TY - JOUR A1 - Barteit, Sandra A1 - Hoepffner, Philip A1 - Huwendiek, Sören A1 - Karamagi, Angela A1 - Munthali, Charles A1 - Theurer, Antje A1 - Neuhann, Florian T1 - Self-directed e-learning at a tertiary hospital in Malawi - a qualitative evaluation and lessons learnt JF - GMS Journal for Medical Education N2 - Background: Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors. Project description: We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns. Method: From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling. Results: E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility. Conclusions: Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs. T2 - Selbstgesteuertes medizinisches Lernen via E-Learning an einem Lehrkrankenhaus in Malawi: Aufbau,Erkenntnisse und Erfahrungen KW - computer-assisted instruction KW - capacity KW - multimedia, KW - ICT KW - virtual patients KW - medical Education KW - understaffed KW - teaching hospital KW - Sub-saharan Africa Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150208 N1 - Deutschsprachige Version des Artikels ab Seite 8 des Dokuments. VL - 32 IS - 1 ER - TY - JOUR A1 - Zannas, Anthony S. A1 - Arloth, Janine A1 - Carrillo-Roa, Tania A1 - Iurato, Stella A1 - Röh, Simone A1 - Ressler, Kerry J. A1 - Nemeroff, Charles B. A1 - Smith, Alicia K. A1 - Bradley, Bekh A1 - Heim, Christine A1 - Menke, Andreas A1 - Lange, Jennifer F. A1 - Brückl, Tanja A1 - Ising, Marcus A1 - Wray, Naomi R. A1 - Erhardt, Angelika A1 - Binder, Elisabeth B. A1 - Mehta, Divya T1 - Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling JF - Genome Biology N2 - Background Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. Results We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Conclusions Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk. KW - aging KW - DNA methylation KW - gene expression KW - glucocorticoids KW - psychological stress KW - aging-related disease KW - epigenetics Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149865 VL - 16 IS - 266 ER - TY - JOUR A1 - Grünblatt, Edna A1 - Bartl, Jasmin A1 - Iuhos, Diana-Iulia A1 - Knezovic, Ana A1 - Trkulja, Vladimir A1 - Riederer, Peter A1 - Walitza, Susanne A1 - Salkovic-Petrisic, Melita T1 - Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction JF - Journal of Molecular Psychiatry N2 - Background The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal’s sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY). Methods Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA. Results SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs. Conclusion Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia. KW - spontaneously hypertensive rat KW - age KW - control strain KW - gender KW - glycogen synthase kinase-3β KW - insulin resistance KW - learning and memory Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149593 VL - 3 IS - 6 ER - TY - JOUR A1 - Boehme, Stephanie A1 - Ritter, Viktoria A1 - Tefikow, Susan A1 - Stangier, Ulrich A1 - Strauss, Bernhard A1 - Miltner, Wolfgang H. R. A1 - Straube, Thomas T1 - Neural correlates of emotional interference in social anxiety disorder JF - PLoS ONE N2 - Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients' interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self-referential and semantic processing of threat words in SAD. KW - threat-related stimuli KW - prefrontal cortex KW - stroop interference KW - processing bias KW - phobia KW - single subject KW - cognitive control KW - amygdala response KW - cytoarchitectonic maps KW - anterior cingulate cortex Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148534 VL - 10 IS - 6 ER - TY - JOUR A1 - Kleint, Nina I. A1 - Wittchen, Hans-Ulrich A1 - Lueken, Ulrike T1 - Probing the interoceptive network by listening to heartbeats: an fMRI study JF - PLoS ONE N2 - Exposure to cues of homeostatic relevance (i.e. heartbeats) is supposed to increase the allocation of attentional resources towards the cue, due to its importance for self-regulatory, interoceptive processes. This functional magnetic resonance imaging (fMRI) study aimed at determining whether listening to heartbeats is accompanied by activation in brain areas associated with interoception, particularly the insular cortex. Brain activity was measured with fMRI during cue-exposure in 36 subjects while listening to heartbeats vs. sinus tones. Autonomic markers (skin conductance) and subjective measures of state and trait anxiety were assessed. Stimulation with heartbeat sounds triggered activation in brain areas commonly associated with the processing of interoceptive information, including bilateral insular cortices, the inferior frontal operculum, and the middle frontal gyrus. A psychophysiological interaction analysis indicated a functional connectivity between the middle frontal gyrus (seed region) and bilateral insular cortices, the left amygdala and the supplementary motor area. The magnitude of neural activation in the right anterior insular cortex was positively associated with autonomic arousal. The present findings indicate that listening to heartbeats induced activity in areas of the interoception network as well as changes in psychophysiological arousal and subjective emotional experience. As this approach constitutes a promising method for studying interoception in the fMRI environment, a clinical application in anxiety prone populations should be addressed by future studies. KW - inferior parietal lobule KW - brain activation KW - cortex KW - awareness KW - perception KW - cardiovascular arousal KW - panic disorder KW - humans KW - anterior insula KW - emotional experience Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148330 VL - 10 IS - 7 ER - TY - JOUR A1 - Rivero, O A1 - Selten, MM A1 - Sich, S A1 - Popp, S A1 - Bacmeister, L A1 - Amendola, E A1 - Negwer, M A1 - Schubert, D A1 - Proft, F A1 - Kiser, D A1 - Schmitt, AG A1 - Gross, C A1 - Kolk, SM A1 - Strekalova, T A1 - van den Hove, D A1 - Resink, TJ A1 - Kasir, N Nadif A1 - Lesch, KP T1 - Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition JF - Translational Psychiatry N2 - Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo) phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13\(^{-/-}\) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13\(^{-/-}\) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism. KW - genome-wide association KW - deficit hyperactivity disorder KW - psychiatric disorders KW - neurodevelopmental disorders KW - synaptic plasticity KW - response inhibition KW - positive interneurons KW - T-cadherin KW - long-term potentiation KW - attention deficit/hyperactivity disorder Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145218 VL - 5 IS - e655 ER - TY - JOUR A1 - Beck, Katherina A1 - Ehmann, Nadine A1 - Andlauer, Till F. M. A1 - Ljaschenko, Dmitrij A1 - Strecker, Katrin A1 - Fischer, Matthias A1 - Kittel, Robert J. A1 - Raabe, Thomas T1 - Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons JF - Disease Models & Mechanisms N2 - Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling. KW - mrsk2 KO mouse KW - S6KII RSK KW - transmission KW - neuromuscular junction KW - synapse KW - MAPK signaling KW - axonal transport KW - motoneuron KW - RSK KW - Drosophila KW - mechanisms KW - plasticity KW - protein kinase KW - signal transduction pathway KW - mitochondrial transport KW - glutamate receptor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145185 VL - 8 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Popp, Sandy A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Göppner, Corinna A1 - Post, Antonia A1 - Reif, Andreas A1 - van den Hove, Daniel A1 - Strekalova, Tatyana A1 - Schmitt, Angelika A1 - Colaςo, Maria B. N. A1 - Sommer, Claudia A1 - Palme, Rupert A1 - Lesch, Klaus-Peter T1 - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice JF - Psychopharmacology N2 - Rationale While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Objective Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Results Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Conclusions Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality. KW - Serotonin KW - Tryptophan hydroxylase-2 (Tph2) KW - chronic stress KW - gene-by-environment interaction KW - anxiety KW - fear KW - depression KW - aggression Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586 VL - 232 SP - 2429 EP - 2441 ER - TY - JOUR A1 - Simon, Christian M. A1 - Rauskolb, Stefanie A1 - Gunnersen, Jennifer M. A1 - Holtmann, Bettina A1 - Drepper, Carsten A1 - Dombert, Benjamin A1 - Braga, Massimiliano A1 - Wiese, Stefan A1 - Jablonka, Sibylle A1 - Pühringer, Dirk A1 - Zielasek, Jürgen A1 - Hoeflich, Andreas A1 - Silani, Vincenzo A1 - Wolf, Eckhard A1 - Kneitz, Susanne A1 - Sommer, Claudia A1 - Toyka, Klaus V. A1 - Sendtner, Michael T1 - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy JF - Acta Neuropathologica N2 - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP. KW - Motor nerve biopsy KW - Diabetic polyneuropathy KW - Neuropathy KW - Neurotrophic factors KW - Axonal degeneration Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154569 VL - 130 SP - 373 EP - 387 ER - TY - JOUR A1 - Biernacka, J. M. A1 - Sangkuhl, K. A1 - Jenkins, G. A1 - Whaley, R. M. A1 - Barman, P. A1 - Batzler, A. A1 - Altman, R. B. A1 - Arolt, V. A1 - Brockmöller, J. A1 - Chen, C. H. A1 - Domschke, K. A1 - Hall-Flavin, D. K. A1 - Hong, C. J. A1 - Illi, A. A1 - Ji, Y. A1 - Kampman, O. A1 - Kinoshita, T. A1 - Leinonen, E. A1 - Liou, Y. J. A1 - Mushiroda, T. A1 - Nonen, S. A1 - Skime, M. K. A1 - Wang, L. A1 - Baune, B. T. A1 - Kato, M. A1 - Liu, Y. L. A1 - Praphanphoj, V. A1 - Stingl, J. C. A1 - Tsai, S. J. A1 - Kubo, M. A1 - Klein, T. E. A1 - Weinshilboum, R. T1 - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response JF - Translational Psychiatry N2 - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. KW - major depressive disorder KW - genetic variation KW - schizophrenia KW - neuregulin-1 KW - population KW - microcephalin 1 KW - susceptibility KW - metaanalysis KW - MCPH1 KW - loci Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223 VL - 5 IS - e553 ER -