Articles of Agreement, 25 February 1833

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The Pleurograms and Seed Surface Patterns of Some Mimosoideae (Leguminosae) Genera

Seeds of twenty species representing eight mimosoid genera were examined with scanning electron microscopy (SEM) to determine if variations in the pleurograms and seed topographies exist and if these variations might have taxonomic potential. The pleurogram has been previously considered a feature of many mimosoid seeds but has not been adequately described and critically evaluated as to its shape and other features. The pleurogram shapes of the examined seeds can be placed in four general categories: elliptic, ovate, obovate, lanceolate. If the length/width ratio of the pleurogram is considered as well as the extent of the openness of the pleurogram toward the hilar end, each species considered in this study can be easily separated. The most common topographic patterns of the seed coats were rugulate and reticulate with one species having a foveolate testa. The results obtained from this initial study provide a base for examination of additional genera and species to resolve the question of taxonomic value of the pleurogram and/or topographic patterns among mimosoid seeds

CASPASE-12 and Rheumatoid Arthritis in African-Americans

CASPASE-12 (CASP12) has a downregulatory function during infection and thus may protect against inflammatory disease. We investigated the distribution of CASP12 alleles (#rs497116) in African-Americans (AA) with rheumatoid arthritis (RA). CASP12 alleles were genotyped in 953 RA patients and 342 controls. Statistical analyses comparing genotype groups were performed using Kruskal–Wallis non-parametric ANOVA with Mann–Whitney U tests and chi-square tests. There was no significant difference in the overall distribution of CASP12 genotypes within AA with RA, but CASP12 homozygous patients had lower baseline joint-narrowing scores. CASP12 homozygosity appears to be a subtle protective factor for some aspects of RA in AA patients

Markers of Treatment Response to Methotrexate in Rheumatoid Arthritis: Where Do We Stand?

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX

Effects of end-stage osteoarthritis on markers of skeletal muscle Long INterspersed Element-1 activity

Objective: Long INterspersed Element-1 (L1) is an autonomous transposable element in the genome. L1 transcripts that are not reverse transcribed back into the genome can accumulate in the cytoplasm and activate an inflammatory response via the cyclic GMP-AMP (cGAS)-STING pathway. We examined skeletal muscle L1 markers as well as STING protein levels in 10 older individuals (63 ± 11 y, BMI= 30.2 ± 6.8 kg/m2) with end-stage osteoarthritis (OA) undergoing total hip (THA, n= 4) or knee (TKA, n= 6) arthroplasty versus 10 young, healthy comparators (Y, 22 ± 2 y, BMI= 23.2 ± 2.5 kg/m2). For OA, muscle was collected from surgical (SX) and contralateral (CTL) sides whereas single vastus lateralis samples were collected from Y. Results: L1 mRNA was higher in CTL and SX compared to Y (p \u3c 0.001 and p= 0.001, respectively). Protein expression was higher in SX versus Y for ORF1p (p= 0.002) and STING (p= 0.022). While these data are preliminary due to limited n-sizes and the lack of a BMI-matched younger control group, higher L1 mRNA expression, ORF1p and STING protein are evident in older versus younger adults. More research is needed to determine whether cGAS-STING signaling contributes to heightened muscle inflammation during aging and/or OA

Indirect Effects of Ploidy Suggest X Chromosome Dose, Not the X:A Ratio, Signals Sex in Drosophila

In the textbook view, the ratio of X chromosomes to autosome sets, X:A, is the primary signal specifying sexual fate in Drosophila. An alternative idea is that X chromosome number signals sex through the direct actions of several X-encoded signal element (XSE) proteins. In this alternative, the influence of autosome dose on X chromosome counting is largely indirect. Haploids (1X;1A), which possess the male number of X chromosomes but the female X:A of 1.0, and triploid intersexes (XX;AAA), which possess a female dose of two X chromosomes and the ambiguous X:A ratio of 0.67, represent critical tests of these hypotheses. To directly address the effects of ploidy in primary sex determination, we compared the responses of the signal target, the female-specific SxlPe promoter of the switch gene Sex-lethal, in haploid, diploid, and triploid embryos. We found that haploids activate SxlPe because an extra precellular nuclear division elevates total X chromosome numbers and XSE levels beyond those in diploid males. Conversely, triploid embryos cellularize one cycle earlier than diploids, causing premature cessation of SxlPe expression. This prevents XX;AAA embryos from fully engaging the autoregulatory mechanism that maintains subsequent Sxl expression, causing them to develop as sexual mosaics. We conclude that the X:A ratio predicts sexual fate, but does not actively specify it. Instead, the instructive X chromosome signal is more appropriately seen as collective XSE dose in the early embryo. Our findings reiterate that correlations between X:A ratios and cell fates in other organisms need not implicate the value of the ratio as an active signal

Socioeconomic factors and self-reported health outcomes in African Americans with rheumatoid arthritis from the Southeastern United States: the contribution of childhood socioeconomic status

Abstract Background There is abundant evidence that low socioeconomic status (SES) is associated with worse health outcomes among people with Rheumatoid Arthritis (RA); however, the influence of socioeconomic disadvantage in early life has yet to be studied within that population. Methods Data originated from the cross-sectional arm of the Consortium Evaluation of African-Americans with Rheumatoid Arthritis (CLEAR II), which recruited African-Americans with RA from six sites in the Southeastern United States. We used linear regression models to evaluate associations of parental homeownership status and educational level at participant time of birth with participant-reported fatigue (Visual Analog scale, cm), pain (Visual Analog scale, cm), disability (Health Assessment Questionnaire) and helplessness (Rheumatology Attitudes Index), independently of participant homeownership status and educational level. Models included random effects to account for intra-site correlations, and were adjusted for variables identified using backward selection, from: age, disease-duration, sex, medication use, body-mass index, smoking history. Results Our sample included 516 CLEAR II participants with full data on demographics and covariates. 89 % of participants were women, the mean age was 54.7 years and mean disease duration was 10.8 years. In age adjusted models, parental non-homeownership was associated with greater fatigue (β = 0.75, 95 % CI = 0.36–1.14), disability (β = 0.12, 95 % CI = 0.04–0.19) and helplessness (β = 0.12, 95 % CI = 0.03–0.21), independently of participant homeownership and education; parental education had a further small influence on self-reported fatigue (β = 0.20, 95 % CI = 0.15–0.24). Conclusions Parental homeownership, and to a small extent parental education, had modest but meaningful relationships with self-reported health among CLEAR II participants

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Does gamma-aminobutyric acid (GABA) influence the development of chronic inflammation in rheumatoid arthritis?

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a role for spinal p38 MAP kinase (MAPK) in the development of chronic inflammation and peripheral arthritis and a role for GABA in the inhibition of p38 MAPK mediated effects. Integrating these data suggests that GABA may play a role in downregulating mechanisms that lead to the production of proinflammatory agents such as interleukin-1, interleukin-6, and matrix metalloproteinase 3 – agents implicated in the pathogenesis of rheumatoid arthritis (RA). Genetic studies have also associated RA with members of the p38 MAPK pathway.</p> <p>Hypothesis</p> <p>We propose a hypothesis for an inefficient GABA signaling system that results in unchecked proinflammatory cytokine production via the p38 MAPK pathway. This model also supports the need for increasing research in the integration of immunology and neuroscience.</p