Cytokine Production by Leukocytes of Military Personnel with Depressive Symptoms after Deployment to a Combat-Zone: A Prospective, Longitudinal Study

Major depressive disorder (MDD) is frequently diagnosed in military personnel returning from deployment. Literature suggests that MDD is associated with a pro-inflammatory state. To the best of our knowledge, no prospective, longitudinal studies on the association between development of depressive symptomatology and cytokine production by peripheral blood leukocytes have been published. The aim of this study was to investigate whether the presence of depressive symptomatology six months after military deployment is associated with the capacity to produce cytokines, as assessed before and after deployment. 1023 military personnel were included before deployment. Depressive symptoms and LPS- and T-cell mitogen-induced production of 16 cytokines and chemokines in whole blood cultures were measured before (T0), 1 (T1), and 6 (T2) months after return from deployment. Exploratory structural equation modeling (ESEM) was used for data reduction into cytokine patterns. Multiple group latent growth modeling was used to investigate differences in the longitudinal course of cytokine production between individuals with (n = 68) and without (n = 665) depressive symptoms at T2. Individuals with depressive symptoms after deployment showed higher T-cell cytokine production before deployment. Moreover, pre-deployment T-cell cytokine production significantly predicted the presence of depressive symptomatology 6 months after return. There was an increase in T-cell cytokine production over time, but this increase was significantly smaller in individuals developing depressive symptoms. T-cell chemokine and LPS-induced innate cytokine production decreased over time and were not associated with depressive symptoms. These results indicate that increased T-cell mitogen-induced cytokine production before deployment may be a vulnerability factor for development of depressive symptomatology in response to deployment to a combat-zone. In addition, deployment to a combat-zone affects the capacity of T-cells and monocytes to produce cytokines and chemokines until at least 6 months after return

The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

Contains fulltext : 98431.pdf (publisher's version ) (Open Access)RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects of stressful events on BDNF levels may in part be conditional upon a common variant on the BDNF gene (Val(66)Met; RS6265), with the Met allele being associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele. METHODS: We investigated cross-sectionally in 1,435 individuals with lifetime MDD the impact of childhood abuse (CA) and recent life events on serum BDNF levels and assessed whether the impact of these events was moderated by the BDNF Val(66)Met polymorphism. RESULTS: Overall, BDNF Met carriers had reduced serum BDNF levels when exposed to CA in a dose-dependent way. Moreover, exposure to recent life events was also associated with decreases in BDNF levels, but this was independent of BDNF Val(66)Met. Moreover, when not exposed to CA, Met carriers had higher BDNF levels than the Val/Val individuals, who did not show decreases in BDNF associated with CA. Finally, these findings were only apparent in the MDD group without comorbid anxiety. CONCLUSIONS: These gene-environment interactions on serum BDNF levels suggest that Met carriers are particularly sensitive to (early) stressful life events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Differential Rho-kinase dependency of full and partial muscarinic receptor agonists in airway smooth muscle contraction

1 In airway smooth muscle (ASM), full and partial muscarinic receptor agonists have been described to have large differences in their ability to induce signal transduction, including Ca2+-mobilization. Despite these differences, partial agonists are capable of inducing a submaximal to maximal ASM contraction. 2 To further elucidate transductional differences between full and partial muscarinic receptor agonists, we investigated the contribution of Rho-kinase ( an important regulator of Ca2+-sensitization) to methacholine-, pilocarpine- and McN-A-343-induced bovine tracheal smooth muscle (BTSM) contraction, using the selective Rho-kinase inhibitor Y-27632. In addition, we measured Ca2+-mobilization and - influx in BTSM cells in response to these agonists in the absence and presence of Y-27632. 3 Whereas treatment with Y-27632 ( 1 mu M) significantly decreased potency (pEC(50)) for all agonists, maximal contraction (E-max) was reduced by 23.4 +/- 2.8 and 50.4 +/- 7.9% for the partial agonists pilocarpine and McN-A-343, respectively, but was unaffected for the full agonist methacholine. However, E-max of methacholine became Rho-kinase dependent after taking away its receptor reserve using the irreversible muscarinic receptor antagonist propylbenzilylcholine mustard. 4 Pilocarpine and McN-A-343 induced a very small Ca2+-mobilization and - influx as compared to methacholine. In addition, an inverse relationship of these two parameters with the Rho-kinase dependency was observed. Interestingly, no inhibitory effects of Y-27632 were observed on Ca2+-mobilization and-influx for all three agonists, indicating that the effects of Y-27632 on contraction are most likely on the level of Ca2+-sensitization. 5 In conclusion, in contrast to the full agonist methacholine, the partial muscarinic receptor agonists pilocarpine and McN-A-343 are dependent on Rho-kinase for their maximal contractile effects, presumably as a consequence of differences in transductional reserve, indicating an agonist-dependent role for Rho-kinase in ASM contraction. Moreover, an inverse relationship exists between Rho-kinase dependency and both Ca2+-mobilization and Ca2+-influx for these agonists

Efficacy of "seeking safety" in a Dutch population of traumatized substance-use disorder outpatients: Study protocol of a randomized controlled trial

Contains fulltext : 121948.pdf (publisher's version ) (Open Access)Background Traumatic experiences and, more specifically, posttraumatic stress disorder (PTSD) are highly prevalent among substance use disorder (SUD) patients. This comorbidity is associated with worse treatment outcomes in substance use treatment programs and more crisis interventions. International guidelines advise an integrated approach to the treatment of trauma related problems and SUD. Seeking Safety is an integrated treatment program that was developed in the United States. The aim of the current study is to test the efficacy of this program in the Netherlands in an outpatient SUD population. Methods/Design A randomized controlled trial (RCT) will be used to test the efficacy of Seeking Safety compared to Cognitive Behavioral Therapy (CBT) in a population of SUD outpatients. Each treatment will consist of 12 group sessions. The primary outcome measure will be substance use severity. Secondary outcome measures are PTSD and trauma symptoms, coping skills, functioning, and cognitions. Questionnaires will be administered at the start of treatment, at the end of treatment (three months after the start of treatment) and at follow-up (six months after the start of treatment). Discussion This study protocol presents a RCT in which the efficacy of an integrated treatment for comorbid PTSD and SUD, Seeking Safety, is evaluated in a SUD outpatient population compared to CBT. It is expected that the intervention group will show significantly more improvement in substance use severity compared to the control group at end-of-treatment and at follow-up. Furthermore, a lower drop-out rate is expected for the intervention group. If the intervention proves to be effective, it can be implemented. A cost-effectiveness analysis will be conducted to evaluate the two treatments.8 p