bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial Cells Derived From Human iPSCS Increase Capillary Density and Improve Perfusion in a Mouse Model of Peripheral Arterial Disease
Authors: Rufaihah Abdul Jalil , Huang Ngan F. , Jamé Sina , Lee Jerry C. , Nguyen Ha N. , Byers Blake , De Abhijit , Okogbaa Janet , Rollins Mark , Reijo-Pera Renee , Gambhir Sanjiv S. , Cooke John P.
Published: August 2011

Objective—

Stem cell therapy for angiogenesis and vascular regeneration has been investigated using adult or embryonic stem cells. In the present study, we investigated the potential of endothelial cells (ECs) derived from human induced pluripotent stem cells (hiPSCs) to promote the perfusion of ischemic tissue in a murine model of peripheral arterial disease.

Methods and Results—

Endothelial differentiation was initiated by culturing hiPSCs for 14 days in differentiation media supplemented with BMP-4 and vascular endothelial growth factor. The hiPSC-ECs exhibited endothelial characteristics by forming capillary-like structures in matrigel and incorporating acetylated-LDL. They stained positively for EC markers such as KDR, CD31, CD144, and eNOS. In vitro exposure of hiPSC-ECs to hypoxia resulted in increased expression of various angiogenic related cytokines and growth factors. hiPSC-ECs were stably transduced with a double fusion construct encoded by the ubiquitin promoter, firefly luciferase for bioluminescence imaging and green fluorescence protein for fluorescent detection. The hiPSC-ECs (5×10
5
) were delivered by intramuscular injection into the ischemic hindlimb of SCID mice at day 0 and again on day 7 after femoral artery ligation (n=8). Bioluminescence imaging showed that hiPSC-ECs survived in the ischemic limb for at least 2 weeks. In addition, laser Doppler imaging showed that the ratio of blood perfusion was increased by hiPSC-EC treatment by comparison to the saline-treated group (0.58±0.12 versus 0.44±0.04;
P
=0.005). The total number of capillaries in the ischemic limb of mice receiving hiPSC-EC injections was greater than those in the saline-treated group (1284±155 versus 797±206 capillaries/mm
2
) (
P
<0.002).

Conclusion—

This study is a first step toward development of a regenerative strategy for peripheral arterial disease based on the use of ECs derived from hiPSCs.
C1q/TNF-Related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation Through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway
Authors: Zheng Qijun , Yuan Yuexing , Yi Wei , Lau Wayne Bond , Wang Yajing , Wang Xiaoliang , Sun Yang , Lopez Bernard L. , Christopher Theodore A. , Peterson Jonathan M. , Wong G. William , Yu Shiqiang , Yi Dinghua , Ma Xin-Liang
Published: August 2011

Objective—

Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN′s metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown.

Methods and Results—

The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects.

Conclusion—

We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
Secreted Frizzled-Related Protein-1 Improves Postinfarction Scar Formation Through a Modulation of Inflammatory Response
Authors: Barandon Laurent , Casassus Fréderic , Leroux Lionel , Moreau Catherine , Allières Cécile , Lamazière Jean-Marie Daniel , Dufourcq Pascale , Couffinhal Thierry , Duplàa Cécile
Published: August 2011

Objective—

The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process.

Methods and Results—

We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro- and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters.

Conclusion—

sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction.
Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum–Sensing Molecule
Authors: Kim Juyong Brian , Xia Yu-Rong , Romanoski Casey E. , Lee Sangderk , Meng YongHong , Shi Yi-Shou , Bourquard Noam , Gong Ke Wei , Port Zachary , Grijalva Victor , Reddy Srinivasa T. , Berliner Judith A. , Lusis Aldons J. , Shih Diana M.
Published: August 2011

Objective—

Chronic infection has long been postulated as a stimulus for atherogenesis.
Pseudomonas aeruginosa
infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression.

Methods and Results—

Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC.

Conclusion—

3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
Expression of Sar1b Enhances Chylomicron Assembly and Key Components of the Coat Protein Complex II System Driving Vesicle Budding
Authors: Levy Emile , Harmel Elodie , Laville Martine , Sanchez Rocio , Emonnot Léa , Sinnett Daniel , Ziv Ehud , Delvin Edgard , Couture Patrick , Marcil Valérie , Sane Alain T.
Published: August 2011

Objective—

SAR1b plays a significant role in the assembly, organization, and function of the coat protein complex II, a critical complex for the transport of proteins from the endoplasmic reticulum to the Golgi. Recently, mutations in
SARA2
have been associated with lipid absorption disorders. However, functional studies on Sar1b-mediated lipid synthesis pathways and lipoprotein packaging have not been performed.

Methods and Results—

Sar1b was overexpressed in Caco-2/15 cells and resulted in significantly augmented triacylglycerol, cholesteryl ester, and phospholipid esterification and secretion and markedly enhanced chylomicron production. It also stimulated monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity and enhanced apolipoprotein B-48 protein synthesis, as well as elevated microsomal triglyceride transfer protein activity. Along with the enhanced chylomicrons, microsomes were characterized by abundant Sec12, the guanine exchange factor that promotes the localization of Sar1b in the endoplasmic reticulum. Furthermore, coimmunoprecipitation experiments revealed high levels of the complex components Sec23/Sec24 and p125, the Sec23-interacting protein. Finally, a pronounced interaction of Sec23/Sec24 with sterol regulatory element binding protein (SREBP) cleavage-activating protein and SREBP-1c was noted, thereby permitting the transfer of the transcription factor SREBP-1c to the nucleus for the activation of genes involved in lipid metabolism.

Conclusion—

Our data suggest that Sar1b expression may promote intestinal lipid transport with the involvement of the coat protein complex II network and the processing of SREBP-1c.
Deficiency of Scavenger Receptor BI Leads to Impaired Lymphocyte Homeostasis and Autoimmune Disorders in Mice
Authors: Feng Hong , Guo Ling , Wang Dan , Gao Haiqing , Hou Guihua , Zheng Zhong , Ai Junting , Foreman Oded , Daugherty Alan , Li Xiang-An
Published: August 2011

Objective—

Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor. Recent studies revealed that SR-BI protects against sepsis via modulating innate immunity. However, its role in adaptive immunity is unclear.

Methods and Results—

SR-BI-null mice exhibited impaired lymphocyte homeostasis as shown by splenomegaly and imbalanced expansion of T and B lymphocytes in the spleens. Importantly, the activated T and B lymphocytes were increased 3- to 4-fold, indicating a heightened active status of T and B lymphocytes. More importantly, in line with the accumulation of the activated T and B lymphocytes, SR-BI-null mice developed systemic autoimmune disorders characterized by the presence of autoantibodies in circulation, the deposition of immune complexes in glomeruli, and the leukocyte infiltration in kidney. Further analyses revealed that SR-BI deficiency enhanced lymphocyte proliferation, caused imbalanced interferon-γ and interleukin-4 production in lymphocytes, and caused elevated inflammatory cytokine production in macrophages. Furthermore, HDL from SR-BI-null mice exhibited less capability of suppressing lymphocyte proliferation.

Conclusion—

SR-BI regulates lymphocyte homeostasis, likely through its roles in modulating the proliferation of lymphocytes, the cytokine production by lymphocytes and macrophages, and the function of HDL. Its deficiency leads to impaired lymphocyte homeostasis and autoimmune disorders. Our findings reveal a previously unrecognized role of SR-BI in adaptive immunity.
Activation of the Annexin A1 Pathway Underlies the Protective Effects Exerted by Estrogen in Polymorphonuclear Leukocytes
Authors: Nadkarni Suchita , Cooper Dianne , Brancaleone Vincenzo , Bena Stefania , Perretti Mauro
Published: August 2011

Objective—

The anti-inflammatory properties of the female sex hormone estrogen have been linked to a reduced incidence of cardiovascular disease. In the present study, we addressed whether estrogen could activate vasculoprotective mechanisms via annexin A1 (AnxA1) mobilization in human polymorphonuclear cells (PMNs).

Methods and Results—

Using whole-blood flow cytometry, we demonstrated that premenopausal women expressed higher levels of surface AnxA1 on circulating PMNs compared with males. This correlated with high plasma estrogen during the menstrual cycle. The addition of estrogen in vitro to male PMNs induced rapid mobilization of AnxA1, optimal at 5 ng/mL and a 30-minute incubation period; this effect was abolished in the presence of the estrogen receptor antagonist ICI182780. Estrogen addition to human PMNs induced a distinct AnxA1
hi
CD62L
lo
CD11b
lo
phenotype, and this was associated with lower cell activation as measured by microparticle formation. Treatment of human PMNs with E
2
inhibited cell adhesion to an endothelial cell monolayer under shear, which was absent when endogenous AnxA1 was neutralized. Of interest, addition of estrogen to PMNs flowed over the endothelial monolayer amplified its upregulation of AnxA1 localization on the cell surface. Finally, in a model of intravital microscopy, estrogen inhibition of white blood cell adhesion to the postcapillary venule was absent in mice nullified for AnxA1.

Conclusion—

We unveil a novel AnxA1-dependent mechanism behind the inhibitory properties of estrogen on PMN activation, describing a novel phenotype with a conceivable impact on the vasculoprotective effects of this hormone.
Heritability of Tpeak-Tend Interval and T-Wave Amplitude
Authors: Haarmark Christian , Kyvik Kirsten O. , Vedel-Larsen Esben , Budtz-Jørgensen Esben , Kanters Jørgen K.
Published: August 2011

Background—

Tpeak-Tend interval (TpTe) and T-wave amplitude (Tamp) carry diagnostic and prognostic information regarding cardiac morbidity and mortality. Heart rate and QT interval are known to be heritable traits. The heritability of T-wave morphology parameters such as TpTe and Tamp is unknown. TpTe and Tamp were evaluated in a large sample of twins.

Methods and Results—

Twins from the GEMINAKAR study (611 pairs, 246 monozygotic, 365 dizygotic; mean age, 38±11 years; 49% men) who had an ECG performed during 1997 to 2000 were included. Tamp was measured in leads V1 and V5. Duration variables (RR interval, QTpeak and QTend interval) were measured and averaged over 3 consecutive beats in lead V5. TpTe was calculated as the QTend- and QTpeak-interval difference. Heritability was assessed using structural equation models adjusting for age, sex, and body mass index. All models were reducible to a model of additive genetics and unique environment. All variables had considerable genetic components. Adjusted heritability estimates were as follows: TpTe, 46%; Tamp lead V1, 34%; Tamp lead V5, 47%; RR interval, 55%; QT interval, 67%; and Bazett-corrected QT interval, 42%.

Conclusions—

RR interval, QT interval, Tamp, and TpTe interval are heritable ECG parameters.
Loss-of-Function Mutations in the
KCNJ8
-Encoded Kir6.1 K
ATP
Channel and Sudden Infant Death Syndrome
Authors: Tester David J. , Tan Bi-Hua , Medeiros-Domingo Argelia , Song Chunhua , Makielski Jonathan C. , Ackerman Michael J.
Published: August 2011

Background—

Approximately 10% of sudden infant death syndrome (SIDS) may stem from cardiac channelopathies. The
KCNJ8
-encoded Kir6.1 (K
ATP
) channel critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, including sepsis.
KCNJ8
-deficient mice are prone to premature sudden death, particularly with infection. We determined the spectrum, prevalence, and function of KCNJ8 mutations in a large SIDS cohort.

Methods and Results—

Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive open reading frame/splice-site mutational analysis of KCNJ8 was performed on genomic DNA isolated from necropsy tissue on 292 unrelated SIDS cases (178 males, 204 white; age, 2.9±1.9 months). KCNJ8 mutations were coexpressed heterologously with SUR2A in COS-1 cells and characterized using whole-cell patch-clamp. Two novel KCNJ8 mutations were identified. A 5-month-old white male had an in-frame deletion (E332del) and a 2-month-old black female had a missense mutation (V346I). Both mutations localized to Kir6.1's C-terminus, involved conserved residues and were absent in 400 and 200 ethnic-matched reference alleles respectively. Both cases were negative for mutations in established channelopathic genes. Compared with WT, the pinacidil-activated K
ATP
current was decreased 45% to 68% for Kir6.1-E332del and 40% to 57% for V346I between −20 mV and 40 mV.

Conclusions—

Molecular and functional evidence implicated loss-of-function KCNJ8 mutations as a novel pathogenic mechanism in SIDS, possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors akin to the mouse models of KCNJ8 deficiency.
Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines
Authors: Boerrigter Guido , Lark Michael W. , Whalen Erin J. , Soergel David G. , Violin Jonathan D. , Burnett John C.
Published: August 2011

Background—

The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic “unbiased” AT1R antagonists block receptor coupling to both G
αq
and ß-arrestin–mediated signals, which desensitize G-protein signaling as well as transduce G-protein–independent signals. TRV120027 is a novel ß-arrestin–biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling. At the AT1R, TRV120027 can inhibit angiotensin II–mediated vasoconstriction, whereas, through ß-arrestin coupling, increase cardiomyocyte contractility. We defined for the first time the acute cardiorenal actions of TRV120027 in healthy and heart failure (HF) canines.

Methods and Results—

Healthy and HF canines (induced by tachypacing) were anesthetized. After instrumentation and equilibration, a 30-minute baseline clearance was performed, followed by further clearance with escalating doses of intravenous TRV120027 (0.01, 0.1, 1, 10, and 100 μg/kg per minute) and a 30-minute washout. In healthy canines, TRV120027 decreased pulmonary capillary wedge pressure and systemic and renal vascular resistances, while increasing cardiac output, renal blood flow, glomerular filtration rate, and urinary sodium excretion. In HF canines, TRV120027 decreased mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure, systemic and renal vascular resistances and increased cardiac output and renal blood flow. Glomerular filtration rate and urinary sodium excretion were maintained.

Conclusions—

We report for the first time the cardiorenal actions of the novel ß-arrestin–biased AT1R ligand TRV120027. In both normal and HF canines, TRV120027 demonstrated cardiac unloading actions while preserving renal function. With this beneficial pharmacological profile, TRV120027 represents a novel strategy for the treatment of HF.
Hyperphosphorylation of Mouse Cardiac Titin Contributes to Transverse Aortic Constriction-Induced Diastolic Dysfunction
Authors: Hudson Bryan , Hidalgo Carlos , Saripalli Chandra , Granzier Henk
Published: August 2011

Rationale:

Mechanisms underlying diastolic dysfunction need to be better understood.

Objective:

To study the role of titin in diastolic dysfunction using a mouse model of experimental heart failure induced by transverse aortic constriction.

Methods and Results:

Eight weeks after transverse aortic constriction surgery, mice were divided into heart failure (HF) and congestive heart failure (CHF) groups. Mechanical studies on skinned left ventricle myocardium measured total and titin-based and extracellular matrix-based passive stiffness. Total passive stiffness was increased in both HF and CHF mice, and this was attributable to increases in both extracellular matrix-based and titin-based passive stiffness, with titin being dominant. Protein expression and titin exon microarray analysis revealed increased expression of the more compliant N2BA isoform at the expense of the stiff N2B isoform in HF and CHF mice. These changes are predicted to lower titin-based stiffness. Because the stiffness of titin is also sensitive to titin phosphorylation by protein kinase A and protein kinase C, back phosphorylation and Western blot assays with novel phospho-specific antibodies were performed. HF and CHF mice showed hyperphosphorylation of protein kinase A sites and the proline glutamate valine lysine (PEVK) S26 protein kinase C sites, but hypophosphorylation of the PEVK S170 protein kinase C site. Protein phosphatase I abolished differences in phosphorylation levels and normalized titin-based passive stiffness levels between control and HF myocardium.

Conclusion:

Transverse aortic constriction-induced HF results in increased extracellular matrix-based and titin-based passive stiffness. Changes in titin splicing occur, which lower passive stiffness, but this effect is offset by hyperphosphorylation of residues in titin spring elements, particularly of PEVK S26. Thus, complex changes in titin occur that combined are a major factor in the increased passive myocardial stiffness in HF.
Incidence of Transient Ischemic Attack and Early Stroke Risk
Authors: Cancelli Iacopo , Janes Francesco , Gigli Gian Luigi , Perelli Anna , Zanchettin Barbara , Canal Giessica , D'Anna Lucio , Russo Valentina , Barbone Fabio , Valente Mariarosaria
Published: August 2011

Background and Purpose—

The importance of transient ischemic attack (TIA) lies on the short-term risk of stroke, and the ABCD2 score may improve early stroke risk prediction. However, population-based studies are still needed. We aimed to provide data on TIA incidence and to evaluate the ABCD2 predictive ability for early recurrent stroke in a population-based study.

Methods—

This study is part of a 2-year prospective community-based registry of all cerebrovascular events in the district of Udine (153 312 inhabitants), Friuli Venezia Giulia region, northeast of Italy, between April 1, 2007 and March 31, 2009. Multiple overlapping sources for finding cases were used, combining hot and cold pursuit.

Results—

We identified 178 TIA, 161 (90.4%) of which were incident. The crude overall annual TIA incidence rate per 1000 residents was 0.52 (95% confidence interval [CI], 0.45–0.61). Incidence rate was 0.45 (95% CI, 0.31–0.65) when standardized to the 2007 Italian population and 0.25 (95% CI, 0.16–0.39) when standardized to the European standard population. Estimates of stroke risk after the index TIA within 2, 7, 30, and 90 days were, respectively, 2.5% (95% CI, 0.7–6.2), 5.6% (95% CI, 2.6–10.3), 6.2% (95% CI, 3.0–11.1), and 11.2% (95% CI, 6.8–17.1). ABCD2 score was strongly associated with stroke occurrence after index TIA: the areas under the receiver operating characteristic curve at 2, 7, 30, and 90 days were, respectively, 0.85 (95% CI, 0.72–0.97), 0.69 (95% CI, 0.56–0.82), 0.69 (95% CI, 0.56–0.85), and 0.76 (95% CI, 0.67–0.86). No patients with an ABCD2 score <4 had a stroke within the 90-day follow-up period.

Conclusions—

This study adds new data on TIA incidence and prognosis and it further validates the ability of the ABCD2 score to identify patients at early risk for stroke.
Neurocognitive Improvement After Carotid Artery Stenting in Patients With Chronic Internal Carotid Artery Occlusion and Cerebral Ischemia
Authors: Lin Mao-Shin , Chiu Ming-Jang , Wu Yen-Wen , Huang Ching-Chang , Chao Chi-Chao , Chen Ying-Hsien , Lin Hung-Ju , Li Hung-Yuan , Chen Ya-Fang , Lin Lung-Chun , Liu Yen-Bin , Chao Chia-Lun , Tseng Wen-Yih Isaac , Chen Ming-Fong , Kao Hsien-Li
Published: August 2011

Background and Purpose—

Chronic cerebral hypoperfusion may lead to impairment in neurocognitive performance in patients with chronic internal carotid artery occlusion, and the effects of carotid artery stenting on neurocognitive function have been unclear.

Methods—

We prospectively enrolled 20 chronic internal carotid artery occlusion patients with objective ipsilateral hemisphere ischemia, in whom carotid artery stenting was attempted. Functional assessments, including the National Institutes of Health Stroke Scale, Barthel Index, and a battery of neuropsychological tests, including the Mini-Mental State Examination, Alzheimer Disease Assessment Scale–Cognitive Subtest, verbal fluency, and Color Trail Making A and B, were administered before and 3 months after intervention.

Results—

Successful recanalization was achieved in 12 of 20 patients (60%). There was no procedural or new cerebral ischemic event, except for 1 intracranial hemorrhage, which occurred during the procedure and had neurologic sequelae; this case was excluded from analysis. The demographics and baseline cognitive performance were similar between the group with a successful outcome (group 1, n=12) and patients who did not (group 2, n=7). Ten of 12 patients in group 1 had improvement in ipsilateral brain perfusion after the procedure, but none in group 2 had improvement. Significant improvement in the scores on the Alzheimer Disease Assessment Scale–Cognitive Subtest (before, 7.7±8.9 versus after, 5.7±7.1;
P
=0.024), Mini-Mental State Examination (before, 25.8±3.8 versus after, 27.7±2.7;
P
=0.015), and Color Trail Making A (before, 123.2±68.6 versus after, 99.3±51.5;
P
=0.017) were found in group 1 but not in group 2.

Conclusions—

Successful carotid artery stenting improves global cognitive function as well as attention and psychomotor processing speed in patients with chronic internal carotid artery occlusion.
Measures of Abdominal Adiposity and the Risk of Stroke
Authors: Bodenant Marie , Kuulasmaa Kari , Wagner Aline , Kee Frank , Palmieri Luigi , Ferrario Marco M. , Montaye Michèle , Amouyel Philippe , Dallongeville Jean
Published: August 2011

Background and Purpose—

Excess fat accumulates in the subcutaneous and visceral adipose tissue compartments. We tested the hypothesis that indicators of visceral adiposity, namely, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), are better predictors of stroke risk than body mass index (BMI).

Methods–

The association of BMI, WC, WHR, and WHtR with stroke was assessed in 31 201 men and 23 516 women, free of vascular disease at baseline, from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. During a mean follow-up of 11 years, 1130 strokes were recorded. Relative risks (95% CI) were calculated by Cox regression after stratification for center and adjustment for age, smoking, educational level, alcohol consumption, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, and BMI and model fit was assessed using log-likelihoods.

Results—

BMI, WC, WHR, and WHtR were associated with the risk of stroke in men. After full adjustment including BMI, the relative risks for stroke remained significant for WC (1.19 [1.02 to 1.34] per 1 SD increase in WC), WHR (1.14 [1.03 to 1.26]), and WHtR (1.50 [1.28 to 1.77]). Among women, the extent of the associations with stroke risk was similar for WHtR (1.31 [1.04 to 1.65]), WC (1.19 [0.96 to 1.47]), and WHR (1.08 [0.97 to 1.22]). Further analyses by World Health Organization obesity categories showed that WC, WHR, and WHtR were associated with the risk of stroke also in lean men and women (BMI <25 kg/m
2
), independently of confounders, cardiovascular risk factors, and BMI.

Conclusions—

Indicators of abdominal adiposity, especially WHtR, are more strongly associated with stroke risk than BMI. These results emphasize the importance of measuring abdominal adiposity, especially in lean subjects.
Early Biomarkers of Clinical–Diffusion Mismatch in Acute Ischemic Stroke
Authors: Rodríguez-Yáñez Manuel , Sobrino Tomás , Arias Susana , Vázquez-Herrero Fernando , Brea David , Blanco Miguel , Leira Rogelio , Castellanos Mar , Serena Joaquín , Vivancos José , Dávalos Antonio , Castillo José
Published: August 2011

Background and Purpose—

Clinical–diffusion mismatch (CDM; National Institutes of Health Stroke Scale score ≥8 and diffusion-weighted imaging lesion volume <25 mL) has been suggested as a surrogate of ischemic brain at risk of infarction and might be used to recognize salvageable ischemic tissue. Our aim was to identify early biomarkers associated with the presence of CDM.

Methods—

We prospectively evaluated CDM in 226 patients (71.6±11.1 years, 58% men) with hemispheric ischemic stroke within 12 hours from symptom onset (median, 3.6 hours). Diffusion-weighted MRI lesion volume was measured by manual segmentation method. Serum levels of glutamate, aspartate, interleukin-10, tumor necrosis factor-α, interleukin-6, S100β, neuron-specific enolase, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, active matrix metalloproteinase-9, and cellular fibronectin were determined by immunoassay or high-performance liquid chromatography techniques in blood samples obtained at admission.

Results—

CDM was found in 61 patients (26.9%). Patients with CDM had higher serum levels of interleukin-10, tumor necrosis factor-α, and glutamate and lower serum levels of neuron-specific enolase, interleukin-6, and active matrix metalloproteinase-9 (all
P
<0.0001). Binary logistic regression showed that tumor necrosis factor-α ≥21 pg/mL (OR, 21), glutamate ≥230 μmol/L (OR, 27), neuron-specific enolase ≥23 ng/mL (OR, 0.05), interleukin-6 ≥10 pg/mL (OR, 0.06), and active matrix metalloproteinase-9 ≥21 ng/mL (OR, 0.28) were independent molecular predictors of CDM after adjustment for covariates. The association of interleukin-10 ≥23 pg/mL and glutamate ≥230 μmol/L levels predicted CDM with a sensitivity of 96% and a specificity of 98%.

Conclusions—

High levels of interleukin-10, tumor necrosis factor-α, and glutamate as well as low levels of neuron-specific enolase, interleukin-6, and active matrix metalloproteinase-9 are associated with CDM.
Intracranial Hemorrhage Is Much More Common After Carotid Stenting Than After Endarterectomy
Authors: McDonald Robert J. , Cloft Harry J. , Kallmes David F.
Published: August 2011

Background and Purpose—

Intracranial hemorrhage (ICH) is a rare and devastating complication of carotid revascularization. We sought to determine the prevalence of, type of, and risk factors associated with ICH among recipients of carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS) within the National Inpatient Sample (NIS).

Methods—

Postoperative cases of ICH after CEA (International Classification of Disease 9
th
edition [ICD-9]: 38.12) or CAS (ICD-9: 00.63) were retrieved from the 2001 to 2008 NIS. Clinical presentation (asymptomatic versus symptomatic), discharge status, in-hospital mortality, demographics, and hospital characteristics were extracted from NIS data. Charlson indices of comorbidity were determined based on ICD-9 and clinical classification software codes. Multivariate regression was used to determine the impact of revascularization procedure type and symptom status on adverse outcomes, including ICH, in-hospital mortality, and unfavorable discharge status.

Results—

Among 57 663 486 NIS hospital admissions, 215 012 CEA and 13 884 CAS procedures were performed. Symptomatic presentations represented the minority of CEA (N=10 049; 5%) and CAS cases (N=1251; 10%). ICH occurred significantly more frequently after CAS than CEA in both symptomatic (4.4% versus 0.8%;
P
<0.0001) and asymptomatic presentations (0.5% versus 0.06%;
P
<0.0001). Multivariate regression suggested that symptomatic presentations (versus asymptomatic) and CAS procedures (versus CEA) were both independently predictive of 6-fold to 7-fold increases in the frequency of postoperative ICH. ICH was independently predictive in a 30-fold increased risk of mortality before discharge.

Conclusions—

CAS procedures are associated with elevated adverse outcomes, including ICH, in-hospital death, and unfavorable discharges, especially among symptomatic presentations.
Low Carotid Calcium Score Is Associated With Higher Levels of Glycosaminoglycans, Tumor Necrosis Factor-Alpha, and Parathyroid Hormone in Human Carotid Plaques
Authors: Edsfeldt Andreas , Dias Nuno , Elmståhl Barbara , Müller Markus F. , Berg Katarina , Nitulescu Mihaela , Persson Ana , Ekberg Olle , Gonçalves Isabel
Published: August 2011

Background and Purpose—

Computed tomography (CT) is used to study coronary artery plaques, but little is known about its potential to characterize plaque composition. This study assesses the relation between carotid calcium score (CCS) by CT and plaque composition, namely extracellular matrix, inflammatory mediators, and calcium metabolites.

Methods—

Thirty patients with significant carotid stenosis underwent preoperative CT. CCS was quantified by Agaston calcium score. Plaque components were studied histologically and biochemically (collagen, elastin, and glycosaminoglycans). Fraktalkine, interferon-γ, interleukin-10, interleukin-12 p70, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, platelet-derived growth factor-AB/BB, RANTES and tumor necrosis factor-α, and parathyroid hormone were measured using Luminex technology.

Results—

Plaques with CCS ≥400 had more calcium (
P
=0.012), less glycosaminoglycan (
P
=0.002), tumor necrosis factor-α (
P
=0.013), and parathyroid hormone (
P
=0.028) than those with CCS <400. CCS correlated with plaque content of calcium (
r
=0.62;
P
<0.001) and inversely with glycosaminoglycan (
r
=−0.49;
P
=0.006) and tumor necrosis factor-α (
r
=−0.56;
P
=0.001).

Conclusions—

Human carotid plaques with high CCS are richer in calcium and have lower amounts of glycosaminoglycan, parathyroid hormone, and tumor necrosis factor-α, which is one of the main proinflammatory cytokines involved in atherosclerosis. This suggests that CCS not only reflects the degree of calcification, but also other important biological components relevant for stability such as inflammation.
Chronically Epileptic Human and Rat Neocortex Display a Similar Resistance Against Spreading Depolarization In Vitro
Authors: Maslarova Anna , Alam Mesbah , Reiffurth Clemens , Lapilover Ezequiel , Gorji Ali , Dreier Jens P.
Published: August 2011

Background and Purpose—

Experimental and clinical evidence suggests that prolonged spreading depolarizations (SDs) are a promising target for therapeutic intervention in stroke because they recruit tissue at risk into necrosis by protracted intracellular calcium surge and massive glutamate release. Unfortunately, unlike SDs in healthy tissue, they are resistant to drugs such as N-methyl-d-aspartate-receptor antagonists. This drug resistance of SD in low perfusion areas may be due to the gradual rise of extracellular potassium before SD onset. Brain slices from patients undergoing surgery for intractable epilepsy allow for screening of drugs, targeting pharmacoresistant SDs under elevated potassium in human tissue. However, network changes associated with epilepsy may interfere with tissue susceptibility to SD. This could distort the results of pharmacological tests.

Methods—

We investigated the threshold for SD, induced by a gradual rise of potassium, in neocortex slices of patients with intractable epilepsy and of chronically epileptic rats as well as age-matched and younger control rats using combined extracellular potassium/field recordings and intrinsic optical imaging.

Results—

Both age and epilepsy significantly increased the potassium threshold, which was similarly high in epileptic rat and human slices (23.6±2.4 mmol/L versus 22.3±2.8 mmol/L).

Conclusions—

Our results suggest that chronic epilepsy confers resistance against SD. This should be considered when human tissue is used for screening of neuroprotective drugs. The finding of similar potassium thresholds for SD in epileptic human and rat neocortex challenges previous speculations that the resistance of the human brain against SD is markedly higher than that of the rodent brain.
Remote Ischemic Per-Conditioning
Authors: Hahn Cecil D. , Manlhiot Cedric , Schmidt Michael R. , Nielsen Torsten T. , Redington Andrew N.
Published: August 2011

Background and Purpose—

Remote ischemic preconditioning is a phenomenon by which a short period of sublethal ischemia to an organ protects against subsequent ischemia in another organ. We have recently demonstrated that remote ischemic conditioning by transient hind limb ischemia delivered during ischemia and before reperfusion can provide potent cardioprotection, a phenomenon we termed per-conditioning. This study evaluated whether remote ischemic per-conditioning may provide neuroprotection in a clinically relevant rat model of acute ischemic stroke.

Methods—

Remote ischemic conditioning by transient limb ischemia was used in a rat transient middle cerebral artery occlusion model of acute stroke. A total of 39 P60 rats were randomly allocated to receive preconditioning, per-conditioning, or sham conditioning. Cerebral ischemia was maintained for 120 minutes followed by reperfusion. The resulting infarct size at 24 hours was quantified using computerized image analysis of 2–3-5-triphenyl tetrazolium chloride-stained brain sections.

Results—

Compared with control, both pre- and per-conditioning significantly reduced brain infarct size with the more clinically relevant per-conditioning stimulus being superior to preconditioning.

Conclusions—

Remote per-conditioning by transient limb ischemia is a facile, clinically relevant stimulus that provides potent neuroprotection in a model of regional brain ischemia–reperfusion injury. Further studies are required to better understand the mechanisms and biology of this response before translation to randomized controlled trials of remote per-conditioning for acute ischemic stroke.
Tight Analysis of the (1+1)-EA for the Single Source Shortest Path Problem
Authors: Doerr Benjamin , Happ Edda , Klein Christian
Published: August 2011

We conduct a rigorous analysis of the (1+1) evolutionary algorithm for the single source shortest path problem proposed by Scharnow, Tinnefeld, and Wegener (The analyses of evolutionary algorithms on sorting and shortest paths problems, 2004, Journal of Mathematical Modelling and Algorithms, 3(4):349–366). We prove that with high probability, the optimization time is O(n2 max{ℓ, log(n)}), where ℓ is the smallest integer such that any vertex can be reached from the source via a shortest path having at most ℓ edges.

This bound is tight. For all values of n and ℓ we provide a graph with edge weights such that, with high probability, the optimization time is of order Ω(n2 max{ℓ, log(n)}).

To obtain such sharp bounds, we develop a new technique that overcomes the coupon collector behavior of previously used arguments. Also, we exhibit a simple Chernoff type inequality for sums of independent geometrically distributed random variables, and one for sequences of random variables that are not independent, but show a desired behavior independent of the outcomes of the previous random variables. We are optimistic that these tools find further applications in the analysis of evolutionary algorithms.
Encouraging Behavioral Diversity in Evolutionary Robotics: An Empirical Study
Authors: Mouret J.-B. , Doncieux S.
Published: August 2011

Evolutionary robotics (ER) aims at automatically designing robots or controllers of robots without having to describe their inner workings. To reach this goal, ER researchers primarily employ phenotypes that can lead to an infinite number of robot behaviors and fitness functions that only reward the achievement of the task—and not how to achieve it. These choices make ER particularly prone to premature convergence. To tackle this problem, several papers recently proposed to explicitly encourage the diversity of the robot behaviors, rather than the diversity of the genotypes as in classic evolutionary optimization. Such an approach avoids the need to compute distances between structures and the pitfalls of the noninjectivity of the phenotype/behavior relation; however, it also introduces new questions: how to compare behavior? should this comparison be task specific? and what is the best way to encourage diversity in this context? In this paper, we review the main published approaches to behavioral diversity and benchmark them in a common framework. We compare each approach on three different tasks and two different genotypes. The results show that fostering behavioral diversity substantially improves the evolutionary process in the investigated experiments, regardless of genotype or task. Among the benchmarked approaches, multi-objective methods were the most efficient and the generic, Hamming-based, behavioral distance was at least as efficient as task specific behavioral metrics.
Making the Climate a Part of the Human World
Authors: Donner Simon D.
Published: August 2011

Doubts about the scientific evidence for anthropogenic climate change persist among the general public, particularly in North America, despite overwhelming consensus in the scientific community about the human influence on the climate system. The public uncertainty may be rooted in the belief, held by many cultures across the planet, that the climate is not directly influenced by people. The belief in divine control of weather and climate can, in some cases, be traced back to the development of agriculture and the early city-states. Drawing upon evidence from anthropology, theology, and communication studies, this article suggests that in many regions this deeply ingrained belief may limit public acceptance of the evidence for anthropogenic climate change. Successful climate change education and outreach programs should be designed to help overcome perceived conflict between climate science and long-held cultural beliefs, drawing upon lessons from communication and education regarding other potentially divisive subjects, such as evolution.
Analysis of Local Air–Sea Interaction in East Asia Using a Regional Air–Sea Coupled Model
Authors: Qian Huang , Suxiang Yao , Yaocun Zhang
Published: August 2011

A regional air–sea coupled climate model based on the third regional climate model (RegCM3) and the regional oceanic model [the Princeton Ocean Model (POM)] is used to analyze the local air–sea interaction over East Asia in this study. The results indicate that the simulated sea surface temperature (SST) of the coupled model RegCM3–POM is reasonably accurate, and that the spatial pattern and temporal variation are consistent with that of the Global Sea Ice and Sea Surface Temperature dataset (GISST). The correlation between the SST and the atmospheric variables shows that the uncoupled model RegCM3 forced by the given SST cannot reproduce the real-time and SST lag correlation between SST and precipitation, and between SST and surface wind speed, whereas the relationship in the coupled model RegCM3–POM is reasonably accurate. RegCM3–POM reflects the air–sea interaction in the South China Sea and western Pacific Ocean, where the SST lead correlation is the inverse of the SST lag correlation between SST and precipitation, and strong winds bring warm water to the midlatitudes, so the correlation between wind speed and SST is negative in low latitudes and positive in the Kuroshio area. The uncoupled model fails to reproduce the effect of the atmosphere on the ocean. The further study on air–sea interaction in the South China Sea indicates that the earlier warm seawater corresponds to strong sensible heat flux, evaporation, precipitation, and weak net solar radiation, and the early strong sensible heat flux, evaporation, wind at the 10-m level, and weak net solar radiation cause the cold SST.
Simulated Interannual Variations of Freshwater Content and Sea Surface Height in the Beaufort Sea*
Authors: Long Z. , Perrie W. , Tang C. L. , Dunlap E. , Wang J.
Published: August 2011

The authors investigate the interannual variations of freshwater content (FWC) and sea surface height (SSH) in the Beaufort Sea, particularly their increases during 2004–09, using a coupled ice–ocean model (CIOM), adapted for the Arctic Ocean to simulate the interannual variations. The CIOM simulation exhibits a (relative) salinity minimum in the Beaufort Sea and a warm Atlantic water layer in the Arctic Ocean, which is similar to the Polar Hydrographic Climatology (PHC), and captures the observed FWC maximum in the central Beaufort Sea, and the observed variation and rapid decline of total ice concentration, over the last 30 years. The model simulations of SSH and FWC suggest a significant increase in the central Beaufort Sea during 2004–09. The simulated SSH increase is about 8 cm, while the FWC increase is about 2.5 m, with most of these increases occurring in the center of the Beaufort gyre. The authors show that these increases are due to an increased surface wind stress curl during 2004–09, which increased the FWC in the Beaufort Sea by about 0.63 m yr−1 through Ekman pumping. Moreover, the increased surface wind is related to the interannual variation of the Arctic polar vortex at 500 hPa. During 2004–09, the polar vortex had significant weakness, which enhanced the Beaufort Sea high by affecting the frequency of synoptic weather systems in the region. In addition to the impacts of the polar vortex, enhanced melting of sea ice also contributes to the FWC increase by about 0.3 m yr−1 during 2004–09.
Seasonal and Interannual Variations of the SST above the Seychelles Dome
Authors: Yokoi Takaaki , Tozuka Tomoki , Yamagata Toshio
Published: August 2011

The seasonal and interannual variations of the sea surface temperature (SST) above the Seychelles Dome (SD) are investigated using outputs from an OGCM. The SST warms from August to April and cools from May to July. The surface heat flux plays the most important role in the seasonal variation, and it is mostly due to shortwave radiation. The horizontal advection tends to warm the SST in austral winter owing to the southward Ekman heat transport associated with the Indian summer monsoon. The cooling by the vertical turbulent diffusion becomes most effective in austral summer owing to the thin mixed layer during that time. On the interannual time scale, the SST becomes anomalously warm (cool) when the SD is weak (strong). In contrast to the seasonal variation, the vertical diffusion plays the most important role and causes anomalous warming (cooling). This warming (cooling) is due to the anomalously warm (cold) water below the mixed layer as a result of the deeper (shallower) thermocline in response to ocean dynamics. Also, the cooling by the vertical diffusion becomes less (more) efficient, because the mixed layer is anomalously thick (thin). The horizontal advection contributes to the anomalous warming (cooling) due to the anomalous southward (northward) Ekman heat transport. On the other hand, the anomalous surface heat flux tends to cool (warm) the mixed layer, because the warming of the mixed layer by the shortwave radiation becomes less (more) efficient due to the anomalously thick (thin) mixed layer.