Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

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Betz and Hackett's (1981) career self-efficacy model was extended using an ethnically mixed (White, Hispanic, American Indian) rural high school population (467 girls and 426 boys). A modified form of Betz and Hackett's interest and self-efficacy instrument was used as well as measures of ethnicity, socioeconomic status, stressful life events, and self-esteem. Gender differences were observed in interest and self-efficacy estimates for same-gender and cross-gender occupations, marked by boys' restricted consideration of cross-gender options. Ethnic differences were noted as well, particularly regarding self-efficacy estimates, with American Indian efficacy lowest for 7 of IS occupations studied. Stepwise multiple regression analyses with interest and efficacy as the dependent variables yielded equations that varied by ethnicity.

A total of 12,988 adolescents completed a questionnaire which assessed experience with cigarettes, inhalants, alcohol, marijuana, cocaine, and level of ego identity (EOM‐EIS). Discriminant analyses of substance use, across the achievement, moratorium, foreclosure, and diffusion identity statuses, yielded significant functions for each grade comparison (7th to 12th). Frequencies of experience for diffused respondents were consistently higher than estimates for the achieved and moratorium respondents; and, foreclosed adolescents reported the lowest frequency of experience. Diffused adolescents were about twice as likely to have tried cigarettes and alcohol, three times as likely to have tried marijuana, four times as likely to have tried inhalants, and five times as likely to have used cocaine than their foreclosed peers. The achieved, moratorium, and unclassified respondents reported frequencies of experience that fell between the two extreme groups. Implications for identifying adolescents “at risk”, and tailoring prevention/intervention efforts to address developmental differences are addressed.