IntroductionImmunologic self-tolerance is critical for the prevention of autoimmunity and maintenance of immune homeostasis. The ability of the immune system to discriminate between self and nonself is controlled by central and peripheral tolerance mechanisms. The former involves deletion of self-reactive T cells in the thymus at an early stage of development, 1,2 whereas peripheral tolerance involves several mechanisms, including T-cell anergy and ignorance. Since these mechanisms are not completely effective and potentially autoantigen-reactive lymphocytes escape into the periphery, additional mechanisms are involved in the maintenance of self-tolerance. A number of subsets of regulatory T cells play an important role in preventing activation of autoantigenreactive T cells. Among these are naturally occurring "professional" regulatory T cells (Tregs). In this regard, studies carried out during the past decade provided strong evidence for the existence of a unique CD4 ϩ CD25 ϩ population of naturally occurring regulatory/suppressor T cells that actively prevent both the activation and the effector function of autoreactive T cells that have escaped other mechanisms of tolerance. [3][4][5] Removal of this population from normal rodents leads to the spontaneous development of various autoimmune diseases, organ specific as well as systemic. Notably, the generation of CD4 ϩ CD25 ϩ T-regulatory cells in the immune system is developmentally and genetically controlled, as recent studies have demonstrated that the transcription factor, FoxP3, is essential for their thymic development 6 and is sufficient to activate a program of suppressor function in peripheral CD4 ϩ CD25 Ϫ T cells. 7 Genetic defects that affect the development or function of CD4 ϩ CD25 ϩ Tregs can be a primary cause of autoimmune and other inflammatory disorders in humans. 8 It has been proposed that during the initiation of an adaptive immune response, dendritic cells can induce effector CD4 ϩ T cells to become resistant to the suppressive effects of Tregs by secreting IL-6, thus allowing a productive immune response to take place. 9 Similarly, glucocorticoid-induced tumor necrosis factor-like receptor (GITR) engagement on effector T cells by its ligand (GITRL) expressed on antigen-presenting cells (APCs) has been claimed to render them resistant to suppression by CD4 ϩ CD25 ϩ Tregs, 10 and may also have an effect on the function of Tregs. 11 Recent studies have revealed the presence of CD4 ϩ CD25 ϩ Tregs in human peripheral blood, where they constitute up to 5% of the CD4 ϩ T cells. 12,13 These cells are similar to those described in the mouse in that they require cell-to-cell contact to exert their suppressive effect. Whether a soluble factor is involved depends on the experimental system used. 14,15 Tumor necrosis factor (TNF) is a pleiotropic cytokine critical for cell trafficking, inflammation, maintenance of secondary lymphoid organ structure, and host defense against various pathogens. 16 Because of this panoply of effects, TNF plays a critic...

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IMPORTANCE Depression among hearing impaired US adults has not been studied previously. OBJECTIVE To estimate the prevalence of and risk factors for depression among adults with hearing loss. DESIGN, SETTING, AND PARTICIPANTS Adults aged 18 years or older (N = 18 318) who participated in the National Health and Nutrition Examination Survey (NHANES), 2005–2010, a nationally representative sample. INTERVENTIONS Multistage probability sampling of US population. MAIN OUTCOMES AND MEASURES Depression, assessed by the 9-item Patient Health Questionnaire (PHQ-9) scale, and hearing impairment (HI), assessed by self-report and audiometric examination for adults aged 70 years or older. RESULTS The prevalence of moderate to severe depression (PHQ-9 score, ≥10) was 4.9% for individuals reporting excellent hearing, 7.1% for those with good hearing, and 11.4% for participants who reported a little trouble or greater HI. Using excellent hearing as the reference, after adjusting for all covariates, multivariate odds ratios (ORs) for depression were 1.4 (95% CI, 1.1–1.8) for good hearing, 1.7 (1.3–2.2) for a little trouble, 2.4 (1.7–3.2) for moderate trouble, 1.5 (0.9–2.6) for a lot of trouble, and 0.6 (0.1–2.6) for deaf. Moderate HI (defined by better ear pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz within the range 35- to 49-dB hearing level) was significantly associated with depression among older women (OR, 3.9; 95% CI, 1.3–11.3), after adjusting for age, sex, race/ethnicity, lifestyle characteristics, and selected health conditions. CONCLUSIONS AND RELEVANCE After accounting for health conditions and other factors, including trouble seeing, self-reported HI and audiometrically determined HI were significantly associated with depression, particularly in women. Health care professionals should be aware of an increased risk for depression among adults with hearing loss.

ObjeCtive To identify the number of drug-disease and drug-drug interactions for exemplar index conditions within National Institute of Health and Care Excellence (NICE) clinical guidelines. DesignSystematic identification, quantification, and classification of potentially serious drug-disease and drug-drug interactions for drugs recommended by NICE clinical guidelines for type 2 diabetes, heart failure, and depression in relation to 11 other common conditions and drugs recommended by NICE guidelines for those conditions. setting NICE clinical guidelines for type 2 diabetes, heart failure, and depression.

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Background Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases. Objective To compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis. Design Randomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment. Setting 2 U.S. academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). Patients 121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints. Intervention TwHF extract, 60 mg 3 times daily, or sulfasalazine, 1 g twice daily. Patients could continue stable doses of oral prednisone or nonsteroidal anti-inflammatory drugs but had to stop taking disease-modifying antirheumatic drugs at least 28 days before randomization. Measurements The primary outcome was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. Secondary end points were safety; radiographic scores of joint damage; and serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotropic hormone. Results Outcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P = 0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups. Limitations Only 62% and 41% of patients continued receiving TwHF extract and sulfasalazine, respectively, during the 24 weeks of the study. Long-term outcome data were not collected on participants who discontinued treatment. Conclusion In patients who continued treatment for 24 weeks and could also use stable oral prednisone and nonsteroidal anti-inflammatory drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine. Primary Funding Source National Institute of Arthritis and Musculoskeletal and Skin Diseases.

IntroductionDisturbances in peripheral blood memory B cell subpopulations have been observed in various autoimmune diseases, but have not been fully delineated in rheumatoid arthritis (RA). Additionally, the possible role of tumour necrosis factor (TNF) in regulating changes in specific peripheral blood memory B cell subsets in RA is still unclear.MethodsThe frequency and distribution of B cell subsets in the peripheral blood and synovial membrane of active RA patients with long-standing disease have been analysed. Additionally, the possible role of TNF in causing disturbances in memory B cell subsets in RA patients was assessed in a clinical trial with the specific TNF-neutralising antibody, infliximab.ResultsRA patients, independent of disease duration, have a significantly lower frequency of peripheral blood pre-switch IgD+CD27+ memory B cells than healthy individuals, whereas post-switch IgD-CD27+ accumulate with increased disease duration. Notably, both pre-switch IgD+CD27+ and post-switch IgD-CD27+ memory B cells accumulate in the synovial membrane of RA patients. Finally, anti-TNF therapy increased the frequency of pre-switch IgD+CD27 memory B cells in the peripheral blood.ConclusionsThe data suggest that decreases in peripheral blood IgD+CD27+ pre-switch memory B cells in RA reflect their accumulation in the synovial tissue. Moreover, the significant increase in the peripheral blood pre-switch memory B cells in patients who underwent specific TNF-blockade with infliximab indicates that trafficking of memory B cells into inflamed tissue in RA patients is regulated by TNF and can be corrected by neutralising TNF.