bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic assessment of the impact of adenovirus infection on a captive reintroduction project for red squirrels (Sciurus vulgaris)
Authors: Everest D. J. , Shuttleworth C. M. , Grierson S. S. , Duff J. P. , Jackson N. , Litherland P. , Kenward R. E. , Stidworthy M. F. 
Published: July 2012

PCR was used to amplify adenoviral DNA, and transmission electron microscopy (TEM) to detect adenovirus particles in tissue and intestinal content samples from red squirrels (Sciurus vulgaris) associated with a reintroduction study on Anglesey (North Wales), from other populations on the island and from stock held at the Welsh Mountain Zoo, 38 km to the east. Samples were collected during the routine surveillance postmortem examinations of all 60 red squirrels with carcases retrieved in a suitable condition between 2004 and 2010, including 29 captive and 31 free‐living animals. Following significant clusters of mortality in captive red squirrels, adenovirus was identified retrospectively in faecal material from 12 of 13 (92 per cent) examined carcases from squirrels captive on Anglesey, and 14 of 16 (88 per cent) from the Welsh Mountain Zoo. Virus was identified in 13 of 31 (42 per cent) free‐living wild animals, with evidence of both subclinical and clinically significant enteric adenoviral infections in wild squirrels. Without ancillary PCR and TEM testing, the extent of adenovirus infection in such populations would have been underestimated. Screening protocols that include examinations for adenovirus should, therefore, be part of the routine biosecurity measures protecting reintroduction or captive breeding programmes for red squirrels.
TGF-β and αvβ6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression
Authors: Hezel Aram F. , Deshpande Vikram , Zimmerman Stephanie M. , Contino Gianmarco , Alagesan Brinda , O'Dell Michael R. , Rivera Lee B. , Harper Jay , Lonning Scott , Brekken Rolf A. , Bardeesy Nabeel 
Published: July 2012

Abstract
The TGF-β pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that αvβ6 integrin acted as a key upstream activator of TGF-β in evolving pancreatic cancers. In addition, TGF-β or αvβ6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGF-β signaling. Therefore, our findings indicate that αvβ6 and TGF-β act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression. Cancer Res; 72(18); 4840–5. ©2012 AACR.
SOX4 Induces Epithelial–Mesenchymal Transition and Contributes to Breast Cancer Progression
Authors: Zhang Jianchao , Liang Qian , Lei Yang , Yao Min , Li Lili , Gao Xiaoge , Feng Jingxin , Zhang Yu , Gao Hongwen , Liu Dong-Xu , Lu Jun , Huang Baiqu 
Published: July 2012

Abstract
Epithelial–mesenchymal transition (EMT) is a developmental program, which is associated with breast cancer progression and metastasis. Here, we report that ectopic overexpression of SOX4 in immortalized human mammary epithelial cells is sufficient for acquisition of mesenchymal traits, enhanced cell migration, and invasion, along with epithelial stem cell properties defined by the presence of a CD44high/CD24low cell subpopulation. SOX4 positively regulated expression of known EMT inducers, also activating the TGF-β pathway to contribute to EMT. SOX4 itself was induced by TGF-β in mammary epithelial cells and was required for TGF-β–induced EMT. Murine xenograft experiments showed that SOX4 cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in clinical specimens of human breast cancer, we found that SOX4 was abnormally overexpressed and correlated with the triple-negative breast cancer subtype (ER−/PR−/HER2−). Our findings define an important function for SOX4 in the progression of breast cancer by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease. Cancer Res; 72(17); 4597–608. ©2012 AACR.
Targeting the Glyoxalase Pathway Enhances TRAIL Efficacy in Cancer Cells by Downregulating the Expression of Antiapoptotic Molecules
Authors: Taniguchi Hiroya , Horinaka Mano , Yoshida Tatsushi , Yano Kimihiro , Goda Ahmed E. , Yasuda Shusuke , Wakada Miki , Sakai Toshiyuki 
Published: July 2012

Abstract
Methylglyoxal is an essential component in glycolysis and is known to be an inducer of apoptosis. Glyoxalase I (GLO1) metabolizes and inactivates methylglyoxal. GLO1 is known to be overexpressed in cancer cells and causes resistance to anticancer agents. We show for the first time that methylglyoxal treatment or the silencing of GLO1 enhances sensitivity to the promising anticancer agent TRAIL in malignant tumor cells. Methylglyoxal suppressed the expression of antiapoptotic factors, X-linked inhibitor of apoptosis protein (XIAP), survivin, cIAP1, Bcl-2, and Bcl-xL, without affecting TRAIL receptors, DR4 and DR5. Knockdown of XIAP or survivin by siRNA also enhanced TRAIL-induced apoptosis, indicating that downregulation of XIAP and survivin expression by methylglyoxal contributes to the enhancement of TRAIL activity. Furthermore, methylglyoxal decreased NF-κB activity with or without TRAIL treatment. On the other hand, the knockdown of GLO1 by siRNA enhanced TRAIL-induced apoptosis via the downregulation of XIAP and survivin expression. In conclusion, our results strongly suggest that sensitivity to TRAIL is increased by inhibition of the glyoxalase pathway and that the combination of TRAIL with methylglyoxal or glyoxalase inhibitors may be useful for a novel combination chemotherapy. Mol Cancer Ther; 11(10); 2294–300. ©2012 AACR.
A Clinical Risk Prediction Model for Barrett Esophagus
Authors: Thrift Aaron P. , Kendall Bradley J. , Pandeya Nirmala , Vaughan Thomas L. , Whiteman David C. ,   for the Study of Digestive Health
Published: July 2012

Abstract
Barrett esophagus is the only known precursor to esophageal adenocarcinoma. As definitive diagnosis requires costly endoscopic investigation, we sought to develop a risk prediction model to aid in deciding which patients with gastroesophageal reflux symptoms to refer for endoscopic screening for Barrett esophagus.
The study included data from patients with incident nondysplastic Barrett esophagus (n = 285) and endoscopy control patients with esophageal inflammatory changes without Barrett esophagus (“inflammation controls”, n = 313). We used two phases of stepwise backwards logistic regression to identify the important predictors for Barrett esophagus in men and women separately: first, including all significant covariates from univariate analyses and then fitting non-significant covariates from univariate analyses to identify those effects detectable only after adjusting for other factors. The final model pooled these predictors and was externally validated for discrimination and calibration using data from a Barrett esophagus study conducted in western Washington State.
The final risk model included terms for age, sex, smoking status, body mass index, highest level of education, and frequency of use of acid suppressant medications (area under the ROC curve, 0.70; 95%CI, 0.66–0.74). The model had moderate discrimination in the external dataset (area under the ROC curve, 0.61; 95%CI, 0.56–0.66). The model was well calibrated (Hosmer–Lemeshow test, P = 0.75), with predicted probability and observed risk highly correlated.
The prediction model performed reasonably well and has the potential to be an effective and useful clinical tool in selecting patients with gastroesophageal reflux symptoms to refer for endoscopic screening for Barrett esophagus. Cancer Prev Res; 5(9); 1115–23. ©2012 AACR.
Distribution and Risk Profile of Paroxysmal, Persistent, and Permanent Atrial Fibrillation in Routine Clinical Practice
Authors: Chiang Chern-En , Naditch-Brûlé Lisa , Murin Jan , Goethals Marnix , Inoue Hiroshi , O’Neill James , Silva-Cardoso Jose , Zharinov Oleg , Gamra Habib , Alam Samir , Ponikowski Piotr , Lewalter Thorsten , Rosenqvist Mårten , Steg Philippe Gabriel 
Published: July 2012

Background—
There is a paucity of international data on the various types of atrial fibrillation (AF) outside the highly selected populations from randomized trials. This study aimed to describe patient characteristics, risk factors, comorbidities, symptoms, management strategy, and control of different types of AF in real-life practice.

Methods and Results—

Real-life global survey evaluating patients with atrial fibrillation (RealiseAF) was a contemporary, large-scale, cross-sectional international survey of patients with AF who had ≥1 episode in the past 12 months. Investigators were randomly selected to avoid bias. Among 9816 eligible patients from 831 sites in 26 countries, 2606 (26.5%) had paroxysmal, 2341 (23.8%) had persistent, and 4869 (49.6%) had permanent AF. As AF progressed from paroxysmal to persistent and permanent forms, the prevalence of comorbidities, such as heart failure (32.9%, 44.3%, and 55.6%), coronary artery disease (30.0%, 32.9%, and 34.3%), cerebrovascular disease (11.7%, 10.8%, and 17.6%), and valvular disease (16.7%, 21.2%, and 35.8%), increased, and the prevalence of lone AF decreased. Similarly, there was an increase in mean CHADS
2
[cardiac failure, hypertension, age, diabetes, stroke (doubled)] score (1.7, 1.8, and 2.2), and more than half of patients (51.0%, 56.7%, and 67.3%) qualified for oral anticoagulants. Almost 90% of patients received ≥1 antiarrhythmic drug, but >60% had European Heart Rhythm Association symptom scores from II to IV. Furthermore, 40.7% of persistent and 49.8% of permanent AF patients were still in AF with a heart rate >80 beats per minute.

Conclusions—
This survey disclosed high cardiovascular risks and an unmet need in daily practice for patients with any type of AF, especially those with the permanent form.
Effect of Bipolar Electrode Spacing on Phrenic Nerve Stimulation and Left Ventricular Pacing Thresholds
Authors: Biffi Mauro , Foerster Laurie , Eastman William , Eggen Michael , Grenz Nathan A. , Sommer John , De Santo Tiziana , Haddad Tarek , Varbaro Annamaria , Yang Zhongping 
Published: July 2012

Background—
Phrenic nerve stimulation (PNS) is a common complication of cardiac resynchronization therapy when left ventricular (LV) pacing occurs via a coronary vein. The purpose of this study was to evaluate the effects of bipolar electrode spacing on PNS and LV pacing thresholds.

Methods and Results—

Electrophysiology catheters with standard (2 mm-5 mm-2 mm) or modified (1 mm-5 mm-1 mm) interelectrode spacing was, respectively, inserted in a posterior/lateral cardiac vein in a randomized order in 6 anesthetized dogs via jugular access. The phrenic nerve was dissected via a left minithoracotomy and repositioned over the vein as close as possible to one of the electrodes. The presence of PNS was verified (ie, PNS threshold <2 V at 0.5 ms in unipolar configuration). Bipolar pacing was delivered using the electrode closest to the phrenic nerve as the cathode, and multiple bipolar electrode spacing configurations were tested. During bipolar pacing, PNS threshold increased as bipolar electrode spacing was reduced (
P
<0.05), whereas LV pacing thresholds did not change significantly (
P
>0.05). Compared with a standard bipolar electrode spacing of 20 mm for LV leads, 1 and 2 mm bipolar electrode spacing resulted in a PNS threshold increase of 5.5±2.2 V (
P
=0.003) and 2.8±1.7 V (
P
<0.001), respectively. Similarly, PNS threshold increased by 6.5±3.7 V with 1 mm and by 3.8±1.9 V with 2 mm bipolar pacing (both
P
<0.001), compared with unipolar pacing.

Conclusions—
This study suggests that reducing LV bipolar electrode spacing from the standard 20 mm to 1 or 2 mm may significantly increase the PNS threshold without compromising LV pacing thresholds.
Videoscopic Left Cardiac Sympathetic Denervation for Patients With Recurrent Ventricular Fibrillation/Malignant Ventricular Arrhythmia Syndromes Besides Congenital Long-QT Syndrome
Authors: Coleman Mira A. , Bos J. Martijn , Johnson Jonathan N. , Owen Heidi J. , Deschamps Claude , Moir Christopher , Ackerman Michael J. 
Published: July 2012

Background—
Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non–long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting.

Methods and Results—
In this institutional review board–approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event.

Conclusions—
LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.
Fluoroscopic Screening of Asymptomatic Patients Implanted With the Recalled Riata Lead Family
Authors: Liu Jeffrey , Rattan Rohit , Adelstein Evan , Barrington William , Bazaz Raveen , Brode Susan , Jain Sandeep , Mendenhall G. Stuart , Nemec Jan , Razak Eathar , Shalaby Alaa , Schwartzman David , Voigt Andrew , Wang Norman C. , Saba Samir 
Published: July 2012

Background—
The Food and Drug Administration recently issued a class I recall of the St. Jude Medical Riata implantable cardioverter-defibrillator lead presumably because of increased risk of electric failure and mechanical separation via inside-out abrasion. We sought to examine the incidence and time dependence of inside-out abrasion in asymptomatic patients implanted with the Riata lead.

Methods and Results—

Asymptomatic patients implanted with the Riata lead at our institution were offered voluntary fluoroscopic screening in 3 views. Electric testing of the Riata lead with provocative isometric muscle contraction was performed at the time of fluoroscopic screening. Of the 245 patients undergoing fluoroscopic screening, 53 (21.6%) patients showed clear evidence of lead separation. Of these externalized leads, 0%, 13%, and 26% had a dwell time of <3 years, 3 to 5 years, and >5 years, respectively (
P
=0.037). Externalized leads had a significantly pronounced decrease in R-wave amplitude (−1.7±2.9 mV versus +0.35±2.5 mV;
P
<0.001), and more patients with externalized leads had ≥25% decrease in R-wave amplitude from baseline (28.0% versus 8.1%;
P
=0.018). One patient with externalization exhibited new noise on near-field electrogram.

Conclusions—
The Riata lead exhibits time-dependent high rates of cable externalization exceeding 20% at >5 years of dwell time. Externalized leads are associated with a more pronounced decrease in R-wave amplitude, which may be an early marker of future electric failure. The use of fluoroscopic and electric screening of asymptomatic patients with the Riata lead remains controversial in the management of patients affected by the recent Food and Drug Administration recall.
Toll-Like Receptor 7 Protects From Atherosclerosis by Constraining “Inflammatory” Macrophage Activation
Authors: Salagianni Maria , Galani Ioanna E. , Lundberg Anna M. , Davos Constantinos H. , Varela Aimilia , Gavriil Ariana , Lyytikäinen Leo-Pekka , Lehtimäki Terho , Sigala Fragiska , Folkersen Lasse , Gorgoulis Vassilis , Lenglet Sébastien , Montecucco Fabrizio , Mach François , Hedin Ulf , Hansson Göran K. , Monaco Claudia , Andreakos Evangelos 
Published: July 2012

Background
Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking.

Methods and Results

We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self–nucleic acid complexes, is protective in atherosclerosis. In
Apoe
−/−
mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C
hi
inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10.

Conclusions
These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy.
Physical and Sexual Abuse in Childhood as Predictors of Early-Onset Cardiovascular Events in Women
Authors: Rich-Edwards Janet W. , Mason Susan , Rexrode Kathryn , Spiegelman Donna , Hibert Eileen , Kawachi Ichiro , Jun Hee Jin , Wright Rosalind J. 
Published: July 2012

Background—
Although child abuse is widespread and has been associated with cardiovascular disease (CVD) risk factors, its association with CVD events is not established.

Methods and Results—
We examined associations of child abuse with CVD events among 66 798 women in the Nurses' Health Study 2. Proportional hazards models estimated hazard ratios and 95% confidence intervals (CIs) for myocardial infarction (n=262), stroke (n=251), and total CVD (n=513). Severe physical abuse was reported by 9% and forced sex by 11% of participants. After adjustment for age, race, childhood body type, parental education, and family CVD history, the hazard ratios for CVD events were 0.91 (95% CI, 0.70–1.17) for mild physical abuse, 1.02 (95% CI, 0.82–1.26) for moderate physical abuse, and 1.46 (95% CI, 1.11–1.92) for severe physical abuse compared with no abuse. Compared with women without childhood sexual abuse, the hazard ratio was 1.10 (95% CI, 0.88–1.35) for unwanted sexual touching and 1.56 (95% CI, 1.23–1.99) for forced sex. After adjustment for adult lifestyle and medical risk factors, the hazard ratio for severe physical abuse was 1.13 (95% CI, 0.85–1.51) and that for forced sex was 1.25 (95% CI, 0.98–1.60); these intermediates accounted for much of the association of severe child abuse with CVD. Associations were similar for retrospectively and prospectively reported events. Women with abuse were less likely to release medical records. The associations were stronger for unconfirmed self-reported events than end points that were corroborated with additional information or medical record review.

Conclusion—
Severe child abuse is a prevalent risk for early adult CVD that is partially mediated by preventable risk factors.
Use of first- and second-generation antipsychotic medications in older patients with schizophrenia in Asia (2001–2009)
Authors: Xiang Yu-Tao , Kreyenbuhl Julie , Dickerson Faith B , Ungvari Gabor S , Wang Chuan-Yue , Si Tian-Mei , Lee Edwin H , He Yan-Ling , Chiu Helen F , Yang Shu-Yu , Chong Mian-Yoon , Tan Chay-Hoon , Kua Ee-Heok , Fujii Senta , Sim Kang , Yong Michael K , Trivedi Jitendra K , Chung Eun-Kee , Udomratn Pichet , Chee Kok-Yoon , Sartorius Norman , Shinfuku Naotaka 
Published: July 2012

Objective: This study examined the prescribing patterns of several first- (FGAs) and second-generation antipsychotic (SGAs) medications administered to older Asian patients with schizophrenia during the period between 2001 and 2009. Method: Information on hospitalized patients with schizophrenia aged 65 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001–2009). There were no older patients in Thailand, therefore data on 467 patients in eight Asian countries and territories including China, Hong Kong SAR, India, Japan, Korea, Malaysia, Singapore, and Taiwan were analysed. Cross-sectional socio-demographic data, clinical characteristics and antipsychotic prescriptions were assessed using a standardized protocol and data collection procedure. Results: Of the 467 patients, 192 patients (41.1%) received FGAs only, 166 (35.5%) received SGAs only and 109 (23.3%) received a combination of FGAs and SGAs. Of the FGAs, haloperidol was the most commonly used (31.3%; mean 9.4 ± 6.7 mg/day), followed by chlorpromazine (15.4%; mean 126.4 ± 156.4 mg/day) and sulpiride (6.6%; mean 375.0 ± 287.0 mg/day). Of the SGAs, risperidone was the most commonly used (31.5%; mean 4.5 ± 2.7 mg/day), followed by olanzapine (13.1%; mean 13.6 ± 6.5 mg/day), quetiapine (7.3%; mean 325.0 ± 237.3 mg/day) and aripiprazole (1.9%; mean 17.6 ± 7.7 mg/day). Conclusions: FGAs and higher doses of certain SGAs (risperidone, olanzapine and quetiapine) were still commonly dispensed to older Asian patients with schizophrenia. Considering older patients’ reduced tolerability of potentially severe side effects associated with FGAs and higher doses of certain SGAs, continuing education and training addressing the rational use of antipsychotics in this population is clearly needed.