bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II signalling and calcineurin in cardiac fibroblasts: differential effects of calcineurin inhibitors FK506 and cyclosporine A
Authors: White Michel , Montezano Augusto C. , Touyz Rhian M. 
Published: December 2011

Introduction: Cardiac remodelling is controlled by complex systems, including activation of the renin-angiotensin system (RAS) and signalling through MAP kinases and Ca2+-activated calcineurin. Whether Ang II, which increases [Ca2+]i and stimulates MAP kinases, mediates myocardial effects through calcineurin-dependent pathways remain unclear. We investigated effects of two calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (FK506) (10-10-10-6 mol/L, 20 mins) on activation of MAP kinases and on growth, pro-fibrotic and pro-inflammatory responses in Ang II-stimulated rat cardiac fibroblasts. Methods and Results: Ang II increased phosphorylation of ERK1/2 and p38MAPK (1.5-1.8-fold, p<0.05) without effect on JNK. FK506, but not CsA, attenuated Ang II-stimulated MAP kinase activation. Molecular indices of cell growth (proliferating cell nuclear antigen (PCNA)), fibrosis (fibronectin, pro-collagen) and inflammation (iNOS), were upregulated by Ang II (12 hrs). FK506 and CsA inhibited PCNA effects. Ang II-induced pro-fibrotic and pro-inflammatory responses were inhibited by CsA. Ang II receptors, AT1R and AT2R, were not influenced by calcineurin inhibitors. Our data indicate differential calcineurin inhibitor sensitivity of MAP kinases and cellular responses in Ang II-stimulated fibroblasts. p38MAP kinase and ERK1/2 are regulated in a FK506-sensitive manner, whereas fibrosis and inflammation are CsA-sensitive. Cell proliferation is inhibited by both FKC506 and CsA. These are post-receptor phenomena, since AT1R and AT2R status was unaltered by treatment. Conclusions: Our findings identify an important role for calcineurin in MAP kinase/growth/pro-fibrotic/pro-inflammatory signalling by Ang II in cardiac fibroblasts. Although both FK506 and CsA inhibit calcineurin, they exert differential effects on molecular and cellular responses. Such differences may contribute to variable clinical responses of these agents.
Risk factors for COPD spirometrically defined from the lower limit of normal in the BOLD project
Authors: Hooper Richard , Burney Peter , Vollmer William M. , McBurnie Mary Ann , Gislason Thorarinn , Tan Wan C. , Jithoo Anamika , Kocabas Ali , Welte Tobias , Buist A. Sonia 
Published: December 2011

Chronic obstructive pulmonary disease (COPD) is predicted to become the third most common cause of death and disability worldwide by 2020.The prevalence of COPD defined by the lower limit of normal was estimated using high-quality spirometry in surveys of 14 populations aged ≥40 yrs. The strength and consistency of associations were assessed using random effects meta-analysis.Pack-years of smoking were associated with risk of COPD at each site. After adjusting for this effect, we still observed significant associations of COPD risk with age (OR 1.52 for a 10 yr age difference, 95% CI 1.35–1.71), body mass index in obese compared with normal weight (OR 0.50, 95% CI 0.37–0.67), level of education completed (OR 0.76, 95% CI 0.67–0.87), hospitalisation with a respiratory problem before age 10 yrs (OR 2.35, 95% CI 1.42–3.91), passive cigarette smoke exposure (OR 1.24, 95% CI 1.05–1.47), tuberculosis (OR 1.78, 95%CI 1.17–2.72) and a family history of COPD (OR 1.50, 95% CI 1.19–1.90).Although smoking is the most important risk factor for COPD, other risk factors are also important. More research is required to elucidate relevant risk factors in low- and middle-income countries where the greatest impact of COPD will occur.
A breath test for malignant mesothelioma using an electronic nose
Authors: Chapman Eleanor A. , Thomas Paul S. , Stone Emily , Lewis Craig , Yates Deborah H. 
Published: December 2011

Malignant mesothelioma (MM) is a rare tumour which is difficult to diagnose in its early stages. Earlier detection of MM could potentially improve survival. Exhaled breath sampling of volatile organic compounds (VOCs) using a carbon polymer array (CPA) electronic nose recognises specific breath profiles characteristic of different diseases, and can distinguish between patients with lung cancer and controls. With MM, the potential confounding effect of other asbestos-related diseases (ARDs) needs to be considered. We hypothesised that as CPA electronic nose would distinguish patients with MM, patients with benign ARDs, and controls with high sensitivity and specificity.20 MM, 18 ARD and 42 control subjects participated in a cross-sectional, case–control study. Breath samples were analysed using the Cyranose 320 (Smiths Detection, Pasadena, CA, USA), using canonical discriminant analysis and principal component reduction.10 MM subjects created the training set. Smell prints from 10 new MM patients were distinguished from control subjects with an accuracy of 95%. Patients with MM, ARDs and control subjects were correctly identified in 88% of cases.Exhaled breath VOC profiling can accurately distinguish between patients with MM, ARDs and controls using a CPA electronic nose. This could eventually translate into a screening tool for high-risk populations.
Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis
Authors: Lee J.S. , Song J.W. , Wolters P.J. , Elicker B.M. , King T.E. , Kim D.S. , Collard H.R. 
Published: December 2011

Some patients with idiopathic pulmonary fibrosis experience acute exacerbations in their respiratory status leading to substantial morbidity and mortality. Occult aspiration of gastric contents has been proposed as one possible mechanism leading to these acute exacerbations. We sought to determine whether pepsin, a marker of gastric aspiration, is elevated in bronchoalveolar lavage fluid obtained from patients during acute exacerbation of idiopathic pulmonary fibrosis, compared with that obtained in stable disease.Lavage samples were obtained in a case–control study of well-characterised patients. Acute exacerbation was defined using standard criteria. Levels of lavage pepsin were compared in cases and controls, and were correlated with clinical features and disease course.24 cases with acute exacerbations and 30 stable controls were identified. There were no significant differences in baseline demographics between the two groups. Pepsin level was an indicator of acute exacerbation status (p=0.04). On average, pepsin appeared higher in patients with acute exacerbations compared with stable controls. This difference was driven by a subgroup of eight patients (33%) with pepsin levels ≥70 ng·mL−1. Pepsin level was not an independent predictor of survival time.These results suggest occult aspiration may play a role in some cases of acute exacerbation of idiopathic pulmonary fibrosis.
The association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with OSA: a meta-analysis
Authors: Lee Peilin , Douglas Neil J. , Riha Renata L. 
Published: December 2011

Obstructive sleep apnoea (OSA) is an independent risk factor for hypertension. Increased angiotensin-converting enzyme (ACE) activity may be a possible promoting mechanism with different ACE insertion/deletion (I/D) genotypes influencing this activity. Studies investigating the association of ACE I/D polymorphisms with OSA have shown conflicting results. We aimed to undertake a meta-analysis of existing studies exploring the association of ACE I/D polymorphisms with the risk of OSA and hypertension.10 studies were included in a random effects meta-analysis, comprising 1,227 OSA subjects and 1,227 controls.The effect size was measured using the odds ratio. The risk of having OSA in carriers of the D allele was 0.92 (95% CI 0.69–1.23). There was statistically significant heterogeneity across the studies (I2=42%, p=0.08 and I2=74%, p<0.0001 for genotype and allele frequency, respectively). The association of D allele frequency with the risk of OSA remained nonsignificant after stratification based on ethnicity, source of population sample, and the presence of hypertension. Subgroup analysis failed to show any influence of genotype and allele frequency on OSA severity.This meta-analysis revealed no association between the ACE I/D polymorphisms and OSA susceptibility.
Stanford Seven-Day Physical Activity Recall questionnaire in COPD
Authors: Garfield Benjamin E. , Canavan Jane L. , Smith Cayley J. , Ingram Karen A. , Fowler Ria P. , Clark Amy L. , Polkey Michael I. , Man William D-C. 
Published: December 2011

Quantification of daily physical activity is of clinical interest in chronic obstructive pulmonary disease (COPD). Objective measures using activity monitors may take several days to obtain reliable results. The aim of our study was to evaluate the Stanford Seven-Day Physical Activity Recall questionnaire (PAR) against the SenseWear armband (SWA) and compare its validity with three other physical activity questionnaires.43 COPD patients wore the SWA for 7 days. Patients completed the PAR, Baecke, Physical Activity Scale for the Elderly (PASE) and Zutphen questionnaires. Spearman rank correlation, intraclass correlation coefficients (ICC) and receiver-operating characteristics (ROC) curves were used to assess the relationship between the questionnaires and SWA.Assessed by PAR, time spent at ≥3.0 metabolic equivalents (METs) correlated significantly (r=0.54, p<0.001) with equivalent measures from SWA, with an ICC of 0.40. No relationship was seen between the other questionnaires and the SWA. The PAR predicted active patients (≥30 min at ≥3.0 METs or a physical activity level (PAL) ≥1.55) and very inactive patients (PAL <1.40) with an area under ROC curve of 0.83, 0.77 and 0.70, respectively.While the PAR did not measure physical activity sufficiently accurately to make individual recommendations, it was able to identify COPD patients at extremes of the physical activity spectrum, potentially reducing the number of patients requiring direct measurement.
Knowledge of tuberculosis-treatment prescription of health workers: a systematic review
Authors: van der Werf Marieke J. , Langendam Miranda W. , Huitric Emma , Manissero Davide 
Published: December 2011

Treating tuberculosis (TB) patients with inappropriate treatment regimens can lead to treatment failure and, thus, patients who have not been cured and/or to the development of (multi)-drug resistance. A systematic review was performed to assess the knowledge of appropriate TB drug regimens among all categories of healthcare workers (HCWs).In January 2011, MEDLINE, EMBASE and other databases were searched for relevant articles. Observational studies published as of the year 2000 that assessed HCW knowledge of TB treatment were selected. A treatment regimen, drug dosage or treatment duration was considered inappropriate if it was not recommended by national guidelines or by the World Health Organization (WHO).Of 1,896 studies, 31 were included from 14 different countries. No study was performed in Europe. In all studies, HCWs with inappropriate knowledge of treatment regimens (8–100%) or treatment duration (5–99%) were observed. The few studies providing detailed data showed that HCWs mainly reported giving treatment regimens with too many drugs and for too long. Knowledge of appropriate doses was also insufficient in most studies.The available studies show that there is a lack of knowledge of national or international TB treatment guidelines and recommendations. Generalisation of the findings to other settings and countries should be done with caution.
Carotid body inflammation and cardiorespiratory alterations in intermittent hypoxia
Authors: Del Rio Rodrigo , Moya Esteban A. , Parga María J. , Madrid Carlos , Iturriaga Rodrigo 
Published: December 2011

Chronic intermittent hypoxia (CIH), a main feature of obstructive sleep apnoea (OSA), increases hypoxic ventilatory responses and elicits hypertension, partially attributed to an enhance carotid body (CB) responsiveness to hypoxia. As inflammation has been involved in CIH-induced hypertension and chemosensory potentiation, we tested whether ibuprofen may block CB chemosensory and cardiorespiratory alterations induced by CIH in a rat model of OSA.We studied the effects of ibuprofen (40 mg·kg−1·day−1) on immunohistochemical interleukin (IL)-1β and tumour necrosis factor (TNF)-α levels in the CB, the number of c-fos-positive neurons in the nucleus tractus solitarii (NTS), CB chemosensory and ventilatory responses to hypoxia, and arterial blood pressure in male rats either exposed for 21 days to 5% O2(12 episodes·h−1, 8 h·day−1) or kept under sham condition.CIH increased CB TNF-α and IL-1β and c-fos-positive neurons in the NTS, enhanced carotid chemosensory and ventilatory hypoxic responses, and produced hypertension. Ibuprofen prevented CB cytokine overexpression and CIH-induced increases in c-fos-positive neurons in the NTS, the enhanced hypoxic ventilatory responses and hypertension, but failed to impede the CB chemosensory potentiation.Results suggest that pro-inflammatory cytokines may contribute to the CIH-induced cardiorespiratory alterations, acting at several levels of the hypoxic chemoreflex and cardiovascular control pathways.
Age- and height-based prediction bias in spirometry reference equations
Authors: Quanjer Philip H. , Hall Graham L. , Stanojevic Sanja , Cole Tim J. , Stocks Janet 
Published: December 2011

Prediction bias in spirometry reference equations can arise from combining equations for different age groups, rounding age or height to integers or using self-reported height.To assess the bias arising from these sources, the fit of 13 prediction equations was tested against the Global Lungs Initiative (GLI) dataset using spirometric data from 55,136 healthy Caucasians (54% female). The effects on predicted values of using whole-year ageversusdecimal age, and of a 1% bias in height, were quantified.In children, the prediction bias relative to GLI ranged from -22% to +17%. Switching equations at 18 yrs of age led to biases of between -846 (-14%) and +1,309 (+38%) mL. Using age in whole years rather than decimal age introduced biases from -8% to +7%, whereas a 1% overestimation of height introduced bias that ranged from +1% to +40%. Bias was greatest in children and adolescents, and in short elderly subjects.Using a single spirometry equation applicable across all ages and populations reduces prediction bias. Measuring and recording age and height accurately are also essential if bias is to be minimised.
Antigen-specific multifunctional T-cells in sarcoidosis patients with Löfgren’s syndrome
Authors: Wikén Maria , Ostadkarampour Mahyar , Eklund Anders , Willett Matthew , Chen Edward , Moller David , Grunewald Johan , Wahlström Jan 
Published: December 2011

Sarcoidosis is a granulomatous disease of unknown aetiology, mainly affecting the lungs. Recently, T-cell responses towards a specific mycobacterial protein, catalase–peroxidase (mKatG), were observed in sarcoidosis patients.Bronchoalveolar lavage (BAL) fluid and peripheral blood were obtained from a total of 23 sarcoidosis patients, of whom 13 had Löfgren’s syndrome and lung accumulations of T-cell receptor AV2S3+ T-cells. Using six-colour flow cytometry in combination with intracellular cytokine staining, T-cell subsets were studied with regard to interferon (IFN)-γ, tumour necrosis factor (TNF) and interleukin-2 production, after stimulation with mKatG orMycobacterium tuberculosispurified protein derivate (PPD).Stimulation with mKatG resulted in higher simultaneous IFN-γ and TNF production, but less single IFN-γ production, from total BAL fluid CD4+ T-cells of Löfgren’s syndrome patients, when compared with non-Löfgren’s patients. In contrast, PPD stimulation gave rise to largely similar cytokine responses in both patient subgroups. Furthermore, mKatG stimulated higher IFN-γ production in BAL fluid and blood AV2S3+ T-cells than AV2S3- T-cells, whereas the opposite was seen in BAL fluid with PPD stimulation.Our finding that patients with Löfgren’s syndrome exhibited a more pronounced multifunctional cytokine profile (simultaneous IFN-γ and TNF production) towards the mycobacterial protein mKatG may help to explain the distinct disease presentation in this patient subgroup.
Theileria annulata-transformed cell lines are efficient antigen-presenting cells for in vitro analysis of CD8 T cell responses to bovine herpesvirus-1
Authors: Hart Jane , MacHugh Niall D , Morrison W Ivan 
Published: December 2011

AbstractContinuously growing cell lines infected with the protozoan parasiteTheileria annulatacan readily be established by in vitro infection of leukocytes with the sporozoite stage of the parasite. The aim of the current study was to determine whether such transformed cell lines could be used as antigen presenting cells to analyse the antigenic specificity of bovine CD8 T cell responses to viral infections. Bovine herpes virus 1 (BHV-1), which is known to induce CD8 T cell responses, was used as a model.T. annulata- transformed cells were shown to express high levels of CD40 and CD80 and were susceptible to infection with BHV-1, vaccinia and canarypox viruses. The capacity of the cells to generate antigen-specific CD8 T cell lines was initially validated using a recombinant canarypox virus expressing a defined immunodominantT. parvaantigen (Tp1). AutologousT. annulata-transformed cells infected with BHV-1 were then used successfully to generate specific CD8 T cell lines and clones from memory T cell populations of BHV-1-immune animals. These lines were BHV-1-specific and class I MHC-restricted. In contrast to previous studies, which reported recognition of the glycoproteins gB and gD, the CD8 T cell lines generated in this study did not recognise these glycoproteins. Given the ease with whichT. annulata-transformed cell lines can be established and maintained in vitro and their susceptibility to infection with poxvirus vectors, these cell lines offer a convenient and efficient in vitro system to analyse the fine specificity of virus-specific CD8 T cell responses in cattle.
Cost sensitive hierarchical document classification to triage PubMed abstracts for manual curation
Authors: Seymour Emily , Damle Rohini , Sette Alessandro , Peters Bjoern 
Published: December 2011

Abstract

Background
The Immune Epitope Database (IEDB) project manually curates information from published journal articles that describe immune epitopes derived from a wide variety of organisms and associated with different diseases. In the past, abstracts of scientific articles were retrieved by broad keyword queries of PubMed, and were classified as relevant (curatable) or irrelevant (not curatable) to the scope of the database by a Naïve Bayes classifier. The curatable abstracts were subsequently manually classified into categories corresponding to different disease domains. Over the past four years, we have examined how to further improve this approach in order to enhance classification performance and to reduce the need for manual intervention.

Results
Utilizing 89,884 abstracts classified by a domain expert as curatable or uncuratable, we found that a SVM classifier outperformed the previously used Naïve Bayes classifier for curatability predictions with an AUC of 0.899 and 0.854, respectively. Next, using a non-hierarchical and a hierarchical application of SVM classifiers trained on 22,833 curatable abstracts manually classified into three levels of disease specific categories we demonstrated that a hierarchical application of SVM classifiers outperformed non-hierarchical SVM classifiers for categorization. Finally, to optimize the hierarchical SVM classifiers' error profile for the curation process, cost sensitivity functions were developed to avoid serious misclassifications. We tested our design on a benchmark dataset of 1,388 references and achieved an overall category prediction accuracy of 94.4%, 93.9%, and 82.1% at the three levels of categorization, respectively.

Conclusions
A hierarchical application of SVM algorithms with cost sensitive output weighting enabled high quality reference classification with few serious misclassifications. This enabled us to significantly reduce the manual component of abstract categorization. Our findings are relevant to other databases that are developing their own document classifier schema and the datasets we make available provide large scale real-life benchmark sets for method developers.
The MEK2-binding tumor suppressor hDlg is recruited by E-cadherin to the midbody ring
Authors: Gaudet Suzanne , Langlois Marie-Josée , Lue Robert A , Rivard Nathalie , Viel Alain 
Published: December 2011

Abstract

Background
The human homologue of the Drosophila Discs-large tumor suppressor protein, hDlg, is a multi-domain cytoplasmic protein that localizes to the membrane at intercellular junction sites. At both synaptic junctions and epithelia cell-cell junctions, hDlg is known to recruit several signaling proteins into macromolecular complexes. hDlg is also found at the midbody, a small microtubule-rich structure bridging the two daughter cells during cytokinesis, but its function at this site is not clear.

Results
Here we describe the interaction of hDlg with the activated form of MEK2 of the canonical RAF/MEK/ERK pathway, a protein that is found at the midbody during cytokinesis. We show that both proteins localize to a sub-structure of the midbody, the midbody ring, and that the interaction between the PDZ domains of hDlg and the C-terminal portion of MEK2 is dependent on the phosphorylation of MEK2. Finally, we found that E-cadherin also localizes to the midbody and that its expression is required for the isoform-specific recruitment of hDlg, but not activated MEK2, to that structure.

Conclusion
Our results suggest that like at other cell-cell junction sites, hDlg is part of a macromolecular complex of structural and signaling proteins at the midbody.
PhosTryp: a phosphorylation site predictor specific for parasitic protozoa of the family trypanosomatidae
Authors: Palmeri Antonio , Gherardini Pier Federico , Tsigankov Polina , Ausiello Gabriele , Späth Gerald F , Zilberstein Dan , Helmer-Citterich Manuela 
Published: December 2011

Abstract

Background
Protein phosphorylation modulates protein function in organisms at all levels of complexity. Parasites of the Leishmania genus undergo various developmental transitions in their life cycle triggered by changes in the environment. The molecular mechanisms that these organisms use to process and integrate these external cues are largely unknown. However Leishmania lacks transcription factors, therefore most regulatory processes may occur at a post-translational level and phosphorylation has recently been demonstrated to be an important player in this process. Experimental identification of phosphorylation sites is a time-consuming task. Moreover some sites could be missed due to the highly dynamic nature of this process or to difficulties in phospho-peptide enrichment.

Results
Here we present PhosTryp, a phosphorylation site predictor specific for trypansomatids. This method uses an SVM-based approach and has been trained with recent Leishmania phosphosproteomics data. PhosTryp achieved a 17% improvement in prediction performance compared with Netphos, a non organism-specific predictor. The analysis of the peptides correctly predicted by our method but missed by Netphos demonstrates that PhosTryp captures Leishmania-specific phosphorylation features. More specifically our results show that Leishmania kinases have sequence specificities which are different from their counterparts in higher eukaryotes. Consequently we were able to propose two possible Leishmania-specific phosphorylation motifs.
We further demonstrate that this improvement in performance extends to the related trypanosomatids Trypanosoma brucei and Trypanosoma cruzi. Finally, in order to maximize the usefulness of PhosTryp, we trained a predictor combining all the peptides from L. infantum, T. brucei and T. cruzi.

Conclusions
Our work demonstrates that training on organism-specific data results in an improvement that extends to related species. PhosTryp is freely available at http://phostryp.bio.uniroma2.it