In two randomized double-blind controlled trials on 63 depressed female in-patients subject to recurrent affective disorder (bipolar and unipolar manic-depressive psychosis) lithium was shown to have major acute antidepressant effects. At the end of three weeks lithium produced more uniform improvement than did imipramine; lithium in combination with tryptophan (in the form of Optimax) was superior to tryptophan alone--the latter drug having no discernible antidepressant activity in this group of patients. Lithium did not produce an antidepressant effect until the second and third week of both trials.

Brucellosis is one of the most common global zoonoses and is caused by facultative intracellular bacteria of the genus Brucella . Numerous studies have found that MyD88 signaling contributes to protection against Brucella , however the underlying mechanism has not been entirely defined. Here we show that MyD88 signaling in hematopoietic cells contributes both to inflammation and to control of Brucella melitensis infection in vivo . While the protective role of MyD88 in Brucella infection has often been attributed to promotion of IFN-γ production, we found that MyD88 signaling restricts host colonization by B. melitensis even in the absence of IFN-γ. In vitro , we show that MyD88 promotes macrophage glycolysis in response to B. melitensis . Interestingly, a B. melitensis mutant lacking the glucose transporter, GluP, was more highly attenuated in MyD88 -/- than in WT mice, suggesting MyD88 deficiency results in an increased availability of glucose in vivo which Brucella can exploit via GluP. Metabolite profiling of macrophages identified several metabolites regulated by MyD88 in response to B. melitensis , including itaconate. Subsequently, we found that itaconate has antibacterial effects against Brucella and also regulates the production of pro-inflammatory cytokines in B. melitensis -infected macrophages. Mice lacking the ability to produce itaconate were also more susceptible to B. melitensis in vivo . Collectively, our findings indicate that MyD88-dependent changes in host metabolism contribute to control of Brucella infection.

Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a globally important zoonotic disease for which arthritis is the most common focal complication in humans. Wild-type mice infected systemically with Brucella typically do not exhibit arthritis, but mice lacking IFN-develop arthritis regardless of the route of Brucella infection. Here, we investigated mechanisms by which IFN-suppresses Brucella-induced arthritis. Several cell types, including innate lymphoid cells, contributed to IFN-production and suppression of joint swelling. IFN-deficiency resulted in elevated joint IL-1 levels, and severe joint inflammation that was entirely inflammasome dependent, and in particular, reliant on the NLRP3 inflammasome. IFN-was vital for induction of the nitric oxide producing enzyme, iNOS, in infected joints, and nitric oxide directly inhibited IL-1 production and inflammasome activation in Brucella-infected macrophages in vitro. During in vivo infection, iNOS deficiency resulted in an increase in IL-1 and inflammation in Brucella-infected joints. Collectively, this data indicate that IFN-prevents arthritis both by limiting Brucella infection, and by inhibiting excessive inflammasome activation through the induction of nitric oxide. K E Y W O R D Sbrucellosis, caspase-1, innate lymphoid cell, NLRP3Recently, we reported that inflammasomes induce joint inflammation, but also contribute to control of infection during Brucella-induced arthritis. 15 Inflammasomes are multiprotein structures that use sensors, such as NLRP3 and AIM2, to detect intracellular, cytosolic threats. 16 Upon sensor activation, canonical inflammasomes recruit pro-caspase-1, and cleave it into its functional form, caspase-1.

To understand the role of major histocompatibility complex class I (MHC-I) and MHC-II in vaccine-mediated protection against Coxiella burnetii, we evaluated the protective efficacy of a formalin-inactivated C. burnetii Nine Mile phase I vaccine (PIV) in β2-microglobulin-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice. Vaccination reduced disease severity in wild-type (WT) and B2m KO mice but failed to reduce bacterial burden in MHC-II KO mice. This suggests that the MHC-II antigen presentation pathway is required for PIV-mediated protection against C. burnetii infection. MHC-I and MHC-II affect antibody isotype switching, since both PIV-vaccinated B2m KO and MHC-II KO mice produced less Coxiella-specific IgG than PIV-vaccinated WT mice. Interestingly, MHC-II and CD4 deficiencies were not equivalent in terms of splenomegaly and bacterial clearance. This demonstrates a partial role for CD4+ T cells while revealing MHC-II-restricted, CD4-independent mechanisms. Adoptive transfer of CD4+ T cells from PIV-vaccinated WT mice to naive CD4-deficient (CD4 KO) mice demonstrated that antigen-experienced CD4+ T cells are sufficient to generate protection. Conversely, transfer of naive CD4+ T cells to PIV-vaccinated CD4 KO mice exacerbates disease. Using Tbet-deficient (Tbet KO) mice, we showed a partial role for Th1 subset CD4+ T cells in vaccine protection. Furthermore, Th1-independent roles for Tbet were suggested by significant differences in disease between PIV-vaccinated Tbet KO and CD4 KO mice. Interferon gamma was shown to contribute to the host inflammatory response but not bacterial clearance. Collectively, these findings suggest that vaccine-induced protective immunity against a murine model of experimental Q fever requires MHC-II-restricted, CD4+ T cell-dependent and -independent mechanisms that can be exploited for a new-generation human Q fever vaccine.