bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plaque-Associated Vasa Vasorum in Aged Apolipoprotein E–Deficient Mice Exhibit Proatherogenic Functional Features In Vivo
Authors: Rademakers Timo , Douma Kim , Hackeng Tilman M. , Post Mark J. , Sluimer Judith C. , Daemen Mat J. A. P. , Biessen Erik A. L. , Heeneman Sylvia , van Zandvoort Marc A. M. J. 
Published: December 2012

Objective—
Neovascularization of human atherosclerotic plaques is implicated in plaque progression and destabilization, although its functional implications are yet unresolved. Here, we aimed to elucidate functional and morphological properties of plaque microvessels in mice in vivo.

Methods and Results—
Atherosclerotic carotid arteries from aged (>40 weeks) apolipoprotein E–deficient mice were imaged in vivo using multiphoton laser scanning microscopy. Two distinct groups of vasa vasorum microvessels were observed at sites of atherosclerosis development (median diameters of 18.5 and 5.9 μm, respectively), whereas microvessels within the plaque could only rarely be found. In vivo imaging showed ongoing angiogenic activity and injection of fluorescein isothiocyanate-dextran confirmed active perfusion. Plaque vasa vasorum showed increased microvascular leakage, combined with a loss of endothelial glycocalyx. Mean blood flow velocity in plaque-associated vasa vasorum was reduced by ±50% compared with diameter-matched control capillaries, whereas mean blood flow was reduced 8-fold. Leukocyte adhesion and extravasation were increased 6-fold in vasa vasorum versus control capillaries.

Conclusion—
Using a novel in vivo functional imaging strategy, we showed that plaque-associated vasa vasorum were angiogenically active and, albeit poorly, perfused. Moreover, plaque-associated vasa vasorum showed increased permeability, reduced blood flow, and increased leukocyte adhesion and extravasation (ie, characteristics that could contribute to plaque progression and destabilization).
Antioxidant Enzymes Reduce DNA Damage and Early Activation of Valvular Interstitial Cells in Aortic Valve Sclerosis
Authors: Branchetti Emanuela , Sainger Rachana , Poggio Paolo , Grau Juan B. , Patterson-Fortin Jeffrey , Bavaria Joseph E. , Chorny Michael , Lai Eric , Gorman Robert C. , Levy Robert J. , Ferrari Giovanni 
Published: December 2012

Objective—
Accumulation of reactive oxygen species (ROS) and remodeling of the microstructure of the cusp characterize aortic valve sclerosis, the early phase of calcific aortic valve disease. These events are associated with activation of valvular interstitial cells (VICs) toward an osteogenic-like phenotype. Because ROS cause DNA damage and transcriptional activation we investigated the relationship between ROS, DNA damage response, and transdifferentiation of VICs.

Methods and Results—
Human aortic valve cusps and patient-matched VICs were collected from 39 patients both with and without calcific aortic valve disease. VICs were exposed to hydrogen peroxide (0.1–1 mmol/L) after cell transduction with extracellular superoxide dismutase/catalase adenoviruses and characterized for DNA-damage response, osteogenic transdifferentiation, and calcification. ROS induce relocalization of phosphorylated γH2AX, MRE11, and XRCC1 proteins with expression of osteogenic signaling molecule RUNX2 via AKT. We report a sustained activation of γH2AX in aortic valve sclerosis-derived VICs suggesting their impaired ability to repair DNA damage. Adenovirus superoxide dismutase/catalase transduction decreases ROS-induced DNA damage and VIC transdifferentiation in aortic valve sclerosis-derived cells. Finally, adenoviral transduction with catalase reverts ROS-mediated calcification and cellular transdifferentiation.

Conclusion—
We conclude that the ROS-induced DNA damage response is dysfunctional in early asymptomatic stages of calcific aortic valve disease. We unveiled an association among ROS, DNA-damage response, and cellular transdifferentiation, reversible by antioxidant enzymes delivery.
Fatty Acid Amide Hydrolase Deficiency Enhances Intraplaque Neutrophil Recruitment in Atherosclerotic Mice
Authors: Lenglet Sébastien , Thomas Aurélien , Soehnlein Oliver , Montecucco Fabrizio , Burger Fabienne , Pelli Graziano , Galan Katia , Cravatt Benjamin , Staub Christian , Steffens Sabine 
Published: December 2012

Objective—
Endocannabinoid levels are elevated in human and mouse atherosclerosis, but their causal role is not well understood. Therefore, we studied the involvement of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in atherosclerotic plaque vulnerability.

Methods and Results—

We assessed atherosclerosis in apolipoprotein E–deficient (ApoE
–/–
) and ApoE
–/–
FAAH
–/–
mice. Before and after 5, 10, and 15 weeks on high-cholesterol diet, we analyzed weight, serum cholesterol, and endocannabinoid levels, and atherosclerotic lesions in thoracoabdominal aortas and aortic sinuses. Serum levels of FAAH substrates anandamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were 1.4- to 2-fold higher in case of FAAH deficiency. ApoE
–/–
FAAH
–/–
mice had smaller plaques with significantly lower content of smooth muscle cells, increased matrix metalloproteinase-9 expression, and neutrophil content. Circulating and bone marrow neutrophil counts were comparable between both genotypes, whereas CXC ligand1 levels were locally elevated in aortas of FAAH-deficient mice. We observed enhanced recruitment of neutrophils, but not monocytes, to large arteries of ApoE
–/–
mice treated with FAAH inhibitor URB597. Spleens of ApoE
–/–
FAAH
–/–
mice had reduced CD4+FoxP3+regulatory T-cell content, and in vitro stimulation of splenocytes revealed significantly elevated interferon-γ and tumor necrosis factor-α production in case of FAAH deficiency.

Conclusion—
Increased anandamide and related FAAH substrate levels are associated with the development of smaller atherosclerotic plaques with high neutrophil content, accompanied by an increased proinflammatory immune response.
Intramural Coronary Arterial Course Is Associated With Coronary Arterial Stenosis and Prognosis of Major Cardiac Events
Authors: Wang Yibo , Lv Bin , Chen Jinxing , Zhang Yu , Luo Fang , Lu Na , Sun Kai , Hou Zhihui , Cao Huili , Zeb Irfan , Budoff Matthew , Hui Rutai 
Published: December 2012

Objective—
The clinical significance of an intramural course (or bridging) of the coronary artery remains controversial. We investigated the relationship between intramural coronary arteries (ICAs) and coronary stenosis and prognosis of subjects with ICA.

Methods and Results—

ICA and coronary stenosis were assessed by multidetector computed tomography coronary angiography. ICAs in the left anterior descending artery were studied, which were further classified as superficial (≤2 mm) or deep type (>2 mm). Coronary stenosis was classified as nonstenosis, insignificant stenosis (<50%), and significant stenosis (≥50%). A total of 261 subjects with ICA in left anterior descending artery were identified from 2318 enrolled subjects. Most of the ICAs (66.3%) were superficial. ICA was positively associated with insignificant stenosis, and the odds ratios were 2.055 (95% confidence interval, 1.405–3.007), 3.314 (1.818–6.039), and 1.640 (1.036–2.597) for overall, deep, and superficial ICA (all
P
<0.05), respectively. In the case of significant stenosis, ICA was negatively associated, and the odds ratios were 0.555 (0.416–0.739) and 0.413 (0.288–0.590) for overall and superficial ICA (both
P
<0.05), respectively, and 0.985 (0.611–1.588;
P
>0.05) for deep ICA type. The depth and location of ICA correlated with stenosis. The major cardiac events, including cardiovascular death, myocardial infarction, and revascularization, were recorded during 3-year follow-up. ICA predicted a lower incidence of major cardiac events, especially superficial type; the adjusted hazard ratios were 0.585 (0.375–0.911;
P
=0.018) and 0.535 (0.300–0.954;
P
=0.034) for total and superficial type, respectively.

Conclusion—
ICA, especially deep type, is positively associated with insignificant stenosis proximal to ICA. Meanwhile, ICA, especially superficial type, is negatively associated with significant stenosis proximal to ICA and predicts a better prognosis not only in normal subjects but also in patients with coronary artery disease.
Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis Effects of Antioxidant Therapy With NADPH Oxidase Inhibition
Authors: Liu Yani , Davidson Brian P. , Yue Qi , Belcik Todd , Xie Aris , Inaba Yoichi , McCarty Owen J. T. , Tormoen Garth W. , Zhao Yan , Ruggeri Zaverio M. , Kaufmann Beat A. , Lindner Jonathan R. 
Published: December 2012

Background—
In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial–platelet interactions, thereby interrupting progression to high-risk plaque phenotype.

Methods and Results—
Mice deficient for both the low-density lipoprotein receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg per day orally). In vivo molecular imaging of vascular cell adhesion molecule-1 (VCAM 1) P-selectin, and platelet glycoprotein-1bα (GPIbα) in the thoracic aorta was performed with targeted contrast-enhanced ultrasound molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultrahigh frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in nontreated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 weeks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group.

Conclusions—
Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion, which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.
Cardiovascular Outcomes After the Arterial Switch Operation for D-Transposition of the Great Arteries
Authors: Khairy Paul , Clair Mathieu , Fernandes Susan M. , Blume Elizabeth D. , Powell Andrew J. , Newburger Jane W. , Landzberg Michael J. , Mayer John E. 
Published: December 2012

Background—
Data regarding long-term outcomes after the arterial switch operation for D-transposition of the great arteries are scarce.

Methods and Results—

A single-institution retrospective cohort study was conducted to assess cardiovascular outcomes after an arterial switch operation between 1983 and 1999. Patients without follow-up visits within 3 years were contacted and secondary sources of information obtained. Overall, 400 patients, 154 (38.3%) with a ventricular septal defect, 238 (59.5%) with an intact septum, and 9 (2.3%) with a Taussig-Bing anomaly, were followed for a median of 18.7 years. In perioperative survivors, overall and arrhythmia-free survival rates at 25 years were 96.7±1.8% and 96.6±0.1%, respectively. Late mortality was predominantly a result of sudden deaths and myocardial infarction. At 25 years, 75.5±2.5% remained free from surgical or catheter-based reintervention. Freedom from an adverse cardiovascular event was 92.9±1.9% at 25 years. Independent predictors were a single right coronary artery (hazard ratio, 4.58; 95% confidence interval, 1.32-15.90),
P
=0.0166) and postoperative heart failure (hazard ratio, 6.93; 95% confidence interval, 1.57-30.62;
P
=0.0107). At last follow-up, the left ventricular ejection fraction was 60.3±8.9%, 97.3% had class I symptoms, and 5.2% obstructive coronary artery disease. Peak oxygen uptake was 35.1±7.6 mL/kg/min (86.1±15.1% predicted), with a chronotropic index <80% in 34.2%. At least moderate neoaortic and pulmonary regurgitation were present in 3.4% and 6.6%, respectively, and more than mild neoaortic and pulmonary stenosis in 3.2% and 10.3%.

Conclusions—
Long-term and arrhythmia-free survival is excellent after arterial switch operation. Although sequelae include chronotropic incompetence and neoaortic, pulmonary, and coronary artery complications, most patients maintain normal systolic function and exercise capacity.
Human Dental Pulp-Derived Stem Cells Protect Against Hypoxic-Ischemic Brain Injury in Neonatal Mice
Authors: Yamagata Mari , Yamamoto Akihito , Kako Eisuke , Kaneko Naoko , Matsubara Kohki , Sakai Kiyoshi , Sawamoto Kazunobu , Ueda Minoru 
Published: December 2012

Background and Purpose—
Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury.

Methods—
Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these cells was injected into the injured brain. The effects of cell transplantation or conditioned medium injection on the animals’ neurological and pathophysiological recovery were evaluated.

Results—
Transplanted SHED, but not fibroblasts, significantly reduced the HI-induced brain-tissue loss and improved neurological function. SHED also improved the survival of the HI mice. The engrafted SHED rarely differentiated into neural lineages; however, their transplantation inhibited the expression of proinflammatory cytokines, increased the expression of anti-inflammatory ones, and significantly reduced apoptosis. Notably, the intracerebral administration of SHED-conditioned medium also significantly improved the neurological outcome, inhibited apoptosis, and reduced tissue loss.

Conclusions—
SHED transplantation into the HI-injured brain resulted in remarkable neurological and pathophysiological recovery. Our findings indicate that paracrine factors derived from SHED support a neuroprotective microenvironment in the HI brain. SHED graft and SHED-conditioned medium may provide a novel neuroprotective therapy for HI.
Psychosocial Distress and Stroke Risk in Older Adults
Authors: Henderson Kimberly M. , Clark Cari J. , Lewis Tené T. , Aggarwal Neelum T. , Beck Todd , Guo Hongfei , Lunos Scott , Brearley Ann , Mendes de Leon Carlos F. , Evans Denis A. , Everson-Rose Susan A. 
Published: December 2012

Background and Purpose—
To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults.

Methods—
Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in 3 contiguous neighborhoods on the south side of Chicago, IL. Participants were community-dwelling black and non-Hispanic white adults, aged 65 years and older (n=4120 for stroke mortality; n=2649 for incident stroke). Psychosocial distress was an analytically derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up.

Results—
Stroke deaths (151) and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28–1.70) for stroke mortality and 1.18 (95% CI=1.07–1.30) for incident stroke. Associations were reduced after adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10–1.52) but not for incident stroke (HR=1.09; 95% CI=0.98–1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28–2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91–1.15) in fully adjusted models.

Conclusions—
Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.
Polarimetric Radar Observations in the Ice Region of Precipitating Clouds at C-Band and X-Band Radar Frequencies
Authors: Bechini R. , Baldini L. , Chandrasekar V. 
Published: December 2012

AbstractData collected by C-band and X-band radars in northwestern Italy are analyzed to study the behavior of the polarimetric variables in the ice region of precipitating clouds, with special emphasis on the specific differential phase Kdp. It is found that stratiform precipitation, irrespective of the precipitation type at the ground and as opposed to convective systems, is characterized by well-pronounced positive differential reflectivity Zdr and Kdp values near the model-predicted −15°C isotherm. The regions of enhanced Zdr and Kdp are likely related to the growth of dendrite crystals in the region where the difference between the saturation vapor pressure over water and the saturation vapor pressure over ice is greatest. Coincident C-band and X-band measurements, in conjunction with electromagnetic scattering simulations, demonstrate that Kdp scales with frequency, indicating that the ice particles in the vapor deposition preferential growth zone are Rayleigh scatterers. Peak values around 2.0° and 3.5° km−1 are observed at C band and X band, respectively. Most noteworthy is that an extended analysis of hourly and daily vertical profiles of C-band data over 1 year has shown that Kdp observations around the −15°C temperature level in stratiform precipitation are well correlated (0.8) with the reflectivity in the underlying rain layer.
The Influence of Atlantic Tropical Cyclones on Drought over the Eastern United States (1980–2007)
Authors: Kam Jonghun , Sheffield Justin , Yuan Xing , Wood Eric F. 
Published: December 2012

Abstract
To assess the influence of Atlantic tropical cyclones (TCs) on the eastern U.S. drought regime, the Variable Infiltration Capacity (VIC) land surface hydrologic model was run over the eastern United States forced by the North American Land Data Assimilation System phase 2 (NLDAS-2) analysis with and without TC-related precipitation for the period 1980–2007. A drought was defined in terms of soil moisture as a prolonged period below a percentile threshold. Different duration droughts were analyzed—short term (longer than 30 days) and long term (longer than 90 days)—as well as different drought severities corresponding to the 10th, 15th, and 20th percentiles of soil moisture depth. With TCs, droughts are shorter in duration and of a lesser spatial extent. Tropical cyclones variously impact soil moisture droughts via late drought initiation, weakened drought intensity, and early drought recovery. At regional scales, TCs decreased the average duration of moderately severe short-term and long-term droughts by less than 4 (10% of average drought duration per year) and more than 5 (15%) days yr−1, respectively. Also, they removed at least two short-term and one long-term drought events over 50% of the study region. Despite the damage inflicted directly by TCs, they play a crucial role in the alleviation and removal of drought for some years and seasons, with important implications for water resources and agriculture.
Intensification of Geostrophic Currents in the Canada Basin, Arctic Ocean
Authors: McPhee Miles G. 
Published: December 2012

Abstract
Continuous sampling of upper-ocean hydrographic data in the Canada Basin from various sources spanning from 2003 through 2011 provides an unprecedented opportunity to observe changes occurring in a major feature of the Arctic Ocean. In a 112-km-radius circle situated near the center of the traditional Beaufort Gyre, geopotential height referenced to 400 dbar increased by about 0.3 gpm from 2003 to 2011, and by the end of the period had increased by about 65% from the climatological value. Near the edges of the domain considered, the anomalies in dynamic height are much smaller, indicating steeper gradients. A rough dynamic topography constructed from profiles collected between 2008 and 2011 shows the center of the gyre to have shifted south by about 2° in latitude, along the 150°W meridian. Geostrophic currents are much stronger on the periphery of the gyre, reaching amplitudes 5–6 times higher than climatological values at grid points just offshore from the Beaufort and Chukchi shelf slopes. Estimates of residual buoy drift velocity after removing the expected wind-driven component are consistent with surface geostrophic currents calculated from hydrographic data. A three-decade time series of integrated ocean surface stress curl during late summer near the center of the Beaufort Gyre shows a large increase in downward Ekman pumping on decadal scales, emphasizing the importance of atmospheric forcing in the recent accumulation of freshwater in the Canada Basin. Geostrophic current intensification appears to have played a significant role in the recent disappearance of old ice in the Canada Basin.
Copy number variation in pediatric multiple sclerosis
Authors: McElroy JP , Krupp LB , Johnson BA , McCauley JL , Qi Z , Caillier SJ , Gourraud PA , Yu J , Nathanson L , Belman AL , Hauser SL , Waubant E , Hedges DJ , Oksenberg JR 
Published: December 2012

Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient’s disease course and prognosis.