Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

Introduction

The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods

In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results

During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions

In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial registrations

ISRCTN11916566 and EudraCT2006-006186-16     

A Neutralizing Monoclonal Antibody Targeting the Acid-Sensitive Region in Chikungunya Virus E2 Protects from Disease

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV.     

Genotypic and phenotypic characterization of a large,diverse population of maize near‐isogenic lines

Genome‐wide association (GWA) studies can identify quantitative trait loci (QTL) putatively underlying traits of interest, and nested association mapping (NAM) can further assess allelic series. Near‐isogenic lines (NILs) can be used to characterize, dissect and validate QTL, but the development of NILs is costly. Previous studies have utilized limited numbers of NILs and introgression donors. We characterized a panel of 1270 maize NILs derived from crosses between 18 diverse inbred lines and the recurrent inbred parent B73, referred to as the nested NILs (nNILs). The nNILs were phenotyped for flowering time, height and resistance to three foliar diseases, and genotyped with genotyping‐by‐sequencing. Across traits, broad‐sense heritability (0.4–0.8) was relatively high. The 896 genotyped nNILs contain 2638 introgressions, which span the entire genome with substantial overlap within and among allele donors. GWA with the whole panel identified 29 QTL for height and disease resistance with allelic variation across donors. To date, this is the largest and most diverse publicly available panel of maize NILs to be phenotypically and genotypically characterized. The nNILs are a valuable resource for the maize community, providing an extensive collection of introgressions from the founders of the maize NAM population in a B73 background combined with data on six agronomically important traits and from genotyping‐by‐sequencing. We demonstrate that the nNILs can be used for QTL mapping and allelic testing. The majority of nNILs had four or fewer introgressions, and could readily be used for future fine mapping studies.     

A targeted molecular dynamics study of WPD loop movement in PTP1B

Targeted molecular dynamics was used to examine the mechanism of WPD loop closure in PTP1B, which is essential for the activity of the enzyme. Two important regions are identified: the R-loop (residues 113-118), which assists in substrate binding, and the S-loop (residues 198-209), which undergoes a conformational change that appears to be vital for the movement of the WPD loop. The S-loop is adjacent to the alpha3-helix, and its conformational change is coupled with a change of interactions between the alpha3- and alpha7-helices. This latter observation is of particular interest in connection with a novel class of allosteric inhibitors of PTP1B [Wiesmann et al., Nat. Struc. Mol. Biol. 11 (2004) 730-737]. These compounds prevent the closure of the WPD loop, forcing the enzyme to remain in a catalytically inactive conformation, by blocking the rearrangement of the alpha3-helix relative to the alpha7-helix.     

Kinetics of ATP release following compression injury of a peripheral nerve trunk

Compression and/or contusion of a peripheral nerve trunk can result in painful sensations. It is possible that release of ATP into the extracellular space may contribute to this symptom. In the present study, we used real-time measurements of ATP-induced bioluminescence together with electrophysiological recordings of compound action potentials to follow changes in the extracellular ATP concentration of isolated rat spinal roots exposed to mechanical stimuli. Nerve compression for about 8 s resulted in an immediate release of ATP into the extracellular space and in a decrease in the amplitude of compound action potentials. On average, a rise in ATP to 60 nM was observed when nerve compression blocked 50% of the myelinated axons. After the compression, the extracellular concentration of ATP returned to the resting level within a few minutes. The importance of ecto-nucleotidases for the recovery period was determined by exposure of isolated spinal roots to high concentrations of ATP and by use of inhibitors of ecto-nucleotidases. It was observed that spinal roots have a high capacity for ATP hydrolysis which is only partially blocked by βγ-methylene ATP and ARL 67156. In conclusion, acute nerve compression produces an increase in the extracellular concentration of ATP and of its metabolites which may be sufficient for activation of purinergic P2 and/or P1 receptors on axons of nociceptive afferent neurons.     

Effects of copper deficiency on mouse yolk sac vasculature and expression of angiogenic mediators

BACKGROUND: Cu deficiency results in embryonic defects and yolk sac (YS) vasculature abnormalities. In diverse model systems, Cu treatment modulates angiogenesis, perhaps by influencing the activity of angiogenic mediators such as vascular endothelial growth factor (VEGF). Conversely, Cu chelators can suppress angiogenesis. METHODS: Gestation day (GD) 8.5 embryos from mice fed Cu-adequate (Cu+) or Cu-deficient (Cu-) diets were cultured in Cu+ or Cu- medium for 48 hr. Growth and development were evaluated, and YS vessel diameters were measured. Using RT-PCR and immunohistochemistry, the mRNA and protein expressions of VEGF, Flt-1, Flk-1, Angiopoietin-1 (Ang-1), and Tie-2 were analyzed. RESULTS: Cu+/Cu+ embryos developed normally, whereas Cu-/Cu- embryos showed a high incidence of developmental anomalies. Cu-/Cu- YS had a high proportion of vessels that were large in diameter compared to the Cu+/Cu+ YS. The mRNA expression of angiogenic mediators in Cu-/Cu- YS was similar to that in Cu+/Cu+ YS. The protein expression of VEGF in the Cu-/Cu- YS without any vessel defects, and Tie-2 in the Cu-/Cu- YS with both vessel defects and blood islands was significantly lower than that in the Cu+/Cu+ YS. The protein expression of Flt-1, Flk-1 and Ang-1 was similar among groups regardless of the presence, or type, of vessel defects. CONCLUSIONS: Results from the current study support the concept that Cu is required for the normal development of YS vasculature. Our data suggest that the impaired vascularization of Cu-deficient YS cannot be explained fully by the altered protein expression of the angiogenic growth factors reported here.     

Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1�� Expression

Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1–6 cells to 10–30 μm PQQ for 24–48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1α, and increased PGC-1α mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1α or CREB expression. Consistent with activation of the PGC-1α pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction.     

Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition

The structure based drug design, synthesis and structure–activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.