bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variations in Platelet Proteins Associated With ST-Elevation Myocardial Infarction
Authors: Parguiña Andrés F. , Grigorian-Shamagian Lilian , Agra Rosa M. , López-Otero Diego , Rosa Isaac , Alonso Jana , Teijeira-Fernández Elvis , González-Juanatey José Ramón , García Ángel 
Published: September 2011

Objective—
Our aim in this study was to provide novel information on the molecular mechanisms playing a major role in the unwanted platelet activation associated with ST-elevation myocardial infarction (STEMI).

Methods and Results—
We compared the platelet proteome of 11 STEMI patients to a matched control group of 15 stable chronic ischemic cardiopathy patients. In addition, we did a prospective study to follow the STEMI patients over time. Proteins were separated by high-resolution 2D gel electrophoresis, identified by mass spectrometry, and validated by Western blotting. Platelets from STEMI patients on admission displayed 56 protein spot differences (corresponding to 42 unique genes) compared with the control group. The number of differences decreased with time during the patients' follow-up. Interestingly, the adapter protein CrkL and the active form of Src (phosphorylated in Tyr418) were found to be upregulated in platelets from STEMI patients. Major signaling pathways related to the proteins identified include integrin, integrin-linked kinase, and glycoprotein VI (GPVI) signaling. Interestingly, a study on an independent cohort of patients showed a higher degree of activation of GPVI signaling in STEMI patients.

Conclusion—
CrkL, the active form of Src, and GPVI signaling are upregulated in platelets from STEMI patients.
A Systematic Review of Endoglin Gene Expression in Preeclampsia
Authors: Bell Mandy J. , Conley Yvette P. 
Published: September 2011

Objective: To synthesize scientific literature that addresses the role of endoglin (ENG) gene expression in preeclampsia (PE). Data sources: A literature search of PubMed and Ovid MEDLINE was conducted using the keywords endoglin, gene, and preeclampsia. Restrictions included English language and humans. Additional articles were identified/selected for evaluation via PubMed e-mail updates (keywords: endoglin and preeclampsia) and review of article reference lists obtained from the search. Study selection: The initial 14 abstracts retrieved from the literature search were reviewed and 9 studies were selected for evaluation. Review articles and studies not addressing ENG expression (messenger RNA [mRNA] level) in the context of PE were excluded. An additional six articles were selected from PubMed e-mail updates and reference lists. Data extraction: Data related to study objective, design, setting, subject information, phenotype, tissue type, data collection method, statistics, and results were extracted. Data synthesis: Regardless of PE definition, ancestral background, gene expression analysis method, tissue type, and time of specimen collection, endoglin appears to play a role in PE development. Moreover, results suggest that a variety of biological mechanisms have the ability to modulate ENG expression in PE, demonstrating the potential complexity associated with endoglin's role in PE. Conclusions: This review article is the first to systematically synthesize evidence related to ENG expression in PE. Findings can be utilized to design future studies that (a) address methodological limitations observed in the reviewed studies and (b) specifically examine why ENG expression levels are altered and address mechanisms explaining how these alterations are involved in PE development.
Multiple Sclerosis Severity Scale and whole-brain N-acetylaspartate concentration for patients’ assessment
Authors: Rigotti DJ , Gass A , Achtnichts L , Inglese M , Babb JS , Naegelin Y , Hirsch J , Amann M , Kappos L , Gonen O 
Published: September 2011

Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking. Objective: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients’ disease course. Methods: The MSSS and average WBNAA loss rate (ΔWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined. Some 27 patients exhibited a ‘benign’ disease course, characterized by an Expanded Disability Status Scale score (EDSS) of 3.0 or less, and 34 were ‘non-benign’: EDSS score higher than 3.0. Results: The two cohorts were indistinguishable in age and disease duration. Benign patients’ EDSS and MSSS (2.1 ± 0.7, 1.15 ± 0.60) were significantly lower than non-benign (4.6 ± 1.0, 3.6 ± 1.2; both p < 10−4). Their respective average ΔWBNAA, 0.10 ± 0.16 and 0.11 ± 0.12 mM/year, however, were not significantly different ( p > 0.7). While MSSS is both sensitive to (92.6%) and specific for (97.0%) benign MS, ΔWBNAA is only sensitive (92.6%) but not specific (2.9%). Conclusion: Since the WBNAA loss rate is similar in both phenotypes, the only difference between them is their clinical classification, characterized by MSSS and EDSS. This may indicate that ‘benign’ MS probably reflects fortuitous sparing of clinically eloquent brain regions and better utilization of brain plasticity.
Simvastatin improves final visual outcome in acute optic neuritis: a randomized study
Authors: Tsakiri Anna , Kallenbach Klaus , Fuglø Dan , Wanscher Benedikte , Larsson Henrik , Frederiksen Jette 
Published: September 2011

Background: In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS). Objective: To investigate whether simvastatin treatment (80 mg daily for 6 months) in patients with optic neuritis (ON) had a beneficial effect on visual outcome and on brain MRI. Methods: Sixty-four patients with acute ON were randomized to simvastatin treatment ( n = 32) or placebo ( n = 32) for 6 months. None of the patients had been on immunosuppressive therapy for 6 months prior to inclusion or treated with steroids from symptom onset. Contrast sensitivity (Arden plates), visual acuity, colour perception, visual evoked potentials (VEP) – latency and amplitude, Visual Analogue Scale (VAS) score, and gadolinium enhancing and T2 lesions on brain MRI were evaluated at screening visit, day 14 (except brain MRI), day 90 and day 180. Results: Simvastatin had a beneficial effect on VEP in both latency ( p = 0.01) and amplitude ( p = 0.01), a borderline effect on the Arden score ( p = 0.06) and VAS ( p = 0.04), and no effect on brain MRI or on relapse rate between the groups. Conclusion: This study provides Class I evidence that simvastatin 80 mg daily is well tolerated and possibly effective in patients with acute ON.
Using cure models and multiple imputation to utilize recurrence as an auxiliary variable for overall survival
Authors: Conlon Anna SC , Taylor Jeremy MG , Sargent Daniel J , Yothers Greg 
Published: September 2011

Background Intermediate outcome variables can often be used as auxiliary variables for the true outcome of interest in randomized clinical trials. For many cancers, time to recurrence is an informative marker in predicting a patient's overall survival outcome and could provide auxiliary information for the analysis of survival times. Purpose To investigate whether models linking recurrence and death combined with a multiple imputation procedure for censored observations can result in efficiency gains in the estimation of treatment effects and be used to shorten trial lengths. Methods Recurrence and death times are modeled using data from 12 trials in colorectal cancer. Multiple imputation is used as a strategy for handling missing values arising from censoring. The imputation procedure uses a cure model for time to recurrence and a time-dependent Weibull proportional hazards model for time to death. Recurrence times are imputed, and then death times are imputed conditionally on recurrence times. To illustrate these methods, trials are artificially censored 2 years after the last accrual, the imputation procedure implemented, and a log-rank test and Cox model used to analyze and compare these new data with the original data. Results The results show modest, but consistent gains in efficiency in the analysis using the auxiliary information in recurrence times. Comparison of analyses show the treatment effect estimates and log-rank test results from the 2-year censored imputed data to be in between the estimates from the original data and the artificially censored data, indicating that the procedure was able to recover some of the lost information due to censoring. Limitations The models used are all fully parametric, requiring distributional assumptions of the data. Conclusions The proposed models may be useful in improving the efficiency in estimation of treatment effects in cancer trials and shortening trial length.
Challenges in the design and analysis of non-inferiority trials: a case study
Authors: Durkalski Valerie , Silbergleit Robert , Lowenstein Daniel 
Published: September 2011

Background The literature on the design, conduct, and analysis of non-inferiority trials is continuously evolving. Several design issues continue to be researched including the choice of active control, choice of non-inferiority margin, and optimal analytic approaches. To date, there has been relatively little in the literature documenting actual experiences with implementing available methodology for non-inferiority trials. Purpose This article serves as a case study and highlights some of the challenges encountered in the design of a Phase III non-inferiority trial in status epilepticus that is being conducted under a Food and Drug Administration Investigational New Drug Application (IND). Methods The IND application was put on clinical hold by the Food Drug and Administration due to concerns with the design. Specifically, support for theactive control, non-inferiority margin, and overall interpretability of trial results were questioned, and a recommendation was made to consider a superiority design. The authors describe their interactions with the Food Drug and Administration and their application of available methods and approaches to address these concerns. Results The investigators’ response to the clinical hold provided detailed information to support the conduct of a non-inferiority trial. The study team received Food Drug and Administration approval to initiate the trial in October 2008. The trial enrollment began in June 2009 and is being conducted by roughly 800 paramedic units in over 40 Emergency Medicine Service systems across the United States. Limitations There is still a great deal of methodological research needed to fully understand the application and impact of the non-inferiority trial design. Conclusions It is evident that non-inferiority trials have an important place in clinical trial design and analysis. These trials may be the only way and only opportunity to answer certain questions; so, they must be designed and conductedwith rigor. This case study is an attempt to share our experiences in implementation.
A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization
Authors: Pereboom Tamara C. , van Weele Linda J. , Bondt Albert , MacInnes Alyson W. 
Published: September 2011

Abstract
Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in nop10 mutants. Our data support a model of DC whereupon in early development mutations involved in the H/ACA complex contribute to bone marrow failure through p53 deregulation and loss of initial stem cell numbers while their role in telomere maintenance does not contribute to DC until later in life.
Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia
Authors: Walker Aisha L. , Steward Shirley , Howard Thad A. , Mortier Nicole , Smeltzer Matthew , Wang Yong-Dong , Ware Russell E. 
Published: September 2011

AbstractHydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the Gγ-globin promoter and miRNA expression within primary CD71+ erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated Gγ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175).
Soluble RAGE is deficient in neutrophilic asthma and COPD
Authors: Sukkar M.B. , Wood L.G. , Tooze M. , Simpson J.L. , McDonald V.M. , Gibson P.G. , Wark P.A.B. 
Published: September 2011

The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD).Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n=16) or COPD (n=37), or from healthy controls (n=18), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n=101) and COPD (n=34) subjects.Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels.Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.
Adipose tissue in obesity and obstructive sleep apnoea
Authors: Bonsignore M.R. , McNicholas W.T. , Montserrat J.M. , Eckel J. 
Published: September 2011

A European Respiratory Society research seminar on “Metabolic alterations in obstructive sleep apnoea (OSA)” was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA.Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models orin vitrosystems. Since most OSA patients are obese, their management requires a multidisciplinary approach.This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children.Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.
Validity of an automated telephonic system to assess COPD exacerbation rates
Authors: Bischoff Erik W.M.A. , Boer Lonneke M. , Molema Johan , Akkermans Reinier , van Weel Chris , Vercoulen Jan H. , Schermer Tjard R.J. 
Published: September 2011

Current tools for recording chronic obstructive pulmonary disease (COPD) exacerbations are limited and often lack validity testing. We assessed the validity of an automated telephonic exacerbation assessment system (TEXAS) and compared its outcomes with existing tools.Over 12 months, 86 COPD patients (22.1% females; mean age 66.5 yrs; mean post-bronchodilator forced expiratory volume in 1 s 53.4% predicted) were called once every 2 weeks by TEXAS to record changes in respiratory symptoms, unscheduled healthcare utilisation and use of respiratory medication. The responses to TEXAS were validated against exacerbation-related information collected by observations made by trained research assistants during home visits. No care assistance was provided in any way. Diagnostic test characteristics were estimated using commonly used definitions of exacerbation. Detection rates, compliance and patient preference were assessed, and compared with paper diary cards and medical record review.A total of 1,824 successful calls were recorded, of which 292 were verified by home visits (median four calls per patient, interquartile range three to five calls per patient). Independent of the exacerbation definition used, validity was high, with sensitivities and specificities between 66% and 98%. Detection rates and compliance differed extensively between the different tools, but were highest with TEXAS. Patient preference did not differ.TEXAS is a valid tool to assess COPD exacerbation rates in prospective clinical studies. Using different tools to record exacerbations strongly affects exacerbation occurrence rates.
Severity and outcomes of hospitalised community-acquired pneumonia in COPD patients
Authors: Liapikou A. , Polverino E. , Ewig S. , Cillóniz C. , Marcos M.A. , Mensa J. , Bello S. , Martin-Loeches I. , Menéndez R. , Torres A. 
Published: September 2011

Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with community-acquired pneumonia (CAP). We investigated the impact of COPD on outcomes of CAP patients.We prospectively studied the clinical presentation of 1,379 patients admitted with CAP during a 4-yr period. A comparative analysis of disease severity and course was performed between 212 patients with COPD, as confirmed by spirometry, and 1,167 non-COPD patients.COPD patients (mean forced expiratory volume in 1 s 47.7±16.3% predicted) were older and more likely to have previously received antibiotics (37.1%versus28.3%; p<0.01) than those without COPD. They presented with more severe respiratory failure (arterial oxygen tension/inspiratory oxygen fraction 270.4versus287.8; p<0.01) and more severe pneumonia (pneumonia severity index 118.3versus108.5; p<0.001) compared with non-COPD patients. However, COPD patients had less multilobar infiltration (44 (21%)versus349 (30%); p<0.01) and fewer pulmonary complications (24 (14%)versus241 (24%); p<0.01). A total of 89 (6.5%) patients died within 30 days. COPD patients had no significant difference in their 30-day mortality rate compared with non-COPD patients (nine (4.2%) patientsversus81 (7%); p=0.14).Despite worse clinical presentation, COPD patients had a similar mortality rate compared to non-COPD patients. Previous antibiotic treatment and the decreased incidence of pulmonary complications in COPD may account for these findings.
Quantitative PCR to diagnosePneumocystispneumonia in immunocompromised non-HIV patients
Authors: Mühlethaler K. , Bögli-Stuber K. , Wasmer S. , von Garnier C. , Dumont P. , Rauch A. , Mühlemann K. , Garzoni C. 
Published: September 2011

The utility of quantitativePneumocystis jiroveciiPCR in clinical routine for diagnosingPneumocystispneumonia (PCP) in immunocompromised non-HIV patients is unknown.We analysed bronchoalveolar lavage fluid with real-time quantitativeP. jiroveciiPCR in 71 cases with definitive PCP defined by positive immunofluorescence (IF) tests and in 171 randomly selected patients with acute lung disease. In those patients, possible PCP cases were identified by using a novel standardised PCP probability algorithm and chart review. PCR performance was compared with IF testing, clinical judgment and the PCP probability algorithm.QuantitativeP. jiroveciiPCR values >1,450 pathogens·mL−1had a positive predictive value of 98.0% (95% CI 89.6–100.0%) for diagnosing definitive PCP. PCR values of between 1 and 1,450 pathogens·mL−1were associated with both colonisation and infection; thus, a cut-off between the two conditions could not be identified and diagnosis of PCP in this setting relied on IF and clinical assessment. Clinical PCP could be ruled out in 99.3% of 153 patients with negative PCR results.Quantitative PCR is useful for diagnosing PCP and is complementary to IF. PCR values of >1,450 pathogens·mL−1allow reliable diagnosis, whereas negative PCR results virtually exclude PCP. Intermediate values require additional clinical assessment and IF testing. On the basis of our data and for economic and logistical limitations, we propose a clinical algorithm in which IF remains the preferred first test in most cases, followed by PCR in those patients with a negative IF and strong clinical suspicion for PCP.