In this study, candidate loci for periodic catatonia (SCZD10, OMIM #605419) on chromosome 15q15 and 22q13.33 have been fine mapped and investigated. Previously, several studies found evidences for a major susceptibility locus on chromosome 15q15 and a further potential locus on 22q13.33 pointing to genetic heterogeneity. Fine mapping was done in our multiplex families through linkage and mutational analysis using genomic markers selected from public databases. Positional candidate genes like SPRED1 and BRD1, and ultra-conserved elements were investigated by direct sequencing in these families. The results narrow down the susceptibility locus on chromosome 15q14-15q15.1 to a region between markers D15S1042 and D15S968, as well as exclusion of SPRED1 and ultra-conserved elements as susceptibility candidates. Fine mapping for two chromosome 23q13.33-linked families showed that the recombination events would place the disease-causing gene to a telomeric ~577 Kb interval and SNP rs138880 investigation revealed an A-allele in the affected person, therefore excludes BRD1 as well as confirmed MLC1 to be the candidate gene for periodic catatonia.

Das Konzept psychologischer und philosophischer Hilfe des niederländischen Psychologen und Philosophen Jac van Essen (1908-1989) ist in der wissenschaftlichen Literatur bislang weitgehend unbekannt. Es beruht auf dem sog. Allmenschlichkeitsgedanken. Zunächst wird Theorie und Praxis der Allmenschlichkeit eingehend als eigenständiger Ansatz dargestellt. Danach werden exemplarisch diverse Konzepte psychologischer Hilfe (Freud, Jung, Adler, Kognitive Therapie, Rogers u.a.) im Licht dieses Ansatzes diskutiert. Er erweist sich als geeigneter Prüfstein dafür, inwieweit Theorie und Praxis jener Konzepte zugleich wissenschaftlich und integral humanitär befriedigen, auch in bezug auf existentielle Aspekte.

The glucocorticoid (GC) cortisol, main mediator of the hypothalamic-pituitary-adrenal axis, has many implications in metabolism, stress response and the immune system. GC function is mediated mainly via the glucocorticoid receptor (GR) which binds as a transcription factor to glucocorticoid response elements (GREs). GCs are strong immunosuppressants and used to treat inflammatory and autoimmune diseases. Long-term usage can lead to several irreversible side effects which make improved understanding indispensable and warrant the adaptation of current drugs. Several large scale gene expression studies have been performed to gain insight into GC signalling. Nevertheless, studies at the proteomic level have not yet been made. The effects of cortisol on monocytes and macrophages were studied in the THP-1 cell line using 2D fluorescence difference gel electrophoresis (2D DIGE) combined with MALDI-TOF mass spectrometry. More than 50 cortisol-modulated proteins were identified which belonged to five functional groups: cytoskeleton, chaperones, immune response, metabolism, and transcription/translation. Multiple GREs were found in the promoters of their corresponding genes (+10 kb/-0.2 kb promoter regions including all alternative promoters available within the Database for Transcription Start Sites (DBTSS)). High quality GREs were observed mainly in cortisol modulated genes, corroborating the proteomics results. Differential regulation of selected immune response related proteins were confirmed by qPCR and immuno-blotting. All immune response related proteins (MX1, IFIT3, SYWC, STAT3, PMSE2, PRS7) which were induced by LPS were suppressed by cortisol and belong mainly to classical interferon target genes. Mx1 has been selected for detailed expression analysis since new isoforms have been identified by proteomics. FKBP51, known to be induced by cortisol, was identified as the strongest differentially expressed protein and contained the highest number of strict GREs. Genomic analysis of five alternative FKBP5 promoter regions suggested GC inducibility of all transcripts. 2D DIGE combined with 2D immunoblotting revealed the existence of several previously unknown FKBP51 isoforms, possibly resulting from these transcripts. Additionally multiple post-translational modifications were found, which could lead to different subcellular localization in monocytes and macrophages as seen by confocal microscopy. Similar results were obtained for the different cellular subsets of human peripheral blood mononuclear cells (PBMCs). FKBP51 was found to be constitutively phosphorylated with up to 8 phosphosites in CD19+ B lymphocytes. Differential Co-immunoprecipitation for cytoplasm and nucleus allowed us to identify new potential interaction partners. Nuclear FKBP51 was found to interact with myosin 9, whereas cytosolic FKBP51 with TRIM21 (synonym: Ro52, Sjögren`s syndrome antigen). The GR has been found to interact with THOC4 and YB1, two proteins implicated in mRNA processing and transcriptional regulation. We also applied proteomics to study rapid non-genomic effects of acute stress in a rat model. The nuclear proteome of the thymus was investigated after 15 min restraint stress and compared to the non-stressed control. Most of the identified proteins were transcriptional regulators found to be enriched in the nucleus probably to assist gene expression in an appropriate manner. The proteomic approach allowed us to further understand the cortisol mediated response in monocytes/macrophages. We identified several new target proteins, but we also found new protein variants and post-translational modifications which need further investigation. Detailed study of FKBP51 and GR indicated a complex regulation network which opened a new field of research. We identified new variants of the anti-viral response protein MX1, displaying differential expression and phosphorylation in the cellular compartments. Further, proteomics allowed us to follow the very early effects of acute stress, which happen prior to gene expression. The nuclear thymocyte proteome of restraint stressed rats revealed an active preparation for subsequent gene expression. Proteomics was successfully applied to study differential protein expression, to identify new protein variants and phosphorylation events as well as to follow translocation. New aspects for future research in the field of cortisol-mediated immune modulation have been added.

The aim of the thesis was to investigate the role of the immune system in fibromyalgia (FM), as part of a dynamic co-regulation between different bodily systems. FM is a chronic musculoskeletal disorder characterized by widespread pain and specific tender points, combined with other symptoms including fatigue, sleep disturbances, morning stiffness and anxiety. The main goal of the work was to identify possible dysregulation of peripheral immune and endocrine parameters in patients with FM compared to matched healthy controls. Moreover, the possible relation between symptom complaints and the specific parameters measured was also evaluated. A first approach was to investigate possible differences between FM patients and controls in the expression of cytokines, as they have been implicated in the occurrence of several of the symptoms associated with FM. Furthermore, adhesion molecules which are involved in cell-to-cell communication and immune cell trafficking were also studied. The latter are known to be regulated by both cytokines and glucocorticoids (GCs) and their expression is often found altered in patients with immune dysregulation. It was expected that subjects with FM would have an increased production of proinflammatory cytokines and/or a reduced antiinflammatory cytokine production and that certain cytokines and/or adhesion molecules would be differently regulated by dexamethasone (DEX). Unstimulated blood was used in the analysis of adhesion molecule expression by flow cytometry while stimulated whole blood cell cultures were used in cytokine flow cytometry assays. Peripheral blood mononuclear cells (PBMCs) were also cultured and the supernatants collected to determine the concentration of cytokines by biochip protein array. In addition, serum samples were used in enzyme-linked immunosorbent assays (ELISA) for quantification of soluble adhesion molecules. L-selectin was found elevated on monocytes and neutrophils of FM patients. A bias toward lower IL-4 levels was observed in FM patients. Based on studies showing differences in glucocorticoid receptor (GR) affinity and disturbances associated with loss of hypothalamic-pituitary-adrenal (HPA) axis resiliency in FM, it was hypothesized whether FM would be associated with abnormalities in glucocorticoid sensitivity. Total plasma cortisol and salivary free cortisol were quantified by ELISA and time-resolved fluorescence immunoassay, respectively. GR sensitivity through DEX inhibition of IL-6, in stimulated whole blood, was evaluated after cytokine quantification by ELISA. The corticosteroid receptors, GR alpha and mineralocorticoid receptor (MR), as well as the glucocorticoid-induced leucine zipper (GILZ) and the FK506 binding protein 5 mRNA expression were assessed in PBMCs by real-time reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, sequencing of RT-PCR products and/or genomic DNA was used for mutational analysis of the corticosteroid receptors. We observed lower basal plasma cortisol levels (borderline statistical significance) and a lower expression of corticosteroid receptors and GILZ in FM patients when compared to healthy controls. The minor allele of the MR single nucleotide polymorphism (SNP) rs5522 was found more often in FM patients than in controls. In addition, female carriers of this SNP seemed to have reduced salivary cortisol responses to a strong psychological stressor (Trier Social Stress Test) compared to non-carriers. FM patient carriers of an MR intronic SNP (rs17484245), before exon 3, were associated with significantly higher scores of depression symptoms compared to patient non-carriers. The thesis includes also a comprehensive analysis of the complexity of GR regulation and the role of alternative mRNA splicing. It focuses on the differential expression of the untranslated GR first exons, their high sequence homology among different species and how genetic determinants, without apparent relevance, may have implications in health and disease. In FM patients, GR exon 1-C expression was found lower and a significant difference was observed when comparing GR 1-C expression between antidepressant-free and patients who had taken antidepressants until two weeks before sample collection. In summary, the study shows a slight disturbance of some components of the innate immune system of FM patients and suggests an enhanced adhesion and possible recruitment of leukocytes to inflammatory sites. The reduced expression of corticosteroid receptors and possibly the reduced MR function may be associated with an impaired function of the HPA axis in these patients. A hyporesponsiveness of the HPA axis under stress or disturbances of the stress response could make these patients more vulnerable to cytokines and inflammation which, compounded by lower antiinflammatory mediators, may sustain some of the symptoms that contribute to the clinical picture of FM.

The human brain is characterised by two apparently symmetrical cerebral hemispheres. However, the functions attributed to each half of the brain are very distinct with a relative specialisation of the left hemisphere for language processing. Most laterality research has been performed on a behavioural level, using techniques such as visual half-field presentation. The visual half-field technique involves the presentation of stimuli in the left or right visual field for a very short time (about 200 ms). During the presentation of lateralized stimuli, the gaze of the participants is fixated on a centrally presented fixation cross. This technique takes advantage of the anatomy of the visual pathway as the temporal hemiretinae project ipsilateral, while the nasal hemiretinae project contralateral. Thus, stimuli presented in the left or right visual field are initially processed in the contralateral hemisphere. Language organisation can also be directly investigated using functional magnetic resonance imaging (fMRI). Both behavioural and neuroimaging studies showed that about 95% of right-handed men have a left hemispheric specialisation for language. In contrast, data on language organisation in women are ambiguous. It is supposed that this ambivalent picture might be associated with changes in gonadal steroid levels in blood during the menstrual cycle. However, gonadal steroid effects are complex and their role in functional cerebral lateralization is still open to discussion. The aim of this PhD project was to investigate, using fMRI: (1) the processing of linguistic information initially received in the specialised, non-specialised or both hemispheres; (2) linking the associated brain activation pattern with progesterone levels during the menstrual cycle. Firstly, brain activation was measured in 16 right-handed, healthy males during processing of different components of language (orthography, phonology and semantics) after reception in the left, right or both hemispheres. Secondly, to investigate changes in language organisation during the menstrual cycle, we conducted an event-related fMRI study during semantic and phonological processing also using visual half-field and central presentation of linguistic stimuli. Our results revealed higher BOLD signal intensity change in the visual cortex contralateral to the visual field of stimulus presentation compared to the ipsilateral visual cortex reflecting the crossing of visual pathways. We also found support for the hypothesis that the superiority of word recognition in the left VWFA is the result of a reduced activity in the right VWFA under left hemispheric control. Further, linguistic information received in the subdominant RH, is interhemispheric transferred to the left hemisphere for phonological processing. Semantic processing in contrast occurs in the specialised and in the non-specialised hemisphere. For the group of women, data analysis revealed that during semantic processing, salivary progesterone levels correlated positively with brain activity of the left superior frontal gyrus, left middle and inferior occipital gyri and bilateral fusiform gyrus. In contrast, the brain activation pattern for phonological processing did not change significantly across the menstrual cycle. In conclusion, the effect of serum progesterone levels on brain activity is task and region specific.

Im Lebensrückblick wird bedeutsamen Ereignissen lebensgeschichtliche Bedeutung zugeschrieben; diese werden sodann als zugehörig zur eigenen Person und Lebensgeschichte wahrgenommen. Dieser Vorgang wurde als "Stiftung von Kohärenz" bezeichnet und für ein zurückliegendes belastendes Ereignis explorativ untersucht. In einer Fragebogenerhebung mit Daten von insgesamt N = 260 Probanden im Alter zwischen 41 und 86 Jahren wurde die Stiftung von Kohärenz für ein belastendes Ereignis daraufhin untersucht, inwieweit diese mit verschiedenen Formen der gedanklichen Auseinandersetzung mit dem Ereignis zusammenhängt. Weiterhin wurden die Zusammenhänge der Kohärenzstiftung mit ereignisbedingten Veränderungen des Selbstbildes und bestimmter Lebensumstände sowie mit Merkmalen des Ereignisses und der Person exploriert.

Nach getroffenen Entscheidungen werden gewählte Alternativen typischerweise aufgewertet, abgewählte Alternativen werden abgewertet (spreading apart of alternatives). Die vorliegende Arbeit ordnet solche tendenziösen Umwertungen in einen handlungstheoretischen Zusammenhang ein und untersucht vor diesem Hintergrund mögliche Bedingungen solcher Umwertungen. Ausgangspunkt der Überlegungen ist das Assimilations-Akkommodations-Modell von Brandtstädter. Demnach sind die beschriebenen Umwertungen Ausdruck eines akkommodativen Modus der Zielablösung und sollten zum einen von der Irreversibilität der Entscheidung abhängen, zum anderen von zwei dispositionellen Faktoren, die die Stärke akkommodativer Prozesse bestimmen (Flexibilität der Zielanpassung, Hartnäckigkeit der Zielverfolgung). Drei Studien bestätigen die Vorhersagen des Assimilations-Akkommodations-Modells und geben zudem Hinweise auf vermittelnde Prozesse der Umwertung von Alternativen. So scheinen insbesondere solche Attribute aufgewertet zu werden, deren Zutreffen bei der betreffenden Alternative subjektiv nicht abzuleugnen ist. Die individuelle Ausprägung solcher selektiven Umwertungen wird in einem Anpassungsindex (AI) abgebildet. Abschließend wird der empirische Befund diskutiert und auf die Frage der Rationalität der gefundenen Umwertungen eingegangen.