Alzheimer's brains show inter-related changes in RNA and lipid metabolism.

Alzheimer's disease (AD) involves changes in both lipid and RNA metabolism, but it remained unknown if these differences associate with AD's cognition and/or post-mortem neuropathology indices. Here, we report RNA-sequencing evidence of inter-related associations between lipid processing, cognition level, and AD neuropathology. In two unrelated cohorts, we identified pathway-enriched facilitation of lipid processing and alternative splicing genes, including the neuronal-enriched NOVA1 and hnRNPA1. Specifically, this association emerged in temporal lobe tissue samples from donors where postmortem evidence demonstrated AD neuropathology, but who presented normal cognition proximate to death. The observed changes further associated with modified ATP synthesis and mitochondrial transcripts, indicating metabolic relevance; accordingly, mass-spectrometry-derived lipidomic profiles distinguished between individuals with and without cognitive impairment prior to death. In spite of the limited group sizes, tissues from persons with both cognitive impairment and AD pathology showed elevation in several drug-targeted genes of other brain, vascular and autoimmune disorders, accompanied by pathology-related increases in distinct lipid processing transcripts, and in the RNA metabolism genes hnRNPH2, TARDBP, CLP1 and EWSR1. To further detect 3'-polyadenylation variants, we employed multiple cDNA primer pairs. This identified variants that showed limited differences in scope and length between the tested cohorts, yet enabled superior clustering of demented and non-demented AD brains versus controls compared to total mRNA expression values. Our findings indicate inter-related cognition-associated differences in AD's lipid processing, alternative splicing and 3'-polyadenylation, calling for pursuing the underlying psychological and therapeutics implications.

[Children and adolescents after child abuse and neglect: Do they receive appropriate treatment?]. / Kinder und Jugendliche mit Misshandlungserfahrungen: bekommen sie die Versorgung, die sie brauchen?

BACKGROUND: Child abuse and neglect (CAN) is a risk factor for the development of psychiatric disorders. Untreated, disorders can sustain into adulthood. OBJECTIVES: This study compares rates of psychiatric disorders to mental health care utilization in victims of CAN. METHODS: From three regions in Germany, 322 children and adolescents aged between 4 and 17 and a non-abusive caregiver were assessed for the child's history of CAN, mental health and mental health care utilization via semi-structured interviews. RESULTS: Approximately two thirds of the participants (present state 64.29 %; lifetime 69.57 %) suffered from a psychiatric disorder classifiable with ICD-10. Posttraumatic stress disorder (25.16 %), conduct disorders (21.34 %) and attention and hyperactivity disorders (16.15 %) were most frequently diagnosed. Merely 19.88 % were using mental health care at the time of the assessment. CONCLUSIONS: The provision of mental health care for victims of CAN is insufficient. To improve access to appropriate services for this vulnerable clientele, cooperation between psychiatrists and psychotherapists and the child welfare system is essential. The implementation and dissemination of evidence-based diagnostic methods and treatments must be further advanced.

Co-Crystal Formation of Partially Fluorinated 1,3,5-Tris(phenylethynyl)benzenes.

Several rigid 1,3,5-tris(phenylethynyl)benzenes with different fluorination patterns were synthesized through selective Sonogashira-Hagihara coupling reactions to analyze the packing behavior in solid-state structures. The aggregation is dominated by various intermolecular interactions between aryl substituents, triple bonds, C-H bonds and H⋅⋅⋅F contacts. Co-crystallization experiments for the analysis of preferred aryl-aryl-interactions led to 1 : 1 complexes. Intermolecular phenyl-perfluorophenyl interactions with short centroid-centroid distances are dominating these co-crystal structures. They lead to melting point increases of up to 49 °C for the co-crystals compared to the pure substances.

Fear extinction learning and anandamide: an fMRI study in healthy humans.

Anxiety- and trauma-related disorders are severe illnesses with high prevalence. Current treatment options leave room for improvement and the endocannabinoid system (ECS) has become a key target in psychopharmacological research. Rodent models suggest an anxiolytic effect of endocannabinoids and demonstrated that the ECS is involved in the modulation of fear learning and aversive memory consolidation. So far, one prominent target was inhibition of fatty acid amino hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide (AEA). Research in humans remains scarce, but genetic studies have found that the single-nucleotide polymorphism (SNP) FAAH C385A (rs324420) is associated with lower catabolic performance of FAAH and increased levels of AEA. Translational research on the ECS in fear learning processes is rare, yet crucial to understand the mechanisms involved. To address this lack of research, we designed a fear conditioning, extinction learning paradigm with 51 healthy, male humans who underwent functional magnetic resonance imaging (fMRI) before analysing baseline and task-related changes of AEA, as well as the FAAH polymorphism (rs324420). The results indicate higher AEA levels in AC-heterozygotes than in CC-individuals (SNP rs324420), but no difference between the groups during extinction learning. However, neural activation of the anterior cingulate cortex and anterior insular cortex during extinction learning correlated positively with AEA baseline levels, and task-related changes in AEA were found particularly during fear extinction, with a modulatory effect on neural activation related to extinction learning. Results indicate a putative role for AEA in fear extinction learning. Pre-treatment with AEA-enhancing drugs could promote extinction learning during psychotherapeutic interventions.

[Nonsuicidal self-injury in adolescence]. / Selbstverletzendes Verhalten im Jugendalter.

Nonsuicidal self-injury (NSSI) usually starts in adolescence. International studies report prevalence rates between 3 and 37% (for Germany between 15 and 26%) in adolescents. From a neurobiological perspective, there is evidence that primarily the serotonergic system is involved in the origin and maintenance of this behaviour. NSSI is often used by adolescents to influence aversive affective states, but sometimes serves other functions as well, such as self-punishment or anti-dissociation. To date there are many assessment instruments, some of which are available in a German translation. Regarding psychotherapeutic interventions there is evidence for a good efficacy of dialectical behavioral therapy for adolescents (DBT-A). There is little evidence for psychopharmacological interventions in childhood and adolescence; thus treatment should focus on psychotherapeutic interventions.

The symptom representation of posttraumatic stress disorder in a sample of unaccompanied and accompanied refugee minors in Germany: a network analysis.

Background: Given the unprecedented number of traumatized refugee minors in Europe and the increased prevalence of mental disorders such as PTSD in this vulnerable population, new methodologies that help us to better understand their symptomatology are crucial. Network analysis might help clinicians to both understand which symptoms might trigger other symptoms, and to identify relevant targets for treatment. However, to date only two studies have applied the network analysis approach to an (adult) refugee population and only three studies examined this approach in children and adolescents. Objective: The aim of this study is to explore the network structure and centrality of DSM-5 PTSD symptoms in a cross-sectional sample of severely traumatized refugee minors. Method: A total of N = 419 (M age = 16.3; 90.7% male) unaccompanied (79.9%) and accompanied (20.1%) refugee minors were recruited in five studies in southern Germany. PTSD symptoms were assessed using the Child and Adolescent Trauma Screen (CATS). The network was estimated using state-of-the-art regularized partial correlation models using the R-package qgraph. Results: The most central symptoms were nightmares, physiological and psychological reactivity, and concentration problems. The strongest connections between symptoms were established for psychological and physiological reactivity, irritability/anger and self-destructive/reckless behaviour, intrusions and nightmares, nightmares and sleep disturbance, and between concentrations problems and sleep disturbance. Conclusion: This study furnishes information relevant to research and the clinical management of PTSD in refugee minors, and also in terms of comparisons with trauma-exposed children and adolescents without a migration background. Re-experiencing symptoms seem to be central in the refugee minor PTSD profile and thus merit special consideration in the diagnostic and treatment evaluation process. Investigating the PTSD network longitudinally and complementing between-subject analyses with within-subject ones might provide further insight into the symptomatology of refugee minors and how to treat them successfully.

Antecedentes: Dado el número sin precedentes de menores traumatizados refugiados en Europa y la prevalencia aumentada de trastornos mentales tales como el TEPT en esta población vulnerable, nuevas metodologías que nos ayuden a una mejor comprensión de su sintomatologiía son cruciales. El análisis de redes podría ayudar a los clínicos, tanto para comprender qué síntomas podrían gatillar otros síntomas y para identificar blancos relevantes para el tratamiento. Sin embargo, a la fecha sólo dos estudios han aplicado la aproximación de análisis de redes a una población de refugiados (adultos) y sólo tres estudios examinaron esta aproximación en niños y adolescentes.Objetivo: El objetivo de este estudio es explorar la estructura de redes y centralidad de los síntomas de TEPT del DSM-5 en una muestra transversal de menores refugiados severamente traumatizados.Método: Fueron recrutados un total de N= 419 (edad M= 16.3; 90,7% masculino) menores refugiados en cinco estudios en el sur de Alemania, no acompañados (79,9%) y acompañados (20,1%). Los síntomas de TEPT fueron evaluados usando el Tamizaje de Trauma para niños y adolescentes (CATS por sus siglas en inglés). La red se estimó utilizando modelos de correlación parcial regularizados de última generación utilizando el gráfico de paquete R.Resultados: Los síntomas más centrales fueron las pesadillas, la reactividad fisiológica y psicológica y los problemas de concentración. Las conexiones más potentes entre síntomas estuvieron establecidas por la reactividad psicológica y fisiológica, la irritabilidad/rabia y conducta autodestructiva/impulsiva, intrusiones y pesadillas, pesadillas y alteraciones del sueño, y entre problemas de concentración y alteraciones del sueño.Conclusión: Este estudio proporciona información relevante para la investigación y el manejo clínico del TEPT en menores refugiados, y también en términos de comparaciones con niños y adolescentes expuestos a trauma sin antecedentes de migración. Los síntomas de re-experimentación parecen ser centrales en el perfil de TEPT en los menores refugiados y por lo tanto merece una consideración especial en el proceso de evaluación diagnóstica y el tratamiento. La investigación longitudinal de la red del TEPT y la complementación de los análisis entre sujetos con los de otro sujeto podrían proporcionar una mayor comprensión de la sintomatología de los menores refugiados y cómo tratarlos en forma exitosa.

Effectiveness of manualized case management on utilization of evidence-based treatments for children and adolescents after maltreatment: A randomized controlled trial.

The objective of this study was to compare structured case management (CM) to usual care (UC) for helping victims of child abuse and neglect (CAN) with mental disorders access evidence-based treatment (EBT). N=121 children and adolescents aged 4-17 with a history of CAN and a current mental disorder were recruited in three German states in a multi-center parallel group trial. They were randomly assigned, stratified by study site and level of psychosocial functioning, to receive CM additionally to UC or only UC. CM was delivered by trained professionals and volunteers, most of them affiliated to local child welfare agencies or NGOs. UC comprised child welfare services typically delivered in Germany. The primary outcome was EBT utilization after 6 months. Secondary outcome was the time until commencement of EBT. Outcomes were determined by semi-structured clinical interviews with assessors blinded to group allocation. Predictors of access to EBT and barriers to utilization of treatment were analyzed. The intent to treat analysis showed that after 6 months 23 of 60 participants recruited to CM (38%) and 19 of 61 participants recruited to UC (31%) were using EBT, χ2 (1, N=121)=0.689, p=.261. Female gender, out-of-home placement, and home state were significant predictors of access to EBT. Less than 40% of participants across both groups were successfully referred to EBT. Access to EBT seems to be in part due to system-level barriers, namely lack of implementation of EBT in community settings. TRIAL REGISTRATION: DRKS00003979 German Clinical Trials Register.

InFusion: Advancing Discovery of Fusion Genes and Chimeric Transcripts from Deep RNA-Sequencing Data.

Analysis of fusion transcripts has become increasingly important due to their link with cancer development. Since high-throughput sequencing approaches survey fusion events exhaustively, several computational methods for the detection of gene fusions from RNA-seq data have been developed. This kind of analysis, however, is complicated by native trans-splicing events, the splicing-induced complexity of the transcriptome and biases and artefacts introduced in experiments and data analysis. There are a number of tools available for the detection of fusions from RNA-seq data; however, certain differences in specificity and sensitivity between commonly used approaches have been found. The ability to detect gene fusions of different types, including isoform fusions and fusions involving non-coding regions, has not been thoroughly studied yet. Here, we propose a novel computational toolkit called InFusion for fusion gene detection from RNA-seq data. InFusion introduces several unique features, such as discovery of fusions involving intergenic regions, and detection of anti-sense transcription in chimeric RNAs based on strand-specificity. Our approach demonstrates superior detection accuracy on simulated data and several public RNA-seq datasets. This improved performance was also evident when evaluating data from RNA deep-sequencing of two well-established prostate cancer cell lines. InFusion identified 26 novel fusion events that were validated in vitro, including alternatively spliced gene fusion isoforms and chimeric transcripts that include intergenic regions. The toolkit is freely available to download from http:/bitbucket.org/kokonech/infusion.

Self-mutilation induced by psychotropic substances: a systematic review.

Self-mutilation (SM) not only occurs among patients with schizophrenia, personality disorders or transsexuality but also as a phenomenon induced by psychotropic substances (PS). We intended to find characteristics of patients at risk to perform SM induced by PS (SMIPS), frequent PS within this phenomenon and typical presentations of SMIPS. A systematic review of the literature (including Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Scopus) was conducted. On October 2011 we identified 26 cases (23 publications) of SM related to PS. Majority of patients (85%) was male, mean age was 30 years (median 41 years). Seventy-three percent of patients developed SM subsequent to the use of one PS, 27% presented SM after the use of more than one PS. Alcohol (25%), hallucinogens (25%) and amphetamines (22%) were found most frequently among the reported substances. Major impairment was present in 80%. Our findings suggest male sex, young age, a previous history of abuse of PS and the current use of alcohol, hallucinogens or amphetamines to favour SMIPS.