bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA genotyping in the international Type 1 Diabetes Genetics Consortium
Authors: Mychaleckyj Josyf C , Noble Janelle A , Moonsamy Priscilla V , Carlson Joyce A , Varney Michael D , Post Jeff , Helmberg Wolfgang , Pierce June J , Bonella Persia , Fear Anna Lisa , Lavant Eva , Louey Anthony , Boyle Sean , Lane Julie A , Sali Paul , Kim Samuel , Rappner Rebecca , Williams Dustin T , Perdue Letitia H , Reboussin David M , Tait Brian D , Akolkar Beena , Hilner Joan E , Steffes Michael W , Erlich Henry A ,   T1DGC
Published: July 2010

Background Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers. Purpose In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years. Methods Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences. Results A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances. Limitations The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required. Conclusions High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies. Clinical Trials 2010; 7: S75—S87. http:// ctj.sagepub.com
LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis
Authors: Gutierrez Albert , Tschumper Renee C. , Wu Xiaosheng , Shanafelt Tait D. , Eckel-Passow Jeanette , Huddleston Paul M. , Slager Susan L. , Kay Neil E. , Jelinek Diane F. 
Published: July 2010

Abstract
The canonical Wnt signaling pathway is pathogenic in a variety of cancers. We previously identified aberrant expression of the Wnt pathway transcription factor and target gene lymphoid enhancer binding factor-1 (LEF1) in chronic lymphocytic leukemia (CLL). This suggested that the Wnt signaling pathway has a role in the biology of CLL. In this study, we performed a Wnt pathway analysis using gene expression profiling and identified aberrant regulation of Wnt pathway target genes, ligands, and signaling members in CLL cells. Furthermore, we identified aberrant protein expression of LEF-1 specifically in CLL but not in normal mature B-cell subsets or after B-cell activation. Using the T cell–specific transcription factor/LEF (TCF/LEF) dual luciferase reporter assay, we demonstrated constitutive Wnt pathway activation in CLL, although the pathway was inactive in normal peripheral B cells. Importantly, LEF-1 knockdown decreased CLL B-cell survival. We also identified LEF-1 expression in CD19+/CD5+ cells obtained from patients with monoclonal B-cell lymphocytosis, suggesting a role for LEF-1 early in CLL leukemogenesis. This study has identified the constitutive activation and prosurvival function of LEF-1 and the Wnt pathway in CLL and uncovered a possible role for these factors in the preleukemic state of monoclonal B-cell lymphocytosis.
Screening for sleep-disordered breathing in neuromuscular disease using a questionnaire for symptoms associated with diaphragm paralysis
Authors: Steier J. , Jolley C.J. , Seymour J. , Teschler H. , Luo Y.M. , Polkey M.I. , Moxham J. 
Published: July 2010

Patients with neuromuscular disease (NMD) are at risk of developing sleep-disordered breathing (SDB) following respiratory muscle involvement. We hypothesised that a questionnaire based on clinical symptoms and signs of diaphragm weakness can be used to screen for SDB in such patients.We developed a self-administered multiple choice questionnaire containing five questions (Sleep-Disordered Breathing in Neuromuscular Disease Questionnaire (SiNQ)-5), scoring 0–10 points. 125 patients were enrolled: 32 with respiratory muscle weakness, 35 subjects with normal respiratory muscle strength and 58 patients with obstructive sleep apnoea (OSA). All subjects underwent full polysomnography.NMD patients with involvement of the respiratory muscles scored mean±sd6.8±2.3 out of 10 points, significantly higher than both OSA patients 2.5±2.3 and normal subjects 1.0±2.0 (p<0.001). A score of five or more points in the SiNQ-5 had a sensitivity of 86.2%, specificity of 88.5%, positive predictive value of 69.4% and a negative predictive value of 95.5% to identify NMD with combined SDB.A short self-administered questionnaire, the SiNQ-5, based on clinical symptoms can reliably screen for SDB in patients with diaphragm weakness. However, comorbidities, such as heart failure, that have symptoms influenced by posture could alter diagnostic accuracy.
Nasal inflammation in sleep apnoea patients using CPAP and effect of heated humidification
Authors: Koutsourelakis I. , Vagiakis E. , Perraki E. , Karatza M. , Magkou C. , Kopaka M. , Roussos C. , Zakynthinos S. 
Published: July 2010

Nasal continuous positive airway pressure (CPAP) can cause undesirable nasal symptoms, such as congestion to obstructive sleep apnoea (OSA) patients, whose symptoms can be attenuated by the addition of heated humidification. However, neither the nature of nasal symptoms nor the effect of heated humidification on nasal pathophysiology and pathology are convincingly known.20 patients with OSA on nasal CPAP who exhibited symptomatic nasal obstruction were randomised to receive either 3 weeks of CPAP treatment with heated humidification or 3 weeks of CPAP treatment with sham-heated humidification, followed by 3 weeks of the opposite treatment, respectively. Nasal symptom score, nasal resistance, nasal lavage interleukin-6, interleukin-12 and tumour necrosis factor-α and nasal mucosa histopathology were assessed at baseline and after each treatment arm.Heated humidification in comparison with sham-heated humidification was associated with decrease in nasal symptomatology, resistance and lavage cytokines, and attenuation of inflammatory cell infiltration and fibrosis of the nasal mucosa.In conclusion, nasal obstruction of OSA patients on CPAP treatment is inflammatory in origin and the addition of heated humidification decreases nasal resistance and mucosal inflammation.
Case fatality of COPD exacerbations: a meta-analysis and statistical modelling approach
Authors: Hoogendoorn M. , Hoogenveen R.T. , Rutten-van Mölken M.P. , Vestbo J. , Feenstra T.L. 
Published: July 2010

The aim of our study was to estimate the case fatality of a severe exacerbation from long-term survival data presented in the literature.A literature search identified studies reporting ≥1.5 yr survival after a severe chronic obstructive pulmonary disease (COPD) exacerbation resulting in hospitalisation. The survival curve of each study was divided into a critical and a stable period. Mortality during the stable period was then estimated by extrapolating the survival curve during the stable period back to the time of exacerbation onset. Case fatality was defined as the excess mortality that results from an exacerbation and was calculated as 1 minus the (backwardly) extrapolated survival during the stable period at the time of exacerbation onset. The 95% confidence intervals (CI) of the estimated case fatalities were obtained by bootstrapping. A random effect model was used to combine all estimates into a weighted average with 95% CI.The meta-analysis based on six studies that fulfilled the inclusion criteria resulted in a weighted average case-fatality rate of 15.6% (95% CI 10.9–20.3), ranging from 11.4% to 19.0% for the individual studies.A severe COPD exacerbation requiring hospitalisation not only results in higher mortality risks during hospitalisation, but also in the time-period after discharge and contributes substantially to total COPD mortality.
Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma
Authors: Smith N.L. , Denning D.W. 
Published: July 2010

Chronic pulmonary aspergillosis (CPA) is a condition caused by the ubiquitous fungusAspergillus fumigatusin non-immunocompromised individuals. Numerous underlying conditions have been associated with CPA.Details of the underlying conditions of 126 CPA patients attending our tertiary referral clinic from all over the UK were extracted from the clinical notes, and the distribution of these underlying conditions was analysed. For those with several underlying pulmonary conditions, one was nominated as the primary condition.Many patients presented with multiple underlying conditions, and a total of 232 underlying conditions were identified for the 126 patients. Previous classical tuberculosis and non-tuberculous mycobacterial infection were the most common primary underlying conditions (15.3% and 14.9%, respectively). Others included allergic bronchopulmonary aspergillosis (ABPA), chronic obstructive pulmonary condition (COPD) and/or emphysema, pneumothorax and prior treated lung cancer. Some conditions were found more often as one of multiple underlying conditions, while others were found only as secondary underlying conditions.Tuberculosis, non-tuberculous mycobacterial infection and ABPA remain the predominant risk factors for development of CPA, with COPD, prior pneumothorax or treated lung cancer also relatively common among our referrals. Many patients have multiple underlying pulmonary conditions. CPA should be considered when upper lobe cavitary or fibrotic disease and systemic symptoms are present in those with lung disease.
Procedure volume is one determinant of centre effect in mechanically ventilated patients
Authors: Darmon M. , Azoulay E. , Fulgencio J-P. , Garrigues B. , Gouzes C. , Moine P. , Villers D. , Teboul V. , le Gall J-R. , Chevret S. 
Published: July 2010

Survival rates vary significantly between intensive care units, most notably in patients requiring mechanical ventilation (MV). The present study sought to estimate the effect of hospital MV volume on hospital mortality.We included 179,197 consecutive patients who received mechanical ventilation in 294 hospitals. Multivariate logistic regression models with random intercepts were used to estimate the effect of annual MV volume in each hospital, adjusting for differences in severity of illness and case mix.Median annual MV volume was 162 patients (interquartile range 99–282). Hospital mortality in MV patients was 31.4% overall, 40.8% in the lowest annual volume quartile and 28.2% in the highest quartile. After adjustment for severity of illness, age, diagnosis and organ failure, higher MV volume was associated with significantly lower hospital mortality among MV patients (OR 0.9985 per 10 additional patients, 95% CI 0.9978–0.9992; p = 0.0001). A significant centre effect on hospital mortality persisted after adjustment for volume effect (p<0.0001).Our study demonstrated higher hospital MV volume to be independently associated with increased survival among MV patients. Significant differences in outcomes persisted between centres after adjustment for hospital MV volume, supporting a role for other significant determinants of the centre effect.
Brain metastases from lung cancer responding to erlotinib: the importance ofEGFRmutation
Authors: Porta R. , Sánchez-Torres J.M. , Paz-Ares L. , Massutí B. , Reguart N. , Mayo C. , Lianes P. , Queralt C. , Guillem V. , Salinas P. , Catot S. , Isla D. , Pradas A. , Gúrpide A. , de Castro J. , Polo E. , Puig T. , Tarón M. , Colomer R. , Rosell R. 
Published: July 2010

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene.We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib.EGFRmutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according toEGFRmutational status.69 NSCLC patients with brain metastases were identified, 17 of whom harbouredEGFRmutations. Objective response rate in patients withEGFRmutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouringEGFRmutations was 11.7 (7.9–15.5) months, compared to 5.8 (5.2–6.4) months for control patients whoseEGFRmutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2–19.7) months and 3.1 (2.5–3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed.Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of theEGFRgene.
Orthology confers intron position conservation
Authors: Henricson Anna , Forslund Kristoffer , Sonnhammer Erik LL 
Published: July 2010

Abstract

Background
With the wealth of genomic data available it has become increasingly important to assign putative protein function through functional transfer between orthologs. Therefore, correct elucidation of the evolutionary relationships among genes is a critical task, and attempts should be made to further improve the phylogenetic inference by adding relevant discriminating features. It has been shown that introns can maintain their position over long evolutionary timescales. For this reason, it could be possible to use conservation of intron positions as a discriminating factor when assigning orthology. Therefore, we wanted to investigate whether orthologs have a higher degree of intron position conservation (IPC) compared to non-orthologous sequences that are equally similar in sequence.

Results
To this end, we developed a new score for IPC and applied it to ortholog groups between human and six other species. For comparison, we also gathered the closest non-orthologs, meaning sequences close in sequence space, yet falling just outside the ortholog cluster. We found that ortholog-ortholog gene pairs on average have a significantly higher degree of IPC compared to ortholog-closest non-ortholog pairs. Also pairs of inparalogs were found to have a higher IPC score than inparalog-closest non-inparalog pairs. We verified that these differences can not simply be attributed to the generally higher sequence identity of the ortholog-ortholog and the inparalog-inparalog pairs.
Furthermore, we analyzed the agreement between IPC score and the ortholog score assigned by the InParanoid algorithm, and found that it was consistently high for all species comparisons. In a minority of cases, the IPC and InParanoid score ranked inparalogs differently. These represent cases where sequence and intron position divergence are discordant. We further analyzed the discordant clusters to identify any possible preference for protein functions by looking for enriched GO terms and Pfam protein domains. They were enriched for functions important for multicellularity, which implies a connection between shifts in intronic structure and the origin of multicellularity.

Conclusions
We conclude that orthologous genes tend to have more conserved intron positions compared to non-orthologous genes. As a consequence, our IPC score is useful as an additional discriminating factor when assigning orthology.
Plant microRNAs and their role in defense against viruses: a bioinformatics approach
Authors: Pérez-Quintero Álvaro L , Neme Rafik , Zapata Andrés , López Camilo 
Published: July 2010

Abstract

Background
microRNAs (miRNAs) are non-coding short RNAs that regulate gene expression in eukaryotes by translational inhibition or cleavage of complementary mRNAs. In plants, miRNAs are known to target mostly transcription factors and are implicated in diverse aspects of plant growth and development. A role has been suggested for the miRNA pathway in antiviral defense in plants. In this work, a bioinformatics approach was taken to test whether plant miRNAs from six species could have antiviral activity by targeting the genomes of plant infecting viruses.

Results
All plants showed a repertoire of miRNAs with potential for targeting viral genomes. The viruses were targeted by abundant and conserved miRNA families in regions coding for cylindrical inclusion proteins, capsid proteins, and nuclear inclusion body proteins. The parameters for our predicted miRNA:target pairings in the viral genomes were similar to those for validated targets in the plant genomes, indicating that our predicted pairings might behave in-vivo as natural miRNa-target pairings. Our screening was compared with negative controls comprising randomly generated miRNAs, animal miRNAs, and genomes of animal-infecting viruses. We found that plant miRNAs target plant viruses more efficiently than any other sequences, but also, miRNAs can either preferentially target plant-infecting viruses or target any virus without preference.

Conclusions
Our results show a strong potential for antiviral activity of plant miRNAs and suggest that the miRNA pathway may be a support mechanism to the siRNA pathway in antiviral defense.
Development and validation of self-reported line drawings for assessment of knee malalignment and foot rotation: a cross-sectional comparative study
Authors: Ingham Sarah L , Moody Amanda , Abhishek Abhishek , Doherty Sally A , Zhang Weiya , Doherty Michael 
Published: July 2010

Abstract

Background
For large scale epidemiological studies clinical assessments and radiographs can be impractical and expensive to apply to more than just a sample of the population examined. The study objectives were to develop and validate two novel instruments for self-reported knee malalignment and foot rotation suitable for use in questionnaire studies of knee pain and osteoarthritis.

Methods
Two sets of line drawings were developed using similar methodology. Each instrument consisted of an explanatory question followed by a set of drawings showing straight alignment, then two each at 7.5° angulation and 15° angulation in the varus/valgus (knee) and inward/outward (foot) directions. Forty one participants undertaking a community study completed the instruments on two occasions. Participants were assessed once by a blinded expert clinical observer with demonstrated excellent reproducibility. Validity was assessed by sensitivity, specificity and likelihood ratio (LR) using the observer as the reference standard. Reliability was assessed using weighted kappa (κ). Knee malalignment was measured on 400 knee radiographs. General linear model was used to assess for the presence of a linear increase in knee alignment angle (measured medially) from self-reported severe varus to mild varus, straight, mild valgus and severe valgus deformity.

Results
Observer reproducibility (κ) was 0.89 and 0.81 for the knee malalignment and foot rotation instruments respectively. Self-reported participant reproducibility was also good for the knee (κ 0.73) and foot (κ 0.87) instruments. Validity was excellent for the knee malalignment instrument, with a sensitivity of 0.74 (95%CI 0.54, 0.93) and specificity of 0.97 (95%CI 0.94, 1.00). Similarly the foot rotation instrument was also found to have high sensitivity (0.92, 95%CI 0.83, 1.01) and specificity (0.96, 95%CI 0.93, 1.00). The knee alignment angle increased progressively from self reported severe varus to mild varus, straight, mild valgus and severe valgus knee malalignment (ptrend <0.001).

Conclusions
The two novel instruments appear to provide a valid and reliable assessment of self-reported knee malalignment and foot rotation, and may have a practical use in epidemiological studies.
Solution structure of the human signaling protein RACK1
Authors: Gonçalves Kaliandra A , Borges Julio C , Silva Julio C , Papa Priscila F , Bressan Gustavo C , Torriani Iris L , Kobarg Jörg 
Published: July 2010

Abstract

Background
The adaptor protein RACK1 (receptor of activated kinase 1) was originally identified as an anchoring protein for protein kinase C. RACK1 is a 36 kDa protein, and is composed of seven WD repeats which mediate its protein-protein interactions. RACK1 is ubiquitously expressed and has been implicated in diverse cellular processes involving: protein translation regulation, neuropathological processes, cellular stress, and tissue development.

Results
In this study we performed a biophysical analysis of human RACK1 with the aim of obtaining low resolution structural information. Small angle X-ray scattering (SAXS) experiments demonstrated that human RACK1 is globular and monomeric in solution and its low resolution structure is strikingly similar to that of an homology model previously calculated by us and to the crystallographic structure of RACK1 isoform A from Arabidopsis thaliana. Both sedimentation velocity and sedimentation equilibrium analytical ultracentrifugation techniques showed that RACK1 is predominantly a monomer of around 37 kDa in solution, but also presents small amounts of oligomeric species. Moreover, hydrodynamic data suggested that RACK1 has a slightly asymmetric shape. The interaction of RACK1 and Ki-1/57 was tested by sedimentation equilibrium. The results suggested that the association between RACK1 and Ki-1/57(122-413) follows a stoichiometry of 1:1. The binding constant (KB) observed for RACK1-Ki-1/57(122-413) interaction was of around (1.5 ± 0.2) × 106 M-1 and resulted in a dissociation constant (KD) of (0.7 ± 0.1) × 10-6 M. Moreover, the fluorescence data also suggests that the interaction may occur in a cooperative fashion.

Conclusion
Our SAXS and analytical ultracentrifugation experiments indicated that RACK1 is predominantly a monomer in solution. RACK1 and Ki-1/57(122-413) interact strongly under the tested conditions.