bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fourier transform infrared spectroscopy imaging of live epithelial cancer cells under non-aqueous media
Authors: Soh JunYi , Chueng Adeline , Adio Aminat , Cooper Alan J , Birch Brian R , Lwaleed Bashir A 
Published: February 2013

AimsFourier transform infrared (FT-IR) imaging is increasingly being applied to biomedical specimens, but strong IR absorption by water complicates live cell imaging. This study investigates the viability of adherent epithelial cells maintained for short periods under mineral oils in order to facilitate live cell spectroscopy using FT-IR with subsequent imaging.MethodsThe MGH-U1 urothelial or CaCo2 colorectal cancer cell lines were grown on plastic surfaces or mid-range infrared transparent windows. Medium in established cultures was replaced with paraffin mineral oil, or Fluorolube, for up to 2 h, and viability assessed by supravital staining. Drug handling characteristics were also assessed. Imaging of preparations was attempted by reflectance and transmission using a Varian FT-IR microscope.ResultsCells covered by mineral oil remained viable for 2 h, with recovery into normal medium possible. MTT ((3-(4,5-dimethylthlazol-2-yl)-2,5-diphenyl tetrazolium) conversion to crystalline formazan and differential patterns of drug uptake were maintained. The combination of a calcium fluoride substrate, Fluorolube oil, and transmission optics proved best for spectroscopy. Spectral features were used to obtain images of live cells.ConclusionsThe viability of cells overlaid with IR transparent oils was assessed as part of a technique to optimise conditions for FT-IR imaging. Images of untreated cells were obtained using both reflectance and transmission. This represents an effective means of imaging live cells by IR spectroscopy, and also means that imaging is not necessarily a terminal event. It also increases options for producing images based on real-time biochemistry in a range of in vitro experimental and ‘optical biopsy’ contexts.
Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice
Authors: Sabir Ian N , Matthews Gareth D K , Huang Christopher L-H 
Published: February 2013

Abstract
Atrial fibrillation, the commonest cardiac arrhythmia, predisposes to thrombus formation and consequently increases risk of ischaemic stroke. Recent years have seen approval of a number of novel oral anticoagulants. Nevertheless, warfarin and aspirin remain the mainstays of therapy. It is widely appreciated that both these agents increase the likelihood of bleeding: there is a popular conception that this risk is greater with warfarin. In fact, well-managed warfarin therapy (INR 2–3) has little effect on bleeding risk and is twice as effective as aspirin at preventing stroke. Patients with atrial fibrillation and a further risk factor for stroke (CHA2DS2-VASc &gt;0) should therefore either receive warfarin or a novel oral agent. The remainder who are at the very lowest risk of stroke are better not prescribed antithrombotic therapy. For stroke prevention in atrial fibrillation; aspirin is rarely the right choice.
Hyperactivated JNK Is a Therapeutic Target in pVHL-Deficient Renal Cell Carcinoma
Authors: An Jiabin , Liu Huiren , Magyar Clara E. , Guo Yanchuan , Veena Mysore S. , Srivatsan Eri S. , Huang Jiaoti , Rettig Matthew B. 
Published: February 2013

Abstract
Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-α) is the most well-studied effect of VHL inactivation, direct inhibition of HIFα or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e., HIF-α) and gene replacement therapy of tumor suppressor genes (i.e., VHL). Here, we have established that phosphorylated c-Jun, a substrate of the c-Jun-NH2-kinase (JNK), is selectively activated in clear cell RCC patient specimens. Using multiple isogenic cell lines, we show that HIF-α–independent JNK hyperactivation is unique to the pVHL-deficient state. Importantly, pVHL-deficient RCCs are dependent upon JNK activity for in vitro and in vivo growth. A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a CARD9/BCL10/TRAF6 complex as a proximal signal to sequentially stimulate TAK1 (MAPKKK), MKK4 (MAPKK), and JNK (MAPK). JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos to form a transcriptionally competent AP1 complex that drives transcription of the Twist gene and induces epithelial–mesenchymal transition. Thus, JNK represents a novel molecular target that is selectively activated in and drives the growth of pVHL-deficient clear cell RCCs. These findings can serve as the preclinical foundation for directed efforts to characterize potent pharmacologic inhibitors of the JNK pathway for clinical translation. Cancer Res; 73(4); 1374–85. ©2012 AACR.
Long-Term Use of Lipid-Lowering Drugs Slows Progression of Carotid Atherosclerosis
Authors: Herder Marit , Arntzen Kjell Arne , Johnsen Stein Harald , Eggen Anne Elise , Mathiesen Ellisiv B. 
Published: February 2013

Objective—
Data on the effect of lipid-lowering drugs (LLD) on carotid atherosclerosis outside clinical trials are limited. The aim of this study was to determine the effect of LLD on change in carotid intima media thickness and total plaque area in a general population.

Approach and Results—

Subjects were 1532 women and 1442 men who participated in a longitudinal population-based study with ultrasound examination of intima media thickness and total plaque area in the right carotid artery at baseline and after 13 years follow-up. Long-term use of LLD was defined as use for >5 years, any-time use of LLD was defined as use at baseline or at 6 years or at 13 years of follow-up. In multivariable models adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent cardiovascular disease, and daily smoking, long-term use of LLD had a protective effect on progression of both intima media thickness (β=–0.0387 mm;
P
=0.002) and total plaque area (β=–0.400 mm
2
;
P
=0.006). There was a weaker protective effect of any-time use of LLD on progression of intima media thickness (β=–0.024 mm;
P
=0.046) and total plaque area (β=–0.318 mm
2
;
P
=0.06).

Conclusions—
LLD protected against progression of carotid atherosclerosis. The protective effect was strongest in long-term users.
A 28-kDa Splice Variant of NADPH Oxidase-4 Is Nuclear-Localized and Involved in Redox Signaling in Vascular Cells
Authors: Anilkumar Narayana , Jose Gorka San , Sawyer Iain , Santos Celio X.C. , Sand Claire , Brewer Alison C. , Warren Derek , Shah Ajay M. 
Published: February 2013

Objective—
Reactive oxygen species–generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase proteins (Noxs) are involved in cell differentiation, migration, and apoptosis. Nox4 is unique among Noxs in being constitutively active, and its subcellular localization may therefore be particularly important. In this study, we identified and characterized a novel nuclear-localized 28-kDa splice variant of Nox4 in vascular cells.

Approach and Results—
Nox4 immunoreactivity was noted in the nucleus and nucleolus of vascular smooth muscle cells and multiple other cell types by confocal microscopy. Cell fractionation, sequence analyses, and siRNA studies indicated that the nuclear-localized Nox4 is a 28-kDa splice variant, Nox4D, which lacks putative transmembrane domains. Nox4D overexpression resulted in significant NADPH-dependent reactive oxygen species production as detected by several different methods and caused increased phosphorylation of extracellular-signal-regulated kinase1/2 and the nuclear transcription factor Elk-1. Overexpression of Nox4D could also induce DNA damage as assessed by γ-H2AX phosphorylation. These effects were inhibited by a single amino acid substitution in the Nox4D NADPH-binding region.

Conclusions—
Nox4D is a nuclear-localized and functionally active splice variant of Nox4 that may have important pathophysiologic effects through modulation of nuclear signaling and DNA damage.
Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes
Authors: Moran Corey S. , Jose Roby J. , Moxon Joseph V. , Roomberg Alicia , Norman Paul E. , Rush Catherine , Körner Heinrich , Golledge Jonathan 
Published: February 2013

Objective—
We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E–deficient mouse model.

Approach and Results—
Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of interferon (IFN)-γ and IFNγ-induced CCR2 expression in apolipoprotein E–deficient mouse bone marrow monocytes. Further, everolimus diminished IFNγ/lipopolysaccharide-stimulated M1 polarization in apolipoprotein E–deficient mouse bone marrow monocyte–differentiated macrophages.

Conclusions—
Systemic administration of everolimus limits aortic aneurysm in the A2-infused apolipoprotein E–deficient mouse model via suppressed development of bone marrow CCR2 monocytes and reduced egress of these cells into the circulation.
Panoramic Electrophysiological Mapping but not Electrogram Morphology Identifies Stable Sources for Human Atrial Fibrillation
Authors: Narayan Sanjiv M. , Shivkumar Kalyanam , Krummen David E. , Miller John M. , Rappel Wouter-Jan 
Published: February 2013

Background—
The foundation for successful arrhythmia ablation is the mapping of electric propagation to identify underlying mechanisms. In atrial fibrillation (AF), however, mapping is difficult so that ablation has often targeted electrogram features, with mixed results. We hypothesized that wide field-of-view (panoramic) mapping of both atria would identify causal mechanisms for AF and allow interpretation of local electrogram features, including complex fractionated atrial electrograms (CFAE).

Methods and Results—

Contact mapping was performed using biatrial multipolar catheters in 36 AF subjects (29 persistent). Stable AF rotors (spiral waves) or focal sources were seen in 35 of 36 cases and targeted for ablation (focal impulse and rotor modulation) before pulmonary vein isolation. In 31 of 36 subjects (86.1%), AF acutely terminated (n=20; 16 to sinus rhythm) or organized (n=11; 19±8% slowing) with 2.5 minutes focal impulse and rotor modulation (interquartile range, 1.0–3.1) at one source, defined as the primary source. Subjects exhibited 2.1±1.0 concurrent AF sources of which the primary, by phase mapping, precessed in limited areas (persistent 2.5±1.7 versus paroxysmal 1.7±0.5 cm
2
;
P
=0.30). Notably, source regions showed mixed electrogram amplitudes and CFAE grades that did not differ from surrounding atrium (
P
=NS). AF sources were not consistently surrounded by CFAE (
P
=0.67).

Conclusions—

Stable rotors and focal sources for human AF were revealed by contact panoramic mapping (focal impulse and rotor modulation mapping), but not by electrogram footprints. AF sources precessed within areas of ≈2 cm
2
, with diverse voltage characteristics poorly correlated with CFAE. Most CFAE sites lie remote from AF sources and are not suitable targets for catheter ablation of AF.
Validation of a Cardiopulmonary Exercise Test Score in Heart Failure
Authors: Myers Jonathan , Oliveira Ricardo , Dewey Frederick , Arena Ross , Guazzi Marco , Chase Paul , Bensimhon Daniel , Peberdy Mary Ann , Ashley Euan , West Erin , Cahalin Lawrence P. , Forman Daniel E. 
Published: February 2013

Background—
Cardiopulmonary exercise test (CPX) responses are strong predictors of outcomes in patients with heart failure. We recently developed a CPX score that integrated the additive prognostic information from CPX. The purpose of this study was to validate the score in a larger, independent sample of patients.

Methods and Results—

A total of 2625 patients with heart failure underwent CPX and were followed for cardiovascular (CV) mortality and major CV events (death, transplantation, left ventricular assist device implantation). Net reclassification improvement (NRI) for the score and each of its components were determined at 3 years. The VE/VCO
2
slope was the strongest predictor of risk and was attributed a relative weight of 7, with weighted scores for abnormal heart rate recovery, oxygen uptake efficiency slope, end-tidal CO
2
pressure, and peak VO
2
having scores of 5, 3, 3, and 2, respectively. A summed score of >15 was associated with an annual mortality rate of 12.2% and a relative risk >9 for total events, whereas a score of <5 was associated with an annual mortality rate of 1.2%. The composite score was the most accurate predictor of CV events among all CPX responses considered (C indexes, 0.70 for CV mortality and 0.72 for the composite outcome). Each component of the score provided significant NRI compared with peak VO
2
(category-free NRI, 0.61–0.77), and the score provided significant NRI above clinical risk factors for both CV events and mortality (NRI, 0.63 and 0.65 for CPX score compared with clinical variables alone).

Conclusions—
These results validate the application of a simple, integrated multivariable score based on readily available CPX responses.
Donor Predictors of Allograft Use and Recipient Outcomes After Heart Transplantation
Authors: Khush Kiran K. , Menza Rebecca , Nguyen John , Zaroff Jonathan G. , Goldstein Benjamin A. 
Published: February 2013

Background—
Despite a national organ-donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft nonuse, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.

Methods and Results—
We studied a cohort of 1872 potential organ donors managed by the California Transplant Donor Network from 2001 to 2008. Forty-five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft nonuse included age>50 years, female sex, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay, left-ventricular dysfunction and regional wall motion abnormalities, and left-ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes mellitus was predictive of increased recipient mortality.

Conclusions—
Whereas there are many donor predictors of allograft discard in the current era, these characteristics seem to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.
Relationship of Right- to Left-Sided Ventricular Filling Pressures in Advanced Heart Failure
Authors: Drazner Mark H. , Velez-Martinez Mariella , Ayers Colby R. , Reimold Sharon C. , Thibodeau Jennifer T. , Mishkin Joseph D. , Mammen Pradeep P.A. , Markham David W. , Patel Chetan B. 
Published: February 2013

Background—
Although right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) are correlated in heart failure, in a sizeable minority of patients, the RAP and PCWP are not tightly coupled. The basis of this variability in the RAP/PCWP ratio, and whether it conveys prognostic value, is not known.

Methods and Results—

We analyzed the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial database. Baseline characteristics, including echocardiographic assessment of right ventricular (RV) structure and function, and invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP ratio. Multivariable Cox proportional hazard models assessed the association of RAP/PCWP ratio with the primary ESCAPE outcome (6-month death or hospitalization [days]) adjusting for systolic blood pressure, blood urea nitrogen, 6-minute walk distance, and PCWP. The RAP/PCWP tertiles were 0.27 to 0.4 (tertile 1); 0.41 to 0.615 (tertile 2), and 0.62 to 1.21 (tertile 3). Increasing RAP/PCWP was associated with increasing median right atrial area (23, 26, 29 cm
2
, respectively;
P
<0.005), RV area in diastole (21, 27, 27 cm
2
, respectively;
P
<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units, respectively;
P
=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g·m/m
2
per beat, respectively;
P
<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months (hazard ratio, 1.16 [1, 1.4];
P
<0.05).

Conclusions—
Increased RAP/PCWP ratio was associated with higher pulmonary vascular resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke work index), and an increased risk of adverse outcomes in patients with advanced heart failure.
Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke
Authors: Lees Kennedy R. , Bornstein Natan , Diener Hans-Christoph , Gorelick Philip B. , Rosenberg Gilad , Shuaib Ashfaq 
Published: February 2013

Background and Purpose—
DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke.

Methods—
The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intent-to-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was an exploratory end point.

Results—

Enrollment terminated at n=446 after the planned interim analysis determined futility; follow-up continued. Final modified Rankin score distributions were equal between DP-b99 and placebo-treated groups (
P
=0.10;
P
adj
adjusted for baseline age and National Institutes of Health Stroke Scale=0.21). Fewer patients recovered to modified Rankin score ≤1 in the DP-b99–treated group (45/218; 20.6%) than after placebo (63/219; 28.8%) (
P
=0.05;
P
adj
=0.10). Similarly, fewer patients attained National Institutes of Health Stroke Scale ≤1 after DP-b99 (42/218; 19.3%) than placebo (56/219; 25.6%;
P
=0.10;
P
adj
=0.26). Mortality was similar between DP-b99 and placebo intent-to-treat groups (36/218; 16.5% vs 33/219; 15.1%;
P
=0.68). Home time was unchanged by treatment (median 36 vs 36.5 days;
P
=0.25).

Conclusions—
Despite encouraging preclinical and phase II trial data, DP-b99 shows no evidence of efficacy in treating human ischemic stroke.
Simvastatin Attenuates Stroke-induced Splenic Atrophy and Lung Susceptibility to Spontaneous Bacterial Infection in Mice
Authors: Jin Rong , Zhu Xiaolei , Liu Lin , Nanda Anil , Granger D. Neil , Li Guohong 
Published: February 2013

Background and Purpose—
Statins are widely used in the primary and secondary prevention of ischemic stroke, but their effects on stroke-induced immunodepression and poststroke infections are elusive. We investigated the effects of simvastatin treatment on stroke-induced splenic atrophy and lung susceptibility to bacterial infection in acute experimental stroke in mice.

Methods—
Ischemic stroke was induced by transient middle cerebral artery occlusion, followed by reperfusion. In some experiments, splenectomies were performed 2 weeks before middle cerebral artery occlusion. Animals were randomly assigned to sham and middle cerebral artery occlusion groups treated subcutaneously with vehicle or simvastatin (20 mg/kg per day). Brain infarction, neurological function, brain interferon-γ expression, splenic atrophy and apoptosis, and lung infection were examined.

Results—
Simvastatin reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial antiapoptotic Bcl-2 expression and decreased proapoptotic Bax translocation from cytosol into mitochondria. Splenectomy reduced brain interferon-γ (3 days) and infarct size (5 days) after stroke, and these effects were reversed by adoptive transfer of splenocytes. Simvastatin inhibited brain interferon-γ (3 days) and reduced infarct volume and neurological deficits (5 days) after stroke, and these protective effects were observed not only in naive stroke mice but also in splenectomied stroke mice adoptively transferred with splenocytes. Simvastatin also decreased the stroke-associated lung susceptibility to spontaneous bacterial infection.

Conclusions—
Results provide the first direct experimental evidence that simvastatin ameliorates stroke-induced peripheral immunodepression by attenuating spleen atrophy and lung bacterial infection. These findings contribute to a better understanding of the beneficial effects of statins in the treatment of stroke.
Acute Effect of Ambient Air Pollution on Stroke Mortality in the China Air Pollution and Health Effects Study
Authors: Chen Renjie , Zhang Yuhao , Yang Chunxue , Zhao Zhuohui , Xu Xiaohui , Kan Haidong 
Published: February 2013

Background and Purpose—
There have been no multicity studies on the acute effects of air pollution on stroke mortality in China. This study was undertaken to examine the associations between daily stroke mortality and outdoor air pollution (particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide) in 8 Chinese cities.

Methods—
We used Poisson regression models with natural spline-smoothing functions to adjust for long-term and seasonal trends, as well as other time-varying covariates. We applied 2-stage Bayesian hierarchical statistical models to estimate city-specific and national average associations of air pollution with daily stroke mortality.

Results—

Air pollution was associated with daily stroke mortality in 8 Chinese cities. In the combined analysis, an increase of 10 μg/m
3
of 2-day moving average concentrations of particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide corresponded to 0.54% (95% posterior intervals, 0.28–0.81), 0.88% (95% posterior intervals, 0.54–1.22), and 1.47% (95% posterior intervals, 0.88–2.06) increase of stroke mortality, respectively. The concentration–response curves indicated linear nonthreshold associations between air pollution and risk of stroke mortality.

Conclusions—
To our knowledge, this is the first multicity study in China, or even in other developing countries, to report the acute effect of air pollution on stroke mortality. Our results contribute to very limited data on the effect of air pollution on stroke for high-exposure settings typical in developing countries.