Creativity and Psychopathology: An Interdisciplinary View.

Since ancient philosophy, extraordinary creativity is associated with mental disorders, emotional and cognitive destabilization, and melancholia. We here summarize the results of empirical and narrative studies and analyze the most prominent case of a highly creative person who suffered from dysthymia and major depression with suicidality. Hereby, we focus on the interaction of different phases of the creative process with "bipolar" personality traits. Finally, we offer an interdisciplinary interpretation of the creative dialectics between order and chaos. The results show that severe psychopathology inhibits creativity. Mild and moderate disorders can inspire and motivate creative work but are only leading to new and useful solutions when creators succeed in transforming their emotional instability and cognitive incoherence into stable and coherent forms. The cultural idea that creativity emerges in dialectical processes between order and chaos, is also to be found in the psychologic interplay of coherence and incoherence, and in neuro-scientific models of the dynamics between tightening and loosening of neuronal structures. Consequences are drawn for the psychotherapeutic treatment of persons striving for creativity.

[Changes in Sense of Coherence, Mental Distress and Satisfaction with Life and Studies in the Course of Psychosocial Counselling]. / Veränderungen von Kohärenzgefühl, Symptombelastung und Lebens- sowie Studienzufriedenheit im Verlauf psychosozialer Beratungen.

"Sense of coherence" (SOC) plays an essential role in the maintenance or recovery of health, according to the salutogenetic approach of Aaron Antonovsky. Empirical studies provide evidence of significant links between sense of coherence and different indicators of mental health. In the present study, the effectivity of an integrative counselling concept for the promotion of sense of coherence, reduction of mental distress and improvement of satisfaction with life was tested in a sample of 153 clients and patients. Correlations of SOC with mental distress and satisfaction with life and studies indicate a strong association. After psychosocial counselling according to the integrative ABCDE-model, significant pre-/post- changes with moderate to high effect sizes could be achieved. These findings bring important implications for the modifiability of the sense of coherence and provide evidence that the integrative ABCDE-model of psychosocial counseling might be effective. Correlations between ratings of the dimensions of the model and pre-/post changes are discussed.

[Effectiveness of integrative psychotherapeutic counseling for students]. / Effektivität integrativer psychotherapeutischer Beratung für Studierende.

In this first effectiveness study of psychotherapeutic counseling for students in German-speaking countries, the effectiveness of an integrative model of counseling was evaluated based on a sample of 151 clients. Effectiveness of integrative counseling according to the ABCDE-model was found to be high in comparison to other international studies in this area. Pre-post differences on measures of mental distress and satisfaction were significant and effect sizes were mostly moderate to high. A high percentage of clients improved statistically and clinically significant. Counselors' expert rating and diagnostics according to ICD-10 that have been included in contrast to previous effectiveness studies showed that clients suitable for the counseling setting get treated in the counseling center while more severely disturbed clients in terms of psychopathology or diagnosis get referred to outpatient treatment, drop out or object to provide post-data.

In vitro selection of functional lantipeptides.

In this report we present a method to identify functional artificial lantipeptides. In vitro translation coupled with an enzyme-free protocol for posttranslational modification allows preparation of more than 10(11) different lanthionine containing peptides. This diversity can be searched for functional molecules using mRNA-lantipeptide display. We validated this approach by isolating binders toward Sortase A, a transamidase which is required for virulence of Staphylococcus aureus. The interaction of selected lantipeptides with Sortase A is highly dependent on the presence of a (2S,6R)-lanthionine in the peptide and an active conformation of the protein.

Synthesis and conformational analysis of efrapeptins.

The efrapeptin family of peptide antibiotics produced by the fungus Tolypocladium niveum, and the neo-efrapeptins from the fungus Geotrichum candidumare inhibitors of F(1)-ATPase with promising antitumor, antimalaria, and insecticidal activity. They are rich in C(α)-dialkyl amino acids (Aib, Iva, Acc) and contain one ß-alanine and several pipecolic acid residues. The C-terminus bears an unusual heterocyclic cationic cap. The efrapeptins C-G and three analogues of efrapeptin C were synthesized using α-azido carboxylic acids as masked amino acid derivatives. All compounds display inhibitory activity toward F(1)-ATPase. The conformation in solution of the peptides was investigated with electronic CD spectroscopy, FT-IR spectroscopy, and VCD spectroscopy. All efrapeptins and most efrapeptin analogues were shown to adopt helical conformations in solution. In the case of efrapeptin C, VCD spectra proved that a 3(10)-helix prevails. In addition, efrapeptin C was conformationally studied in detail with NMR and molecular modeling. Besides NOE distance restraints, residual dipolar couplings (RDC) observed upon partial alignment with stretched PDMS gels were used for the conformational analysis and confirmed the 3(10)-helical conformation.

Trauma Psycho Social Support Plus and EMDR therapy for children and adolescents in a post-conflict setting: Mental health training in Kurdistan.

INTRODUCTION: This paper describes the implementation of a pilot project in Kurdistan / Northern Iraq on the use of EMDR in children in post-conflict settings. METHODS: A 4-field scheme aimed at patient stabilisation was taught to social workers for the application with children and adolescents in Northern Iraq. If possible, the stabilisation was followed by procedures aimed at memory reprocessing or modification within the eightphase EMDR protocol and (in all cases) with further care. RESULTS: An initial assessment of the children and adolescents themselves revealed significant traumatic burden. The subjective distress was reduced when the rescue and the present situation were reflected age-appropriately with the help of pictures and sketches. For six children and adolescents, a post-stabilisation treatment within EMDR therapy was offered. The first results in this very small sample were encouraging providing support for a fullscale controlled study.

Health-related quality of life after breast-conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovoltage X-rays.

BACKGROUND: Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach during breast-conserving surgery (BCS). IORT can be used either as a tumor bed boost followed by external-beam radiotherapy (EBRT) or as a single treatment. In a matched-pair study, we assessed quality of life (QoL) in 69 patients with early breast cancer treated with BCS and/or IORT and/or EBRT. METHODS: Patients were matched for age and time since BCS. IORT was provided with 50 kV x-rays (Intrabeam) delivering 20 Gy at the applicator surface. EBRT (46 to 50 Gy in 2-Gy fractions in the IORT with EBRT group, and 56 Gy in 2-Gy fractions in the EBRT group) was initiated after completion of wound healing and/or chemotherapy. The mailed questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 and BR23, FACT-F, HADS, Body Image Scale, and Rosenberg Self-Esteem Scale. At 18 to 70 months' follow-up (median 47 months), all patients were disease free. RESULTS: We found only a few differences between the three groups. There was a trend toward more pain (mean ± standard deviation; 42.8 ± 32.9 vs. 27.5 ± 34.7) and reduced QoL (57.6 ± 20.7 vs. 70.3 ± 23.9) after IORT with EBRT compared with EBRT, respectively. IORT patients reported comparable QoL (70.3 ± 23.0), and less breast symptoms and body image concerns compared to EBRT (8.6 ± 12.3 vs. 19.2 ± 23.8, and 1.7 ± 3.3 vs. 3.4 ± 4.4, respectively). IORT alone resulted in significantly fewer breast symptoms (8.6 ± 12.3; P = 0.012) and less pain (23.9 ± 24.5, P = 0.041) compared with IORT with EBRT (26.1 ± 27.6; 42.8 ± 32.9, respectively). CONCLUSIONS: Patients with early breast cancer after BCS and IORT with or without EBRT present with comparable QoL like patients receiving EBRT without a boost. IORT patients show the lowest rate of breast symptoms.

A transcription-dependent increase in miniature EPSC frequency accompanies late-phase plasticity in cultured hippocampal neurons.

BACKGROUND: The magnitude and longevity of synaptic activity-induced changes in synaptic efficacy is quantified by measuring evoked responses whose potentiation requires gene transcription to persist for more than 2-3 hours. While miniature EPSCs (mEPSCs) are also increased in amplitude and/or frequency during long-term potentiation (LTP), it is not known how long such changes persist or whether gene transcription is required. RESULTS: We use whole-cell patch clamp recordings from dissociated hippocampal cultures to characterise for the first time the persistence and transcription dependency of mEPSC upregulation during synaptic potentiation. The persistence of recurrent action potential bursting in these cultures is transcription-, translation- and NMDA receptor-dependent thus providing an accessible model for long-lasting plasticity. Blockade of GABAA-receptors with bicuculline for 15 minutes induced action potential bursting in all neurons and was maintained in 50-60% of neurons for more than 6 hours. Throughout this period, the frequency but neither the amplitude of mEPSCs nor whole-cell AMPA currents was markedly increased. The transcription blocker actinomycin D abrogated, within 2 hours of burst induction, both action potential bursting and the increase in mEPSCs. Reversible blockade of action potentials during, but not after this 2 hour transcription period suppressed the increase in mEPSC frequency and the recovery of burst activity at a time point 6 hours after induction. CONCLUSION: These results indicate that increased mEPSC frequency persists well beyond the 2 hour transcription-independent phase of plasticity in this model. This long-lasting mEPSC upregulation is transcription-dependent and requires ongoing action potential activity during the initial 2 hour period but not thereafter. Thus mEPSC upregulation may underlie the long term, transcription-dependent persistence of action potential bursting. This provides mechanistic insight to link gene candidates already identified by gene chip analysis to long lasting plasticity in this in vitro model.

Facilitated phospholipid translocation in vesicles and nucleated cells using synthetic small molecule scramblases.

A series of 16 synthetic scramblase candidates were prepared from a tris(aminoethyl)amine (TREN) scaffold and evaluated for ability to facilitate translocation of fluorescent phospholipid probes across vesicle membranes and endogenous phosphatidylserine across the plasma membrane of nucleated cells. More than half of the compounds were found to greatly accelerate phospholipid translocation in vesicles. However, they were generally unable to induce large increases in the amount of phosphatidylserine on the surface of nucleated mammalian cells, which contrasts with previous results using erythrocytes. Fluorescence microscopy showed that the synthetic scramblases are rapidly trafficked out of the cell plasma membrane and into the membranes of internal organelles. Future molecular designs of synthetic scramblases should focus on structures that are more amphiphilic, a structural feature that is expected to increase plasma membrane residence time.

Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability.

Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing. Both acute and long-lasting phases of neuroprotection in the face of apoptotic or excitotoxic insults are dependent on this firing enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box subgroup O (FOXO) export and glycogen synthase kinase 3beta (GSK3beta) inhibition and cAMP response element-binding protein-dependent (CREB-dependent) activation of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of NMDA via this action potential-dependent route. In contrast, NMDA doses on the other side of the toxicity threshold do not favor synaptic NMDA receptor activation because they strongly suppress firing rates below baseline. The classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: via increased firing the synaptic signaling dominates at low doses, whereas firing becomes suppressed and extrasynaptic signaling dominates as the toxicity threshold is crossed.

Long term recordings with microelectrode arrays: studies of transcription-dependent neuronal plasticity and axonal regeneration.

Substrate integrated microelectrode arrays (MEAs) offer an alternative to classical electrophysiological methods like the patch clamp technique for recording the electrical activity from cells and tissue of neuronal or cardiac origin. Since its introduction 30 years ago, this technology has made possible the repeated simultaneous recording from multiple sites in a non-invasive manner. The MEA technology can be applied to any electrogenic cells or tissue (i.e., central and peripheral neurons, heart cells, and muscle cells), either as cultures or acute cell or slice preparations. The combination of culture techniques and MEAs offers the possibility to monitor the activity of a designed specimen over extended periods of time, up to several months. Furthermore, recording the electrical activity of distributed regions of a preparation yields information on spatial effects that might go undetected with other recording methods. Development, plasticity, and regeneration are examples of applications that could especially benefit from long term monitoring of neuronal activity, as they concern processes that develop over extended periods of time. Here we highlight recent MEA studies on signal regulation of neuronal network behavior and axonal regeneration. We illustrate the use of MEAs to study long term potentiation (LTP) and summarize the advantages of MEA technology over traditional electrophysiological methods for studies aimed at understanding the transcription-dependent late phase of plasticity.

Locking GTPases covalently in their functional states.

GTPases act as key regulators of many cellular processes by switching between active (GTP-bound) and inactive (GDP-bound) states. In many cases, understanding their mode of action has been aided by artificially stabilizing one of these states either by designing mutant proteins or by complexation with non-hydrolysable GTP analogues. Because of inherent disadvantages in these approaches, we have developed acryl-bearing GTP and GDP derivatives that can be covalently linked with strategically placed cysteines within the GTPase of interest. Binding studies with GTPase-interacting proteins and X-ray crystallography analysis demonstrate that the molecular properties of the covalent GTPase-acryl-nucleotide adducts are a faithful reflection of those of the corresponding native states and are advantageously permanently locked in a defined nucleotide (that is active or inactive) state. In a first application, in vivo experiments using covalently locked Rab5 variants provide new insights into the mechanism of correct intracellular localization of Rab proteins.

Additional costs for preventing the spread of methicillin-resistant Staphylococcus aureus and a strategy for reducing these costs on a surgical ward.

OBJECTIVE: To determine the added costs of hygienic measures (barrier precautions, isolation, and decontamination) required for MRSA carriers in German hospitals and possible strategies for cost reduction. DESIGN: On a septic surgical ward caring for 35% of all MRSA cases in a university hospital (1,182 beds), additional costs for personnel time and materials were calculated and medical charts of all MRSA cases admitted to the ward during 1 year were analyzed retrospectively. Twelve of the ward's 13 beds were located in rooms with at least 2 beds. PATIENTS: Four hundred ninety-eight MRSA carrier hospital-days (of 20 MRSA cases) could be assessed. All patients (80% men, 50% older than 74.5 years) had broken skin. RESULTS: In 95% of the cases, microbiological findings suggested transmission of MRSA during the current or a previous stay on this ward. The study found total avoidable costs of approximately 142,794.01 euros in 1 year, averaging 371.95 euros for one MRSA patient hospital-day and 9,261.56 euros per MRSA case. The most expensive single measure was blocked beds in multibed rooms (305.75 euros/day), which accounted for 82% of the extra costs. Costs most likely were underestimated. CONCLUSIONS: Daily additional case costs amounted to 96% of social security payments. Blocked beds in multibed rooms accounted for more than 80% of these excess costs. Isolation has been scientifically validated and is required by law in Germany. Building an adequate number of single-bed rooms should help prevent spread and would greatly lower the added costs of infection.

Functional re-establishment of the perforant pathway in organotypic co-cultures on microelectrode arrays.

Co-cultures of entorhinal cortex (EC) and dentate gyrus (DG) explants are a useful model system to study the formation and stabilization of axonal projections. We adapted this model system to EC-DG co-cultures on microelectrode arrays (MEA) for the characterization of axonal projections on a functional level for days and weeks. EC and DG explants were placed on MEA to allow for the reconstitution of perforant pathway projections. Connections formed were characterized by morphological and electrophysiological analyses to verify characteristic features of perforant pathway signal transmission. Morphological analysis reveals proper projection of EC neurons into the molecular layer of the DG. Examination of synaptic transmission after high frequency stimulation imply unidirectional connections that used glutamate receptors of the AMPA/kainate type as main mediators of excitatory signal transmission. The system was evaluated by the introduction of the NCAM binding peptide C3d. In accordance with in vivo and in vitro experiments C3d modulated signal transmission by NCAM-related mechanisms resulting in morphological re-arrangements.

Disease management programs for patients with COPD in Germany: a longitudinal evaluation of routinely collected patient records.

INTRODUCTION: The primary aim of the disease management program (DMP) for patients with COPD is to improve health outcomes and thereby to reduce overall costs. Six years after its introduction in Germany, no consensus has yet been reached as to whether the DMP has been effective in reaching these goals. The objective of the study was an evaluation of the DMP for COPD in Bavaria using routinely collected subject medical records. METHODS: A longitudinal population-based study, comparing the total DMP population of up to 86,560 patients with a stable cohort of 17,549 subjects over a period of 5 years. The effect of subject dropout in the cohort is further estimated by means of inverse probability weighting. RESULTS: The proportion of subjects in the total population who were prescribed and received treatment with oral corticosteroids declined at a constant rate of 1.0% per year (P < .001). The proportion of subjects who were given a prescription for theophylline decreased at a constant rate of 2.0% per year (P < .001). By 2012, 15.6% of the total population and 26% of the cohort had undergone self-management education. While the proportion of smokers in the total population remained constant because of the effect of newly enrolled subjects, the proportion of smokers decreased significantly even after dropout adjustment, from 29% to 21%. The occurrence of exacerbations decreased steadily at a rate of 0.9% (total population) or 0.7% (cohort) per year. While the occurrence of emergency hospital admissions decreased in the total population, an increase was observed within the cohort. CONCLUSIONS: Summarizing all results leads to the suggestion that the German DMP for COPD has been effective in enhancing the quality of care in regard to an improved adherence to guidelines, pharmacotherapy, exacerbations, and self-management education. However, the DMP was not able to prevent an increase in emergency hospital admissions for the stable population in the cohort.

The effects of theophylline on hospital admissions and exacerbations in COPD patients: audit data from the Bavarian disease management program.

BACKGROUND: Theophylline is often used to treat chronic obstructive pulmonary disease (COPD). Current evidence leaves the effectiveness and safety of this drug open to question. Thus, we evaluated the effectiveness of theophylline on the rate of hospitalizations and disease exacerbations by examining routine data from the ambulatory disease management program for COPD in the German state of Bavaria. METHOD: Data sets from a total of 30 330 patients were examined. Logistic regression models were used to calculate propensity scores that controlled for baseline characteristics. These propensity scores, in turn, were used to create comparable patient groups, which were observed for a median follow-up time of 9 quarters (the theophylline group) and 10 quarters (the control group). RESULTS: 1496 patients with first prescription of theophylline were matched with 1496 patients with no record of theophylline treatment. 1. The probability of suffering an exacerbation during the period of observation, was 33.5% for the control group and 43.4% for the theophylline group [hazard ratio (HR) 1.41; 95% confidence interval (CI) 1.24 to 1.60], yielding a number needed to harm (NNH) of 11 (95% CI 7.7 to 20.9). The probability for hospitalization was 11.4% for the control group and 17.4% of the theophylline group (HR 1.61; 95% CI 1.29 to 2.01), yielding a NNH of 17 (95%CI 11.0-34.5). CONCLUSION: Treatment with theophylline is associated with an elevated incidence of exacerbations and hospitalizations. The therapeutic value of this drug should be reconsidered and investigated in further studies.

Disease management programs for patients with asthma in Germany: a longitudinal population-based study.

BACKGROUND: The primary aim of the disease management program (DMP) for patients with asthma is to improve health outcomes and to reduce costs. Five years after its introduction in Germany, no consensus has yet been reached as to whether DMP has been effective in reaching these goals. OBJECTIVE: To evaluate the DMP for asthma in Bavaria using routinely collected subject medical records. METHODS: A longitudinal population-based study encompassing over 100,000 DMP participants between 2006 (when the program began) and 2010. RESULTS: The prescription rate of oral corticosteroids dropped from 15.7% in 2006 to 13.6% in 2007, and again from 7.5% in 2008 to 5.9% in 2010 (P < .001). The proportion of subjects with asthma self-management education increased from 4.4% to 23.4% (P < .001). Utilization of an individual asthma action plan increased from 40.3% to 69.3% (P < .001). Hospitalization decreased from 2.8% to 0.7% (P < .001). CONCLUSIONS: In the first 4 years of DMP there was an improvement in pharmacotherapy and patient self management. The proportion of subjects requiring hospitalization decreased. Our results suggest that the German DMP for asthma has been effective in enhancing the quality of care in regard to an improved symptom frequency, adherence to guidelines, pharmacotherapy, and hospitalization.

Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: results from the randomized phase III trial TARGIT-A.

BACKGROUND: Intraoperative radiotherapy (IORT) is a new treatment approach for early stage breast cancer. This study reports on the effects of IORT on radiation-related quality of life (QoL) parameters. METHODS: Two hundred and thirty women with stage I-III breast cancer (age, 31 to 84 years) were entered into the study. A single-center subgroup of 87 women from the two arms of the randomized phase III trial TARGIT-A (TARGeted Intra-operative radioTherapy versus whole breast radiotherapy for breast cancer) was analyzed. Furthermore, results were compared to non-randomized control groups: n = 90 receiving IORT as a tumor bed boost followed by external beam whole breast radiotherapy (EBRT) outside of TARGIT-A (IORT-boost), and n = 53 treated with EBRT followed by an external-beam boost (EBRT-boost). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 (QLQ-C30) and BR23 (QLQ-BR23). The mean follow-up period in the TARGIT-A groups was 32 versus 39 months in the non-randomized control groups. RESULTS: Patients receiving IORT alone reported less general pain (21.3 points), breast (7.0 points) and arm (15.1 points) symptoms, and better role functioning (78.7 points) as patients receiving EBRT (40.9; 19.0; 32.8; and 60.5 points, respectively, P < 0.01). Patients receiving IORT alone also had fewer breast symptoms than TARGIT-A patients receiving IORT followed by EBRT for high risk features on final pathology (IORT-EBRT; 7.0 versus 29.7 points, P < 0.01). There were no significant differences between TARGIT-A patients receiving IORT-EBRT compared to non-randomized IORT-boost or EBRT-boost patients and patients receiving EBRT without a boost. CONCLUSIONS: In the randomized setting, important radiation-related QoL parameters after IORT were superior to EBRT. Non-randomized comparisons showed equivalent parameters in the IORT-EBRT group and the control groups.

Intraoperative radiotherapy during breast-conserving surgery using a miniature x-ray generator (Intrabeam®): theoretical and experimental background and clinical experience.

Breast cancer is currently the most frequent indication for intraoperative radiotherapy with increasing numbers worldwide. Intraoperative radiotherapy can be used as a tumor bed boost followed by whole breast radiotherapy, or as a distinct form of accelerated partial breast irradiation in selected patients. This article summarizes the theoretical background including pattern of recurrence and distribution of tumor cell foci in the breast and discusses the rationale for intraoperative radiotherapy, especially using a miniature x-ray generator (Intrabeam(®)). The concepts of how to avoid geographic and temporal miss by giving radiotherapy during surgery to the open wound cavity are described. Experimental and clinical experience is presented based on in vitro experiments and more than 300 treated patients in a single department with mature follow-up.