Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis

Introduction

Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. As a result, the present study examined the possibility that effective antirheumatic treatment will decrease the level of synovial citrullination.

Methods

Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intraarticular glucocorticoid injection, and eight healthy volunteers. Synovial inflammation was assessed with double-blind semiquantitative analysis of lining thickness, cell infiltration, and vascularity by using a 4-point scale. Expression of citrullinated proteins (CPs) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically with double-blind semiquantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB), mononuclear cells (MCs), and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed with immunohistochemistry for expression of CP as well as PAD2 and PAD4 enzymes.

Results

The presence of synovial CP was almost exclusive in RA compared with healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination, as demonstrated by the decrease in the level of citrullination and PAD expression after incubation of SFMC and synovial explants with dexamethasone.

Conclusion

Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.     

A comparative genomics study of genetic products potentially encoding ladderane lipid biosynthesis

Background  

The fatty acids of anaerobic ammonium oxidizing (anammox) bacteria contain linearly concatenated cyclobutane moieties, so far unique to biology. These moieties are under high ring strain and are synthesised by a presently unknown biosynthetic pathway.     

Genome-assisted prediction of a quantitative trait measured in parents and progeny: application to food conversion rate in chickens

Accuracy of prediction of yet-to-be observed phenotypes for food conversion rate (FCR) in broilers was studied in a genome-assisted selection context. Data consisted of FCR measured on the progeny of 394 sires with SNP information. A Bayesian regression model (Bayes A) and a semi-parametric approach (Reproducing kernel Hilbert Spaces regression, RKHS) using all available SNPs (p = 3481) were compared with a standard linear model in which future performance was predicted using pedigree indexes in the absence of genomic data. The RKHS regression was also tested on several sets of pre-selected SNPs (p = 400) using alternative measures of the information gain provided by the SNPs. All analyses were performed using 333 genotyped sires as training set, and predictions were made on 61 birds as testing set, which were sons of sires in the training set. Accuracy of prediction was measured as the Spearman correlation (r¯S) between observed and predicted phenotype, with its confidence interval assessed through a bootstrap approach. A large improvement of genome-assisted prediction (up to an almost 4-fold increase in accuracy) was found relative to pedigree index. Bayes A and RKHS regression were equally accurate (r¯S = 0.27) when all 3481 SNPs were included in the model. However, RKHS with 400 pre-selected informative SNPs was more accurate than Bayes A with all SNPs.     

Incomplete posttranslational prohormone modifications in hyperactive neuroendocrine cells

Background  

In black-background-adapted Xenopus laevis, the intermediate pituitary melanotrope cells are hyperactive, producing large amounts of their major secretory cargo proopiomelanocortin (POMC, representing ~80% of all newly synthesised proteins), whereas in white-adapted frogs these cells are only basally active. Here we explored in the hyperactive and basally active melanotrope cells the capacity for posttranslational POMC processing events in the secretory pathway.     

GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma

Background

Anxiety and depression are common and treatable risk factors for re-hospitalisation and death in patients with COPD. The degree of lung function impairment does not sufficiently explain anxiety and depression. The BODE index allows a functional classification of COPD beyond FEV₁. The aim of this cross-sectional study was (1) to test whether the BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms; and (2) to assess which components of the BODE index are associated with these psychological aspects of COPD.

Methods

COPD was classified according to the GOLD stages based on FEV_1%predicted in 122 stable patients with COPD. An additional four stage classification was constructed based on the quartiles of the BODE index. The hospital anxiety and depression scale was used to assess anxious and depressive symptoms.

Results

The overall prevalence of anxious and depressive symptoms was 49% and 52%, respectively. The prevalence of anxious symptoms increased with increasing BODE stages but not with increasing GOLD stages. The prevalence of depressive symptoms increased with both increasing GOLD and BODE stages. The BODE index was superior to FEV_1%predicted for explaining anxious and depressive symptoms. Anxious symptoms were explained by dyspnoea. Depressive symptoms were explained by both dyspnoea and reduced exercise capacity.

Conclusion

The BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms in COPD patients. These psychological consequences of the disease may play a role in future classification systems of COPD.     

An interactive tool for visualization of relationships between gene expression profiles

Background  

Application of phenetic methods to gene expression analysis proved to be a successful approach. Visualizing the results in a 3-dimentional space may further enhance these techniques.     

Distill: a suite of web servers for the prediction of one-, two- and three-dimensional structural features of proteins

Background  

We describe Distill, a suite of servers for the prediction of protein structural features: secondary structure; relative solvent accessibility; contact density; backbone structural motifs; residue contact maps at 6, 8 and 12 Angstrom; coarse protein topology. The servers are based on large-scale ensembles of recursive neural networks and trained on large, up-to-date, non-redundant subsets of the Protein Data Bank. Together with structural feature predictions, Distill includes a server for prediction of C _α traces for short proteins (up to 200 amino acids).     

The effect of oligonucleotide microarray data pre-processing on the analysis of patient-cohort studies

Background  

Intensity values measured by Affymetrix microarrays have to be both normalized, to be able to compare different microarrays by removing non-biological variation, and summarized, generating the final probe set expression values. Various pre-processing techniques, such as dChip, GCRMA, RMA and MAS have been developed for this purpose. This study assesses the effect of applying different pre-processing methods on the results of analyses of large Affymetrix datasets. By focusing on practical applications of microarray-based research, this study provides insight into the relevance of pre-processing procedures to biology-oriented researchers.