bluuebunny/crossref_metadata_2025_split huggingface dataset:
Back to the Future: Mechanism-Based, Mutation-Specific Combination Chemoprevention with a Synthetic Lethality Approach
Authors: Meyskens Frank L. , Gerner Eugene W. 
Published: May 2011

Abstract
There is an increasing recognition that the mutations accompanying carcinogenesis may provide a window of therapeutic advantage designated synthetic lethality, an example of which is reported in this issue of the journal by Huang and colleagues (beginning on page 666). First discovered and studied in yeast, synthetic lethality has basic principles that have encouraged its development for treatment and now prevention in animal models of human cancer, especially malignancies refractory to standard approaches. The pros and cons of this approach and challenges in implementing it clinically are discussed. Cancer Prev Res; 4(5); 628–32. ©2011 AACR.
Incomplete Recovery of Myocyte Contractile Function Despite Improvement of Myocardial Architecture With Left Ventricular Assist Device Support
Authors: Ambardekar Amrut V. , Walker John S. , Walker Lori A. , Cleveland Joseph C. , Lowes Brian D. , Buttrick Peter M. 
Published: May 2011

Background—
Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and LV size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ-level changes.

Methods and Results—

Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (before LVAD) and before cardiac transplantation (after LVAD). These were compared with 8 nonfailing hearts. Isolated skinned myocytes were purified and attached to a force transducer, and dimensions, maximum calcium-saturated force, calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0% to 25.6±11.0%,
P
=0.007), LV size decreased (LV internal dimension at end diastole, 7.6±1.2 to 4.9±1.4 cm;
P
<0.001), and myocyte dimensions decreased (cross-sectional area, 1247±346 to 638±254 μm
2
;
P
=0.001). Maximum calcium-saturated force improved after LVAD (3.6±0.9 to 7.3±1.8 mN/mm
2
,
P
<0.001) implantation but was still lower than in nonfailing hearts (7.3±1.8 versus 17.6±1.8 mN/mm
2
,
P
<0.001). An increase in troponin I (TnI) phosphorylation after LVAD implantation was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD.

Conclusions—
There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was associated only with biochemical changes in TnI, suggesting that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ-level recovery.
Estimation of Total Incremental Health Care Costs in Patients With Atrial Fibrillation in the United States
Authors: Kim Michael H. , Johnston Stephen S. , Chu Bong-Chul , Dalal Mehul R. , Schulman Kathy L. 
Published: May 2011

Background—
Detailed information on the cost burden of atrial fibrillation (AF) is limited. To provide an up-to-date estimate of the national cost of AF, we conducted a retrospective, observational cohort study using administrative claims from the MarketScan Commercial and Medicare Supplemental research data bases, 2004 to 2006.

Methods and Results—

Patients aged ≥20 years with ≥1 inpatient or ≥2 outpatient AF diagnoses in 2005 (first diagnosis=index) and ≥12 months' enrollment before and after index were selected. AF patients were propensity score–matched (1:1) with non-AF control subjects. Medical costs (2008 US$), including AF costs, other cardiovascular, and noncardiovascular costs, were examined over 1 year after index. National incremental costs of AF were based on age-/sex-specific AF prevalence projections for 2010. In total, 89 066 AF patients were matched to non-AF control subjects. Over 1 year, 37.5% of AF versus 17.5% of control subjects were hospitalized and 2.1% versus 0.1% died during hospitalization. For AF versus control subjects, mean annual inpatient costs per patient were $7841 versus $2622 (incremental cost, $5218), outpatient medical costs were $9225 versus $5629 ($3596), and outpatient pharmacy costs were $3605 versus $3714 (−$109) (all
P
<0.001). The total incremental cost of AF was $8705 per patient. The national incremental cost of AF was $26.0 billion (AF, $6.0 billion; other cardiovascular, $9.9 billion; noncardiovascular, $10.1 billion). Cardiovascular costs were based on claims with a primary disease diagnosis and may be underestimates.

Conclusions—
On the basis of current US age- and sex-specific prevalence data, the national incremental AF cost is estimated to range from $6.0 to $26.0 billion.
How Well Do Large-Scale Models Reproduce Regional Hydrological Extremes in Europe?
Authors: Prudhomme Christel , Parry Simon , Hannaford Jamie , Clark Douglas B. , Hagemann Stefan , Voss Frank 
Published: May 2011

AbstractThis paper presents a new methodology for assessing the ability of gridded hydrological models to reproduce large-scale hydrological high and low flow events (as a proxy for hydrological extremes) as described by catalogues of historical droughts [using the regional deficiency index (RDI)] and high flows [regional flood index (RFI)] previously derived from river flow measurements across Europe. Using the same methods, total runoff simulated by three global hydrological models from the Water Model Intercomparison Project (WaterMIP) [Joint U.K. Land Environment Simulator (JULES), Water Global Assessment and Prognosis (WaterGAP), and Max Planck Institute Hydrological Model (MPI-HM)] run with the same meteorological input (watch forcing data) at the same spatial 0.5° grid was used to calculate simulated RDI and RFI for the period 1963–2001 in the same European regions, directly comparable with the observed catalogues. Observed and simulated RDI and RFI time series were compared using three performance measures: the relative mean error, the ratio between the standard deviation of simulated over observed series, and the Spearman correlation coefficient. Results show that all models can broadly reproduce the spatiotemporal evolution of hydrological extremes in Europe to varying degrees. JULES tends to produce prolonged, highly spatially coherent events for both high and low flows, with events developing more slowly and reaching and sustaining greater spatial coherence than observed—this could be due to runoff being dominated by slow-responding subsurface flow. In contrast, MPI-HM shows very high variability in the simulated RDI and RFI time series and a more rapid onset of extreme events than observed, in particular for regions with significant water storage capacity—this could be due to possible underrepresentation of infiltration and groundwater storage, with soil saturation reached too quickly. WaterGAP shares some of the issues of variability with MPI-HM—also attributed to insufficient soil storage capacity and surplus effective precipitation being generated as surface runoff—and some strong spatial coherence of simulated events with JULES, but neither of these are dominant. Of the three global models considered here, WaterGAP is arguably best suited to reproduce most regional characteristics of large-scale high and low flow events in Europe. Some systematic weaknesses emerge in all models, in particular for high flows, which could be a product of poor spatial resolution of the input climate data (e.g., where extreme precipitation is driven by local convective storms) or topography. Overall, this study has demonstrated that RDI and RFI are powerful tools that can be used to assess how well large-scale hydrological models reproduce large-scale hydrological extremes—an exercise rarely undertaken in model intercomparisons.
Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells
Authors: Cho Jae-Ho , Kim Hee-Ok , Webster Kylie , Palendira Mainthan , Hahm Bumsuk , Kim Kyu-Sik , King Cecile , Tangye Stuart G. , Sprent Jonathan 
Published: May 2011

Abstract
Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8+ T cells; these receptors restrain CD8+ responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8+ (but not CD4+) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL-2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-β) but enhanced by others (IL-6, IL-10, and IL-21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo.
A genome-wide association study reveals evidence of association with sarcoidosis at6p12.1
Authors: Hofmann S. , Fischer A. , Till A. , Müller-Quernheim J. , Häsler R. , Franke A. , Gäde K.I. , Schaarschmidt H. , Rosenstiel P. , Nebel A. , Schürmann M. , Nothnagel M. , Schreiber S. ,   the GenPhenReSa Consortium
Published: May 2011

Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors.To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patientsversus1,783 controls).Variant rs10484410 on chromosome6p12.1was significantly associated, with a Bonferroni-corrected p-value of 2.90×10−2in the validation sample and a nominal p-value of 2.64×10−4in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genesBAG2,C6orf65,KIAA1586,ZNF451andRAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case–control sample and quantitative mRNA expression studies point to theRAB23gene as the most likely risk factor.RAB23is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway.The identified association of the6p12.1locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis.
Deterioration of exercise capacity after neonatal extracorporeal membrane oxygenation
Authors: van der Cammen-van Zijp M.H.M. , Gischler S.J. , Hop W.C.J. , de Jongste J.C. , Tibboel D. , IJsselstijn H. 
Published: May 2011

Extracorporeal membrane oxygenation (ECMO) provides life support in acute reversible cardiorespiratory failure. Assessment of long-term morbidity is essential to confirm survival advantage. This study aimed to assess exercise capacity in the first 12 yrs of life after neonatal ECMO, and to evaluate the effect of primary diagnosis, lung function or perinatal characteristics on exercise capacity.120 children who, as neonates, underwent ECMO performed 191 reliable exercise tests according to the Bruce treadmill protocol at ages 5, 8 and/or 12 yrs between 2001 and 2010. Primary diagnoses were meconium aspiration syndrome (n=66), congenital diaphragmatic hernia (n=18) and other diagnoses (n=36).At ages 5, 8 and 12 yrs, ANOVA resulted in mean±sestandard deviation score endurance time on the treadmill of -0.5±0.1, -1.1±0.1, and -1.5±0.2, respectively, all significantly less than zero (p<0.001). Exercise capacity declined significantly over time irrespective of the primary diagnosis.Neonates treated with ECMO are at risk of decreased exercise capacity at school age. We therefore propose prolonged follow-up. Proactive advice on sports participation or referral to a physical therapist is recommended, especially when either the parents or the children themselves report impaired exercise capacity.
T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis
Authors: Kriegova E. , Fillerova R. , Tomankova T. , Hutyrova B. , Mrazek F. , Tichy T. , Kolek V. , du Bois R.M. , Petrek M. 
Published: May 2011

Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with “sarcoidosis-associated” genes.Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry.Patient’s BAL cells expressed higher mRNA T-bet levels than those of controls (mean±sdfold change 3.64±1.72; p=0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p>0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p<0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes.In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.
Recognition of pleural mesothelioma by mucin-1(950–958)/human leukocyte antigen A*0201-specific CD8+ T-cells
Authors: Roulois D. , Vignard V. , Gueugnon F. , Labarrière N. , Grégoire M. , Fonteneau J-F. 
Published: May 2011

Recent clinical investigations have demonstrated that T-cell-based immunotherapy of malignant pleural mesothelioma (MPM) could represent an alternative to the other therapeutic strategies. However, its development suffers from the lack of identified tumour antigenic targets. Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, the objective of this study was to analyse MUC1 expression by MPM cells and to determine whether this antigen can be the target of cytotoxic CD8+ T-cells (cytotoxic T-lymphocytes (CTLs)).We first evaluated the expression and glycosylation of MUC1 by MPM cell lines using different MUC1-specific monoclonal antibodies. We then obtained a CTL clone specific for a MUC1 peptide (residues 950–958) presented by human leukocyte antigen (HLA)-A*0201 and studied its interferon-γ and cytotoxic response to MPM cell lines.We found that all MPM cell lines expressed MUC1 protein at the cell surface with different glycosylation profiles. We also observed that HLA-A*0201+ MPM cell lines are recognised and lysed by a HLA-A*0201/MUC1(950–958)-specific CTL clone independently of the MUC1 glycosylation profile.Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile.
Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs
Authors: Jagger Carol , Collerton Joanna C , Davies Karen , Kingston Andrew , Robinson Louise A , Eccles Martin P , von Zglinicki Thomas , Martin-Ruiz Carmen , James Oliver FW , Kirkwood Tom BL , Bond John 
Published: May 2011

Abstract

Background
Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care.

Methods
Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self-reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender.

Results
Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care-home places by 2030.

Conclusions
This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found.
Association of daily tar and nicotine intake with incident myocardial infarction: Results from the population-based MONICA/KORA Augsburg Cohort Study 1984 - 2002
Authors: Zhang Qiu-Li , Baumert Jens , Ladwig Karl-Heinz , Wichmann H-Erich , Meisinger Christa , Döring Angela 
Published: May 2011

Abstract

Background
Cigarette smoking has been shown to be one of the most important risk factors for cardiovascular diseases. However, little is known about cumulative effects of daily tar and nicotine intake on the risk of incident myocardial infarction (MI) so far. To bridge this gap, we conducted an analysis in a large prospective study from Southern Germany investigating associations of daily tar and nicotine intake with an incident MI event.

Methods
The study was based on 4,099 men and 4,197 women participating in two population-based MONICA Augsburg surveys between 1984 and 1990 and followed up within the KORA framework until 2002. During a mean follow-up of 13.3 years, a number of 307 men and 80 women developed an incident MI event. Relative risks were calculated as hazard ratios (HRs) estimated by Cox proportional hazards models adjusted for cardiovascular risk factors.

Results
In the present study, male regular smokers consumed on average more cigarettes per day than female regular smokers (20 versus 15) and had a higher tar and nicotine intake per day. In men, the MI risk compared to never-smokers increased with higher tar intake: HRs were 2.24 (95% CI 1.40-3.56) for 1-129 mg/day, 2.12 (95% CI 1.37-3.29) for 130-259 mg/day and 3.01 (95% CI 2.08-4.36) for ≥ 260 mg/day. In women, the corresponding associations were comparable but more pronounced for high tar intake (HR 4.67, 95% CI 1.76-12.40). Similar associations were observed for nicotine intake.

Conclusions
The present study based on a large population-based sample adds important evidence of cumulative effects of tar and nicotine intake on the risk of incident MI. Even low or medium tar and nicotine intake revealed substantial risk increases as compared to never-smokers. Therefore, reduction of tar and nicotine contents in cigarettes cannot be seen as a suitable public health policy in preventing myocardial infarction.
Teaching tools in Evidence Based Practice: evaluation of reusable learning objects (RLOs) for learning about Meta-analysis
Authors: Bath-Hextall Fiona , Wharrad Heather , Leonardi-Bee Jo 
Published: May 2011

Abstract

Background
All healthcare students are taught the principles of evidence based practice on their courses. The ability to understand the procedures used in systematically reviewing evidence reported in studies, such as meta-analysis, are an important element of evidence based practice. Meta-analysis is a difficult statistical concept for healthcare students to understand yet it is an important technique used in systematic reviews to pool data from studies to look at combined effectiveness of treatments. In other areas of the healthcare curricula, by supplementing lectures, workbooks and workshops with pedagogically designed, multimedia learning objects (known as reusable learning objects or RLOs) we have shown an improvement in students' perceived understanding in subjects they found difficult. In this study we describe the development and evaluation of two RLOs on meta-analysis. The RLOs supplement associated lectures and aim to improve students' understanding of meta-analysis in healthcare students.

Methods
Following a quality controlled design process two RLOs were developed and delivered to two cohorts of students, a Master in Public Health course and Postgraduate diploma in nursing course. Students' understanding of five key concepts of Meta-analysis were measured before and after a lecture and again after RLO use. RLOs were also evaluated for their educational value, learning support, media attributes and usability using closed and open questions.

Results
Students rated their understanding of meta-analysis as improved after a lecture and further improved after completing the RLOs (Wilcoxon paired test, p < 0.01 in all cases) Whilst the media components of the RLOs such as animations helped most students (86%) understand concepts including for example Forest plots, 93% of students rated usability and control as important to their learning. A small number of students stated they needed the support of a lecturer alongside the RLOs (7% 'Agreed' and 21% 'Neutral').

Conclusions
Meta-analysis RLOs that are openly accessible and unrestricted by usernames and passwords provide flexible support for students who find the process of meta-analysis difficult.