Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

Development and quantification of measures for risky and delayed food and monetary outcome choices.

Probability discounting (PD) measures risky choice patterns between smaller, more certain vs. larger, less certain outcomes. PD is associated with obesity as well as higher intake of foods high in fat and sugar. We developed and validated a brief PD task specifically for food-related choices-the Probabilistic Food Choice Questionnaire (PFCQ). We also validated a brief, existing PD monetary measure, the Probabilistic Monetary Choice Questionnaire (PMCQ) by comparing it to a titrating PD task. Participants (N = 110) were randomly assigned to either a food or money condition. Those assigned to the food condition completed the PFCQ and a more established, adjusting-amount PD task for hypothetical food outcomes. Those assigned to the money condition completed the PMCQ and a more established, adjusting-amount PD task. Participants also completed delay discounting (DD) tasks for the same outcome commodity. The PFCQ and adjusting-amount PD tasks strongly correlated across three magnitudes suggesting that the PFCQ may be a satisfactory and briefer measure for risky food choice. The PMCQ also showed significant correlations with the adjusting-amount monetary PD task, supporting its use for a brief measure of monetary discounting. For DD, the choice questionnaires demonstrated significant correlations with the adjusting-amount DD procedures, replicating previous research.

Developmental exposure to methylmercury alters behavioral sensitivity to D-amphetamine and pentobarbital in adult rats.

Female rats were exposed to 0, 0.5, or 6.4 ppm methylmercury in their drinking water before mating, and throughout gestation and lactation. When the female offspring were 4-6 months old, they were trained to respond under a multiple differential reinforcement of high rate (DRH) 9:4-- Extinction schedule of reinforcement. No differences among exposure groups were apparent in steady-state behavior. Drug challenges were conducted with multiple doses of D-amphetamine, scopolamine, pentobarbital, haloperidol, and dizocilpine, drugs selected for their different pharmacological effects. The ED(50) values for amphetamine's reinforcement rate-reducing effects for the control, 0.5-, and 6.4-ppm groups were 3.1, 1.9, and 0.9 mg amphetamine/kg body weight, respectively, demonstrating an increased sensitivity to D-amphetamine in methylmercury-exposed rats. Rats in the 6.4-ppm group also demonstrated a relative insensitivity to pentobarbital. Further, these exposed rats exhibited an inverted U-shaped dose-effect curve under the pentobarbital dose-effect determination, while controls showed only a declining curve. Exposed rats did not respond differentially to haloperidol, scopolamine, or dizocilpine, suggesting specificity. The present data suggest an involvement of catecholaminergic and GABAergic activity in methylmercury's neurotoxicity.

Aging unmasks adverse effects of gestational exposure to methylmercury in rats.

The consequences of developmental exposure to methylmercury on behavior in aged animals were investigated. Methylmercury exposure was arranged by placing 0, 0.5 or 6.4 ppm Hg in the drinking water of female rats at least 4 weeks before mating and continuing until post-natal (PN) day 16. Brain Hg concentrations in cohorts of low- and high-dose offspring were 0.5 and 9.1 ppm at birth and 0.04 and 0. 52 ppm at weaning (described in another report). Lever pressing of female offspring was maintained under a Multiple Differential Reinforcement of High Rate 9:4 Extinction schedule of food reinforcement (Mult DRH 9:4 EXT). Under the DRH 9:4 schedule, a food reinforcer was delivered when nine responses occurred within 4 s. Under the Extinction schedule, responding had no programmed consequences. No exposure-related differences in reinforcement rate under the DRH schedule or discrimination between the DRH and extinction components were apparent initially. At 950 days of age, the overall response rates of controls had shown a gradual decline over the previous 500 days to about 80% of their beginning levels, but, otherwise, most controls were healthy. A gradual decline in the reinforcement rate began to appear in low- and high-dose rats at about 500 and 800 days of age, respectively. Microanalyses of the nine-response burst maintained by the DRH schedule revealed that the lever-press duration increased, the inter-response time (IRT) was unaffected, and the time between response bursts increased. Overall, the nine-response burst remained intact as a coherent response unit. The increased time between response bursts caused the decline in reinforcement rate. All rats displayed these effects as they aged, but the mercury-exposed rats did so sooner.

Short transcripts of the ternary complex provide insight into RNA polymerase II elongational pausing.

Expression of the hsp70 gene of Drosophila melanogaster is controlled at the level of transcript elongation. In the uninduced state, hsp70 possesses an RNA polymerase II complex, elongationally engaged, but paused early in the transcription unit. In this study, we have used a powerful new selection-amplification technique to analyze the RNA transcripts associated with such "paused polymerases" under non-heat shock and heat shock-induced conditions. They reveal a region of pausing on the uninduced gene in vivo spanning from +21 to +35. This region is interrupted by an area of low polymerase density, centered at about +26. Upon induction, an accumulation of short transcripts, similar in size to those associated with the paused complex, was seen. Models for polymerase pausing and release are discussed in light of these data. The increased sensitivity of our new technique also allowed us to investigate ternary complexes associated with genes with much lower levels of engaged RNA polymerase. These included two of the small heat shock genes (hsp26 and hsp27) and two metabolic genes (Gapdh-1 and Gapdh-2), where paused polymerases were thought to be present, plus two other genes (Mtn and yp1), where polymerase pausing has not been detected in the past. In both of the small heat shock genes, we found evidence of previously unknown sites of transcriptional termination, residing immediately upstream of the regions of polymerase pausing.

In vivo transcriptional pausing and cap formation on three Drosophila heat shock genes.

The regulation of many eukaryotic genes occurs at the level of transcriptional elongation. On the uninduced hsp70 gene of Drosophila melanogaster, for example, an RNA polymerase II complex has initiated transcription but has paused early in elongation. In this study, we examine pausing on hsp70 and two of the small heat shock genes (hsp27 and hsp26) at high resolution, using a technique that utilizes paramagnetic particle-mediated selection of terminated run-on transcripts. This technique provides precise information on the distribution of RNA polymerase within each transcription unit. It also details the progression of 5' cap formation on the elongating transcripts. For each gene, we find polymerases paused over a relatively narrow promoter-proximal region. The regions are generally around 20 nucleotides wide, with two preferred pausing positions spaced roughly 10 nucleotides apart or about one turn of the helix. The bulk of capping occurs as transcripts pass between 20 and 30 nucleotides in length. Interestingly, in the three genes examined here, elongational pausing and 5' cap formation appear largely coincident.