Immune suppressive cells in chronic HIV-1 infection

The loss of efficacy of the CD8 T cell response is a crucial process for the progression of HIV infection. Despite intense research efforts in the last years, the reasons for the so-called immune exhaustion remain elusive. Forefront among supposed causes are inhibitory T cell receptors and immunosuppressive cells. The aim of this dissertation was to specify the impact of immune suppressive cells in chronic HIV infection.Ein entscheidender Prozess in der fortschreitenden HIV-Infektion ist der Verlust der Effektivität der CD8 T-Zellantwort. Trotz intensiver Forschung in den letzten Jahren, sind die Ursachen dieser sogenannten Immunerschöpfung noch nicht vollständig geklärt. Dazu gehören u. a. inhibitorische T-Zellrezeptoren und immunsuppressive Zellen. Ziel dieser Arbeit war es, die Bedeutung von immunsuppressiven Zellen in der chronischen HIV-Infektion näher zu bestimmen

Active Tectonics of the Alps-Dinarides junction – what have we learned?

The collision of the Adriatic Plate with Europe leads to crustal deformation in the Southern Alps-Dinarides transition. Many aspects of this deformation are still unknown. This concerns for example sources of historical earthquakes in the hinterland of the Southern Alpine orogenic front and the overall distribution and the partitioning of strain. Also, the response of the upper crust to deep-seated processes and the influence of the lithospheric architecture on active tectonics has not been fully understood. In many cases, the reason is the very low overall deformation rate in this region. Several projects in the framework of SPP2017 have shed light on these problems, and many new studies unrelated to the SPP have recently published exciting new results. In this presentation I summarize new findings from the fields of geodesy, seismology, structural geology, geomorphology, and earthquake geology. These studies have used GNSS and InSAR data, seismological data from the AlpArray and SWATH-D experiments, new high-resolution digital elevation models, satellite imagery, field mapping, near-surface geophysics, paleoseismology, and Quaternary dating techniques to understand the pattern of Late Quaternary tectonics. In Italy, most of the deformation is accommodated by thrusting on the Southern Alps mountain front, or thrusting has already stepped southward into the Friulian plain, partly on blind faults. This behavior is known from several contractional regimes around the world. Although strong historical earthquakes (M>6) occurred in the interior of the mountain chain, present-day seismicity is rather low. In this region, geological evidence of fault activity is poor because sedimentation/erosion and anthropogenic overprint outpace most tectonic signals on a Quaternary time scale. This is similar to southern Austria, where there is very poor geological evidence of active faulting, despite a record of strong historical earthquakes. New dating results from both deformed and undisturbed geomorphic markers allow us to place constraints on the maximum amount of deformation that is accommodated here. In Slovenia, a system of NW-SE striking right-lateral strike slip faults in a more than 60 km-wide zone takes up most of the deformation. Additionally, many smaller, <15 km long faults show postglacial activity. In general, the deformation is widely distributed. A similar behavior can be observed in may strike-slip fault systems worldwide. In the study area there is a first order correlation between the distribution of seismicity during the Quaternary and gradients of crustal thickness and crustal density. However, other processes like a still ongoing, though very slow eastward extrusion of Eastern Alps crustal material or vertical motions due to glacial isostatic rebound or erosion are likely to contribute to the overall pattern of active tectonics

Neuronale Synchronisation während perzeptueller Organisation in Schizophrenie-Patienten

Current theories of schizophrenia suggest that the pathophysiology of the disorder may be the result of a deficit in the coordination of neural activity within and between areas of the brain, which may lead to impairments in basic cognitive functions such as contextual disambiguation and dynamic grouping (Phillips and Silverstein, 2003). This notion has been supported by recent studies showing that patients with schizophrenia are characterized by reduced synchronous, oscillatory activity in the gamma-frequency band during sensory processing (Spencer et al. 2003, Green et al. 2003, Wynn et al. 2005). However, it is currently unclear to what extent high-frequency gamma-band oscillations (> 60 Hz) contribute to impaired neural synchronization as research has so far focussed on gamma-band oscillations between 30 and 60 Hz. In addition, it is not known whether deficits in high-frequency oscillations are already present at the onset of the disorder and to what extent reductions may be related to the confounding influence of antipsychotic medication. Finally, the neural generators underlying impairments in synchronous oscillatory activity in schizophrenia have not been investigated yet. To address these questions, we recorded MEG activity during a visual closure task (Mooney faces task) in medicated chronic schizophrenia patients, drug-naive first-episode schizophrenia patients and healthy controls. MEG data were analysed for spectral power between 25 and 150 Hz, and beamforming techniques were used to localize the sources of oscillatory gamma-band activity. In healthy controls, we observed that the processing of Mooney faces was associated with sustained high-frequency gamma-band activity (> 60 Hz). A time-resolved analysis of the neural generators underlying perceptual closure revealed a network of distributed sources in occipito-temporal, parietal and frontal regions, which were differentially activated during specific time intervals. In chronic schizophrenia patients, we found a pronounced reduction of high-frequency gamma-band oscillatory activity that was accompanied by an impairment in perceptual organization and involved reduced source power in various brain regions associated with perceptual closure. First-episode patients were also characterized by a deficit in high-frequency gamma-band activity and reductions of source power in multiple areas; these impairments, however, were less pronounced than in chronic patients. Regarding behavioral performance, first-episode patients were not impaired in their ability to detect Mooney faces, but exhibited a loss in specificity of face detection. In conclusion, our results suggest that schizophrenia is associated with a widespread reduction in high-frequency oscillations that indicate local network abnormalities. These dysfunctions are independent of medication status and already present at illness onset, suggesting a possible progressive deficit during the course of the disorder.Aktuelle Theorien gehen davon aus, dass die Pathophysiologie der Schizophrenie auf eine Störung in der Koordination neuronaler Prozesse zurückzuführen ist, welche zu einer Beeinträchtigung in der Integration von Informationen führt und sich in Defiziten bei frühen Wahrnehmungsprozessen und höheren kognitiven Funktionen widerspiegelt. Diese Hypothese wird durch eine Reihe von Studien gestützt, die eine Reduktion oszillatorischer Aktivität im Beta- und Gamma-Frequenzband im Elektroenzephalogramm während visueller Wahrnehmungsprozesse bei Patienten mit Schizophrenie nachweisen konnten. Die Bedeutung von hochfrequenten Gamma-Band Oszillationen (> 60 Hz) für das Verständnis von perzeptuellen Dysfunktionen bei Patienten mit Schizophrenie ist jedoch bislang wenig erforscht. Zudem ist unklar, ob und in welchem Umfang eine Veränderung oszillatorischer Aktivität bereits zu Beginn der Erkrankung und ohne den Einfluss von antipsychotischen Medikamenten vorhanden ist. Des Weiteren gibt es bislang keine Befunde zu den neuronalen Quellen, die den Defiziten oszillatorischer Aktivität bei Schizophrenie-Patienten zugrunde liegen. Um diese Fragen zu untersuchen, wurden im Rahmen der vorliegenden Dissertation drei Studien durchgeführt, in denen die Hirnaktivität während einer visuellen Gestaltaufgabe (Mooney faces-Aufgabe) bei chronischen medizierten Schizophrenie-Patienten, ersterkrankten nicht-medizierten Schizophrenie-Patienten sowie bei gesunden Kontrollprobanden mittels Magnetoenzephalographie (MEG) gemessen wurde. Die Auswertung der MEG-Daten beinhaltete auf der Sensoren-Ebene eine Auswertung der spektralen Power zwischen 25 und 150 Hz und auf der Quellen-Ebene eine Rekonstruktion der Generatoren oszillatorischer Aktivität mit Hilfe von Beamforming-Techniken. Die Hauptbefunde lassen sich wie folgt zusammenfassen: Das neuronale Netzwerk perzeptueller Organisation bei Mooney faces zeigte eine ausgeprägte oszillatorische Aktivität im hochfrequenten Gamma-Band (> 60 Hz) in gesunden Kontrollprobanden und umfasste okzipito-temporale, parietale und frontale Areale, die zu verschiedenen Zeitpunkten der Informationsverarbeitung aktiviert wurden. Unsere Ergebnisse lassen vermuten, dass perzeptuelle Organisationsprozesse bei Mooney faces auf einer frühen Interaktion zwischen Arealen beruhen, die mit der Verarbeitung von Schattierungsreizen zusammenhängen, gesichtsspezifischen Arealen, und Arealen, die mit dem Abruf von Informationen aus dem Langzeitgedächtnis in Verbindung stehen. Im Vergleich zu den Kontrollprobanden zeigten chronische Schizophrenie-Patienten ein deutliches Defizit in der hochfrequenten (60 – 120 Hz) Gamma-Band Power, welches mit reduzierten Detektionsraten bei der Mooney faces-Aufgabe und mit verringerten Aktivierungen in den für perzeptuelle Organisationsprozesse relevanten Arealen einherging. Ersterkrankte nicht-medizierte Schizophrenie-Patienten zeigten ebenfalls eine Reduktion hochfrequenter Gamma-Band Power in verschiedenen Hirnarealen. Dieses Defizit war jedoch weniger stark ausgeprägt als in den chronischen Schizophrenie-Patienten. Im Gegensatz zu den chronischen Patienten zeigten die ersterkrankten Patienten keine Beeinträchtigung bei der Detektion von Gesichtern in aufrecht präsentierten Mooney face Stimuli; jedoch wiesen sie ein Defizit in der Diskrimination zwischen Gesichtern und Nicht-Gesichtern auf. Unsere Befunde deuten darauf hin, dass bei Patienten mit Schizophrenie ausgeprägte Defizite in lokalen Synchronisationsprozessen vorliegen, welche mit perzeptuellen Dysfunktionen einhergehen. Die beeinträchtigte Koordination neuronaler Aktivität könnte auf Veränderungen in GABAergen und glutamatergen Neurotransmittersystemen bei Schizophrenie-Patienten zurückzuführen sein. Unsere Ergebnisse zeigen weiterhin, dass Beeinträchtigungen neuronaler Synchronisation bereits zu Beginn der Erkrankung und ohne den Einfluss von antipsychotischer Medikation vorhanden sind. Die stärkere Beeinträchtigung in den chronischen im Vergleich zu den ersterkrankten Patienten deutet auf einen progressiven Verlauf der Beeinträchtigung oszillatorischer Aktivität bei Schizophrenie-Patienten hin

Risk of basal cell carcinoma after Hodgkin's disease

Background: Basal cell cancer is a common skin cancer, yet studies of second tumors after Hodgkin's disease tend to exclude basal cell cancers as second malignant tumors from analysis. Basal cell carcinomas (BCC) are possibly more common in immunosuppressed patients and were recently implicated as indicators of subsequent malignancies. Materials and Methods: Our database of 1,120 patients with Hodgkin's disease (derived from the tumor registry) was investigated for the occurrence of later BCCs. Kaplan-Meier curves were calculated. Results: A total of 9 cases of BCC were observed 0-20 years after the diagnosis of Hodgkin's disease, One case relapsed after excision. The probability of second BCC was 2.1% after 15 years of follow-up and 7.1% after 20 years. Statistically, the risk for second BCC was increased only in younger patients and with prolonged follow-up, but not in the total group of patients with Hodgkin's disease. Conclusion: BCC is not a major threat: for the survivors of Hodgkin's disease, but continued follow-up is necessary

Holocene surface ruptures of the Rurrand Fault, Germany—insights from palaeoseismology, remote sensing and shallow geophysics

The Lower Rhine Embayment in Central Europe hosts a rift system that has very low deformation rates. The faults in this area have slip rates of less than 0.1 mm/yr, which does not allow to investigate ongoing tectonic deformation with geodetic techniques, unless they cover very long time spans. Instrumental seismicity does only cover a small fraction of the very long earthquake recurrence intervals of several thousands of years. Paleoseismological studies are needed to constrain slip rates and the earthquake history of such faults. Destructive earthquakes are rare in the study area, but did occur in historic times. In 1755/56, a series of strong earthquakes caused significant destruction in the city of Düren (Germany) and the surrounding areas. In this study we document paleoseismological data from the nearby Rurrand Fault. In contrast to earlier studies on the same fault, we found evidence for a surface rupturing earthquake in the Holocene, and we identified at least one more surface rupturing event. Our study shows that the Rurrand Fault currently accommodates deformation in earthquakes rather than by creeping. The coseismic offsets were determined to be between less than 0.5 m per event. We assign maximum possible magnitudes of MW5.9-6.8 for the Rurrand Fault and a slip rate of at least 0.02-0.03 mm/yr for the last ~130-50 kyr. The surface ruptures did not occur at the main fault trace that has a clear morphological expression due to older tectonic motions, but on a younger fault strand in the hanging wall of the main fault. Terrain analyses based on 1 m resolution airborne LiDAR data have been used to image the subtle morphological expression of this young fault zone. Georadar and electric resistivity tomography were applied to image the fault zone at depth and to test if these shallow geophysical methods can be used to identify and trace the fault zone. Georadar failed to produce reliable results, but geoelectrics were successfully applied and allowed us to retrieve slip rate estimates. Our results indicate that the Düren 1755/56 earthquakes did not produce surface ruptures at the Rurrand Fault, either because they did not rupture the surface at all, or because they occurred at another, neighboring fault.This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/gji/ggv55