The effects of latent variables in the development of comorbidity among common mental disorders

Background: Although numerous studies have examined the role of latent predispositions to internalizing and externalizing disorders in the structure of comorbidity among common mental disorders, none examined latent predispositions in predicting development of comorbidity. Methods: A novel method was used to study the role of latent variables in the development of comorbidity among lifetime DSM-IV disorders in the National Comorbidity Surveys. Broad preliminary findings are briefly presented to describe the method. The method used survival analysis to estimate time-lagged associations among 18 lifetime DSM-IV anxiety, mood, behavior, and substance disorders. A novel estimation approach examined the extent to which these predictive associations could be explained by latent canonical variables representing internalizing and externalizing disorders. Results: Consistently significant positive associations were found between temporally primary and secondary disorders. Within-domain time-lagged associations were generally stronger than between-domain associations. The vast majority of associations were explained by a model that assumed mediating effects of latent internalizing and externalizing variables, although the complexity of this model differed across samples. A number of intriguing residual associations emerged that warrant further investigation. Conclusions: The good fit of the canonical model suggests that common causal pathways account for most comorbidity among the disorders considered. These common pathways should be the focus of future research on the development of comorbidity. However, the existence of several important residual associations shows that more is involved than simple mediation. The method developed to carry out these analyses provides a unique way to pinpoint these significant residual associations for subsequent focused study. Depression and Anxiety, 2011. (c) 2011 Wiley-Liss, Inc

The Novel Immunosuppressive Protein Kinase C Inhibitor Sotrastaurin Has No Pro-Viral Effects on the Replication Cycle of Hepatitis B or C Virus

The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients

Stability subtypes of callous–unemotional traits and conduct disorder symptoms and their correlates

Callous unemotional traits and conduct disorder symptoms tend to co-occur across development, with existing evidence pointing to individual differences in the co-development of these problems. The current study identified groups of at risk adolescents showing stable (i.e., high on both conduct disorder and callous-unemotional symptoms, high only on either callous-unemotional or conduct disorder symptoms) or increasing conduct disorder and callous-unemotional symptoms. Data were collected from a sample of 2038 community adolescents between 15 and 18 years (1070 females, Mage = 16) of age. A longitudinal design was followed in that adolescent reports were collected at two time points, one year apart. Increases in conduct disorder symptoms and callous-unemotional traits were accompanied by increases in anxiety, depressive symptoms, narcissism, proactive and reactive aggression and decreases in self-esteem. Furthermore, adolescents with high and stable conduct disorder symptoms and callous-unemotional traits were consistently at high risk for individual, behavioral and contextual problems. In contrast, youth high on callous-unemotional traits without conduct disorder symptoms remained at low-risk for anxiety, depressive symptoms, narcissism, and aggression, pointing to a potential protective function of pure callous-unemotional traits against the development of psychopathological problems

Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation of HCV-Specific CD8+ T Cells

The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control