TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity

Adjunctive Aripiprazole Versus Placebo for Antipsychotic-Induced Hyperprolactinemia: Meta-Analysis of Randomized Controlled Trials

<div><p>Objective</p><p>To compare the safety and efficacy of adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia.</p><p>Methods</p><p>Population: adult patients presenting with antipsychotic-induced hyperprolactinemia diagnosed by prolactin level with or without prolactin-related symptoms. Interventions: adjunctive aripiprazole vs. adjunctive placebo. Outcome measures: adverse events and efficacy of treatment. Studies: randomized controlled trials.</p><p>Results</p><p>Five randomized controlled trials with a total of 639 patients (326 adjunctive aripiprazole, 313 adjunctive placebo) met the inclusion criteria. Adjunctive aripiprazole was associated with a 79.11% (125/158) prolactin level normalization rate. Meta-analysis of insomnia, headache, sedation, psychiatric disorder, extrapyramidal symptom, dry mouth, and fatigue showed no significant differences in the adjunctive aripiprazole treatment group compared with the placebo group (risk difference (Mantel-Haenszel, random or fixed) −0.05 to 0.04 (95% confidence interval −0.13 to 0.16); I² = 0% to 68%, P = 0.20 to 0.70). However, sedation, insomnia, and headache were more frequent when the adjunctive aripiprazole dose was higher than 15 mg/day. Meta-analysis of the prolactin level normalization indicated adjunctive aripiprazole was superior to placebo (risk difference (Mantel-Haenszel, random) 0.76 (95% confidence interval 0.67 to 0.85); I² = 43%, P<0.00001). The subgroup analysis confirmed that the subjects who received adjunctive aripiprazole 5 mg/day showed a degree of prolactin normalization similar to that of all participants. No significant differences between groups in discontinuation and improvements of psychiatric symptoms.</p><p>Conclusion</p><p>Adjunctive aripiprazole is both safe and effective as a reasonable choice treatment for patients with antipsychotic-induced hyperprolactinemia. The appropriate dose of adjunctive aripiprazole may be 5 mg/day.</p></div

Summary of studies.

<p>Summary of studies.</p

GRADE Analysis: quality assessment of adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia.

*<p><b>Decrease quality of evidence:</b> a) single-blind method; b) randomization by the antipsychotic weight; c). I²>50%; <b>^$Increase quality of evidence:</b> d) RR >5 or <0.2; <b>GRADE Working Group grades of evidence: # High quality:</b> Further research is very unlikely to change our confidence in the estimate of effect. <b>Moderate quality:</b> Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. <b>Low quality:</b> Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. <b>Very low quality:</b> We are very uncertain about the estimate.</p

Summary of adverse events and discontinuation.

<p>Summary of adverse events and discontinuation.</p

Adjunctive aripiprazole vs. placebo for antipsychotic-induced hyperprolactinemia: forest plot for a secondary analysis of insomnia, headache, sedation and forest plot for extrapyramidal symptoms, dry mouth, and fatigue.

<p>Adjunctive aripiprazole vs. placebo for antipsychotic-induced hyperprolactinemia: forest plot for a secondary analysis of insomnia, headache, sedation and forest plot for extrapyramidal symptoms, dry mouth, and fatigue.</p

Individual study.

<p>Individual study.</p

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

<p>Risk of bias summary: review authors' judgments about each risk of bias item for each included study.</p

Substance use, childhood traumatic experience, and Posttraumatic Stress Disorder in an urban civilian population.

OBJECTIVE: Exposure to traumatic experiences, especially those occurring in childhood, has been linked to substance use disorders (SUDs), including abuse and dependence. SUDs are also highly comorbid with Posttraumatic Stress Disorder (PTSD) and other mood-related psychopathology. Most studies examining the relationship between PTSD and SUDs have examined veteran populations or patients in substance treatment programs. The present study further examines this relationship between childhood trauma, substance use, and PTSD in a sample of urban primary care patients. METHOD: There were 587 participants included in this study, all recruited from medical and OB/GYN clinic waiting rooms at Grady Memorial Hospital in Atlanta, GA. Data were collected through both screening interviews as well as follow-up interviews. RESULTS: In this highly traumatized population, high rates of lifetime dependence on various substances were found (39% alcohol, 34.1% cocaine, 6.2% heroin/opiates, and 44.8% marijuana). The level of substance use, particularly cocaine, strongly correlated with levels of childhood physical, sexual, and emotional abuse as well as current PTSD symptoms. In particular, there was a significant additive effect of number of types of childhood trauma experienced with history of cocaine dependence in predicting current PTSD symptoms, and this effect was independent of exposure to adult trauma. CONCLUSIONS: These data show strong links between childhood traumatization and SUDs, and their joint associations with PTSD outcome. They suggest that enhanced awareness of PTSD and substance abuse comorbidity in high-risk, impoverished populations is critical to understanding the mechanisms of substance addiction as well as in improving prevention and treatment