receptors. Desensitiz-ation of S1P receptors with S1P (or DhS1P) abolished HDL-induced Cox-2 up-regulation and PGI2 release. Inhibition of S1P receptors by suramin (inhibitor of S1P3), JTE013 (inhibitor of S1P2) or VPC23019 (inhibitor of S1P1 and S1P3) reduced the up-regulation of Cox-2 induced by HDL and S1P. The combination of suramin and JTE013 increased the inhibitory effect compared to that observed in cells treated with each inhibitor alone. siRNA against S1P2 or S1P3 significantly reduced the ability of HDL and S1P to up-regulate Cox-2. Simvastatin induced over-expression of S1P3 and potentiated the induction of Cox-2 expression produced by HDL (or S1P). Finally, suramin, JTE013 and VPC23019 inhibited p38 MAPK and ERK1/2 signaling pathways activated by HDL (or S1P) and the downstream activation of CREB, a key transcription factor involved in Cox-2 transcriptional up-regulation. These results indicate that S1P receptors, in particular S1P2 and S1P3, are involved in the Cox-2-dependent effects of HDL on vascular cells. Strategies aimed to therapeutically modulate S1P or S1P receptors could be useful to improve cardiovascular protection.
Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells
Authors: Ota Hidetaka , Eto Masato , Kano Mitsunobu R. , Ogawa Sumito , Iijima Katsuya , Akishita Masahiro , Ouchi Yasuyoshi
Published: June 2008

Objective—

Cilostazol, a selective inhibitor of PDE3, has a protective effect on endothelium after ischemic vascular damage, through production of nitric oxide (NO). The purpose of the present study was to clarify the molecular mechanisms underlying the preventive effect of treatment with cilostazol on oxidative stress–induced premature senescence in human endothelial cells.

Methods and Results—

Prematurely senescent human umbilical vein endothelial cells (HUVECs) were induced by treatment with hydrogen peroxide (H
2
O
2
) as judged by senescence-associated β-galactosidase assay (SA-βgal), cell morphological appearance, and plasminogen activator inhibitor-1 (PAI-1) expression. Treatment with H
2
O
2
caused 93% of the cells to be SA-βgal positive, whereas 46% of cilostazol (100 μmol/L)-treated cells were positive. HUVECs treated with other cAMP-elevating agents and DETA-NO showed a reduction of SA-βgal–positive cells as well. Cilostazol increased phosphorylation of Akt at Ser
473
and of endothelial nitric oxide synthase (eNOS) at Ser
1177
, with a dose-dependent increase in Sirt1 expression. Moreover, the effect of cilostazol on premature senescence was abrogated through inhibition of Sirt1.

Conclusions—

Our results indicated that cilostazol exerted protective effects against endothelial senescence and dysfunction, and enhancement of NO production is a key mediator in upregulation of Sirt1.
Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes
Authors: Dayal Sanjana , Lentz Steven R.
Published: June 2008

Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine
β
-synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.
GRP78 Upregulation by Atheroprone Shear Stress Via p38-, α2β1-Dependent Mechanism in Endothelial Cells
Authors: Feaver Ryan E. , Hastings Nicole E. , Pryor Andrew , Blackman Brett R.
Published: June 2008

Objective—

The initiation of atherosclerosis is in part dependent on the hemodynamic shear stress environment promoting a proinflammatory phenotype of the endothelium. Previous studies demonstrated increased expression of ER stress protein and unfolded protein response (UPR) regulator, GRP78, within all vascular cells in atherosclerotic lesions and its regulation in the endothelium by several atherosclerotic stressors; however, regulation of GRP78 by shear stress directly has not been established.

Method and Results—

Using an in vitro model to simulate human arterial shear stress waveforms, atheroprone or atheroprotective flow was applied to human endothelial cells. GRP78 was found to be significantly upregulated (3-fold) in a sustained manner under atheroprone, but not atheroprotective flow up to 24 hours. This response was dependent on both sustained activation of p38, as well integrin α2β1. Increased GRP78 correlated with the activation of the ER stress sensing element (ERSE1) promoter by atheroprone flow as a marker of the UPR. Shear stress regulated GRP78 through increased protein stability when compared to other flow regulated proteins, such as connexin-43 and vascular cell adhesion molecule (VCAM)-1. Increased endothelial expression of GRP78 was also observed in atheroprone versus atheroprotective regions of C57BL6 mice.

Conclusions—

This study supports a role of the hemodynamic environment in preferentially inducing GRP78 and the UPR in atheroprone regions, before lesion development, and suggests a potential atheroprotective (ie, prosurvival), compensatory effect in response to ER stress within atherosclerotic lesions.
Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase
Authors: Zhang Qian , Malik Pulkit , Pandey Deepesh , Gupta Sonali , Jagnandan Davin , de Chantemele Eric Belin , Banfi Botond , Marrero Mario B. , Rudic R. Daniel , Stepp David W. , Fulton David J.R.
Published: June 2008

Objectives—

Increased formation of reactive oxygen species (ROS) has been identified as a causative factor in endothelial dysfunction by reducing NO bioavailability and uncoupling endothelial nitric oxide synthase (eNOS). However, the specific contribution of ROS to endothelial function is not well understood.

Methods and Results—

A major source of intracellular ROS is the NADPH oxidase (Nox) family of enzymes. The goal of the current study was to directly assess the contribution of NADPH oxidase derived superoxide to eNOS function by expressing Nox5, a single gene product that constitutively produces superoxide within cells. Paradoxically, we found that instead of inhibiting eNOS, coexpression of Nox5 increased NO release from both bovine and human endothelial cells. To establish the functional significance of this observation in intact blood vessels, the endothelium of mouse aorta was transduced with Nox5 or control adenoviruses. Nox5 potently inhibited Ach-induced relaxation and potentiated contractile responses to phenylephrine. In precontracted aortae, acute exposure to superoxide dismutase induced significant vascular relaxation in vessels exposed to Nox5 versus control and unmasked the ability of Nox5 to activate eNOS in blood vessel endothelium.

Conclusions—

These findings suggest that ROS inhibit eNOS function via consumption of NO rather than direct inhibition of enzymatic activity.
Restoration of Plasma von Willebrand Factor Deficiency Is Sufficient to Correct Thrombus Formation After Gene Therapy for Severe von Willebrand Disease
Authors: De Meyer Simon F. , Vandeputte Nele , Pareyn Inge , Petrus Inge , Lenting Peter J. , Chuah Marinee K.L. , VandenDriessche Thierry , Deckmyn Hans , Vanhoorelbeke Karen
Published: June 2008

Objective—

Gene therapy for severe von Willebrand disease (vWD) seems an interesting treatment alternative with long-term therapeutic potential. We investigated the feasibility of targeting the liver for ectopic expression of physiologically active von Willebrand factor (vWF).

Methods and Results—

The capacity of transgene-encoded murine vWF to restore vWF function was studied in a mouse model of severe vWD after liver-specific gene transfer by hydrodynamic injection. By using a hepatocyte-specific α1 antitrypsin promoter, a considerably higher and longer-lasting vWF expression was obtained when compared with a cytomegalovirus promoter, reaching maximum vWF plasma levels that are 10±1 times higher than the wild-type level. Liver-expressed vWF showed the full range of multimers, including the high molecular weight multimers, and restored factor VIII plasma levels, consistent with correction of the bleeding time 3 but not 7 days after gene transfer. Importantly, transgene encoded plasma vWF restored proper platelet adhesion and aggregation in a FeCl
3
induced thrombosis model.

Conclusions—

High ectopic expression of transgene encoded plasma vWF can be obtained after gene transfer to the liver. Liver-expressed vWF was fully multimerized and able to restore proper platelet plug formation in severe vWD. The liver therefore seems an attractive target for gene therapy for severe vWD.
Disruption of Ang-1/Tie-2 Signaling Contributes to the Impaired Myocardial Vascular Maturation and Angiogenesis in Type II Diabetic Mice
Authors: Chen Jian-Xiong , Stinnett Amanda
Published: June 2008

Objective—

Microvascular insufficiency represents a major cause of end-organ failure among diabetics. The current studies were undertaken to determine whether dysregulation of the angiopoietins/Tie-2 system would result in an impairment of smooth muscle cell (SMC) recruitment and vascular maturation, which contributes to impaired angiogenesis in diabetes.

Methods and Results—

Tie-2 expression was significantly attenuated, whereas angiopoietin-2 (Ang-2) was increased in db/db mice subjected to myocardial ischemia. Our morphological analysis showed that the number of SMC coverage area per neovessel was significantly reduced in db/db mice. This was accompanied by a significant reduction of myocardial capillary density and arteriole formation. Interestingly, Angiopoietin-1(Ang-1)–induced SMC recruitment and vessel outgrowth were severely impaired in db/db mice. Our in vitro studies further demonstrated that exposure of mouse heart endothelial cells to high glucose resulted in a significant upregulation of Ang-2 and a downregulation of Tie-2 expression. These alterations led to a significant impairment of Ang-1–induced Akt and eNOS phosphorylation, along with a remarkable impairment of Ang-1–induced endothelial cell migration and endothelial cell spheroid sprouting. Ang-1 gene transfer restored Tie-2 expression and rescued these abnormalities in diabetes.

Conclusions—

Our findings underscore the important role of Ang-1–Tie-2 signaling in the diabetes-induced impairment of vascular maturation and angiogenesis.
Triglyceride-Rich Lipoprotein-Associated Apolipoprotein C-III Production Is Stimulated by Plasma Free Fatty Acids in Humans
Authors: Pavlic Mirjana , Valéro René , Duez Hélène , Xiao Changting , Szeto Linda , Patterson Bruce W. , Lewis Gary F.
Published: June 2008

Objective—

Insulin resistant states are associated with increased fatty acid flux to liver and intestine, which stimulates the production of triglyceride-rich lipoproteins (TRL). ApoC-III production and plasma and TRL concentrations are increased in insulin resistance and may contribute to the hypertriglyceridemia of these conditions. The mechanism underlying that increase is not known, but because apoC-III and VLDL production are closely linked we hypothesized that FFAs may stimulate TRL apoC-III production.

Methods and Results—

We used Intralipid/heparin (IH) to raise plasma FFA in 12 healthy men in the fed state, and stable isotopes to examine apoC-III metabolism. TRL apoC-III concentration was significantly higher in the IH study, and this increase was associated with higher production (PR) and fractional catabolic rate (FCR). The increase in production was greater than in FCR (90% versus 30%, respectively), accounting for the elevated concentration. Glycerol infusion had no effect on apoC-III concentration, PR, or FCR compared to saline, indicating that the effect was not attributable to glycerol released from intralipid.

Conclusion—

These findings confirm that TRL apoC-III production is stimulated by an acute elevation of plasma FFAs, suggesting a novel regulatory pathway that may play a role in the overproduction of TRL apoC-III in insulin resistant states.
Forced Alignment of Mesenchymal Stem Cells Undergoing Cardiomyogenic Differentiation Affects Functional Integration With Cardiomyocyte Cultures
Authors: Pijnappels Daniël A. , Schalij Martin J. , Ramkisoensing Arti A. , van Tuyn John , de Vries Antoine A.F. , van der Laarse Arnoud , Ypey Dirk L. , Atsma Douwe E.
Published: June 2008

Alignment of cardiomyocytes (CMCs) contributes to the anisotropic (direction-related) tissue structure of the heart, thereby facilitating efficient electrical and mechanical activation of the ventricles. This study aimed to investigate the effects of forced alignment of stem cells during cardiomyogenic differentiation on their functional integration with CMC cultures. Labeled neonatal rat (nr) mesenchymal stem cells (nrMSCs) were allowed to differentiate into functional heart muscle cells in different cell-alignment patterns during 10 days of coculture with nrCMCs. Development of functional cellular properties was assessed by measuring impulse transmission across these stem cells between 2 adjacent nrCMC fields, cultured onto microelectrode arrays and previously separated by a laser-dissected channel (230±10 μm) for nrMSC transplantation. Coatings in these channels were microabraded in a direction (1) parallel or (2) perpendicular to the channel or were (3) left unabraded to establish different cell patterns. Application of cells onto microabraded coatings resulted in anisotropic cell alignment within the channel. Application on unabraded coatings resulted in isotropic (random) alignment. After coculture, conduction across seeded nrMSCs occurred from day 1 (perpendicular and isotropic) or day 6 (parallel) onward. Conduction velocity across nrMSCs at day 10 was highest in the perpendicular (11±0.9 cm/sec; n=12), intermediate in the isotropic (7.1±1 cm/sec; n=11) and lowest in the parallel configuration (4.9±1 cm/sec; n=11) (
P
<0.01). nrCMCs and fibroblasts served as positive and negative control, respectively. Also, immunocytochemical analysis showed alignment-dependent increases in connexin 43 expression. In conclusion, forced alignment of nrMSCs undergoing cardiomyogenic differentiation affects the time course and degree of functional integration with surrounding cardiac tissue.
Local Activation or Implantation of Cardiac Progenitor Cells Rescues Scarred Infarcted Myocardium Improving Cardiac Function
Authors: Rota Marcello , Padin-Iruegas M. Elena , Misao Yu , De Angelis Antonella , Maestroni Silvia , Ferreira-Martins João , Fiumana Emanuela , Rastaldo Raffaella , Arcarese Michael L. , Mitchell Thomas S. , Boni Alessandro , Bolli Roberto , Urbanek Konrad , Hosoda Toru , Anversa Piero , Leri Annarosa , Kajstura Jan
Published: June 2008

Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of ≈42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2
n
karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.
Engineering Robust and Functional Vascular Networks In Vivo With Human Adult and Cord Blood–Derived Progenitor Cells
Authors: Melero-Martin Juan M. , De Obaldia Maria E. , Kang Soo-Young , Khan Zia A. , Yuan Lei , Oettgen Peter , Bischoff Joyce
Published: June 2008

The success of therapeutic vascularization and tissue engineering will rely on our ability to create vascular networks using human cells that can be obtained readily, can be expanded safely ex vivo, and can produce robust vasculogenic activity in vivo. Here we describe the formation of functional microvascular beds in immunodeficient mice by coimplantation of human endothelial and mesenchymal progenitor cells isolated from blood and bone marrow. Evaluation of implants after 1 week revealed an extensive network of human blood vessels containing erythrocytes, indicating the rapid formation of functional anastomoses within the host vasculature. The implanted endothelial progenitor cells were restricted to the luminal aspect of the vessels; mesenchymal progenitor cells were adjacent to lumens, confirming their role as perivascular cells. Importantly, the engineered vascular networks remained patent at 4 weeks in vivo. This rapid formation of long-lasting microvascular networks by postnatal progenitor cells obtained from noninvasive sources constitutes an important step forward in the development of clinical strategies for tissue vascularization.
Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles
Authors: Xiao Changting , Watanabe Takehiko , Zhang Yi , Trigatti Bernardo , Szeto Linda , Connelly Phil W. , Marcovina Santica , Vaisar Tomas , Heinecke Jay W. , Lewis Gary F.
Published: June 2008

A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor–deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E–mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.
Early Disruption of the Blood–Brain Barrier After Thrombolytic Therapy Predicts Hemorrhage in Patients With Acute Stroke
Authors: Kastrup Andreas , Gröschel Klaus , Ringer Thomas M. , Redecker Christoph , Cordesmeyer Robert , Witte Otto W. , Terborg Christoph
Published: June 2008

Background and Purpose—

Leaks of the blood–brain barrier can be detected on postcontrast-enhanced T1-weighted MRIs. Although early disruptions of the blood–brain barrier appear to be an important risk factor for tissue plasminogen activator-related hemorrhages in rodents, little is known about their incidence and consequences in human stroke.

Methods—

This is a retrospective analysis of a prospectively collected stroke database over the past 6 years. In 52 patients, multimodal MRI (including diffusion-weighted, perfusion-weighted, and postcontrast-enhanced T1-weighted MRI to detect blood–brain barrier changes) had been performed immediately before systemic thrombolysis and in 48 patients within a median of 30 minutes (interquartile range: 30 to 60 minutes) after recombinant tissue plasminogen activator treatment. The incidence of symptomatic hemorrhage (SICH), defined as any parenchymal hemorrhage leading to deterioration in the patient’s clinical condition, was related to several clinical and imaging variables, including early blood–brain barrier changes.

Results—

Overall, SICH was detected in 9 (9%) patients and among these, 2 died. Although no blood–brain barrier changes were detectable before thrombolysis, 3 of 48 patients (6.25%) had a parenchymal gadolinium enhancement in the areas of initial infarction after tissue plasminogen activator treatment. All 3 patients developed SICHs at sites corresponding to the areas of enhancement. The presence of a parenchymal enhancement was significantly associated with SICH (
P
<0.01), whereas other clinical and imaging variables did not predict SICH in this series.

Conclusion—

Early parenchymal enhancement after intravenous tissue plasminogen activator is significantly associated with subsequent SICH and could therefore become a useful imaging sign for the rapid initiation of preventive strategies in the future.
A Brief Prehospital Stroke Severity Scale Identifies Ischemic Stroke Patients Harboring Persisting Large Arterial Occlusions
Authors: Nazliel Bijen , Starkman Sidney , Liebeskind David S. , Ovbiagele Bruce , Kim Doojin , Sanossian Nerses , Ali Latisha , Buck Brian , Villablanca Pablo , Vinuela Fernando , Duckwiler Gary , Jahan Reza , Saver Jeffrey L.
Published: June 2008

Background and Purpose—

The Los Angeles Motor Scale (LAMS) is a brief 3-item stroke severity assessment measure designed for prehospital and Emergency Department use.

Methods—

The LAMS and NIHSS were scored in under-12-hour acute anterior circulation ischemic stroke patients. Stroke severity ratings were correlated with cervicocerebral vascular occlusion on CTA, MRA, and catheter angiography. Receiver operating curves, c statistics, and likelihood ratios were used to evaluate the predictive value for vascular occlusion of stroke severity ratings.

Results—

Among 119 patients, mean age was 67 (±18), 45% were male. Time from onset to ED arrival was mean 190 minutes (range 10 to 660). Persisting large vessel occlusions (PLVOs) were present in 62% of patients. LAMS stroke severity scores were higher in patients harboring a vascular occlusion, median 5 (IQR 4 to 5) versus 2 (IQR 1 to 3). Similarly, NIHSS stroke severity scores were higher in PLVO patients, 19 (14 to 24) versus 5 (3 to 7). ROC curves demonstrated that the LAMS was highly effective in identifying patients with PLVOs, c statistic 0.854. At the optimal threshold of 4 or higher, LAMS scores showed sensitivity 0.81, specificity 0.89, and overall accuracy 0.85. LAMS performance was comparable to NIHSS performance (c statistic 0.933). The positive likelihood ratio associated with a LAMS score ≥4 was 7.36 and the negative likelihood ratio 0.21.

Conclusions—

Stroke severity assessed by the LAMS predicts presence of large artery anterior circulation occlusion with high sensitivity and specificity. The LAMS is a promising instrument for use by prehospital personnel to identify select stroke patients for direct transport to Comprehensive Stroke Centers capable of endovascular interventions.
Diagnostic Accuracy of Magnetic Resonance Angiography for Internal Carotid Artery Disease
Authors: Debrey Sarah M. , Yu Hua , Lynch John K. , Lövblad Karl-Olof , Wright Violet L. , Janket Sok-Ja D. , Baird Alison E.
Published: June 2008

Background and Purpose—

Accurate diagnosis of the degree of internal carotid artery (ICA) stenosis is needed for decisions regarding optimal stroke prevention. Noninvasive magnetic resonance angiography (MRA) is being proposed and used as a replacement for the gold standard, intra-arterial angiography. Our purpose was to perform a systematic review and diagnostic meta-analysis to determine the sensitivity and specificity of time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA for the detection of (1) high-grade (≥70% to 99%) ICA stenoses; (2) ICA occlusions; (3) moderately severe (50% to 69%) ICA stenoses; and (4) compare the overall accuracy of the 2 MRA techniques.

Methods—

The medical literature on MRA and the diagnosis of ICA steno-occlusive disease was reviewed through the PubMed, EMBASE, and SCOPUS databases. All publication years were included through to November 2006. Studies were eligible for inclusion if they compared the accuracy of TOF or CE MRA for the detection of ICA disease against intra-arterial angiography and reported sufficient data.

Results—

The overall sensitivity of TOF MRA for the detection of ≥70% to 99% ICA stenoses was 91.2% (95% CI: 88.9% to 93.1%) with a specificity of 88.3% (86.7% to 89.7%), whereas the sensitivity of CE MRA was 94.6% (92.4% to 96.4%) with a specificity of 91.9% (90.3% to 93.4%). For the detection of ICA occlusions, the sensitivity of TOF MRA was 94.5% (91.2% to 96.8%) and the specificity was 99.3% (98.9% to 99.6%), whereas the sensitivity and specificity values for CE MRA were 99.4% (96.8% to 100%) and 99.6% (99.2% to 99.9%), respectively. For moderately severe (50% to 69%) stenoses, TOF MRA had a sensitivity of only 37.9% (29.3% to 47.1%) and a specificity of 92.1% (89.6% to 94.1%); for CE MRA, the pooled sensitivity value was somewhat better at 65.9% (57.0% to 74.0%), whereas the specificity was 93.5% (91.3% to 95.3%).

Conclusions—

TOF MRA and CE MRA showed high accuracy for the detection of high-grade ICA stenoses and occlusions with CE MRA having the edge over TOF MRA, but had only poor (TOF MRA) to fair (CE MRA) sensitivity for the detection of moderately severe stenoses.
Geometry of the Carotid Bifurcation Predicts Its Exposure to Disturbed Flow
Authors: Lee Sang-Wook , Antiga Luca , Spence J. David , Steinman David A.
Published: June 2008

Background and Purpose—

That certain vessels might be at so-called geometric risk of atherosclerosis rests on assumptions of wide interindividual variations in disturbed flow and of a direct relationship between disturbed flow and lumen geometry. In testing these often-implicit assumptions, the present study aimed to determine whether investigations of local risk factors in atherosclerosis can indeed rely on surrogate geometric markers of disturbed flow.

Methods—

Computational fluid dynamics simulations were performed on carotid bifurcation geometries derived from MRI of 25 young adults. Disturbed flow was quantified as the surface area exposed to low and oscillatory shear beyond objectively-defined thresholds. Interindividual variations in disturbed flow were contextualized with respect to effects of uncertainties in imaging and geometric reconstruction. Relationships between disturbed flow and various geometric factors were tested via multiple regression.

Results—

Relatively wide variations in disturbed flow were observed among the 50 vessels. Multiple regression revealed a significant (
P
<0.002) relationship between disturbed flow and both proximal area ratio (β≈0.5) and bifurcation tortuosity (β≈−0.4), but not bifurcation angle, planarity, or distal area ratio. These findings were shown to be insensitive to assumptions about the flow conditions and to the choice of disturbed flow indicator and threshold.

Conclusions—

Certain geometric features of the young adult carotid bifurcation are robust surrogate markers of its exposure to disturbed flow. It may therefore be reasonable to consider large-scale retrospective or prospective imaging studies of local risk factors for atherosclerosis without the need for time-consuming and expensive flow imaging or CFD studies.
Interventional Acute Ischemic Stroke Therapy With Intracranial Self-Expanding Stent
Authors: Zaidat Osama O. , Wolfe Thomas , Hussain Syed I. , Lynch John R. , Gupta Rishi , Delap Joanna , Torbey Michel T. , Fitzsimmons Brian-Fred
Published: June 2008

Background and Purpose—

Rapid and safe recanalization of occluded intracranial arteries in acute ischemic stroke (AIS) is challenging. Newly available self-expanding intracranial atherosclerotic stents (SEIS), which can be deployed rapidly and safely, make acute stenting an option for treating AIS. We present the feasibility of this technique.

Methods—

A retrospective analysis evaluated procedural protocols and clinical response to treatment in patients with AIS treated with SEIS. Descriptive statistics are presented with initial and follow-up National Institutes of Health Stroke Scale and modified Rankin Score.

Results—

Nine patients with AIS underwent acute SEIS placement. There was successful deployment of the Neuroform (n=4) and Wingspan (n=4/5) stents in the M1/M2 (n=5) and M3 (n=1) middle cerebral artery segments, intracranial internal carotid artery (one of 2), and intracranial vertebrobasilar junction (one). Mean time of SEIS deployment from AIS onset was 5.1 hours. Complete (Thrombolysis in Cerebral Ischemia/Thrombolysis in Myocardial Ischemia 3) and partial/complete (Thrombolysis in Cerebral Ischemia/Thrombolysis in Myocardial Ischemia 2 or 3) recanalization occurred in 67% and 89%, respectively. One intracranial hemorrhage (11%) and one acute in-stent thrombosis (successfully treated with abciximab and balloon angioplasty) occurred. Stroke-related mortality occurred in 3 of 9 (33%) patients and survivors had modified Rankin Score ≤2. Follow-up angiography (mean, 8 months; range, 2 to 14 months) in 4 of 9 patients showed no stent restenosis.

Conclusions—

This preliminary experience with SEIS in refractory AIS demonstrated the technical feasibility and high rate of recanalization with acute stenting. Long-term safety and strategies to limit in-stent thrombosis and optimize periprocedural management are crucial before initiating future randomized efficacy studies with SEIS in AIS refractory to standard therapy.
Stroke Outcome in Those Over 80
Authors: Saposnik Gustavo , Cote Robert , Phillips Stephen , Gubitz Gordon , Bayer Neville , Minuk Jeffrey , Black Sandra
Published: June 2008

Background and Purpose—

The prevalence of stroke in elderly patients has been increasing in recent years. However, limited information is available about the burden of stroke in individuals over 80. We sought to evaluate differences in clinical outcomes in Canadians over 80 years old hospitalized for an acute ischemic stroke.

Methods—

The authors conducted a multicenter cohort study including all hospital admissions for ischemic stroke identified from the Canadian Hospital Morbidity and Mortality Database from April 2003 to March 2004. The Hospital Morbidity and Mortality Database contains a national database that contains patient-level sociodemographic, diagnostic, procedural, and administrative information from across Canada. Multivariable analysis was performed using logistic regression. The primary outcome was 7-day case fatality and fatality at discharge. Secondary end points included intensive care unit admissions, medical complications, gender differences, length of hospital stay, and discharge disposition.

Results—

We analyzed 26 676 patients with ischemic stroke admitted to 606 hospitals across Canada. Mean age (SD) was 74±13 years. Overall, 10 171 (38%) were aged 80 years or older. Case fatality at discharge was 5.7% (age <59), 8.6% (age 60 to 69), 13.4% (age 70 to 79), and 24.2% (age ≥80;
P
<0.001). Patients aged 80 and over were less likely to be admitted to the intensive care unit (7.7% versus 15.3%;
P
<0.001) and discharged to their prestroke residence (47.2% for those over 80 versus 61.6% for patients younger than 80;
P
<0.001). Median length of stay was longer in those over 80 (10 days versus 7 days;
P
<0.0001). In the multivariable analysis for the older group, admission to the intensive care unit, low socioeconomic status, and admission to a nonacademic institution were associated with increased fatality after adjusting for covariates.

Conclusions—

Aging of the population is a growing reality in Western societies and this translates into an increasing demand on healthcare systems. In our study, patients with stroke over 80 had higher risk-adjusted fatality, longer hospitalization, and were less likely to be discharged to their original place of residence. Strategies need to be implemented to facilitate equal access to specialized stroke care for the elderly.
Prediction of Functional Outcome in Patients With Primary Intracerebral Hemorrhage
Authors: Rost Natalia S. , Smith Eric E. , Chang Yuchiao , Snider Ryan W. , Chanderraj Rishi , Schwab Kristin , FitzMaurice Emily , Wendell Lauren , Goldstein Joshua N. , Greenberg Steven M. , Rosand Jonathan
Published: June 2008

Background and Purpose—

Intracerebral hemorrhage (ICH) is the most fatal and disabling stroke subtype. Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not designed to predict functional recovery. We developed an acute clinical score to predict likelihood of functional independence.

Methods—

We prospectively characterized 629 consecutive patients with ICH at hospital presentation. Predictors of functional independence (Glasgow Outcome Score ≥4) at 90 days were used to develop a logistic regression-based risk stratification scale in a random subset of two thirds and validated in the remaining one third of the cohort.

Results—

At 90 days, 162 (26%) patients achieved independence. Age, Glasgow Coma Scale, ICH location, volume (all
P
<0.0001), and pre-ICH cognitive impairment (
P
=0.005) were independently associated with Glasgow Outcome Score ≥4. The FUNC score was developed as a sum of individual points (0–11) based on strength of association with outcome. In both the development and validation cohorts, the proportion of patients who achieved Glasgow Outcome Score ≥4 increased steadily with FUNC score. No patient assigned a FUNC score ≤4 achieved functional independence, whereas >80% with a score of 11 did. The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only, consistent with absence of confounding by early withdrawal of care.

Conclusions—

FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus, can provide guidance in clinical decision-making and patient selection for clinical trials.
A Global Joint Model for Semantic Role Labeling
Authors: Toutanova Kristina , Haghighi Aria , Manning Christopher D.
Published: June 2008

We present a model for semantic role labeling that effectively captures the linguistic intuition that a semantic argument frame is a joint structure, with strong dependencies among the arguments. We show how to incorporate these strong dependencies in a statistical joint model with a rich set of features over multiple argument phrases. The proposed model substantially outperforms a similar state-of-the-art local model that does not include dependencies among different arguments.

We evaluate the gains from incorporating this joint information on the Propbank corpus, when using correct syntactic parse trees as input, and when using automatically derived parse trees. The gains amount to 24.1% error reduction on all arguments and 36.8% on core arguments for gold-standard parse trees on Propbank. For automatic parse trees, the error reductions are 8.3% and 10.3% on all and core arguments, respectively. We also present results on the CoNLL 2005 shared task data set. Additionally, we explore considering multiple syntactic analyses to cope with parser noise and uncertainty.
Tree Kernels for Semantic Role Labeling
Authors: Moschitti Alessandro , Pighin Daniele , Basili Roberto
Published: June 2008

The availability of large scale data sets of manually annotated predicate-argument structures has recently favored the use of machine learning approaches to the design of automated semantic role labeling (SRL) systems. The main research in this area relates to the design choices for feature representation and for effective decompositions of the task in different learning models. Regarding the former choice, structural properties of full syntactic parses are largely employed as they represent ways to encode different principles suggested by the linking theory between syntax and semantics. The latter choice relates to several learning schemes over global views of the parses. For example, re-ranking stages operating over alternative predicate-argument sequences of the same sentence have shown to be very effective.

In this article, we propose several kernel functions to model parse tree properties in kernel-based machines, for example, perceptrons or support vector machines. In particular, we define different kinds of tree kernels as general approaches to feature engineering in SRL. Moreover, we extensively experiment with such kernels to investigate their contribution to individual stages of an SRL architecture both in isolation and in combination with other traditional manually coded features. The results for boundary recognition, classification, and re-ranking stages provide systematic evidence about the significant impact of tree kernels on the overall accuracy, especially when the amount of training data is small. As a conclusive result, tree kernels allow for a general and easily portable feature engineering method which is applicable to a large family of natural language processing tasks.
Labeling Chinese Predicates with Semantic Roles
Authors: Xue Nianwen
Published: June 2008

In this article we report work on Chinese semantic role labeling, taking advantage of two recently completed corpora, the Chinese PropBank, a semantically annotated corpus of Chinese verbs, and the Chinese Nombank, a companion corpus that annotates the predicate-argument structure of nominalized predicates. Because the semantic role labels are assigned to the constituents in a parse tree, we first report experiments in which semantic role labels are automatically assigned to hand-crafted parses in the Chinese Treebank. This gives us a measure of the extent to which semantic role labels can be bootstrapped from the syntactic annotation provided in the treebank. We then report experiments using automatic parses with decreasing levels of human annotation in the input to the syntactic parser: parses that use gold-standard segmentation and POS-tagging, parses that use only gold-standard segmentation, and fully automatic parses. These experiments gauge how successful semantic role labeling for Chinese can be in more realistic situations. Our results show that when hand-crafted parses are used, semantic role labeling accuracy for Chinese is comparable to what has been reported for the state-of-the-art English semantic role labeling systems trained and tested on the English PropBank, even though the Chinese PropBank is significantly smaller in size. When an automatic parser is used, however, the accuracy of our system is significantly lower than the English state of the art. This indicates that an improvement in Chinese parsing is critical to high-performance semantic role labeling for Chinese.
The Importance of Syntactic Parsing and Inference in Semantic Role Labeling
Authors: Punyakanok Vasin , Roth Dan , Yih Wen-tau
Published: June 2008

We present a general framework for semantic role labeling. The framework combines a machine-learning technique with an integer linear programming-based inference procedure, which incorporates linguistic and structural constraints into a global decision process. Within this framework, we study the role of syntactic parsing information in semantic role labeling. We show that full syntactic parsing information is, by far, most relevant in identifying the argument, especially, in the very first stage—the pruning stage. Surprisingly, the quality of the pruning stage cannot be solely determined based on its recall and precision. Instead, it depends on the characteristics of the output candidates that determine the difficulty of the downstream problems. Motivated by this observation, we propose an effective and simple approach of combining different semantic role labeling systems through joint inference, which significantly improves its performance.

Our system has been evaluated in the CoNLL-2005 shared task on semantic role labeling, and achieves the highest F1 score among 19 participants.
Step Length Adaptation on Ridge Functions
Authors: Arnold Dirk V. , MacLeod Alexander
Published: June 2008

Step length adaptation is central to evolutionary algorithms in real-valued search spaces. This paper contrasts several step length adaptation algorithms for evolution strategies on a family of ridge functions. The algorithms considered are cumulative step length adaptation, a variant of mutative self-adaptation, two-point adaptation, and hierarchically organized strategies. In all cases, analytical results are derived that yield insights into scaling properties of the algorithms. The influence of noise on adaptation behavior is investigated. Similarities and differences between the adaptation strategies are discussed.
Efficient Evaluation Functions for Evolving Coordination
Authors: Agogino A. , Tumer K.
Published: June 2008

This paper presents fitness evaluation functions that efficiently evolve coordination in large multi-component systems. In particular, we focus on evolving distributed control policies that are applicable to dynamic and stochastic environments. While it is appealing to evolve such policies directly for an entire system, the search space is prohibitively large in most cases to allow such an approach to provide satisfactory results. Instead, we present an approach based on evolving system components individually where each component aims to maximize its own fitness function. Though this approach sidesteps the exploding state space concern, it introduces two new issues: (1) how to create component evaluation functions that are aligned with the global evaluation function; and (2) how to create component evaluation functions that are sensitive to the fitness changes of that component, while remaining relatively insensitive to the fitness changes of other components in the system. If the first issue is not addressed, the resulting system becomes uncoordinated; if the second issue is not addressed, the evolutionary process becomes either slow to converge or worse, incapable of converging to good solutions.

This paper shows how to construct evaluation functions that promote coordination by satisfying these two properties. We apply these evaluation functions to the distributed control problem of coordinating multiple rovers to maximize aggregate information collected. We focus on environments that are highly dynamic (changing points of interest), noisy (sensor and actuator faults), and communication limited (both for observation of other rovers and points of interest) forcing the rovers to evolve generalized solutions. On this difficult coordination problem, the control policy evolved using aligned and component-sensitive evaluation functions outperforms global evaluation functions by up to 400%. More notably, the performance improvements increase when the problems become more difficult (larger, noisier, less communication). In addition we provide an analysis of the results by quantifying the two characteristics (alignment and sensitivity discussed above) leading to a systematic study of the presented fitness functions.
Coupled Air, Sea, and Land Interactions of the South American Monsoon
Authors: Misra Vasubandhu
Published: June 2008

The dominant interannual variation of the austral summer South American monsoon season (SAM) is associated with El Niño–Southern Oscillation (ENSO). Although this teleconnection provides a basis for the seasonal predictability of SAM, it is shown that the conventional tier-2 modeling approach of prescribing observed sea surface temperature (SST) is inappropriate to capture this teleconnection. Furthermore, such a forced atmospheric general circulation model (AGCM) simulation leads to degradation of the SAM precipitation variability.

However, when the same AGCM is coupled to an ocean general circulation model to allow for coupled air–sea interactions, then this ENSO–SAM teleconnection is reasonably well simulated. This is attributed to the role of air–sea coupling in modulating the large-scale east–west circulation, especially associated with Niño-3 SST anomalies. It is also shown that the land–atmosphere feedback in the SAM domain as a result of the inclusion of air–sea coupling is more robust. As a consequence of this stronger land–atmosphere feedback the decorrelation time of the daily rainfall in the SAM region is prolonged to match more closely with the observed behavior.

A subtle difference in the austral summer seasonal precipitation anomalies between that over the Amazon River basin (ARB) and the SAM core region is also drawn from this study in reference to the influence of the air–sea interaction. It is shown that the dominant interannual precipitation variability over the ARB is simulated both by the uncoupled and coupled (to OGCM) AGCM in contrast to that over the SAM core region in southeastern Brazil.