bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombospondin-1 Regulates Blood Flow via CD47 Receptor–Mediated Activation of NADPH Oxidase 1
Authors: Csányi Gábor , Yao Mingyi , Rodríguez Andrés I. , Ghouleh Imad Al , Sharifi-Sanjani Maryam , Frazziano Giovanna , Huang Xiaojun , Kelley Eric E. , Isenberg Jeffrey S. , Pagano Patrick J. 
Published: October 2012

Objective—
Although the matricellular protein thrombospondin-1 (TSP1) is highly expressed in the vessel wall in response to injury, its pathophysiological role in the development of vascular disease is poorly understood. This study was designed to test the hypothesis that TSP1 stimulates reactive oxygen species production in vascular smooth muscle cells and induces vascular dysfunction by promoting oxidative stress.

Methods and Results—

Nanomolar concentrations of TSP1 found in human vascular disease robustly stimulated superoxide (O
2
•−
) levels in vascular smooth muscle cells at both cellular and tissue level as measured by cytochrome
c
and electron paramagnetic resonance. A peptide mimicking the C terminus of TSP1 known to specifically bind CD47 recapitulated this response. Transcriptional knockdown of CD47 and a monoclonal inhibitory CD47 antibody abrogated TSP1-triggered O
2
•−
in vitro and ex vivo. TSP1 treatment of vascular smooth muscle cells activated phospholipase C and protein kinase C, resulting in phosphorylation of the NADPH oxidase organizer subunit p47

phox

and subsequent Nox1 activation, leading to impairment of arterial vasodilatation ex vivo. Further, we observed that blockade of CD47 and NADPH oxidase 1 gene silencing in vivo in rats improves TSP1-induced impairment of tissue blood flow after ischemia reperfusion.

Conclusion—
Our data suggest a highly regulated process of reactive oxygen species stimulation and blood flow regulation promoted through a direct TSP1/CD47-mediated activation of Nox1. This is the first report, to our knowledge, of a matricellular protein acting as a ligand for NADPH oxidase activation and through specific engagement of integrin-associated protein CD47.
Blood Clots Are Rapidly Assembled Hemodynamic Sensors
Authors: Muthard Ryan W. , Diamond Scott L. 
Published: October 2012

Objective—
Blood clots form under flow during intravascular thrombosis or vessel leakage. Prevailing hemodynamics influence thrombus structure and may regulate contraction processes. A microfluidic device capable of flowing human blood over a side channel plugged with collagen (±tissue factor) was used to measure thrombus permeability (κ) and contraction at controlled transthrombus pressure drops.

Methods and Results—

The collagen (κ
collagen
=1.98×10
−11
cm
2
) supported formation of a 20-µm thick platelet layer, which unexpectedly underwent massive platelet retraction on flow arrest. This contraction resulted in a 5.34-fold increase in permeability because of collagen restructuring. Without stopping flow, platelet deposits (no fibrin) had a permeability of κ
platelet
=5.45×10
−14
cm
2
and platelet-fibrin thrombi had κ
thrombus
=2.71×10
−14
cm
2
for ΔP=20.7 to 23.4 mm Hg, the first ever measurements for clots formed under arterial flow (1130 s
−1
wall shear rate). Platelet sensing of flow cessation triggered a 4.6- to 6.5-fold (n=3,
P
<0.05) increase in contraction rate, which was also observed in a rigid, impermeable parallel-plate microfluidic device. This triggered contraction was blocked by the myosin IIA inhibitor blebbistatin and by inhibitors of thromboxane A2 (TXA
2
) and ADP signaling. In addition, flow arrest triggered platelet intracellular calcium mobilization, which was blocked by TXA
2
/ADP inhibitors. As clots become occlusive or blood pools following vessel leakage, the flow diminishes, consequently allowing full platelet retraction.

Conclusion—
Flow dilution of ADP and thromboxane regulates platelet contractility with prevailing hemodynamics, a newly defined flow-sensing mechanism to regulate clot function.
No Shorter Telomeres in Subjects With a Family History of Cardiovascular Disease in the Asklepios Study
Authors: De Meyer Tim , Van daele Caroline M. , De Buyzere Marc L. , Denil Simon , De Bacquer Dirk , Segers Patrick , Cooman Luc , De Backer Guy G. , Gillebert Thierry C. , Bekaert Sofie , Rietzschel Ernst R. 
Published: October 2012

Objective—
Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population-representative Asklepios Study.

Methods and Results—
Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (≈35–55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without.

Conclusion—
These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD.
Prospective Characterization of Catheter–Tissue Contact Force at Different Anatomic Sites During Antral Pulmonary Vein Isolation
Authors: Kumar Saurabh , Morton Joseph B. , Lee Justin , Halloran Karen , Spence Steven J. , Gorelik Alexandra , Hepworth Graham , Kistler Peter M. , Kalman Jonathan M. 
Published: October 2012

Background—
Catheter–tissue contact is critical for effective lesion creation. We characterized the contact force (CF) at different anatomic sites during antral pulmonary vein (PV) isolation for atrial fibrillation.

Methods and Results—

Two experienced operators performed PV isolation in 22 patients facilitated by a novel CF-sensing ablation catheter in a blinded fashion. Average CF and force-time integral data from 1602 lesions were analyzed. The left and right PV antra were divided into the following: carina, superior, inferior, anterior, and posterior quadrants for analysis. There was significant variability in CF within and between different PV quadrants (
P
<0.05). Lowest CF of all left PV sites was at the carina and anterior quadrant, whereas highest CF was at the superior and inferior quadrants (
P
<0.05). Lowest CF of all right PV sites was at the carina, whereas highest CF was at the anterior and inferior quadrants (
P
<0.05). When comparing similar PV quadrants on the left versus right (eg, left carina versus right carina), CF was always higher in the right PVs (
P
<0.05), except at the superior quadrant where CF was similar in the left and right PVs (
P
=0.19). There was no specific pattern of anatomic distribution of excess CF (
P
=0.39).

Conclusions—
Monitoring of catheter–tissue CF during PV isolation demonstrates significant variability in CF within and between different PV antral sites. Sites of lowest CF were the carina and anterior left PVs and the carina of the right PVs. This information may be important for improving ablation efficacy and clinical outcomes during PV isolation.
Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure
Authors: Dupont Matthias , Mullens Wilfried , Skouri Hadi N. , Abrahams Zuheir , Wu Yuping , Taylor David O. , Starling Randall C. , Tang W. H. Wilson 
Published: October 2012

Background—
Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure.

Methods and Results—

We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (
r
=−0.64) and wedge pressure (
r
=−0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively,
P
=0.003). During a mean follow-up of 3.2±2.2 years, both lower PAC (
P
<0.0001) and higher PVR (
P
<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84–1.0,
P
=0.037]). Treatment of heart failure resulted in a decrease in PVR (270±165 to 211±88 dynes·s
–1
·cm
–5
,
P
=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 mL/mm Hg,
P
<0.0001), leading to an increase in pulmonary arterial time constant (PVR×PAC) (0.29±0.12 to 0.37±0.15 second,
P
<0.0001).

Conclusions—
PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy.
The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
Authors: Albrecht-Schgoer Karin , Schgoer Wilfried , Holfeld Johannes , Theurl Markus , Wiedemann Dominik , Steger Christina , Gupta Rajesh , Semsroth Severin , Fischer-Colbrie Reiner , Beer Arno G.E. , Stanzl Ursula , Huber Eva , Misener Sol , Dejaco Daniel , Kishore Raj , Pachinger Otmar , Grimm Michael , Bonaros Nikolaos , Kirchmair Rudolf 
Published: October 2012

Background—
Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.

Methods and Results—
In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein.

Conclusions—
Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.
Evidence for a Strong Genetic Influence on Carotid Plaque Characteristics
Authors: Tarnoki Adam Domonkos , Baracchini Claudio , Tarnoki David Laszlo , Lucatelli Pierleone , Boatta Emanuele , Zini Chiara , Fanelli Fabrizio , Molnar Andrea Agnes , Meneghetti Giorgio , Stazi Maria Antonietta , Medda Emanuela , Cotichini Rodolfo , Nisticò Lorenza , Fagnani Corrado , Osztovits Janos , Jermendy Gyorgy , Preda Istvan , Kiss Robert Gabor , Metneki Julia , Horvath Tamas , Pucci Giacomo , Bata Pal , Karlinger Kinga , Littvay Levente , Berczi Viktor , Garami Zsolt , Schillaci Giuseppe 
Published: October 2012

Background and Purpose—
Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design.

Methods—
One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49±15 years) from Italy, Hungary, and the United States underwent B-mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries.

Results—

Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%–90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%–87%), 69% for plaque size (area in mm
2
in longitudinal plane; < or >50 percentile; 95% CI, 16%–86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%–90%), 74% for plaque numerosity (95% CI, 26%–86%), 68% (95% CI, 40%–84%), and 66% (95% CI, 32%–90%) for the presence of plaque in carotid bulbs and proximal internal carotid arteries. No role of shared environmental factors was found. Unique environmental factors were responsible for the remaining variance (22%–34%). Controlling for relevant covariates did not change the results significantly.

Conclusions—
The heritability of ultrasound characteristics of carotid plaque is high. Unshared environmental effects account for a modest portion of the variance. Our findings should stimulate the search for genes responsible for these traits.
A Randomized Controlled Trial of Prophylactic Intra-aortic Balloon Counterpulsation in High-Risk Aneurysmal Subarachnoid Hemorrhage
Authors: Bulters Diederik Olivier , Birch Anthony A. , Hickey Edward , Tatlow Ian , Sumner Karen , Lamb Robert , Lang Dorothy 
Published: October 2012

Background and Purpose—
To assess whether prophylactic postoperative intraaortic balloon counterpulsation (IABC) reduces the risk of poor outcome because of vasospasm following aneurysmal subarachnoid haemorrhage relative to conventional hypervolemic therapy (HT).

Methods—
This was a single-center, parallel group randomized controlled trial. Patients suffering a subarachnoid hemorrhage at high risk of vasospasm were eligible. Patients were randomly allocated to receive prophylactic IABC (n=35) or HT (n=36). The primary end point was Glasgow Outcome and SF-36 scores assessed at 6 months by a blinded and independent observer and analyzed by intention to treat. Secondary analysis of physiological parameters was by treatment performed.

Results—

Twenty-seven patients in each arm had a good outcome (
P
=0.55). There was no statistical difference in mean SF-36 score (t=0.39,
P
=0.70). There were no long-term complications secondary to IABC. There were no differences in preload (pulmonary artery wedge pressure,
P
=0.97) or afterload (mean arterial pressure,
P
=0.97). IABC was associated with a lower cardiac output (
P
=0.002) and higher systemic vascular resistance (
P
=0.005), although for both groups mean cardiac output was >6 L/min. Cerebral blood flow was not different between groups: HT=41.5 (SD 7.2), IABP=44.9 (SD 8.6) mL/100 g/min (
P
=0.14).

Conclusions—
In this study, prophylactic IABC did not improve perfusion indices or confer any clinical benefit following subarachnoid haemorrhage in patients with normal cardiac function. The study was small, however, and cannot be extrapolated to patients with cardiac failure and medically refractory symptomatic cerebral vasospasm.

Clinical Trial Registration—
This trial was not registered because enrolment began prior to July 1, 2005.
Registry Report on Kinetics of Rescue Antiplatelet Treatment to Abolish Cerebral Microemboli After Carotid Endarterectomy
Authors: Saedon Mahmud , Singer Donald R.J. , Pang Raymand , Tiivas Carl , Hutchinson Charles E. , Imray Christopher H.E. 
Published: October 2012

Background and Purpose—
Cerebral microemboli signals (MES) are associated with increased risk of acute stroke syndromes. We compared the effects on cerebral microemboli after carotid endarterectomy of tirofiban with dextran-40.

Methods—

We used transcranial Doppler ultrasound to study transient MES acutely after carotid endarterectomy between August 2000 and December 2010 in 128 subjects refractory to preoperative antiplatelet treatment. Antithrombotic treatment was given for MES ≥50 hour
−1
(tirofiban: 40 patients [age 74 ± 1 {SEM}, males 27, and white 38]; dextran-40: 34 patients [age 69 ± 2, males 22, white 30]). In 54 patients with MES <50 hour
−1
(age 71 ± 1, male 36, white 52), MES were monitored during their spontaneous resolution (controls). Data are median (interquartile range).

Results—

The time to 50% reduction in MES (tirofiban 23 minutes [15–28]; dextran-56 [43–83]; controls 30 [22–38];
P
<0.001, Kruskal-Wallis analysis) and for complete MES resolution (tirofiban 68 minutes [53–94]; dextran-113 [79–146]; controls 53 [49–68];
P
<0.001, Kruskal-Wallis analysis) were shorter with tirofiban. The early cardiovascular event rate was similar with tirofiban compared with controls but increased in patients who received dextran.

Conclusions—
These findings suggest that transcranial Doppler-directed tirofiban therapy is more effective than dextran-40 in suppression of cerebral microemboli after carotid endarterectomy.
DNA Reactivity as a Mode of Action and Its Relevance to Cancer Risk Assessment
Authors: Preston R. Julian 
Published: October 2012

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose–response curve shape. Thus, the dose–response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events.
The Mortality Observed‐to‐Expected Ratio in Otolaryngology
Authors: Bennett Marc L. , Morath Julie M. , Yarbrough Dell , Sinard Robert , Netterville Jim , Eavey Roland D. 
Published: October 2012

ObjectiveThe mortality observed‐to‐expected (O:E) ratio is rapidly becoming the most important measured quality metric by allowing quantification and comparison of survival outcomes among different providers and institutions. Although the O:E ratio is monitored by external observers, the ratio is unfamiliar to individuals within most institutions.Study DesignRetrospective chart review.SettingVanderbilt University Medical Center.Subjects and MethodsTwenty‐eight patients cared for by the Department of Otolaryngology died while in the hospital between January 2001 and December 2010. All patient charts were reviewed for indicators related to mortality. From January 2006 to December 2010, a standardized mortality O:E ratio had been available using the All Patient Refined–Diagnosis Related Group (APR‐DRG) grouper from the United Healthcare Consortium (UHC). The O:E ratio can be monitored over time to measure and quantify the effect of various interventions.ResultsThe otolaryngology O:E ratio quarterly results have varied from 1.1 to 0.29, based on a standard of 1.0. Internally, results have been primarily the result of mortalities of patients on the Head and Neck Service. Attention to common postoperative complications, accurate coding of comorbidities, and the compassionate use of palliative care consults have led to a significant decrease in the O:E ratio. Conversely, transfers from other hospitals have increased the ratio.ConclusionThe Department of Otolaryngology has reduced the O:E ratio by focusing attention on factors that have been shown to reduce mortality and to enhance compassionate terminal care.
Long-term Outcomes of Postoperative Septic Arthritis After Anterior Cruciate Ligament Reconstruction
Authors: Schub David L. , Schmitz Leah M. , Sakamoto Flavia A. , Winalski Carl S. , Parker Richard D. 
Published: October 2012

Background: Septic arthritis is a rare but potentially devastating complication of anterior cruciate ligament (ACL) reconstruction surgery. Several studies, including one by this group, have reported short- and medium-term outcomes, but to our knowledge there are no long-term follow-up studies. Hypothesis: Postoperative septic arthritis after ACL reconstruction surgery will lead to diminished long-term outcomes compared with surgery without infectious complications, likely related to the development of arthritis. Study Design: Case series; Level of evidence, 4. Methods: Four of 831 consecutive patients undergoing arthroscopically guided ACL reconstruction surgeries performed by 1 surgeon were previously reported on by this group at an average follow-up of 36 months. These same patients were contacted and reevaluated. Each patient underwent a physical examination, functional testing, and subjective evaluations with the SF-36, Lysholm, International Knee Documentation Committee (IKDC), and Tegner activity scale scores. Plain film radiographs and magnetic resonance imaging (MRI) scans were analyzed by 2 musculoskeletal radiologists. Results: Average follow-up time for this study was 17.9 years, and average age was 44.3 years. No other injuries or surgeries had occurred from the time of the previous study. Each patient had a decline in SF-36, Lysholm, and IKDC score, and the average Tegner score was unchanged. Average vertical hop test performance and Biodex dynamometry were both improved. The average side-to-side displacement measured via the KT-1000 arthrometer was increased. Radiographic and MRI studies revealed progression of arthritis in all patients and ACL graft rupture in 1 patient. Conclusion: Patients who develop septic arthritis as a complication of ACL reconstruction surgery have diminished long-term subjective, functional, and radiographic outcomes compared with historical reports of uncomplicated cases, likely related to pain from advanced arthritis. As compared with their own earlier follow-up, these patients had declines in pain-related subjective measures but remained stable or improved in both functional testing and activity-related subjective scales.