Psychische Belastungsfaktoren bei Patienten mit chronischer Hepatitis-C-Infektion während und außerhalb einer antiviralen Interferontherapie

I) Hintergrund Die chronische Hepatitis-C-Infektion stellt global ein wesentliches Gesundheitsproblem dar. Diese Virusinfektion kann bei unbehandelten Patienten zur Leberzirrhose und im weiteren Verlauf bis hin zur Entwicklung eines hepatozellulären Karzinoms führen. Die einzige Behandlungsoption mit der Aussicht auf dauerhafte Viruselimination besteht in modernen Kombinationstherapien, die das Zytokin Interferon alfa enthalten. Wesentliche Merkmale sind – neben inzwischen sehr hohen Ansprechraten – eine Behandlungsdauer zwischen 24 und 48 Wochen, hohe Therapiekosten und ein Nebenwirkungsprofil, das sowohl somatische als auch psychopathologische Symptome umfassen kann. II) Untersuchungsgegenstand und Fragestellungen Sowohl die chronische Virusinfektion an sich als auch die aktuell verfügbaren Therapieverfahren bergen ein erhebliches psychisches Belastungspotential. Hauptgegenstand dieser Dissertation ist die Erfassung der psychologischen Aspekte der Erkrankung und der psychischen und psychopathologischen Nebenwirkungen einer Interferonbehandlung. Wesentliche bearbeitete Fragestellungen sind: - Welchen Belastungsfaktoren sind Hepatitis-C-Patienten bereits ohne aktuelle antivirale Interferontherapie ausgesetzt bzw. welche psychopathologischen Symptome zeigen diese Patienten? - Wie ist der zeitliche Verlauf psychopathologischer Symptome bei Hepatitis-C-Patienten vor, während und nach einer antiviralen Therapie? - Wie wirksam und wie sicher ist eine medikamentöse Behandlung der Interferon-induzierten Depression mit selektiven Serotonin-Wiederaufnahmehemmern (SSRI) unter Fortführung der antiviralen Therapie? III) Patienten und Methoden Studienteilnehmer waren Hepatitis-C-Patienten, die sich ambulant vorstellten bzw. in unsere Ambulanz überwiesen wurden und die jeweiligen Einschlusskriterien erfüllten. Zu den wichtigsten verwendeten psychometrischen Selbstbeurteilungsskalen zählen: HADS (Depressivität, Angst), SCL-90-R (psychopathologische Symptome), SF-36 (Lebensqualität) und FKV (Krankheitsverarbeitung). IV) Wesentliche Forschungsergebnisse Bereits ohne Einfluss des Zytokins Interferon bestehen starke Krankheits-assoziierte psychische bzw. psychosoziale Belastungen der Patienten, die sich in einem erhöhten Depressionsrisiko ausdrücken. Die erhobenen Depressionsscores stehen in signifikantem Zusammenhang mit der Erkrankungsdauer und den individuell bestehenden Optionen und Erfolgsaussichten einer antiviralen Interferontherapie. Prospektive Erfassungen der Auftretenshäufigkeit klinisch relevanter Interferon-assoziierter Depressionen ergeben Raten von ca. 30 %. Diese Größenordnung wurde sowohl in einer eigenen prospektiven Studie als auch im Rahmen einer vorgestellten Übersichtsarbeit bestätigt. Die Umstellung der verwendeten Formulierung des Medikaments von herkömmlichem Interferon alfa auf die pegylierte Variante brachte keine Verbesserung der Verträglichkeit z.B. im Hinblick auf die interferonassoziierte Depression. Ein rechtzeitiges Erkennen der entsprechenden Symptome vorausgesetzt, ist die antidepressive Behandlung der Interferon-assoziierten Depression mit Hilfe von selektiven Serotonin-Reuptake-Inhibitoren auch ohne generelle Prophylaxe sehr effektiv und sicher möglich. V) Diskussion Empfohlen wird ein engmaschiges psychometrisches Monitoring aller Hepatitis-C-Patienten im Therapieverlauf. Ausführliche Aufklärung, enger Arzt-Patienten-Kontakt während der Therapie, sowie die Betreuung durch einen festen Ansprechpartner während der bis zu einem Jahr dauernden Therapie sind wichtige Rahmenbedingungen für eine solche Behandlung. Für die medikamentöse Behandlung der Interferon-induzierten Depression gilt: Bei besonderer Indikation (z.B. Interferon-assoziierte Depression bei früheren Therapieversuchen) sollte eine SSRI-Sekundärprophylaxe in Betracht gezogen werden. Ansonsten ist eine entsprechende SSRI-Intervention beginnend mit dem Einsetzen einer klinisch relevanten Depression ausreichend

Lebenswelten und Sozialisationsbedingungen jugendlicher Baptisten: Ethnographie einer evangelikalen Aussiedlergemeinde

'Der Aufsatz thematisiert die Lebenswelten und Sozialisationsbedingungen von Jugendlichen in streng religiösen Aussiedlergemeinden. Die Erkenntnisse basieren auf einer einjährigen ethnografischen Feldforschung in einer baptistischen Religionsgemeinschaft. Dabei wird fokussiert, wie diese Gemeinden versuchen, sich von der modernen Gesellschaft abzugrenzen und die Jugendlichen zu aktiven Mitgliedern zu erziehen. Der Gemeindepädagogik als methodische Sozialisation der nachwachsenden Generation kommt besondere Aufmerksamkeit zu. Ein weiterer Schwerpunkt des Aufsatzes bezieht sich auf die Beobachtung, dass die Jugendlichen sozialen Wandel in der untersuchten Gemeinde vorantreiben. Sie ordnen sich bestimmten strengen Gemeinderegeln nicht einfach unter, sondern stellen sie in Frage. Es kann aufgezeigt werden, dass sich trotz der religiösen Abgrenzung Einflüsse der modernen Gesellschaft und Außenorientierungen der Jugendlichen nicht verhindern lassen.' (Autorenreferat)'The article broaches the theme of the life worlds and socialisation conditions of adolescents in strict religious ethnic German immigrant communities. The findings are based on ethnographical field research in a Baptist religious community over the duration of one year. It focuses on how the community attempts to disassociate itself from modern society and to encourage the adolescents in becoming active members of the community. The education by the community as a form of methodological socialisation of the upcoming generation will be highlighted. A further focal point of the article relates to the observation that the adolescents themselves advance the social change within the researched community. They do not simply subordinate themselves to the specific and strict community rules; rather they bring the rules into question. It can be shown that despite the religious boundaries set, both the influence of modern society and the outward orientation of the adolescents cannot be impeded.' (author's abstract)

The Cards and Lottery Task: Validation of a New Paradigm Assessing Decision Making Under Risk in Individuals With Severe Obesity

Background: A growing body of research demonstrated impaired executive functions in individuals with severe obesity, including increased sensitivity to reward and impulsive decision making under risk conditions. For the assessment of decision making in patients with severe obesity, studies widely used the Iowa Gambling Task (IGT) or the Delay Discounting Task (DDT), which cover short-term or long-term consequences of decisions only. A further development originating from the field of addiction research is the Cards and Lottery Task (CLT), in which each decision made has conflicting immediate and longterm consequences at the same time. The present study aimed to validate the CLT in individuals with severe obesity. Methods: Patients with severe obesity (N = 78, 67% women, 42.9 ± 10.4 years old, body mass index of 48.1 ± 8.3 kg/m2) were included. Convergent validity was evaluated using the computerized Delay Discounting Task and well-established self-report questionnaires assessing different aspects of impulsivity. For discriminant validity, CLT performance was compared between symptom groups characterized by high versus low impulsivity. The task’s clinical validity was evaluated based on associations with general and eating disorder psychopathology, and body mass index. Test-retest reliability was determined by administering the CLT in n = 31 participants without weight-loss treatment one year later. The task’s sensitivity to change due to weight loss was evaluated by retesting n = 32 patients one year after receiving obesity surgery. Results: The number of advantageous decisions in the CLT was significantly positively associated with delay discounting and effortful control, and significantly negatively correlated with behavioral impulsivity. CLT performance differed significantly between individuals with and without symptoms of attention-deficit/hyperactivity disorder and between samples with severe obesity and healthy controls. Clinically, CLT performance was significantly associated with general, but not eating disorder psychopathology. The CLT showed moderate test-retest reliability after one year in weight-stable individuals and was sensitive to change in those undergoing obesity surgery. Conclusions: This study identified the CLT to be a highly promising, new complex measure of short- and long-term decision making with good reliability and validity in individuals with severe obesity. Future studies should assess its association with the IGT and predictive value for real-life health behavior

Changes in visual attention towards food cues after obesity surgery: An eye-tracking study

Research documented the effectiveness of obesity surgery (OS) for long-term weight loss and improvements in medical and psychosocial sequelae, and general cognitive functioning. However, there is only preliminary evidence for changes in attentional processing of food cues after OS. This study longitudinally investigated visual attention towards food cues from pre- to 1-year post-surgery. Using eye tracking (ET) and a Visual Search Task (VST), attentional processing of food versus non-food cues was assessed in n = 32 patients with OS and n = 31 matched controls without weight-loss treatment at baseline and 1-year follow-up. Associations with experimentally assessed impulsivity and eating disorder psychopathology and the predictive value of changes in visual attention towards food cues for weight loss and eating behaviors were determined. During ET, both groups showed significant gaze duration biases to non-food cues without differences and changes over time. No attentional biases over group and time were found by the VST. Correlations between attentional data and clinical variables were sparse and not robust over time. Changes in visual attention did not predict weight loss and eating disorder psychopathology after OS. The present study provides support for a top-down regulation of visual attention to non-food cues in individuals with severe obesity. No changes in attentional processing of food cues were detected 1-year post-surgery. Further studies are needed with comparable methodology and longer follow-ups to clarify the role of biased visual attention towards food cues for long-term weight outcomes and eating behaviors after OS

Cytotoxic Efficiency of Human CD8+ T Cell Memory Subtypes

Immunological memory is important to protect humans against recurring diseases. Memory CD8+ T cells are required for quick expansion into effector cells but also provide immediate cytotoxicity against their targets. Whereas many functions of the two main cytotoxic subtypes, effector memory CD8+ T cells (TEM) and central memory CD8+ T cells (TCM), are well defined, single TEM and TCM cell cytotoxicity has not been quantified. To quantify cytotoxic efficiency of TEM and TCM, we developed a FRET-based single cell fluorescent assay with NALM6 target cells which allows analysis of target cell apoptosis, secondary necrosis following apoptosis, and primary necrosis after TEM- or TCM-target cell contact. Both, single cell and population cytotoxicity assays reveal a higher cytotoxic efficiency of TEM compared to TCM, as quantified by target cell apoptosis and secondary necrosis. Perforin, granzyme B, FasL, but not TRAIL expression are higher in TEM compared to TCM. Higher perforin levels (likely in combination with higher granzyme levels) mediate higher cytotoxic efficiency of TEM compared to TCM. Both, TEM and TCM need the same time to find their targets, however contact time between CTL and target, time to induce apoptosis, and time to induce secondary necrosis are all shorter for TEM. In addition, immune synapse formation in TEM appears to be slightly more efficient than in TCM. Defining and quantifying single TEM and TCM cytotoxicity and the respective mechanisms is important to optimize future subset-based immune therapies

Identifying pre-bariatric subtypes based on temperament traits, emotion dysregulation, and disinhibited eating: A latent profile analysis

Objective: The efficacy of bariatric surgery has been proven; however, a subset of patients fails to achieve expected long-term weight loss postoperatively. As differences in surgery outcome may be influenced by heterogeneous psychological profiles in pre-bariatric patients, previous subtyping models differentiated patients based on temperament traits. The objective of the present study was to expand these models by additionally considering emotion dysregulation and disinhibited eating behaviors for subtyping, as these factors were associated with maladaptive eating behaviors and poor post-bariatric weight loss outcome. Methods: Within a prospective multicenter registry, N = 370 pre-bariatric patients were examined using interview and self-report questionnaires. A latent profile analysis was performed to identify subtypes based on temperament traits, emotion dysregulation, and disinhibited eating behaviors. Results: Five pre-bariatric subtypes were identified with specific profiles regarding self control, emotion dysregulation, and disinhibited eating behaviors. Subtypes were associated with different levels of eating disorder psychopathology, depression, and quality of life. The expanded model increased variance explanation compared to temperament-based models. Conclusion: By adding emotion dysregulation and disinhibited eating behaviors to previous subtyping models, specific pre-bariatric subtypes emerged with distinct psychological deficit patterns. Future investigations should test the predictive value of these subtypes for post bariatric weight loss and health-related outcomes

Role of NOD2/CARD15 in coronary heart disease

<p>Abstract</p> <p>Background:</p> <p>Bacterial DNA has been repeatedly detected in atheromatous lesions of coronary heart disease (CHD) patients. Phylogenetic signatures in the atheroma lesions that are similar to those of bacterial biofilms on human barrier organs, including the respiratory or gastrointestinal tract, raise the question of a defective barrier function in CHD. NOD2 plays a major role in defense against bacterial invasion. Genetic variation in the <it>CARD15 </it>gene, which encodes NOD2, was previously shown to result in a barrier defect that causes chronic inflammatory disorders (e.g. Crohn disease). In the present study, we investigated the possible involvement of NOD2/<it>CARD15 </it>in the pathology of CHD by <it>i) </it>analyzing the local expression of NOD2 in atherectomy versus healthy tissue (n = 5 each) using histochemical immunofluorescence and <it>ii) </it>by testing the three major functional <it>CARD15 </it>variants (R702W, G908R and 1007fs) for association with early-onset CHD in 900 German patients and 632 healthy controls.</p> <p>Results:</p> <p>In atherectomy tissue of CHD patients, NOD2 was detected in inflammatory cells at the luminal sides of the lesions. However, the allele and genotype frequencies of the three major <it>CARD15 </it>polymorphisms did not differ between CHD patients and controls.</p> <p>Conclusion:</p> <p>The NOD2 up-regulation in atheroma lesions indicates an involvement of this protein in the pathology of CHD. Although NOD2 could be important in local immune response mechanisms, none of the analyzed <it>CARD15 </it>variants seem to play a significant role in the etiology of CHD.</p

Exercise, Arterial Crosstalk-Modulation, and Inflammation in an Aging Population: The ExAMIN AGE Study

Background: Age is a key determinant for the development of cardiovascular disease and higher age coincides with an increased prevalence of obesity and physical inactivity. The study examines the influence of physical activity on aging processes of physiological systems focusing on the mechanisms of vascular aging. Methods/Design: The study consists of two parts. The cross-sectional approach aims at examining the association of physical fitness and cardiovascular risk with large and small artery function in healthy older active (HOA, n = 40) and sedentary (HOS, n = 40) persons as well as older sedentary individuals with increased cardiovascular risk (OSR, n = 80) aged 50–80 years. In the interventional approach, the OSR group is randomized into a 12-week walking-based high intensity interval training (HIIT) group or a control condition, aiming at examining the effects of HIIT on arterial function in diseased older adults. Active lifestyle is defined as &gt;9 metabolic equivalent of task (MET) per week and sedentary as ≤3 MET/week. Inclusion criteria for OSR are overweight or obesity (body mass index ≥30 kg/m2) plus at least one additional cardiovascular risk factor. The primary outcome is arterial stiffness as determined by aortic pulse wave velocity (PWV). The secondary outcomes are retinal arterial and venous diameters. Further cardiovascular assessments include peripheral PWV, central haemodynamics, retinal endothelial function, carotid intima media thickness, cardiac strain and diastolic function as well as autonomic function and inflammation. Physical fitness is measured by a treadmill-based spiroergometry to determine peak oxygen uptake. Discussion: The aim of the study is to demonstrate the importance of and need for specific physical activity programs for seniors to achieve healthier aging as a longterm goal. Vascular function defines disease- and age-related end organ damage and represents the potential to contain health at older age. This research will identify cardiovascular biomarkers that best resemble underlying cardiovascular risk in age and disease. The integrated approach will help define new recommendations for treatment guidance of exercise therapy in an aging population

The ABC transporter MsbA adopts the wide inward-open conformation in E. coli cells

Membrane proteins are currently investigated after detergent extraction from native cellular membranes and reconstitution into artificial liposomes or nanodiscs, thereby removing them from their physiological environment. However, to truly understand the biophysical properties of membrane proteins in a physiological environment, they must be investigated within living cells. Here, we used a spin-labeled nanobody to interrogate the conformational cycle of the ABC transporter MsbA by double electron-electron resonance. Unexpectedly, the wide inward-open conformation of MsbA, commonly considered a nonphysiological state, was found to be prominently populated in Escherichia coli cells. Molecular dynamics simulations revealed that extensive lateral portal opening is essential to provide access of its large natural substrate core lipid A to the binding cavity. Our work paves the way to investigate the conformational landscape of membrane proteins in cells