bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonsteroidal Anti-inflammatory Drugs and Glioma in the NIH-AARP Diet and Health Study Cohort
Authors: Daugherty Sarah E. , Moore Steven C. , Pfeiffer Ruth M. , Inskip Peter D. , Park Yikyung , Hollenbeck Albert , Rajaraman Preetha 
Published: September 2011

Abstract
Several case–control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (&gt;2 times/wk) of aspirin and risk of glioma (HR = 1.16; 95% CI, 0.87–1.56) or glioblastoma (HR = 1.17; 95% CI, 0.83–1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma = 0.90; 95% CI, 0.65–1.25 and HR for glioblastoma = 0.83; 95% CI, 0.56–1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma. Cancer Prev Res; 4(12); 2027–34. ©2011 AACR.
Dysregulated Selectin Expression and Monocyte Recruitment During Ischemia-Related Vascular Remodeling in Diabetes Mellitus
Authors: Carr Chad L. , Qi Yue , Davidson Brian , Chadderdon Scott , Jayaweera Ananda R. , Belcik J. Todd , Benner Cameron , Xie Aris , Lindner Jonathan R. 
Published: September 2011

Objective—
Diabetes mellitus (DM) is associated with impaired ischemia-related vascular remodeling and also dysregulation of the inflammatory response. We sought to determine whether impaired selectin-mediated monocyte recruitment in ischemic tissues contributes to blunted ischemia-mediated angiogenesis in DM.

Methods and Results—

Contrast-enhanced ultrasound perfusion imaging and molecular imaging of endothelial P-selectin expression in the proximal hindlimb were performed at 1, 3, and 21 days after arterial ligation in wild-type and db/db mice. Ligation reduced muscle blood flow to ≈0.05 mL/minute per gram in both strains. Significant recovery of flow occurred only in wild-type mice (60%–65% of baseline flow). On molecular imaging, baseline P-selectin signal was 4-fold higher in db/db compared with wild-type mice (
P
<0.01) but increased minimally at day 1 after ischemia, whereas signal increased approximately 10-fold in wild-type mice (
P
<0.01). Immunohistology of the hindlimb skeletal muscle demonstrated severely reduced monocyte recruitment in db/db mice compared with wild-type mice. Local treatment with monocyte chemotactic protein-1 corrected the deficits in postischemic P-selectin expression and monocyte recruitment in db/db mice and led to greater recovery in blood flow.

Conclusion—
In DM, there is dysregulation of the selectin response to limb ischemia, which leads to impaired monocyte recruitment, which may be mechanistically related to reduced vascular remodeling in limb ischemia.
MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1
Authors: Ramirez Cristina M. , Dávalos Alberto , Goedeke Leigh , Salerno Alessandro G. , Warrier Nikhil , Cirera-Salinas Daniel , Suárez Yajaira , Fernández-Hernando Carlos 
Published: September 2011

Objective—
The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of macrophage cholesterol efflux and protects cells from excess intracellular cholesterol accumulation; however, the mechanism involved in posttranscriptional regulation of ABCA1 is poorly understood. We previously showed that microRNA-33 (miR-33) is 1 regulator. Here, we investigated the potential contribution of other microRNAs (miRNAs) to posttranscriptional regulation of ABCA1 and macrophage cholesterol efflux.

Methods and Results—

We performed a bioinformatic analysis for identifying miRNA target prediction sites in ABCA1 gene and an unbiased genome-wide screen to identify miRNAs modulated by cholesterol excess in mouse peritoneal macrophages. Quantitative real-time reverse transcription–polymerase chain reaction confirmed that miR-758 is repressed in cholesterol-loaded macrophages. Under physiological conditions, high dietary fat excess in mice repressed miR-758 both in peritoneal macrophages and, to a lesser extent, in the liver. In mouse and human cells in vitro, miR-758 repressed the expression of ABCA1, and conversely, the inhibition of this miRNA by using anti-miR-758 increased ABCA1 expression. In mouse cells, miR-758 reduced cellular cholesterol efflux to apolipoprotein A1 (apoA1), and anti-miR-758 increased it. miR-758 directly targets the 3′-untranslated region of
Abca1
as assessed by 3′-untranslated region luciferase reporter assays. Interestingly, miR-758 is highly expressed in the brain, where it also targets several genes involved in neurological functions, including
Slc38a1, Ntm, Epha7
, and
Mytl1
.

Conclusion—
We identified miR-758 as a novel miRNA that posttranscriptionally controls ABCA1 levels in different cells and regulates macrophage cellular cholesterol efflux to apoA1, opening new avenues to increase apoA1 and raise high-density lipoprotein levels.
Angiopoietin-1 Requires IQ Domain GTPase-Activating Protein 1 to Activate Rac1 and Promote Endothelial Barrier Defense
Authors: David Sascha , Ghosh Chandra C. , Mukherjee Aditi , Parikh Samir M. 
Published: September 2011

Objective—
IQ domain GTPase-activating protein 1 (IQGAP1) contributes to cytoskeletal network regulation in epithelial cells by its scaffolding properties and by binding the Rho GTPase Rac1 to maintain its activity. The functions of IQGAP1 in endothelial cells beyond angiogenesis remain unclear. We hypothesized that IQGAP1 participates in the regulation of endothelial barrier function.

Methods and Results—
Silencing IQGAP1 in human microvascular endothelial cells resulted in a disruption of adherens junctions, formation of interendothelial gaps, and a reduction in barrier function. Furthermore, silencing of IQGAP1 abrogated the barrier enhancement effect of angiopoietin-1 (Angpt-1) and abolished the barrier-stabilizing effect of Angpt-1 on thrombin-stimulated cells. Coimmunoprecipitation detected binding of endogenous IQGAP1 with Rac1 at baseline that was stronger when Rac1 was activated and weaker when it was deactivated. Measurement of GTP-bound Rac1 revealed that Angpt-1 failed to activate Rac1 not only if IQGAP1 was silenced but also if cells were transfected with a mutant disabled in Rac1 binding (T1050AX2). Furthermore, a dominant-active Rac1 was sufficient to completely reverse the morphological and functional changes induced by reduction in IQGAP1.

Conclusion—
These experiments are the first demonstration of IQGAP1 regulating barrier function in any cell type. Further, our data show that Angpt-1 requires IQGAP1 as an indispensable activator of Rac1.
Fatty Liver, Abdominal Visceral Fat, and Cardiometabolic Risk Factors
Authors: Liu Jiankang , Fox Caroline S. , Hickson DeMarc , Bidulescu Aurelian , Carr J. Jeffery , Taylor Herman A. 
Published: September 2011

Objective—
The goal of this study was to examine whether fatty liver and abdominal visceral adipose tissue (VAT) are jointly associated with cardiometabolic abnormalities.

Methods and Results—

Black participants were from the Jackson Heart Study (n=2882, 65% women) who underwent computed tomography. Fatty liver was measured by liver attenuation in Hounsfield units (LA), and VAT was quantified volumetrically. Cross-sectional associations between LA, VAT, and cardiometabolic risk factors were assessed using linear and logistic regression, and their joint associations were further examined in 4 subgroups: high-LA/low-VAT (n=1704), low-LA/low-VAT (n=422), high-LA/high-VAT (n=436), and low-LA/high-VAT (n=320). Both LA and VAT were associated with most cardiometabolic traits (all
P
<0.0001), which persisted after additional adjustment for each other (LA,
P
<0.01–0.0001; VAT,
P
<0.0001). In bootstrap analyses, the regression coefficient of VAT was significantly greater than LA for triglycerides, high-density lipoprotein cholesterol, impaired glucose, and metabolic syndrome (
P
=0.009–0.0001). The interaction between LA and VAT was significant for high-density lipoprotein cholesterol (
P
=0.002), impaired glucose (
P
=0.003), and metabolic syndrome (
P
=0.04). Among 4 subgroups, participants with higher VAT and lower LA had higher prevalence of cardiometabolic traits than those with each condition alone.

Conclusion—
Both fatty liver and VAT are independent correlates of cardiometabolic risk, but the associations are stronger for VAT than for fatty liver.
Smooth Muscle Cell Apoptosis Promotes Vessel Remodeling and Repair via Activation of Cell Migration, Proliferation, and Collagen Synthesis
Authors: Yu Haixiang , Clarke Murray C.H. , Figg Nichola , Littlewood Trevor D. , Bennett Martin R. 
Published: September 2011

Objective—
Although vascular smooth muscle cell (VSMC) apoptosis occurs after vessel injury and during remodeling, the direct role of VSMC death in determining final vessel structure is unclear. We sought to determine the role of VSMC apoptosis in vessel remodeling, medial repair, and neointima formation and to identify the mediators involved.

Methods and Results—
The left common carotid artery was ligated in SM22α-human diphtheria toxin receptor mice, in which diphtheria toxin treatment selectively induces VSMC apoptosis. Apoptosis induced from day 7 to day 14 after ligation significantly increased neointimal and medial areas, cell proliferation, migration, and vessel size. Neointima formation depended on VSMCs, as VSMC depletion before ligation significantly reduced neointimal area and cellularity. In culture, conditioned media from apoptotic VSMCs promoted VSMC migration, proliferation, and collagen synthesis. Interleukin-6 (IL-6) secretion increased 5-fold and IL-1α 1.5-fold after apoptosis, whereas IL-6 inhibition negated the effect of apoptotic VSMC supernatants on VSMC migration, proliferation, and matrix synthesis.

Conclusion—
Signaling from apoptotic VSMCs directly promotes vessel remodeling, medial repair, and neointima formation after flow reduction. Although lumen size appears to depend on flow, VSMC apoptosis is an important determinant of vessel, medial, and neointimal size after flow reduction.
The Cholesterol Content of Western Diets Plays a Major Role in the Paradoxical Increase in High-Density Lipoprotein Cholesterol and Upregulates the Macrophage Reverse Cholesterol Transport Pathway
Authors: Escolà-Gil Joan Carles , Llaverias Gemma , Julve Josep , Jauhiainen Matti , Méndez-González Jesús , Blanco-Vaca Francisco 
Published: September 2011

Objective—
A high–saturated fatty acid– and cholesterol-containing (HFHC) diet is considered to be a major risk factor for cardiovascular disease. The present study aimed to determine the effects of this Western-type diet on high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT) from macrophages to feces.

Methods and Results—

Experiments were carried out in mice fed a low-fat, low-cholesterol diet, an HFHC diet, or an HFHC diet without added cholesterol (high–saturated fatty acid and low-cholesterol [HFLC]). The HFHC diet caused a significant increase in plasma cholesterol, HDL cholesterol, and liver cholesterol and enhanced macrophage-derived [
3
H]cholesterol flux to feces by 3- to 4-fold. These effects were greatly reduced in mice fed the HFLC diet. This HFHC diet–mediated induction of RCT was sex independent and was not associated with obesity or insulin resistance. The HFHC diet caused 1.4- and 3-fold increases in [
3
H]cholesterol efflux to plasma and HDL-derived [
3
H]tracer fecal excretion, respectively. Unlike a low-fat, low-cholesterol and HFLC diets, the HFHC diet increased liver ABCG5/G8 expression. The effect of the HFHC diet on fecal macrophage-derived [
3
H]cholesterol excretion was totally blunted in ABCG5/G8-deficient mice.

Conclusion—
Despite its deleterious effects on atherosclerosis, the HFHC diet promoted a sustained compensatory macrophage-to-feces RCT. Our data provide direct evidence of the crucial role of dietary cholesterol signaling through liver ABCG5/G8 upregulation in the HFHC diet–mediated induction of macrophage-specific RCT.
Human Thrombomodulin Knock-In Mice Reveal Differential Effects of Human Thrombomodulin on Thrombosis and Atherosclerosis
Authors: Raife Thomas J. , Dwyre Denis M. , Stevens Jeff W. , Erger Rochelle A. , Leo Lorie , Wilson Katina M. , Fernández Jose A. , Wilder Jennifer , Kim Hyung-Suk , Griffin John H. , Maeda Nobuyo , Lentz Steven R. 
Published: September 2011

Objective—
We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.

Methods and Results—

Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (
P
<0.01) and lung (
P
<0.001). Activation of endogenous protein C following infusion of thrombin was decreased by 90% in knock-in mice compared with wild-type mice (
P
<0.05). Carotid artery thrombosis induced by photochemical injury occurred more rapidly in knock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes;
P
<0.05). No differences in serum cytokine levels were detected between knock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E–deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis.

Conclusion—
Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.
Improving Door-to-Needle Times in Acute Ischemic Stroke
Authors: Fonarow Gregg C. , Smith Eric E. , Saver Jeffrey L. , Reeves Mathew J. , Hernandez Adrian F. , Peterson Eric D. , Sacco Ralph L. , Schwamm Lee H. 
Published: September 2011

Background and Purpose—
The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time-dependent, and guidelines recommend a door-to-needle time of ≤60 minutes. However, fewer than one third of acute ischemic stroke patients who receive tPA are treated within guideline-recommended door-to-needle times. This article describes the design and rationale of Target: Stroke, a national initiative organized by the American Heart Association/American Stroke Association in partnership with other organizations to assist hospitals in increasing the proportion of tPA-treated patients who achieve guideline-recommended door-to-needle times.

Methods—
The initial program goal is to achieve a door-to-needle time ≤60 minutes for at least 50% of acute ischemic stroke patients. Key best practice strategies previously associated with achieving faster door-to-needle times in acute ischemic stroke were identified.

Results—
The 10 key strategies chosen by Target: Stroke include emergency medical service prenotification, activating the stroke team with a single call, rapid acquisition and interpretation of brain imaging, use of specific protocols and tools, premixing tPA, a team-based approach, and rapid data feedback. The program includes many approaches intended to promote hospital participation, implement effective strategies, share best practices, foster collaboration, and achieve stated goals. A detailed program evaluation is also included. In the first year, Target: Stroke has enrolled over 1200 United States hospitals.

Conclusions—
Target: Stroke, a multidimensional initiative to improve the timeliness of tPA administration, aims to elevate clinical performance in the care of acute ischemic stroke, facilitate the more rapid integration of evidence into clinical practice, and improve outcomes.
Cerebrovascular Disease Pathology and Parkinsonian Signs in Old Age
Authors: Buchman Aron S. , Leurgans Sue E. , Nag Sukriti , Bennett David A. , Schneider Julie A. 
Published: September 2011

Background and Purpose—
Mild motor symptoms including parkinsonian signs are common in old age, but their underlying neuropathology is unclear. We tested the hypothesis that cerebrovascular pathologies are related to parkinsonian signs.

Methods—
We studied brain autopsies from 418 deceased participants from the Religious Order Study, who underwent evaluation of parkinsonian signs with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale. Brains were evaluated for macroscopic and microinfarcts and the severity of arteriolosclerosis. Regression analyses were used to examine the association of cerebrovascular pathologies with parkinsonian signs.

Results—

More than 35% of cases (N=149) showed macroscopic infarcts. Almost 30% of cases without macroscopic infarcts showed pathologies not detected by conventional brain imaging: microinfarcts (N=33 [7.9%]), arteriolosclerosis (N=62 [14.8%]), or both (N=24 [5.7%]). Macroscopic infarcts, specifically multiple cortical and ≥1 subcortical macroscopic infarcts, were related to higher global parkinsonian scores. The presence of multiple and cortical microinfarcts was associated with global parkinsonian score. Arteriolosclerosis was associated with global parkinsonian score, but this effect was attenuated and no longer significant after accounting for infarcts. Each of the 3 pathologies was separately associated with parkinsonian gait (macroscopic infarcts [estimate, 0.552; SE, 0.210;
P
=0.009]; microinfarcts [estimate, 0.424; SE, 0.213;
P
=0.047]; arteriolosclerosis [estimate, 0.191; SE, 0.056;
P
<0.001]). Further analyses showed that subcortical macroscopic and microinfarcts were specifically associated with the severity of parkinsonian gait.

Conclusions—
Cerebrovascular pathologies, including macroscopic infarcts, microinfarcts, and arteriolosclerosis, are common in older persons and may be unrecognized common etiologies of mild parkinsonian signs, especially parkinsonian gait, in old age.
Common Carotid Artery Intima-Media Thickness Progression as a Predictor of Stroke in Multi-Ethnic Study of Atherosclerosis
Authors: Polak Joseph F. , Pencina Michael J. , O'Leary Daniel H. , D'Agostino Ralph B. 
Published: September 2011

Background and Purpose—
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We studied whether IMT rate of change is associated with stroke.

Methods—
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) comprising white, Chinese, Hispanic, and black participants free of cardiovascular disease. In this MESA IMT progression study, IMT rate of change (mm/year) was the difference in right common carotid artery far wall IMT (mm) divided by the interval between 2 ultrasound examinations (median interval, 32 months). Common carotid artery IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate of change was measured. Multivariable Cox proportional hazards models generated hazard risk ratios (HR) with cardiovascular risk factors, ethnicity, and education level/income as predictors.

Results—
There were 42 first-time strokes seen during a mean follow-up of 3.22 years (median, 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR, 1.05 per year), systolic blood pressure (HR, 1.02 per mm Hg), lower high-density lipoprotein cholesterol levels (HR, 0.96 per mg/dL), and IMT rate of change (HR, 1.23 per 0.05 mm/year; 95% confidence limit, 1.02–1.48) were significantly associated with incident stroke. The upper quartile of IMT rate of change had HR of 2.18 (95% confidence limit, 1.07–4.46) compared to the lower 3 quartiles combined.

Conclusions—
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
Different approaches of physical training used in the management of type 2 diabetes
Authors: de Moura Bruno Pereira , Natali Antônio José , Marins João Carlos Bouzas , Amorim Paulo Roberto Santos 
Published: September 2011

Background Type 2 diabetes is now a common and serious global health problem, which, for most countries, has evolved in association with rapid cultural and social changes, ageing populations, increasing urbanisation, dietary changes, reduced physical activity and other unhealthy lifestyle and behavioural patterns. Aims To identify the different approaches to physical training used in the last decade in the management of type 2 diabetes. Methods We searched PubMed and Science Direct for all randomised clinical trials from 1999 to 30 May 2010. Results We selected 17 randomised controlled trials, five studies with aerobic exercise, five with resistance exercise and seven combined exercise studies. Conclusions The use of resistance training for the treatment of type 2 diabetes is becoming more commonly used in the management of type 2 diabetes. The number of studies using resistance exercise has been growing over the last decade, and has actually become as widely used as the popular aerobic exercise. In turn, most of the reviewed studies have used interventions combining resistance and aerobic exercise. An exercise programme for diabetic patients should be seen as a form of treatment. Hence, there were no established guidelines for the duration of the programme, because exercise should become a habitual daily task, and assumed in a new lifestyle for long-term glucose control.