bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route
Authors: Douet Jean-Yves , Lacroux Caroline , Litaise Claire , Lugan Séverine , Corbière Fabien , Arnold Mark , Simmons Hugh , Aron Naima , Costes Pierrette , Tillier Cécile , Cassard Hervé , Andréoletti Olivier 
Published: January 2016

ABSTRACT

Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 μl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 μl, but not 10 μl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 10
5
WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R
+
(predominantly B lymphocytes), CD4
+
/CD8
+
(T lymphocytes), and CD14
+
(monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 10
6
CD45
+
or CD4
+
/8
+
living cells was able to transmit the disease, similar numbers of CD14
+
cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine.

IMPORTANCE
Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a relevant model for assessing the blood-borne vCJD transmission risk. In this study, using a sheep TSE model, we characterized the ability of different peripheral blood mononucleated cell populations to infect TSE-free recipients by the transfusion route. Our results indicate that as little as 10
5
WBC and 100 μl of blood collected from asymptomatic scrapie infected animals can transmit the disease. They also demonstrate unambiguously that peripheral blood mononuclear cell subpopulations display dramatically different abilities to transmit the disease. These data represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine.
The NHS Health Check in England: an evaluation of the first 4 years
Authors: Robson John , Dostal Isabel , Sheikh Aziz , Eldridge Sandra , Madurasinghe Vichithranie , Griffiths Chris , Coupland Carol , Hippisley-Cox Julia 
Published: January 2016

ObjectivesTo describe implementation of a new national preventive programme to reduce cardiovascular morbidity.DesignObservational study over 4 years (April 2009—March 2013).Setting655 general practices across England from the QResearch database.ParticipantsEligible adults aged 40–74 years including attendees at a National Health Service (NHS) Health Check.InterventionNHS Health Check: routine structured cardiovascular check with support for behavioural change and in those at highest risk, treatment of risk factors and newly identified comorbidity.ResultsOf 1.68 million people eligible for an NHS Health Check, 214 295 attended in the period 2009–12. Attendance quadrupled as the programme progressed; 5.8% in 2010 to 30.1% in 2012. Attendance was relatively higher among older people, of whom 19.6% of those eligible at age 60–74 years attended and 9.0% at age 40–59 years. Attendance by population groups at higher cardiovascular disease (CVD) risk, such as the more socially disadvantaged 14.9%, was higher than that of the more affluent 12.3%. Among attendees 7844 new cases of hypertension (38/1000 Checks), 1934 new cases of type 2 diabetes (9/1000 Checks) and 807 new cases of chronic kidney disease (4/1000 Checks) were identified. Of the 27 624 people found to be at high CVD risk (20% or more 10-year risk) when attending an NHS Health Check, 19.3% (5325) were newly prescribed statins and 8.8% (2438) were newly prescribed antihypertensive therapy.ConclusionsNHS Health Check coverage was lower than expected but showed year-on-year improvement. Newly identified comorbidities were an important feature of the NHS Health Checks. Statin treatment at national scale for 1 in 5 attendees at highest CVD risk is likely to have contributed to important reductions in their CVD events.
When in Rome…
Authors: Brown Richard 
Published: January 2016

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘When in Rome. . . ’, was submitted and is discussed by Richard Brown. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Delivering profit?’, which was published in the November/December issue of In Practice, appears on page 47.The series is being coordinated by Steven McCulloch. It is hoped it will provide a framework that will help practitioners find solutions when facing similar dilemmas.
Predictive and prognostic values of ERCC1 and XRCC1 in biliary tract cancers
Authors: Mian Muhtashim , McNamara Mairéad G , Doherty Mark , Hedley David , Knox Jennifer J , Serra Stefano 
Published: January 2016

AimsTo investigate the predictive and prognostic values of DNA repair genes excision repair cross-complementation group 1 (ERCC1) and X-ray repair cross-complementing group 1 (XRCC1) in tumour samples from patients with a diagnosis of biliary tract cancer (BTC).MethodsExpressions of ERCC1 and XRCC1 were determined by immunohistochemistry (IHC) for 160 patients with BTC and association with clinicopathological features and patient survival was performed to evaluate their predictive and prognostic values.ResultsNeoplastic tissue showed much lower nuclear expression compared with non-neoplastic tissue for ERCC1 (median immunostaining score (IS)=0.7 (95% CI 0.2 to 1.3) vs 8.0 (95% CI 5.5 to 8.0), p<0.001) and XRCC1 (median IS=4.0 (95% CI 3.0 to 5.5) vs 8.0 (95% CI 8.0 to 12.0), p<0.001). High nuclear expression of both proteins was able to predict better overall survival (OS) in patients with gallbladder adenocarcinoma, distal bile duct and perihilar cholangiocarcinoma undergoing gemcitabine as adjuvant therapy (ERCC1: median OS estimate=39.7 vs 22.9 months, p=0.011; XRCC1: median OS estimate=33.8 vs 14.6 months, p=0.005). Intense cytoplasmic expression of XRCC1 was found in 12 patients; these patients had significantly more frequent lymph node metastasis (90.0% vs 48.1%, p=0.017) and worse OS (median estimate=12.6 months vs 25.6 months, p=0.004) and recurrence-free survival (median estimate=5.7 months vs 15.1 months, p=0.011). Vascular invasion was significantly more frequent in patients with low nuclear expression for ERCC1 (58.7% vs 20.9%, p<0.001) and XRCC1 (69.6% vs 30.3%, p=0.001).ConclusionsIHC expression of ERCC1 and XRCC1 has some predictive and prognostic values in patients with BTC. Nuclear expression of ERCC1 and XRCC1 may be used to predict therapeutic response in patients undergoing gemcitabine monotherapy.
Distorted Copula-Based Probability Distribution of a Counting Hierarchical Variable: A Credit Risk Application
Authors: Bernardi Enrico , Romagnoli Silvia 
Published: January 2016

In this paper, we propose a novel approach for the computation of the probability distribution of a counting variable linked to a multivariate hierarchical Archimedean copula function. The hierarchy has a twofold impact: it acts on the aggregation step but also it determines the arrival policy of the random event. The novelty of this work is to introduce this policy, formalized as an arrival matrix, i.e., a random matrix of dependent 0–1 random variables, into the model. This arrival matrix represents the set of distorted (by the policy itself) combinatorial distributions of the event, i.e., of the most probable scenarios. To this distorted version of the [Formula: see text] approach [see Ref. 7 and Ref. 27], we are now able to apply a pure hierarchical Archimedean dependence structure among variables. As an empirical application, we study the problem of evaluating the probability distribution of losses related to the default of various type of counterparts in a structured portfolio exposed to the credit risk of a selected set among the major banks of European area and to the correlations among these risks.
Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors
Authors: Varešlija Damir , McBryan Jean , Fagan Ailís , Redmond Aisling M. , Hao Yuan , Sims Andrew H. , Turnbull Arran , Dixon J.M. , Ó Gaora Peadar , Hudson Lance , Purcell Siobhan , Hill Arnold D.K. , Young Leonie S. 
Published: January 2016

Abstract
Purpose: Acquired resistance to aromatase inhibitor (AI) therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumor cells develop this resistance remain unclear. Here, the adapted function of estrogen receptor (ER) to an estrogen-depleted environment following AI treatment is reported.
Experimental Design: Global ER chromatin immuno-precipitation (ChIP)-seq analysis of AI-resistant cells identified steroid-independent ER target genes. Matched patient tumor samples, collected before and after AI treatment, were used to assess ER activity.
Results: Maintained ER activity was observed in patient tumors following neoadjuvant AI therapy. Genome-wide ER–DNA-binding analysis in AI-resistant cell lines identified a subset of classic ligand-dependent ER target genes that develop steroid independence. The Kaplan–Meier analysis revealed a significant association between tumors, which fail to decrease this steroid-independent ER target gene set in response to neoadjuvant AI therapy, and poor disease-free survival and overall survival (n = 72 matched patient tumor samples, P = 0.00339 and 0.00155, respectively). The adaptive ER response to AI treatment was highlighted by the ER/AIB1 target gene, early growth response 3 (EGR3). Elevated levels of EGR3 were detected in endocrine-resistant local disease recurrent patient tumors in comparison with matched primary tissue. However, evidence from distant metastatic tumors demonstrates that the ER signaling network may undergo further adaptations with disease progression as estrogen-independent ER target gene expression is routinely lost in established metastatic tumors.
Conclusions: Overall, these data provide evidence of a dynamic ER response to endocrine treatment that may provide vital clues for overcoming the clinical issue of therapy resistance. Clin Cancer Res; 22(11); 2765–77. ©2016 AACR.
Epigenetic Regulation of the Homeobox GeneMSX1Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer
Authors: Bonito Nair A. , Borley Jane , Wilhelm-Benartzi Charlotte S. , Ghaem-Maghami Sadaf , Brown Robert 
Published: January 2016

AbstractPurpose: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity.Experimental Design: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines.Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P &lt; 0.05, q &lt; 0.05, n = 78), have poor RECIST response (P &lt; 0.05, q &lt; 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85–0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression.Conclusions: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. Clin Cancer Res; 22(12); 3097–104. ©2016 AACR.
Multi-analyte profiling in human carotid atherosclerosis uncovers pro-inflammatory macrophage programming in plaques
Authors: Shalhoub Joseph , Viiri Leena E. , Cross Amanda J. , Gregan Scott M. , Allin David M. , Astola Nagore , Franklin Ian J. , Davies Alun H. , Monaco Claudia 
Published: January 2016

SummaryMolecular characterisation of vulnerable atherosclerosis is necessary for targeting functional imaging and plaque-stabilising therapeutics. Inflammation has been linked to atherogenesis and the development of high-risk plaques. We set to quantify cytokine, chemokine and matrix metalloproteinase (MMP) protein production in cells derived from carotid plaques to map the inflammatory milieu responsible for instability. Carotid endarterectomies from carefully characterised symptomatic (n=35) and asymptomatic (n=32) patients were enzymatically dissociated producing mixed cell type atheroma cell suspensions which were cultured for 24 hours. Supernatants were interrogated for 45 analytes using the Luminex 100 platform. Twenty-nine of the 45 analytes were reproducibly detectable in the majority of donors. The in vitro production of a specific network of mediators was found to be significantly higher in symptomatic than asymptomatic plaques, including: tumour necrosis factor α, interleukin (IL) 1β, IL-6, granulocytemacrophage colony-stimulating factor (GM-CSF), macrophage colonystimulating factor (M-CSF), CCL5, CCL20, CXCL9, matrix metalloproteinase (MMP)-3 and MMP-9. Ingenuity pathway analysis of differentially expressed analytes between symptomatic and asymptomatic patients identified a number of key biological pathways (p > 10–25). In conclusion, the carotid artery plaque culprit of ischaemic neurological symptoms is characterised by an inflammatory milieu favouring inflammatory cell recruitment and pro-inflammatory macrophage polarisation.Supplementary Material to this article is available online at www.thrombosis-online.com.
Narrativas transmídias e uma cosm(o)ética ativista e jornalística na “Copa do Brasil”
Authors: Sousa Gisella Meneguelli 
Published: January 2016

<p>Este artigo busca refletir sobre a narrativa transmídia como recurso de criação e de divulgação das manifestações ocorridas no Brasil durante a Copa do Mundo de 2014. Na tentativa de compreendermos os processos narrativos em alguns meios de comunicação e redes sociais, analisamos o componente transmídia como organizador dos discursos de opinião pública, seja no jornalismo tradicional, seja no jornalismo anárquico.</p>
A copa em tweets: análise comparativa do uso das hashtags #EstadaonaCopa e #BairristanaCopa
Authors: Zago Gabriela Da Silva 
Published: January 2016

<p>Neste trabalho, procuramos analisar e comparar a utilização de hashtags de cobertura no Twitter por um site jornalístico e outro humorístico durante a Copa do Mundo de 2014: o jornal O Estado de S. Paulo, que utilizou a hashtag #EstadaonaCopa para sua cobertura em sites de rede social, e o site satírico O Bairrista, que adotou a hashtag #BairristanaCopa. O estudo foi operacionalizado a partir da combinação de observação com análise de redes sociais como métodos para compreender a estrutura e a dinâmica das redes em torno das respectivas hashtags. Resultados apontam para estruturas de rede semelhantes, porém com dinâmicas diferentes observadas em cada um dos casos estudados.</p>
Impact of Complete Versus Incomplete Circumferential Lines Around the Pulmonary Veins During Catheter Ablation of Paroxysmal Atrial Fibrillation
Authors: Kuck Karl-Heinz , Hoffmann Boris A. , Ernst Sabine , Wegscheider Karl , Treszl Andras , Metzner Andreas , Eckardt Lars , Lewalter Thorsten , Breithardt Günter , Willems Stephan 
Published: January 2016

Background—
Ablation of atrial fibrillation (AF) is an established treatment option for symptomatic patients. It is not known whether complete pulmonary vein isolation (PVI) is superior to incomplete PVI with regard to the patients’ clinical outcome.

Methods and Results—

Patients with drug-refractory, symptomatic paroxysmal AF were randomly assigned to either incomplete (group A) or complete PVI (group B). In group A, a persistent gap was intentionally left within the circumferential ablation line, whereas in group B, complete PVI without any gaps was intended. At 3 months, all patients underwent invasive reevaluation to assess the rate of persistent PVI. Clinical follow-up was based on daily 30-s transtelephonic ECG transmissions. Primary study end point was the time to first recurrence of (symptomatic or asymptomatic) AF. A total of 233 patients were enrolled (116 in group A and 117 in group B). AF recurrence within 3 months was observed in a total of 161 patients (136 [84.5%] with symptomatic and 25 [15.5%] with asymptomatic AF); AF recurred in 62.2% of group B patients and 79.2% of group A patients (
P
<0.001), for a difference in favor of complete PVI of 17.1% (95% confidence interval, 5.3%–28.9%). Invasive restudy in 103 group A patients and 93 group B patients revealed conduction gaps in 92 (89.3%) and 65 (69.9%) patients, respectively.

Conclusions—
This study proves the superiority of complete PVI over incomplete PVI with respect to AF recurrence within 3 months. However, the rate of electric reconduction 3 months after PVI is high in patients with initially isolated PVs.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
; Unique identifier: NCT00293943.
Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention
Authors: O’Donoghue Michelle L. , Bhatt Deepak L. , Stone Gregg W. , Steg Ph. Gabriel , Gibson C. Michael , Hamm Christian W. , Price Matthew J. , Prats Jayne , Liu Tiepu , Deliargyris Efthymios N. , Mahaffey Kenneth W. , White Harvey D. , Harrington Robert A. 
Published: January 2016

Background—
Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.

Methods and Results—

The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11 145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48–0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70–1.05;
P
interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20–0.77) and 16% in men (OR, 0.84; 95% CI, 0.53–1.33;
P
interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%,
P
=0.30 [women]; 0.1% versus 0.1%,
P
=0.41 [men];
P
interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%,
P
=0.02), but not in men (0.2% versus 0.2%,
P
=0.68;
P
interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50–0.92) and men (OR, 0.87; 95% CI, 0.71–1.06;
P
interaction=0.26).

Conclusions—
In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01156571.
Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping
Authors: Heusser Karsten , Tank Jens , Brinkmann Julia , Schroeder Christoph , May Marcus , Großhennig Anika , Wenzel Daniela , Diedrich André , Sweep Fred C. G. J. , Mehling Heidrun , Luft Friedrich C. , Jordan Jens 
Published: January 2016

Background
Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.

Methods and Results

We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (
P
<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.

Conclusions
HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00865917.