bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Compound Inhibits Reconstituted High-Density Lipoprotein Assembly and Blocks Nascent High-Density Lipoprotein Biogenesis Downstream of Apolipoprotein AI Binding to ATP-Binding Cassette Transporter A1–Expressing Cells
Authors: Lyssenko Nicholas N. , Brubaker Gregory , Smith Bradley D. , Smith Jonathan D. 
Published: August 2011

Objective—
Nascent high-density lipoprotein (HDL) particles form from cellular lipids and extracellular lipid-free apolipoprotein AI (apoAI) in a process mediated by ATP-binding cassette transporter A1 (ABCA1). We have sought out compounds that inhibit nascent HDL biogenesis without affecting ABCA1 activity.

Methods and Results—
Reconstituted HDL (rHDL) formation and cellular cholesterol efflux assays were used to show that 2 compounds that bond via hydrogen with phospholipids inhibit rHDL and nascent HDL production. In rHDL formation assays, the inhibitory effect of compound 1 (methyl 3α-acetoxy-7α,12α-di[(phenylaminocarbonyl)amino]-5β-cholan-24-oate), the more active of the 2, depended on its ability to associate with phospholipids. In cell assays, compound 1 suppressed ABCA1-mediated cholesterol efflux to apoAI, the 18A peptide, and taurocholate with high specificity, without affecting ABCA1-independent cellular cholesterol efflux to HDL and endocytosis of acetylated low-density lipoprotein and transferrin. Furthermore, compound 1 did not affect ABCA1 activity adversely, as ABCA1-mediated shedding of microparticles proceeded unabated and apoAI binding to ABCA1-expressing cells increased in its presence.

Conclusion—
The inhibitory effects of compound 1 support a 3-step model of nascent HDL biogenesis: plasma membrane remodeling by ABCA1, apoAI binding to ABCA1, and lipoprotein particle assembly. The compound inhibits the final step, causing accumulation of apoAI in ABCA1-expressing cells.
Therapeutic Angiogenesis of Human Early Endothelial Progenitor Cells Is Enhanced by Thrombomodulin
Authors: Li Jiun-Yi , Su Cheng-Huang , Wu Yih-Jer , Tien Ting-Yi , Hsieh Chin-Ling , Chen Chih-Hao , Tseng Ya-Ming , Shi Guey-Yueh , Wu Hua-Lin , Tsai Cheng-Ho , Lin Fang-Yue , Yeh Hung-I 
Published: August 2011

Objective—
We examined the effect of thrombomodulin (TM) domains 2 and 3 (TMD23) on human early endothelial progenitor cells (EPCs).

Methods and Results—
TM was expressed and released by human EPCs cultured from peripheral blood mononuclear cells (PBMCs). Addition of TMD23 (100 ng/mL) to the cultured PBMCs increased the colony-forming units, chemotactic motility, matrix metalloproteinase activity, and interleukin-8 secretion but decreased tumor necrosis factor-α (TNF-α) release. Analysis of the signal pathway showed that TMD23 activated Akt. Inhibition of phosphatidylinositol-3 kinase–Akt blocked the effects of TMD23 on chemotactic motility, matrix metalloproteinase-9, interleukin-8, and TNF-α. In hindlimb ischemia mice, laser Doppler perfusion imaging of the ischemic limb during the 21 days after arterial ligation showed that the perfusion recovered best with intraperitoneal infusion of TMD23 plus local injection of early EPCs, followed by either infusion of TMD23 or injection of the cells. Animals without either treatment had the worst results. Animals treated with TMD23 also had lower circulating and tissue levels of TNF-α.

Conclusion—
TM is expressed and released by human circulating EPCs. Exogenous TMD23 enhances the angiogenic potential of early EPCs in vitro through activation of phosphatidylinositol-3 kinase-Akt pathway. Coadministration of TMD23 plus early EPCs augments therapeutic angiogenesis of the EPCs in ischemic tissues.
Impaired Mitochondrial Biogenesis Precedes Heart Failure in Right Ventricular Hypertrophy in Congenital Heart Disease
Authors: Karamanlidis Georgios , Bautista-Hernandez Victor , Fynn-Thompson Francis , del Nido Pedro , Tian Rong 
Published: August 2011

Background—
The outcome of the surgical repair in congenital heart disease correlates with the degree of myocardial damage. In this study, we determined whether mitochondrial DNA depletion is a sensitive marker of right ventricular (RV) damage and whether impaired mitochondrial DNA (mtDNA) replication contributes to the transition from compensated hypertrophy to failure.

Methods and Results—

RV samples obtained from 31 patients undergoing cardiac surgery were compared with 5 RV samples from nonfailing hearts (control). Patients were divided into compensated hypertrophy and failure groups, based on preoperative echocardiography, catheterization, and/or MRI data. Mitochondrial enzyme activities (citrate synthase and succinate dehydrogenase) were maintained during hypertrophy and decreased by ≈40% (
P
<0.05 versus control) at the stage of failure. In contrast, mtDNA content was progressively decreased in the hypertrophied RV through failure (by 28±8% and 67±11%, respectively,
P
<0.05 for both), whereas mtDNA-encoded gene expression was sustained by increased transcriptional activity during compensated hypertrophy but not in failure. Mitochondrial DNA depletion was attributed to reduced mtDNA replication in both hypertrophied and failing RV, and it was independent of PGC-1 downregulation but was accompanied by reduced expression of proteins constituting the mtDNA replication fork. Decreased mtDNA content in compensated hypertrophy was also associated with pathological changes of mitochondria ultrastructure.

Conclusions—
Impaired mtDNA replication causes early and progressive depletion of mtDNA in the RV of the patients with congenital heart disease during the transition from hypertrophy to failure. Decreased mtDNA content probably is a sensitive marker of mitochondrial injury in this patient population.
Molecular MRI of Acute Necrosis With a Novel DNA-Binding Gadolinium Chelate
Authors: Huang Shuning , Chen Howard H. , Yuan Hushan , Dai Guangping , Schuhle Daniel T. , Mekkaoui Choukri , Ngoy Soeun , Liao Ronglih , Caravan Peter , Josephson Lee , Sosnovik David E. 
Published: August 2011

Background—
Current techniques to image cell death in the myocardium are largely nonspecific. We report the use of a novel DNA-binding gadolinium chelate (Gd-TO) to specifically detect the exposed DNA in acutely necrotic (ruptured) cells in vivo.

Methods and Results—

In vivo MRI was performed in 20 mice with myocardial infarction (MI). The mice were injected with Gd-TO or Gd-DTPA at varying time points after MI. MRI was performed 2 hours after probe injection, to avoid nonspecific signal from the late gadolinium enhancement effect. Cell rupture (Gd-TO uptake) was present within 2 hours of infarction but peaked 9 to 18 hours after the onset of injury. A significant increase in the longitudinal relaxation rate (R
1
) in the infarct was seen in mice injected with Gd-TO within 48 hours of MI, but not in those injected more than 72 hours after MI (R
1
=1.24±0.08 and 0.92±0.03 s
−1
, respectively,
P
<0.001). Gd-DTPA, unlike Gd-TO, washed completely out of acute infarcts within 2 hours of injection (
P
<0.001). The binding of Gd-TO to exposed DNA in acute infarcts was confirmed with fluorescence microscopy.

Conclusions—
Gd-TO specifically binds to acutely necrotic cells and can be used to image the mechanism and chronicity of cell death in injured myocardium. Cell rupture in acute MI begins early but peaks many hours after the onset of injury. The ruptured cells are efficiently cleared by the immune system and are no longer present in the myocardium 72 hours after injury.
The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain
Authors: Andres Robert H. , Choi Raymond , Pendharkar Arjun V. , Gaeta Xavier , Wang Nancy , Nathan Jaya K. , Chua Joshua Y. , Lee Star W. , Palmer Theo D. , Steinberg Gary K. , Guzman Raphael 
Published: August 2011

Background and Purpose—
The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia.

Methods—

Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2
+/+
and CCR2
−/−
reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test.

Results—

Using NSC isolated from CCR2
+/+
and CCR2
−/−
mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2
−/−
mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2
+/+
cells within 6 hours after transplantation in contrast to CCR2
−/−
cells. Mice receiving CCR2
+/+
grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2
−/−
NSC.

Conclusions—
The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.
Mesenchymal Stem Cells Primed With Valproate and Lithium Robustly Migrate to Infarcted Regions and Facilitate Recovery in a Stroke Model
Authors: Tsai Li-Kai , Wang Zhifei , Munasinghe Jeeva , Leng Yan , Leeds Peter , Chuang De-Maw 
Published: August 2011

Background and Purpose—
The migratory efficiency of mesenchymal stem cells (MSC) toward cerebral infarct after transplantation is limited. Valproate (VPA) and lithium enhance in vitro migration of MSC by upregulating CXC chemokine receptor 4 and matrix metalloproteinase-9, respectively. Ability of VPA and lithium to promote MSC homing and to improve functional recovery was assessed in a rat model of cerebral ischemia.

Methods—
MSC primed with VPA (2.5 mmol/L, 3 hours) and/or lithium chloride (2.5 mmol/L, 24 hours) were transplanted into rats 24 hours after transient middle cerebral artery occlusion (MCAO). Neurological function was assessed via rotarod test, Neurological Severity Score, and body asymmetry test for 2 weeks. Infarct volume was analyzed by MRI. The number of homing MSC and microvessel density in the infarcted regions were measured 15 days after MCAO using immunohistochemistry.

Results—
Priming with VPA or lithium increased the number of MSC homing to the cerebral infarcted regions, and copriming with VPA and lithium further enhanced this effect. MCAO rats receiving VPA-primed and/or lithium-primed MSC showed improved functional recovery, reduced infarct volume, and enhanced angiogenesis in the infarcted penumbra regions. These beneficial effects of VPA or lithium priming were reversed by AMD3100, a CXC chemokine receptor 4 antagonist, and GM6001, a matrix metalloproteinase inhibitor, respectively.

Conclusions—
Priming with VPA and/or lithium promoted the homing and migration ability of MSC, improved functional recovery, reduced brain infarct volume, and enhanced angiogenesis in a rat MCAO model. These effects were likely mediated by VPA-induced CXC chemokine receptor 4 overexpression and lithium-induced matrix metalloproteinase-9 upregulation.
Diabetes Mellitus and Risk of Stroke and Its Subtypes Among Japanese
Authors: Cui Renzhe , Iso Hiroyasu , Yamagishi Kazumasa , Saito Isao , Kokubo Yoshihiro , Inoue Manami , Tsugane Shoichiro 
Published: August 2011

Background and Purpose—
Although diabetes mellitus has been recognized as a risk factor for ischemic stroke, evidence is limited for ischemic stroke subtypes among Asians.

Methods—
A survey was conducted of a total of 13 129 men and 22 528 women aged 40 to 69 years at baseline. During the median 12.0-year follow-up, there were 526 incidences of ischemic strokes (259 lacunar infarctions, 91 large-artery occlusive, and 140 embolic infarctions).

Results—
The risk of ischemic stroke for both sexes was approximately 2 to 4 times higher for diabetic subjects than for those with normal glucose levels. Significant excess risks of lacunar and embolic infarction for both sexes and of large-artery occlusive infarctions for women were also observed in diabetic subjects. Diabetes mellitus was not associated with risk of intraparenchymal or subarachnoid hemorrhage for either sex.

Conclusions—
Diabetes mellitus is a significant risk factor for ischemic stroke and all subtypes of ischemic stroke for middle-aged Japanese.
The Unrecognized Psychosocial Factors Contributing to Bleeding Risk in Warfarin Therapy
Authors: Diug Basia , Evans Sue , Lowthian Judy , Maxwell Ellen , Dooley Michael , Street Alison , Wolfe Rory , Cameron Peter , McNeil John 
Published: August 2011

Background and Purpose—
Warfarin is an effective drug for the prevention of thromboembolism in the elderly. The major risk for patients taking warfarin is bleeding. We aimed to assess the impact of psychosocial factors, including mood, cognition, social isolation, and health literacy on warfarin instability among community-based elderly patients.

Methods—
A case–control study was conducted between March 2008 and June 2009 in a community-based setting. Cases were patients previously stabilized on warfarin who recorded an international normalized ratio ≥6.0. Control subjects were patients whose international normalized ratio measurement was maintained within the therapeutic range. Patient interviews investigated potential predisposing factors to elevated International Normalized Ratio levels.

Results—
A total of 486 patients were interviewed: 157 cases and 329 control subjects, with an approximate mean age of 75 years. Atrial fibrillation was the most common primary indication. Adjusted multivariate logistic regression revealed impaired cognition (OR, 1.9; 95% CI, 1.0 to 3.6), depressed mood (OR, 2.2; 95% CI, 1.2 to 3.9), and inadequate health literacy (OR, 4.0;95% CI, 2.1 to 7.4) were associated with increased risk of an elevated International Normalized Ratio.

Conclusions—
This study identified impaired cognition, depressed mood, and inadequate health literacy as risk factors for warfarin instability. These had a similar impact to well-recognized demographic, clinical, and medication-related factors and are prevalent among the elderly. These findings suggest that elderly patients prescribed warfarin should be reviewed regularly for psychosocial deficits.
Depression and Incident Stroke in Women
Authors: Pan An , Okereke Olivia I. , Sun Qi , Logroscino Giancarlo , Manson JoAnn E. , Willett Walter C. , Ascherio Alberto , Hu Frank B. , Rexrode Kathryn M. 
Published: August 2011

Background and Purpose—
Depression has been associated with an increased risk of coronary heart disease, but prospective data for the association with stroke are limited.

Methods—
We followed-up 80 574 women aged 54 to 79 years in Nurses' Health Study without a history of stroke from 2000 to 2006. Depressive symptoms were assessed at multiple time points by a Mental Health Index score (1992, 1996, and 2000), and clinical significant depressive symptoms were defined as a score ≤52. Antidepressant medication use was asked biennially beginning in 1996, and physician-diagnosed depression was reported biennially beginning in 2000. Depression was defined as currently reporting or having a history of any of these 3 conditions.

Results—
During 6 years of follow-up, 1033 incident strokes were documented (538 ischemic, 124 hemorrhagic, and 371 unknown strokes). Having a history of depression was associated with a multivariate-adjusted hazard ratio (HR) of 1.29 (95% confidence interval [CI], 1.13–1.48) for total stroke. Women who used antidepressant medications were at increased risk for stroke, whether they also had a Mental Health Index score ≤52 or diagnosed depression (HR, 1.39; 95% CI, 1.15–1.69) or not (HR, 1.31; 95% CI, 1.03–1.67). Furthermore, for each cycle, participants who reported current depression had an increased risk of stroke (HR, 1.41; 95% CI, 1.18–1.67), whereas individuals who only had a history of depression were at nonsignificantly elevated risk (HR, 1.23; 95% CI, 0.97–1.56) compared with women who never reported a diagnosis of depression or antidepressant medication use.

Conclusions—
Our results suggest that depression is associated with a moderately increased risk of subsequent stroke.
Baseline and Longitudinal Increases in Diastolic Blood Pressure Are Associated With Greater White Matter Hyperintensity Volume
Authors: Marcus Justin , Gardener Hannah , Rundek Tatjana , Elkind Mitchell S.V. , Sacco Ralph L. , DeCarli Charles , Wright Clinton B. 
Published: August 2011

Background and Purpose—
Elevated blood pressure (BP) is a risk factor for stroke and dementia, but the effect of BP, and change in BP over time, on white matter hyperintensity volume (WMHV) is not fully understood. Few studies have included Hispanics, who are at greater risk of stroke and dementia than non-Hispanic whites. We examined BP in relation to WMHV in a stroke-free cohort.

Methods—
The Northern Manhattan Study includes 1290 stroke-free participants who had brain MRI. We examined baseline systolic and diastolic (DBP) BP, and changes in BP from baseline to MRI, and WMHV.

Results—

There were 1281 participants with brain MRI and 2 BP measurements (mean age, 64 years; SD=8; range, 40 to 94 years). Baseline DBP was associated with greater WMHV (
P
<0.0001) independent of sociodemographic and vascular risk factors. Each 10 mm Hg above the mean baseline DBP (83±11 mm Hg) was associated with a 1.17% greater WMHV. Over 7 years average follow-up, participants with an increase >5 mm Hg DBP from baseline to MRI had 1.21% greater WMHV relative to those whose BP did not increase (
P
=0.02). The association between baseline DBP and WMHV was strongest for blacks compared with Hispanics and whites (interaction
P
=0.04).

Conclusions—
Baseline DBP and longitudinal increases in DBP were independently associated with a greater WMHV, and the association between DBP and WMHV was greatest among blacks.
Proliferating Reactive Astrocytes Are Regulated by Notch-1 in the Peri-Infarct Area After Stroke
Authors: Shimada Issei S. , Borders Alyssa , Aronshtam Alexander , Spees Jeffrey L. 
Published: August 2011

Background and Purpose—
The formation of reactive astrocytes is common after central nervous system injuries such as stroke. However, the signaling pathway(s) that control astrocyte formation and functions are poorly defined. We assess the effects of Notch 1 signaling in peri-infarct-reactive astrocytes after stroke.

Methods—

We examined reactive astrocyte formation in the peri-infarct area 3 days after distal middle cerebral artery occlusion with or without γ-secretase inhibitor treatment. To directly study the effects of inhibiting a γ-secretase cleavage target in reactive astrocytes, we generated glial fibrillary acidic protein-CreER
TM
:Notch 1 conditional knockout mice.

Results—

Gamma-secretase inhibitor treatment after stroke decreased the number of proliferative glial fibrillary acidic protein-positive reactive astrocytes and RC2-positive reactive astrocytes directly adjacent to the infarct core. The decrease in reactive astrocytes correlated with an increased number of CD45-positive cells that invaded into the peri-infarct area. To study the influence of reactive astrocytes on immune cell invasion, ex vivo immune cell invasion assays were performed. We found that a γ-secretase-mediated pathway in astrocytes affected Jurkat cell invasion. After tamoxifen treatment, glial fibrillary acidic protein-CreER
TM
:Notch 1 conditional knockout mice had a significantly decreased number of proliferating reactive astrocytes and RC2-positive reactive astrocytes. Tamoxifen treatment also led to an increased number of CD45-positive cells that invaded the peri-infarct area.

Conclusions—
Our results demonstrate that proliferating and RC2-positive reactive astrocytes are regulated by Notch 1 signal transduction and control immune cell invasion after stroke.
Long-Term Outcome After Stroke in Belarus
Authors: Kulesh Sergey D. , Kastsinevich Tatsiana M. , Kliatskova Liudmila A. , Sauchanka Maryia E. , Filina Nina A. , Shumskas Mechyslovas S. , Schwab Stefan , Hilz Max J. , Kolominsky-Rabas Peter L. 
Published: August 2011

Background and Purpose—
Data concerning the long-term prognosis after stroke in low-income and middle-income countries are limited. We aimed to establish survival and dependency at 5 years after a first-ever-in-a-lifetime stroke in Grodno, Belarus.

Methods—
All residents of Grodno with a suspected acute stroke were registered prospectively and assessed over a period of 12 months in 2001. Patients were followed-up prospectively at 3 and 12 months, and then annually up to 5 years after the index event.

Results—
There were 671 cases of first-ever-in-a-lifetime stroke, and follow-up data after 5 years were available for 653 of these patients (97.3%); 18 people (2.7%) were lost to follow-up. One hundred ninety patients (29.1%) died during the first 28 days of stroke. The case fatality rate at 3 months was 32.2% (210/653), at 12 months it was 37.4% (244/653), and at 5 years it was 58.8% (384/653). Of the 269 survivors at 5 years, 130 (48.3%) were independent (modified Rankin score, 0–2), and 139 (51.7%) were disabled (modified Rankin score, ≥3). At 5 years, the cumulative risk of death or disability after first-ever-in-a-lifetime stroke was 80.1% (523/653).

Conclusions—
Stroke in Belarus is associated with a very high risk of death or dependency at 5 years.
Evaluating Error Propagation in Coupled Land–Atmosphere Models
Authors: Pijanowski Bryan , Moore Nathan , Mauree Dasaraden , Niyogi Dev 
Published: August 2011

Abstract
This study examines how land-use errors from the Land Transformation Model (LTM) propagate through to climate as simulated by the Regional Atmospheric Model System (RAMS). The authors conducted five simulations of regional climate over East Africa: one using observed land cover/land use (LULC) and four utilizing LTM-derived LULC. The study examined how quantifiable errors generated by the LTM impact typical land–climate variables: precipitation, land surface temperature, air temperature, soil moisture, and latent heat flux. Error propagation was not evident when domain averages for the land–climate variables of the yearlong simulation were examined. However, the authors found that spatial errors from the LTM propagate through in complex ways, temporally affecting the seasonal distributions of rainfall, surface temperature, soil moisture, and latent heat flux. In particular, rainy seasons exhibited greater precipitation in LTM-RAMS simulations than in the reference simulation and less precipitation occurred during the dry season. Complex interactions of precipitation and soil moisture were also evident. Overall, results indicate that small errors from a land change model could grow as a “coupling drift” if both are used to forecast into the future; these couplings could create larger combined errors of land–climate interactions because of time-scale differences into the future. Thus, although land-use change projection is necessary for a more accurate climate projection, existing errors from a land change model will likely amplify through the climate simulation. This finding affects interpretation of large-scale versus land-use/land-cover feedbacks on climate projections.