Pharmakologische Charakterisierung der Wirkungen von Glukokortikoiden auf die Atmungskette und die ATP-Synthese in adrenokortikotrophen Hypophysenzellen (AtT20)

Um die Effekte des Glukokortikoids Dexamethason auf Parameter des mitochondrialen Energiestoffwechsels zu untersuchen, wurden in vitro Versuche an einer AtT20-Zelllinie durchgeführt (Hypophysenvorderlappenzellen der Maus). Die untersuchten Parameter waren die ATP-Konzentration und ein mitochondrialer Funktionstest (EZ4U). Bei Langzeitinkubation (>30 Min.) zeigten sich vorwiegend supprimierende Effekte, bei kurzer Inkubationszeit (≤30 Min.) waren die Effekte unterschiedlich und dosisabhängig. Die Kurzzeiteffekte im mitochondrialen Funktionstest konnten durch den Glukokortikoidrezeptorantagonisten RU38486 nicht aufgehoben werden. Diese wahrscheinlich nicht-genomischen Effekte könnten in Regulationsvorgänge oder Störungen der Regulation innerhalb der Hypothalamus-Hypophysen-Nebennierenrindenachse involviert sein

A simple method for isolation of PCR fragments from silver-stained polyacrylamide gels by scratching with a fine needle

This project investigated how NoSQL databases can be used together with a logical layer, instead of a relational database with separated backend logic, to search for products with customer specific constraints in an e-commerce scenario. The motivation behind moving from a relational database was the scalability issues and increased read latencies experienced as the data increased. The work resulted in a framework called Cauldron that uses pipelines a sequence of execution steps to expose its data stored in an in-memory key-value store and a document database. Cauldron uses write replication between distributed instances to increase read throughput at the cost of write latency. A product database with customer specific constraints was implemented using Cauldron to compare it against an existing solution based on a relational database. The new product database can serve search queries 10 times faster in the general case and up to 25 times faster in extreme cases compared to the existing solution.Projektet undersökte hur NoSQL databaser tillsammans med ett logiskt lager, istället för en relationsdatabas med separat backend logik, kan användas för att söka på produkter med kundunika restriktioner. Motivationen till att byta ut relationsdatabasen berodde på skalbarhetsproblem och långsammare svarstider när datamängden ökade. Arbetet resulterade i ett ramverk vid namn Cauldron som använder pipelines sammankopplade logiska steg för att exponera sin data från en minnesbunden nyckel-värde-databas och en dokumentdatabas. Cauldron använder replikering mellan distribuerade instanser för att öka läsgenomstömmningen på bekostnad av högre skrivlatenser. En produktdatabas med kundunika restriktioner implementerades med hjälp av Cauldron för att jämföra den mot en befintlig lösning baserad på en relationsdatabas. Den nya databasen kan besvara sökförfrågningar 10 gånger snabbare i normalfallen och upp till 25 gånger snabbare i extremfallen jämfört med den befintliga lösningen

Heidelberg coping scales for delusions: psychometric evaluation of an expert rating instrument

Background: Coping is of substantial relevance in the treatment and course of psychiatric disorders. Standardized instruments to assess coping with psychotic symptoms, particularly delusions, are rare. The aim of this study was to develop and evaluate the psychometric properties of a new instrument to assess coping strategies in the context of delusional experiences: the Heidelberg Coping Scales for Delusions (HCSD). Methods: Two hundred and twelve inpatients with schizophrenia spectrum disorders and affective disorders currently experiencing delusions were interviewed with the HCSD and other coping assessment instruments. Psychometric properties and factor structure were analyzed. Results: The HCSD showed good inter-rater reliability and convergent validity. Factor analysis yielded an interpretable structure with five factors: resource-oriented coping, medical care, distraction, cognitive coping, and depressive coping. Symptomatic behavior, due to its particular characteristics, was considered apart. Conclusion: The HCSD is a reliable and valid instrument for the assessment of coping strategies in patients with delusions. Further research is needed to evaluate coping changes over time and their influence on treatment and clinical outcomes. Copyright (C) 2012 S. Karger AG, Base

THE IMPACT OF ATTACHMENT PARAMETERS IN CHILDHOOD ON THE PERSONALITY OF ADULTS WITH MENTAL DISORDERS

Background: Attachment parameters have an effect on later relationship patterns and the development of parameters of selfconcept and personality. In the current study the role of attachment parameters on personality dimensions was investigated, especially with respect to personality disorders. Subjects and methods: 134 psychiatric inpatients were examined on attachment and personality parameters using the schedule FEB as a questionnaire on the parental attachment and the SKI as a self-concept inventory. Results: Regression and correlation analyses suggest positive influences of parental care and negative influences of parental overprotection on the development of ego-strength in adulthood. Patients with personality disorders reported to have experienced less maternal care during their childhood and showed a trend towards a reduced ego-strength in adulthood compared to patients with others mental disorders. Conclusions: Relationships of attachment parameters in childhood with personality dimension are explorable. This approach seems meaningful for a better understanding of the development of personality disorders. Clinicians should be familiar with attachment patterns when treating people with mental disorders in order to adequately include appropriate personality dimensions in the therapy

Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL) on human obesity

BACKGROUND: Since both excess glucocorticoid secretion and central obesity are clinical features of some obese patients, it is worthwhile to study a possible association of glucocorticoid receptor gene (GRL) variants with obesity. Previous studies have linked the N363S variant of the GRL gene to increased glucocorticoid effects such as higher body fat, a lower lean-body mass and a larger insulin response to dexamethasone. However, contradictory findings have been also reported about the association between this variant and obesity phenotypes. Individual studies may lack statistical power which may result in disparate results. This limitation can be overcome using meta-analytic techniques. METHODS: We conducted a meta-analysis to assess the association between the N363S polymorphism of the GRL gene and obesity risk. In addition to published research, we included also our own unpublished data -three novel case-control studies- in the meta-analysis The new case-control studies were conducted in German and Spanish children, adolescents and adults (total number of subjects: 1,117). Genotype was assessed by PCR-RFLP (Tsp509I). The final formal meta-analysis included a total number of 5,909 individuals. RESULTS: The meta-analysis revealed a higher body mass index (BMI) with an overall estimation of +0.18 kg/m(2 )(95% CI: +0.004 to +0.35) for homo-/heterozygous carriers of the 363S allele of the GRL gene in comparison to non-carriers. Moreover, differences in pooled BMI were statistically significant and positive when considering one-group studies from the literature in which participants had a BMI below 27 kg/m(2 )(+ 0.41 kg/m(2 )[95% CI +0.17 to +0.66]), but the differences in BMI were negative when only our novel data from younger (aged under 45) and normal weight subjects were pooled together (-0.50 kg/m(2 )[95% CI -0.84 to -0.17]). The overall risk for obesity for homo-/heterozygous carriers of the 363S allele was not statistically significant in the meta-analysis (pooled OR = 1.02; 95% CI: 0.56–1.87). CONCLUSION: Although certain genotypic effects could be population-specific, we conclude that there is no compelling evidence that the N363S polymorphism of the GRL gene is associated with either average BMI or obesity risk

Genomics yields biological and phenotypic insights into bipolar disorder

Bipolar disorder is a leading contributor to the global burden of disease(1). Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown(2). We analysed data from participants of European, East Asian, African American and Latino ancestries (n=158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings(3), and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder(4), highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD