Rheumatoid factor and anti-citrullinated protein antibody positivity,but not level,are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts

Introduction

This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).

Methods

Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.

Results

A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).

Conclusions

Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0483-3) contains supplementary material, which is available to authorized users.     

Segmental Helical Motions and Dynamical Asymmetry Modulate Histidine Kinase Autophosphorylation

Histidine kinases (HKs) are dimeric receptors that participate in most adaptive responses to environmental changes in prokaryotes. Although it is well established that stimulus perception triggers autophosphorylation in many HKs, little is known on how the input signal propagates through the HAMP domain to control the transient interaction between the histidine-containing and ATP-binding domains during the catalytic reaction. Here we report crystal structures of the full cytoplasmic region of CpxA, a prototypical HK involved in Escherichia coli response to envelope stress. The structural ensemble, which includes the Michaelis complex, unveils HK activation as a highly dynamic process, in which HAMP modulates the segmental mobility of the central HK α-helices to promote a strong conformational and dynamical asymmetry that characterizes the kinase-active state. A mechanical model based on our structural and biochemical data provides insights into HAMP-mediated signal transduction, the autophosphorylation reaction mechanism, and the symmetry-dependent control of HK kinase/phosphatase functional states.     

Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross

Background

Sheep carcasses with yellow fat are sporadically observed at Norwegian slaughter houses. This phenomenon is known to be inherited as a recessive trait, and is caused by accumulation of carotenoids in adipose tissue. Two enzymes are known to be important in carotenoid degradation in mammals, and are therefore potential candidate genes for this trait. These are beta-carotene 15,15'-monooxygenase 1 (BCMO1) and the beta-carotene oxygenase 2 (BCO2).

Results

In the present study the coding region of the BCMO1 and the BCO2 gene were sequenced in yellow fat individuals and compared to the corresponding sequences from control animals with white fat. In the yellow fat individuals a nonsense mutation was found in BCO2 nucleotide position 196 (c.196C>T), introducing a stop codon in amino acid position 66. The full length protein consists of 575 amino acids. In spite of a very low frequency of this mutation in the Norwegian AI-ram population, 16 out of 18 yellow fat lambs were found to be homozygous for this mutation.

Conclusion

In the present study a nonsense mutation (c.196C>T) in the beta-carotene oxygenase 2 (BCO2) gene is found to strongly associate with the yellow fat phenotype in sheep. The existence of individuals lacking this mutation, but still demonstrating yellow fat, suggests that additional mutations may cause a similar phenotype in this population. The results demonstrate a quantitatively important role for BCO2 in carotenoid degradation, which might indicate a broad enzyme specificity for carotenoids. Animals homozygous for the mutation are not reported to suffer from any negative health or development traits, pointing towards a minor role of BCO2 in vitamin A formation. Genotyping AI rams for c.196C>T can now be actively used in selection against the yellow fat trait.     

Molecular evolution of bacteriophages: evidence of selection against the recognition sites of host restriction enzymes

Restriction enzymes produced by bacteria serve as a defense against invading bacteriophages, and so phages without other protection would be expected to undergo selection to eliminate recognition sites for these enzymes from their genomes. The observed frequencies of all restriction sites in the genomes of all completely sequenced DNA phages (T7, lambda, phi X174, G4, M13, f1, fd, and IKe) have been compared to expected frequencies derived from trinucleotide frequencies. Attention was focused on 6-base palindromes since they comprise the typical recognition sites for type II restriction enzymes. All of these coliphages, with the exception of lambda and G4, exhibit significant avoidance of the particular sequences that are enterobacterial restriction sites. As expected, the sequenced fraction of the genome of phi 29, a Bacillus subtilis phage, lacks Bacillus restriction sites. By contrast, the RNA phage MS2, several viruses that infect eukaryotes (EBV, adenovirus, papilloma, and SV40), and three mitochondrial genomes (human, mouse, and cow) were found not to lack restriction sites. Because the particular palindromes avoided correspond closely with the recognition sites for host enzymes and because other viruses and small genomes do not show this avoidance, it is concluded that the effect indeed results from natural selection.      

Increased variation in sex organ positions can increase reciprocity and pollination success in heterostylous plant populations

The reciprocal position of sexual organs in complementary floral morphs is central to our understanding of heterostyly. Reciprocity indices are used to quantify the spatial match between complementary sex organs, but previous indices fail to appropriately account for intra-population variation in sex organ positions. In this study, we examine how an increase in intra-population variation in sex organ heights affects reciprocity and consequently reproductive success. We formulated a reciprocity index that incorporates this variation and asked if estimates of reciprocity can predict reproductive success in naturally occurring heterostylous populations. We developed a reciprocity index that assumed pollen transfer success equalled one for a perfectly matched stigma–anther pair, and decreased to zero with increasing mismatch. We examined the relationship between intra-population variation in organ position and reciprocity, compared previously proposed indices using simulated populations and empirical data from natural populations, and tested the ability of the indices to predict reproductive success. We observed that when differences between mean complementary sex-organ heights are small, increasing intra-population variation in heights resulted in a decrease in reciprocity. However, when this difference is larger, reciprocity increased, reached a peak, and then decreased with increasing variation. Previous indices failed to capture this behavior. Seed set was positively related to reciprocity for our index. These results challenge the current understanding that increasing variation in sex-organ heights will always decrease reciprocity in heterostylous populations. This may help explain why heterostylous systems exhibit and tolerate high amounts of intra-population variation in sex organ heights.