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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.
Educational assessment tends to rely on more or less standardized tests, teacher judgments, and observations. Although teachers spend approximately half of their professional conduct in assessment-related activities, most of them enter their professional life unprepared, as classroom assessment is often not part of their educational training. Since teacher judgments matter for the educational development of students, the judgments should be up to a high standard. The present dissertation comprises three studies focusing on accuracy of teacher judgments (Study 1), consequences of (mis-)judgment regarding teacher nomination for gifted programming (Study 2) and teacher recommendations for secondary school tracks (Study 3), and individual student characteristics that impact and potentially bias teacher judgment (Studies 1 through 3). All studies were designed to contribute to a further understanding of classroom assessment skills of teachers. Overall, the results implied that, teacher judgment of cognitive ability was an important constant for teacher nominations and recommendations but lacked accuracy. Furthermore, teacher judgments of various traits and school achievement were substantially related to social background variables, especially the parents" educational background. However, multivariate analysis showed social background variables to impact nomination and recommendation only marginally if at all. All results indicated differentiated but potentially biased teacher judgments to impact their far-reaching referral decisions directly, while the influence of social background on the referral decisions itself seems mediated. Implications regarding further research practices and educational assessment strategies are discussed. The implications on the needs of teachers to be educated on judgment and educational assessment are of particular interest and importance.
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.
Numerous RCTs demonstrate that cognitive behavioral therapy (CBT) for depression is effective. However, these findings are not necessarily representative of CBT under routine care conditions. Routine care studies are not usually subjected to comparable standardizations, e.g. often therapists may not follow treatment manuals and patients are less homogeneous with regard to their diagnoses and sociodemographic variables. Results on the transferability of findings from clinical trials to routine care are sparse and point in different directions. As RCT samples are selective due to a stringent application of inclusion/exclusion criteria, comparisons between routine care and clinical trials must be based on a consistent analytic strategy. The present work demonstrates the merits of propensity score matching (PSM), which offers solutions to reduce bias by balancing two samples based on a range of pretreatment differences. The objective of this dissertation is the investigation of the transferability of findings from RCTs to routine care settings.
The efficacy and effectiveness of psychotherapeutic interventions have been proven time and again. We therefore know that, in general, evidence-based treatments work for the average patient. However, it has also repeatedly been shown that some patients do not profit from or even deteriorate during treatment. Patient-focused psychotherapy research takes these differences between patients into account by focusing on the individual patient. The aim of this research approach is to analyze individual treatment courses in order to evaluate when and under which circumstances a generally effective treatment works for an individual patient. The goal is to identify evidence based clinical decision rules for the adaptation of treatment to prevent treatment failure. Patient-focused research has illustrated how different intake indicators and early change patterns predict the individual course of treatment, but they leave a lot of variance unexplained. The thesis at hand analyzed whether Ecological Momentary Assessment (EMA) strategies could be integrated into patient-focused psychotherapy research in order to improve treatment response prediction models. EMA is an electronically supported diary approach, in which multiple real-time assessments are conducted in participants" everyday lives. We applied EMA over a two-week period before treatment onset in a mixed sample of patients seeking outpatient treatment. The four daily measurements in the patients" everyday environment focused on assessing momentary affect and levels of rumination, perceived self-efficacy, social support and positive or negative life events since the previous assessment. The aim of this thesis project was threefold: First, to test the feasibility of EMA in a routine care outpatient setting. Second, to analyze the interrelation of different psychological processes within patients" everyday lives. Third and last, to test whether individual indicators of psychological processes during everyday life, which were assessed before treatment onset, could be used to improve prediction models of early treatment response. Results from Study I indicate good feasibility of EMA application during the waiting period for outpatient treatment. High average compliance rates over the entire assessment period and low average burdens perceived by the patients support good applicability. Technical challenges and the results of in-depth missing analyses are reported to guide future EMA applications in outpatient settings. Results from Study II shed further light on the rumination-affect link. We replicated results from earlier studies, which identified a negative association between state rumination and affect on a within-person level and additionally showed a) that this finding holds for the majority but not every individual in a diverse patient sample with mixed Axis-I disorders, b) that rumination is linked to negative but also to positive affect and c) that dispositional rumination significantly affects the state rumination-affect association. The results provide exploratory evidence that rumination might be considered a transdiagnostic mechanism of psychological functioning and well-being. Results from Study III finally suggest that the integration of indicators derived from EMA applications before treatment onset can improve prediction models of early treatment response. Positive-negative affect ratios as well as fluctuations in negative affect measured during patients" daily lives allow the prediction of early treatment response. Our results indicate that the combination of commonly applied intake predictors and EMA indicators of individual patients" daily experiences can improve treatment response predictions models. We therefore conclude that EMA can successfully be integrated into patient-focused research approaches in routine care settings to ameliorate or optimize individual care.
A lack of ability to inhibit prepotent responses, or more generally a lack of impulse control, is associated with several disorders such as attention-deficit/hyperactivity disorder and schizophrenia as well as general damage to the prefrontal cortex. A stop-signal task (SST) is a reliable and established measure of response inhibition. However, using the SST as an objective assessment in diagnostic or research-focused settings places significant stress on participants as the task itself requires concentration and cognitive effort and is not particularly engaging. This can lead to decreased motivation to follow task instructions and poor data quality, which can affect assessment efficacy and might increase drop-out rates. Gamification—the application of game-based elements in nongame settings—has shown to improve engaged attention to a cognitive task, thus increasing participant motivation and data quality.
Stress and pain are common experiences in human lives. Both, the stress and the pain system have adaptive functions and try to protect the organism in case of harm and danger. However, stress and pain are two of the most challenging problems for the society and the health system. Chronic stress, as often seen in modern societies, has much impact on health and can lead to chronic stress disorders. These disorders also include a number of chronic pain syndromes. However, pain can also be regarded as a stressor itself, especially when we consider how much patients suffer from long-lasting pain and the impact of pain on life quality. In this way, the effects of stress on pain can be fostered. For the generation and manifestation of chronic pain symptoms also learning processes such as classical conditioning play an important role. Processes of classical conditioning can also be influenced by stress. These facts illustrate the complex and various interactions between the pain and the stress systems. Both systems communicate permanently with each other and help to protect the organism and to keep a homeostatic state. They have various ways of communication, for example mechanisms related to endogenous opioids, immune parameters, glucocorticoids and baroreflexes. But an overactivation of the systems, for example caused by ongoing stress, can lead to severe health problems. Therefore, it is of great importance to understand these interactions and their underlying mechanisms. The present work deals with the relationship of stress and pain. A special focus is put on stress related hypocortisolism and pain processing, stress induced hypoalgesia via baroreceptor related mechanisms and stress related cortisol effects on aversive conditioning (as a model of pain learning). This work is a contribution to the wide field of research that tries to understand the complex interactions of stress and pain. To demonstrate the variety, the selected studies highlight different aspects of these interactions. In the first chapter I will give a short introduction on the pain and the stress systems and their ways of interaction. Furthermore, I will give a short summary of the studies presented in Chapter II to V and their background. The results and their meaning for future research will be discussed in the last part of the first chapter. Chronic pain syndromes have been associated with chronic stress and alterations of the HPA axis resulting in chronic hypocortisolism. But if these alterations may play a causal role in the pathophysiology of chronic pain remains unclear. Thus, the study described in Chapter II investigated the effects of pharmacological induced hypocortisolism on pain perception. Both, the stress and the pain system are related to the cardiovascular system. Increase of blood pressure is part of the stress reaction and leads to reduced pain perception. Therefore, it is important for the usage of pain tests to keep in mind potential interferences from activation of the cardiovascular system, especially when pain inhibitory processes are investigated. For this reason we compared two commonly and interchangeably used pain tests with regard to the triggered autonomic reactions. This study is described in chapter III. Chapter IV and V deal with the role of learning processes in pain and related influences of stress. Processes of classical conditioning play an important role for symptom generation and manifestation. In both studies aversive eyeblink conditioning was used as a model for pain learning. In the study described in Chapter IV we compared classical eyeblink conditioning in healthy volunteers to patients suffering from fibromyalgia, a chronic pain disorder. Also, differences of the HPA axis, as part of the stress system, were taken in account. The study of Chapter V investigated effects of the very first stress reaction, particularly rapid non-genomic cortisol effects. Healthy volunteers received an intravenous cortisol administration immediately before the eyeblink conditioning. Rapid effects have only been demonstrated on a cellular level and on animal behavior so far. In general, the studies presented in this work may give an impression of the broad variety of possible interactions between the pain and the stress system. Furthermore, they contribute to our knowledge about theses interactions. However, more research is needed to complete the picture.
Background
Identifying pain-related response patterns and understanding functional mechanisms of symptom formation and recovery are important for improving treatment.
Objectives
We aimed to replicate pain-related avoidance-endurance response patterns associated with the Fear-Avoidance Model, and its extension, the Avoidance-Endurance Model, and examined their differences in secondary measures of stress, action control (i.e., dispositional action vs. state orientation), coping, and health.
Methods
Latent profile analysis (LPA) was conducted on self-report data from 536 patients with chronic non-specific low back pain at the beginning of an inpatient rehabilitation program. Measures of stress (i.e., pain, life stress) and action control were analyzed as covariates regarding their influence on the formation of different pain response profiles. Measures of coping and health were examined as dependent variables.
Results
Partially in line with our assumptions, we found three pain response profiles of distress-avoidance, eustress-endurance, and low-endurance responses that are depending on the level of perceived stress and action control. Distress-avoidance responders emerged as the most burdened, dysfunctional patient group concerning measures of stress, action control, maladaptive coping, and health. Eustress-endurance responders showed one of the highest levels of action versus state orientation, as well as the highest levels of adaptive coping and physical activity. Low-endurance responders reported lower levels of stress as well as equal levels of action versus state orientation, maladaptive coping, and health compared to eustress-endurance responders; however, equally low levels of adaptive coping and physical activity compared to distress-avoidance responders.
Conclusions
Apart from the partially supported assumptions of the Fear-Avoidance and Avoidance-Endurance Model, perceived stress and dispositional action versus state orientation may play a crucial role in the formation of pain-related avoidance-endurance response patterns that vary in degree of adaptiveness. Results suggest tailoring interventions based on behavioral and functional analysis of pain responses in order to more effectively improve patients quality of life.
The search for relevant determinants of knowledge acquisition has a long tradition in educational research, with systematic analyses having started over a century ago. To date, a variety of relevant environmental and learner-related characteristics have been identified, providing a wide body of empirical evidence. However, there are still some gaps in the literature, which are highlighted in the current dissertation. The dissertation includes two meta-analyses summarizing the evidence on the effectiveness of electrical brain stimulation and the effects of prior knowledge on later learning outcomes and one empirical study employing latent profile transition analysis to investigate the changes in conceptual knowledge over time. The results from the three studies demonstrate how learning outcomes can be advanced by input from the environment and that they are highly related to the students" level of prior knowledge. It is concluded that the effects of environmental and learner-related variables impact both the biological and cognitive processes underlying knowledge acquisition. Based on the findings from the three studies, methodological and practical implications are provided, followed by an outline of four recommendations for future research on knowledge acquisition.
Software and interactive systems that adapt their behavior to the user are often referred to as Adaptive Systems. These systems infer the user's goals, knowledge or preferences by observing the user's actions. A synposis of 43 published studies demonstrated that only few of the existing systems are evaluated empirically. Most studies failed to show an advantage of the user model. A new framework is proposed that categorizes existing studies and defines an evaluation procedure which is able to uncover failures and maladaptations in the user model. It consists of four layers: evaluation of input data, evaluation of inference, evaluation of adaptation decision and evaluation of total interaction. Exemplary, the framework has been applied to the HTML-Tutor, an online-course that adapts to the learners' knowledge. Several empirical studies are described that test the accuracy of the user models, and explore the effects of adaptation to knowledge respectively prior knowledge. Generalization issues of the approach are discussed.