The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.

T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma/leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studies demonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due to interactions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs). Based on our mathematical modeling approach, we identified parameter configurations of our model, which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation.

We often form intentions but have to postpone them until the appropriate situation for retrieval and execution has come, an ability also referred to as event-based prospective memory. After intention completion, our cognitive system has to deactivate no-more-relevant intention representations from memory to avoid interference with subsequent tasks. In everyday life, we frequently rely on these abilities also in stressful situations. Surprisingly, little is known about potential stress effects on these functions. Therefore, the present study aimed to examine the reliability of event-based prospective memory and of intention deactivation in conditions of acute psychosocial stress. To this aim, eighty-two participants underwent the Trier Social Stress Test, a standardized stress protocol, or a standardized control situation. Following this treatment, participants performed a computerized event-based prospective memory task with non-salient and focal prospective memory cues in order to assess prospective memory performance and deactivation of completed intentions. Although the stress group showed elevated levels of salivary cortisol as marker of a stress-related increase in hypothalamus-pituitary-adrenal axis activity throughout the cognitive testing period compared to the no-stress group, prospective memory performance and deactivation of completed intentions did not differ between groups. Findings indicate that cognitive control processes subserving intention retrieval and deactivation after completion may be mostly preserved even under conditions of acute stress.

Background: Several studies suggest that most school-age children are poorly informed about cancer risk factors. This study examines the effectiveness of the ‘Be smart against cancer’ (BSAC) program in promoting cancer awareness and intentions to engage in health-promoting behavior. Methods: 235 seventh-grade students were randomized to either the intervention (N = 152) or the wait-control group (N = 83). The intervention included the modules: “What is cancer?,” “Sun protection,” “Non smoking,” and “Physical activity, Healthy nutrition, and Limited alcohol consumption.” Outcomes measured at baseline and at the end of the one week BSAC program included knowledge of cancer and its behavioral risk factors, health-promoting intentions, and reported risk behavior. Results: BSAC was effective in increasing knowledge about cancer and risk factors for cancer (p < .001), as well as in increasing intentions to engage in health-promoting behavior (p < .001), independent of a student’s risk profile. Knowledge did not serve as a mediator for intention building. Conclusions: The BSAC is an effective school-based program for raising awareness of cancer, associated risk factors and intentions to engage in cancer-preventive behavior. The results indicate that the effectiveness of BSAC is independent of a student’s risk profile. Therefore, it holds considerable promise as a broadly applicable program to raise cancer awareness and promote healthy behavior intentions.

Paradoxically enhanced cognitive processes in neurological disorders provide vital clues to understanding neural function. However, what determines whether the neurological damage is impairing or enhancing is unclear. Here we use the performance of patients with two disorders of the striatum to dissociate mechanisms underlying cognitive enhancement and impairment resulting from damage to the same system. In a two-choice decision task, Huntington\'s disease patients were faster and less error prone than controls, yet a patient with the rare condition of benign hereditary chorea (BHC) was both slower and more error prone. EEG recordings confirmed significant differences in neural processing between the groups. Analysis of a computational model revealed that the common loss of connectivity between striatal neurons in BHC and Huntington\'s disease impairs response selection, but the increased sensitivity of NMDA receptors in Huntington\'s disease potentially enhances response selection. Crucially the model shows that there is a critical threshold for increased sensitivity: below that threshold, impaired response selection results. Our data and model thus predict that specific striatal malfunctions can contribute to either impaired or enhanced selection, and provide clues to solving the paradox of how Huntington\'s disease can lead to both impaired and enhanced cognitive processes.

Introduction: The study ‘Mental healthcare provision for adults with intellectual disability and a mental disorder’ (MEMENTA) is a cross-sectional epidemiological study carried out in three different regions of Germany. Its main aim is to assess the prevalence of mental disorders in adults with intellectual disability (ID) as well as quality of mental healthcare for this population. Methods and analysis: The target population are persons aged between 18 and 65 years with a mild or moderate ID. The study population will be recruited through service providers. A representative sample is realised by two-stage sampling. First, institutions providing services for people with ID (sheltered workshops) are selected in a stratified cluster sampling, with strata being (1) types of service-providing non-governmental organisations and (2) sizes of their sheltered workshops. Then persons working in selected sheltered workshops are selected by simple random sampling. An estimated number of 600 adults with ID will be included. Information will be obtained from the group leaders in the sheltered workshops, informal carers or staff members in sheltered housing institutions and the person with ID. Besides the main outcome parameter of psychiatric symptomatology and problem behaviour, other outcome parameters such as needs for care, quality of life, caregiver burden, health services utilisation and costs for care are assessed using well-established standardised instruments. If a comorbid mental disorder is diagnosed, quality of mental healthcare will be assessed with open questions to all interview partners and, in addition, problem-focused interviews with a small subgroup. Analyses will be carried out using quantitative and qualitative methods. Ethics and dissemination: Approval of all three local ethics committees was obtained. Research findings will add much needed empirical information in order to improve services provided to this vulnerable group of patients.

Background: Bipolar disorders (BD) are among the most severe mental disorders with first clinical signs and symptoms frequently appearing in adolescence and early adulthood. The long latency in clinical diagnosis (and subsequent adequate treatment) adversely affects the course of disease, effectiveness of interventions and health-related quality of life, and increases the economic burden of BD. Despite uncertainties about risk constellations and symptomatology in the early stages of potentially developing BD, many adolescents and young adults seek help, and most of them suffer substantially from symptoms already leading to impairments in psychosocial functioning in school, training, at work and in their social relationships. We aimed to identify subjects at risk of developing BD and investigate the efficacy and safety of early specific cognitive-behavioural psychotherapy (CBT) in this subpopulation. Methods/Design: EarlyCBT is a randomised controlled multi-centre clinical trial to evaluate the efficacy and safety of early specific CBT, including stress management and problem solving strategies, with elements of mindfulness-based therapy (MBT) versus unstructured group meetings for 14 weeks each and follow-up until week 78. Participants are recruited at seven university hospitals throughout Germany, which provide in- and outpatient care (including early recognition centres) for psychiatric patients. Subjects at high risk must be 15 to 30 years old and meet the combination of specified affective symptomatology, reduction of psychosocial functioning, and family history for (schizo)affective disorders. Primary efficacy endpoints are differences in psychosocial functioning and defined affective symptomatology at 14 weeks between groups. Secondary endpoints include the above mentioned endpoints at 7, 24, 52 and 78 weeks and the change within groups compared to baseline; perception of, reaction to and coping with stress; and conversion to full BD. Discussion: To our knowledge, this is the first study to evaluate early specific CBT in subjects at high risk for BD. Structured diagnostic interviews are used to map the risk status and development of disease. With our study, the level of evidence for the treatment of those young patients will be significantly raised.

Background: Controversy surrounds the questions whether co-occurring depression has negative effects on cognitivebehavioral therapy (CBT) outcomes in patients with panic disorder (PD) and agoraphobia (AG) and whether treatment for PD and AG (PD/AG) also reduces depressive symptomatology. Methods: Post-hoc analyses of randomized clinical trial data of 369 outpatients with primary PD/AG (DSM-IV-TR criteria) treated with a 12-session manualized CBT (n = 301) and a waitlist control group (n = 68). Patients with comorbid depression (DSM-IV-TR major depression, dysthymia, or both: 43.2% CBT, 42.7% controls) were compared to patients without depression regarding anxiety and depression outcomes (Clinical Global Impression Scale [CGI], Hamilton Anxiety Rating Scale [HAM-A], number of panic attacks, Mobility Inventory [MI], Panic and Agoraphobia Scale, Beck Depression Inventory) at post-treatment and follow-up (categorical). Further, the role of severity of depressive symptoms on anxiety/depression outcome measures was examined (dimensional). Results: Comorbid depression did not have a significant overall effect on anxiety outcomes at post-treatment and follow-up, except for slightly diminished post-treatment effect sizes for clinician-rated CGI (p = 0.03) and HAM-A (p = 0.008) when adjusting for baseline anxiety severity. In the dimensional model, higher baseline depression scores were associated with lower effect sizes at post-treatment (except for MI), but not at follow-up (except for HAM-A). Depressive symptoms improved irrespective of the presence of depression. Conclusions: Exposure-based CBT for primary PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbid depression or depressive symptomatology. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

This paper presents the Social Phobia Psychotherapy Research Network. The research program encompasses a coordinated group of studies adopting a standard protocol and an agreed-on set of standardized measures for the assessment and treatment of social phobia (SP). In the central project (study A), a multicenter randomized controlled trial, refined models of manualized cognitive-behavioral therapy and manualized short-term psychodynamic psychotherapy are compared in the treatment of SP. A sample of 512 outpatients will be randomized to either cognitive-behavioral therapy, short-term psychodynamic psychotherapy or waiting list. Assessments will be made at baseline, at the end of treatment and 6 and 12 months after the end of treatment. For quality assurance and treatment integrity, a specific project using highly elaborated measures has been established (project Q). Study A is complemented by 4 interrelated add-on projects focusing on attachment style (study B1), on cost-effectiveness (study B2), on variation in the serotonin transporter gene in SP (study C1) and on structural and functional deviations of the hippocampus and amygdala (study C2). Thus, the Social Phobia Psychotherapy Research Network program enables a highly interdisciplinary research into SP. The unique sample size achieved by the multicenter approach allows for studies of subgroups (e.g. comorbid disorders, isolated vs. generalized SP), of responders and nonresponders of each treatment approach, for generalization of results and for a sufficient power to detect differences between treatments. Psychological and biological parameters will be related to treatment outcome, and variables for differential treatment indication will be gained. Thus, the results provided by the network may have an important impact on the treatment of SP and on the development of treatment guidelines for SP. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Factors predicting survival in men with lymph node-positive prostate cancer are still poorly defined. Patients and Methods: 193 prostate cancer patients with histopathologically proven lymph node involvement with a median follow-up of 7.3 years were studied. 94% of patients received immediate hormonal therapy. Kaplan-Meier curves were calculated to evaluate overall survival rates and compared with the log-rank test. Cumulative disease-specific and competing mortality rates were calculated by competing risk analysis and compared with the Pepe-Mori test. Cox proportional hazard models were used to determine the independent significance of predictors of all-cause mortality. Results: Age (70 years or older vs. younger), Gleason score (8–10 vs. 7 or lower) and the number of involved nodes (3 or more vs. 1–2) were identified as independent predictors of all-cause mortality. When patients with 0–1 of these risk factors were compared with those with 2–3 risk factors, all-cause (rates after 10 years 21% vs. 71%, p < 0.0001), disease-specific (12 vs. 37%, p = 0.009) and competing mortality (9 vs. 33%, p = 0.02) differed significantly. Conclusions: Some of the excess mortality in patients with poor-risk lymph node-positive prostate cancer may be attributed to increased competing mortality, possibly caused by an interaction between comorbid diseases and hormonally treated persistent or progressive prostate cancer. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.