TY - THES A1 - Schuster, Daniel T1 - „Da schleicht hinein ein böser Gast“ - Körper- und Krankheitsmetaphern in der medizinischen Ratgeberliteratur des 16. und 17. Jahrhunderts T1 - "An Evil Guest Is Creeping In" - Metaphors for Illness and the Body in 16th and 17th Century Health Guides N2 - Metaphern prägen unser Verständnis des Körpers und seiner Krankheiten. Die Kommunikation zwischen Heilkundigen und Kranken basiert daher maßgeblich auf Metaphern. Dieser Beitrag untersucht deutschsprachige Gesundheitsratgeber des 16. und 17. Jahrhunderts, die von gelehrten Ärzten für ein Laienpublikum verfasst wurden. Mit den Methoden der qualitativen Metaphernanalyse soll das Bild einer kommunikativen Praxis vor dem Hintergrund ihrer kulturhistorischen Rahmenbedingungen gezeichnet werden. Metaphern erweisen sich als wichtiges Werkzeug, um die sprachliche und intellektuelle Kluft zwischen Laien- und Gelehrtenwelt zu überbrücken. Geschickt lenken die ärztlichen Autoren mit Hilfe von Metaphern den Blick des Lesers. Dabei bieten sie ihm auch sinnstiftende Erkenntnisse und Ansätze zur Teilhabe am therapeutischen Prozess. N2 - Metaphors can shape our conception of the body and our understanding of its diseases. Communication between medical practitioners and patients, therefore, has often relied on metaphors. This study examines 16th and 17th century health guides written in German vernacular by university-trained medical practitioners. Using qualitative metaphor analysis, a communications practice and its historical background are explored [for insights into patient-practitioner communications]. Metaphors emerge to create a linguistic and intellectual common ground between experts in medicine and the lay reading public. They could serve to manipulate the patient but also to facilitate participation in the therapeutic process and to satisfy the patients’ need for understanding. KW - Metaphernanalyse KW - Ratgeber KW - Medizin KW - Frühe Neuzeit KW - Volkssprache KW - Gesundheitsratgeber KW - Gout KW - Early Modern KW - Vernakularisierung KW - Gicht KW - Podagra KW - Pest KW - health guide KW - metaphor analysis KW - vernacular medicine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286477 ER - TY - THES A1 - Aumann, Ralf T1 - Vorkommen und Expression des opcA Gens in Meningokokkenstämmen von Erkrankten und asymptomatischen Trägern T1 - Prevalence and expression of the opcA gene in meningococci from invasive and carrier strains N2 - Das Opc-Protein ist ein Außenmembranprotein von Meningokokken, das über extrazelluläre Matrixproteine mit Integrinen der Wirtszelle interagiert. Opc ist in Menschen immunogen und induziert bakterizide Antikörper. Das Opc-Protein wurde daher als aussichtsreicher Impfstoff-Kandidat angesehen, da es außerdem relativ gut konserviert ist. Allerdings wird das Opc-Protein nicht von allen Meningokokkenstämmen exprimiert. Einerseits fehlt das opc-Gen in einigen klonalen Komplexen (z.B. ST-8, ST-11, ST-53), andererseits ist die Opc-Expression nicht konstitutiv wegen einer phasenvariablen Transkription, die auf einem Poly-Cytidin-Bereich im Promotor des opc-Gens beruht. In dieser Arbeit wurde die Präsenz des opc-Gens und die Opc-Expression in zwei großen Sammlungen deutscher Meningokokkenisolate von invasiven Erkrankungen (n=1141) und gesunden Trägern (n=792) untersucht. Das opc-Gen war bei 71% der invasiven und 77% der Trägerstämme nachweisbar. Der größte Teil der opc-Gen negativen Stämme gehörte zu den klonalen Komplexen ST-8, ST-11, ST-213, ST-231, ST-334 und ST-53. Der Anteil opc-positiver Stämme, die Opc in vitro exprimieren, war bei den invasiven Stämmen kleiner als bei den Trägerstämmen (13% vs. 29%, p<0,001, Chi-square-Test). Der größere Anteil Opc-exprimierender Trägerstämme ist u.a. am ehesten mit der Überrepräsentation von wenig pathogenen klonalen Komplexen (ST-23, ST-35, ST-198) mit einer hohen Opc-Expressionsrate zu erklären. 24 von den 176 invasiven Stämmen mit einer Anzahl von 11 - 14 Cs in der Promotor-Region, die die Opc-Expression begünstigt, zeigten weder im ELISA noch im Westernblot eine Opc-Expression. Bei 14 dieser 24 Stämme wurde als Ursache ein phasenvariabler, intragenischer Poly-Adenin-Bereich identifiziert, der zu einer Leserasterverschiebung führte. Die Vermutung mehrerer Autoren, dass die Opc-Expression mit dem klinischen Bild der Meningitis verknüpft ist, konnte mit der hier genutzten großen Stammsammlung nicht bestätigt werden. Invasive Stämme, die das Opc-Protein exprimierten, wurden genauso häufig von Patienten mit dem klinischen Bild der Meningitis isoliert wie Stämme, die das Opc-Protein nicht exprimierten (46% vs. 47%, Chi-square-Test: p<0,9). Allerdings gibt es eine starke Assoziation der Gegenwart des opc-Gens mit dem klinischen Merkmal Meningitis. Dieser Befund gibt Anlass zu der Hypothese, dass in vitro und in vivo Expression von Opc sich unterscheiden. Zusammenfassend lässt sich festhalten, dass das Opc-Protein nur in 19,8% aller Isolate (invasive und Trägerstämme zusammengenommen) exprimiert wurde. Es zeigte sich eine Tendenz zu häufigerer Opc-Expression in apathogenen Trägerisolaten. Das Vorhandensein des opc-Gens, nicht aber die in vitro Expression konnten mit dem klinischen Merkmal Meningitis assoziiert werden. Zusätzlich wurde ein weiterer Mechanismus der intragenischen Phasenvariation beschrieben. N2 - Presence of opc was associated with meningitis, mostly because ST-11/ST-8 cc meningococci with low meningitis rates were consistently opc negative. On the other hand, lack of opc did not exclude meningitis. Opc was expressed in only 13% of all invasive isolates. In vitro Opc expression was not associated with meningitis. Limitation: Definite conclusion about expression in vivo is not possible with cultured isolates. Evidence for intragenic opc phase-variation was provided. KW - Neisseria meningitidis KW - opc KW - Medizin KW - Mikrobiologie KW - Meningitis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157278 ER - TY - THES A1 - Pohl, Roman T1 - Die Gleichrichtung von multifokalen visuell evozierten Potenzialen im pattern-pulse Verfahren zur Verbesserung der Signalqualität der pattern-onset VEP Messung T1 - Reliability of pattern onset VEPs can be improved by synthesizing full-field responses from pattern-pulse multifocal recordings N2 - Aus Untersuchungen mit dem multifokalen VEP (mfVEP) weiß man, dass sich multifokal visuell evozierte Potenziale aus unterschiedlichen Teilen des Gesichtsfeldes störend beeinflussen und auslöschen können. Ziel dieser Studie war es zu untersuchen, ob die Signalqualität des pattern-onset VEPs erhöht und die Reproduzierbarkeit der Signalantworten mit Hilfe des mfVEPs verbessert werden kann, indem man einzelne mfVEPs gleichrichtet. 20 Normalpersonen nahmen an dieser Untersuchung teil. Ein kortikal skaliertes Schachbrettmuster von 30° Größe wurde in 6 keilförmige Teilfelder unterteilt. Innerhalb jedes Teilfeldes wurden kortikal skalierte Schachbrettmuster mit einer mittleren Leuchtdichte von 50 cd/m2 und einem Kontrast von 99% im pattern-pulse Verfahren präsentiert. Die durchschnittliche Stimulationsfrequenz betrug 2,0 Hz. MfVEPs des rechten Auges wurden über eine Oz-Fpz und bipolare Ableitung zwischen zwei 4 cm um das Inion angeordnete Elektroden abgeleitet. Durch Summierung der 6 mfVEP Ableitungen mit unterschiedlichen Vorzeichen wurden zwei Ganzfeld-VEPs synthetisiert, von denen eine die frühen C1 und C2 Komponenten, die andere die späte C3-Komponente des pattern onset VEPs erhöhte. Amplituden und Latenzunterschiede zwischen den synthetisierten Antwortkurven und der Ganzfeldantwort aller 6 Felder wurden auf Signifikanz getestet. Die Daten legen nahe, dass die inter-individuelle Variabilität des Standard Ganzfeld pattern onset VEPs auf die Auslöschung von großen und wenig variablen VEP Signalen aus unterschiedlichen Bereichen des Gesichtfsfeldes zurückgeführt werden kann. Die Gleichrichtung dieser VEP-Signale führte zu einem hochsignifikanten Anstieg der Amplitude und zu einer reduzierten Variabilität der synthetisierten Ganzfeldantworten im Vergleich zur gemessenen Ganzfeldantwort. Neben der objektiven Perimetrie kann die Anwendung multifokaler Techniken zu einer gesteigerten Sensitivität beim Aufspüren visueller Pathologien führen verglichen mit Standard Ganzfeldmessungen. N2 - From multifocal VEP (mfVEP) recordings to dartboard stimulus patterns we know that cortical electrophysiological signals from different parts of the visual field may be annihilated by destructive interference. The aim of this study was to test whether the signal strength and the latency reliability of full-field pattern onset VEPs can be improved by rectifying multifocal visual evoked potentials (mfVEP). 20 visually normal subjects participated in the study. A dartboard pattern was used as stimulus with a diameter of 30° and was subdivided into 6 wedge-shaped stimulus fields. Within each field checkerboard patterns with eccentrically scaled check size, a mean luminance of 50 cd/m2 and a contrast of 99% were presented with a pattern pulse stimulation mode. The average temporal frequency was 2.0 Hz. MfVEPs from the right eye were recorded with an Oz-Fpz derivation and a bipolar derivation between two electrodes placed 4 cm above and below the inion. By summation of the 6 mfVEP traces with different signs two synthesized full-field VEPs were calculated that boosted either the early C1 and C2 components, or the late C3 component of the pattern onset VEP. Amplitude and latency differences between A or B and a full-field stimulation of all 6 fields were tested for signifcance with a paired t-test. The data suggest that the inter-individual variability of standard full-field pattern onset VEPs may be due to the annihilation of large and less variable VEP signals from different parts of the visual field. Rectifying these signals led to a dramatic increase in amplitude and to a decrease in variability of a synthesized full-field responses when compared to a recorded full-field response. Beyond objective perimetry the multifocal technique may increase the dynamic range of recorded VEP signals and may help to detect visual dysfunction better than with standard full-field recordings. KW - Patterns KW - Medizin KW - Augenheilkunde KW - mfVEP KW - pattern-pulse KW - pattern onset VEP KW - Signalqualität KW - Gleichrichtung KW - evozierte Potenziale Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114915 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Mantel, Frederick A1 - Gerszten, Peter C. A1 - Flickinger, John C. A1 - Sahgal, Arjun A1 - Létourneau, Daniel A1 - Grills, Inga S. A1 - Jawad, Maha A1 - Fahim, Daniel K. A1 - Shin, John H. A1 - Winey, Brian A1 - Sheehan, Jason A1 - Kersh, Ron T1 - Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis N2 - Purpose To evaluate patient selection criteria, methodology, safety and clinical outcomes of stereotactic body radiotherapy (SBRT) for treatment of vertebral metastases. Materials and methods Eight centers from the United States (n = 5), Canada (n = 2) and Germany (n = 1) participated in the retrospective study and analyzed 301 patients with 387 vertebral metastases. No patient had been exposed to prior radiation at the treatment site. All patients were treated with linac-based SBRT using cone-beam CT image-guidance and online correction of set-up errors in six degrees of freedom. Results 387 spinal metastases were treated and the median follow-up was 11.8 months. The median number of consecutive vertebrae treated in a single volume was one (range, 1-6), and the median total dose was 24 Gy (range 8-60 Gy) in 3 fractions (range 1-20). The median EQD210 was 38 Gy (range 12-81 Gy). Median overall survival (OS) was 19.5 months and local tumor control (LC) at two years was 83.9%. On multivariate analysis for OS, male sex (p < 0.001; HR = 0.44), performance status <90 (p < 0.001; HR = 0.46), presence of visceral metastases (p = 0.007; HR = 0.50), uncontrolled systemic disease (p = 0.007; HR = 0.45), >1 vertebra treated with SBRT (p = 0.04; HR = 0.62) were correlated with worse outcomes. For LC, an interval between primary diagnosis of cancer and SBRT of ≤30 months (p = 0.01; HR = 0.27) and histology of primary disease (NSCLC, renal cell cancer, melanoma, other) (p = 0.01; HR = 0.21) were correlated with worse LC. Vertebral compression fractures progressed and developed de novo in 4.1% and 3.6%, respectively. Other adverse events were rare and no radiation induced myelopathy reported. Conclusions This multi-institutional cohort study reports high rates of efficacy with spine SBRT. At this time the optimal fractionation within high dose practice is unknown. KW - Medizin Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110638 ER - TY - JOUR A1 - Schreier, Peter A1 - Binns, Colin A1 - Wu, Dayong T1 - To surrender or to persevere? N2 - Second Editorial of Open Access Journal "Nutrition and Medicine (NUME)" published by Würzburg University Press: http://nume.de KW - Impact-Faktor KW - Wissenschaftliches Arbeiten KW - Ernährung KW - Medizin KW - nutrition KW - medicine Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-101096 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, Josef T1 - The relative importance of mutagens and carcinogens in the diet. N2 - Known mutagens and carcinogens in the dict were compiled and the risk of cancer was estimated on the basis of average exposure Ievels in Switzerland and carcinogenic potencies from rodent bioassays. The analysis showed that, except for a1cohol, the sum of all known dietary carcinogens could only explain a few percent of the cancer deaths attributed by epidemiologists to dietary factors. The discrepancy was explained by a "carcinogenicity" of excess macronutrients. This hypothesis was based on an evaluation of dietary restriction experiments in rats and mice, where a dramatic reducing effect on spontaneaus tumour formation was seen. From these experiments, a "carcinogenic potency" was deduced for food in excess (TD50 approximately 16 g/kg per day). Ovemutrition in Switzerland was converted into excess food intake and the cancer risk estimated on the basis ofthe TD50 value. The resulting risk of60,000 cases per one million lives wou1d aJlow to explain by overnutrition almost all "diet-related" cancer deaths in humans. KW - Medizin Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86311 ER - TY - CHAP A1 - Cantoreggi, S. A1 - Gupta, R. C. A1 - Lutz, Werner K. T1 - An improved 32P-postlabelling assay for detection and quantitation of styrene 7,8-oxide-DNA adducts N2 - Using DNA modified with [7-3H]styrene 7,8-oxide (SO) in vitro we have standardized the 32P-postlabelling assay for detecting SO-DNA adducts. Nuclease P 1-enriched adducts were 32P-labelled and purified by high-salt ( 4.0 M ammonium formate, pH 6.1} C1s reverse-phase TLC. After elution from the layer with 2-butoxyethanol:H20 (4:6), adducts were separated by two-dimensional PEI cellulose TLC in non-urea solvents (2.0 M ammonium formate, pH 3.5, and 2.7 M sodium phosphate, pH 5.6). One major, three minor and several trace adducts were detected. The efficiency of the kinase reaction depended on the ATP concentration. Use of standard labelling conditions (['Y· 32P]ATP, <3000 Ci/mmol; <2 Mikromol) resulted in poor ( 4-7%) adduct recovery. An ATP concentration of 40 Mikromol, however, increased the labeJling efficiency by a factor of 5-8 (35-55% based on 3H-SO labelied DNA). The results indicate that the new separation technique is suitable for the relatively polar SO-DNA adducts and that high labelling efficiency can be achieved. KW - Medizin Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86305 ER - TY - CHAP A1 - Shephard, S. E. A1 - Hegi, M. E. A1 - Lutz, Werner K. T1 - In-vitro assays to detect alkylating and mutagenic activities of dietary components nitrosated in situ N2 - Nitrosation of dietary components has been combined with the 4-(para-nitrobenzyl)pyridine (NBP) colorimetric test for screening alkylating agents and with the Ames test for the detection of mutagenic activity. This allowed the investigation of short-hved nitrosation products of dietary components which generate electrophilic degradation products requiring no metabolic activation (natural amino acids and some derivatives, ureas, guanidines, primary alkyl and aryl amines). In a first system, precursor, nitrous acid and NBP were present simultaneously. All amino acids tested, except glutamic acid and glutamine, gave positive results. The reactivities spanned more than three orders of magnitude, with the aromatic amino acids and methionine the most active; two primary amines, tryptamine and histamine, were also strongly reactive. All guanidines tested, except the amino acid arginine, gave negative results. A second system consisted of two phases: NBP was added only after destruction of residual nitrite and adjustment of the pH to neutrality. This system was useful for the study of ureas, which are stable in acid but not in neutral media. The range of responses covered more than two orders of magnitude. Most amino acids and primary amines also gave positive results, but could be assessed only after analysing the kinetics of the competing reactions and choosing appropriate reaction times. In a third system, Salmonella typhimurium strain TA1OO replaced NBP. Representatives of the class of amino acids, ureas, the primary amine tryptamine, and aniline became higbly mutagenic upon nitrosation. Methylguanidine was only weakly mutagenic under the present assay conditions. The results indicate that further studies with unstable nitrosation products of dietary components are required to understand more thoroughly the role of endogenous nitrosation in gastric cancer. KW - Medizin Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86194 ER - TY - JOUR A1 - Busch, Albert A1 - Tschernitz, Sebastian A1 - Thurner, Anette A1 - Kellersmann, Richard A1 - Lorenz, Udo T1 - Fatal Paraneoplastic Embolisms in Both Circulations in a Patient with Poorly Differentiated Neuroendocrine Tumour JF - Case Reports in Vascular Medicine N2 - Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97335 ER - TY - JOUR A1 - Schuster, Frank A1 - Johannsen, Stephan A1 - Roewer, Norbert T1 - A Minimal-Invasive Metabolic Test Detects Malignant Hyperthermia Susceptibility in a Patient after Sevoflurane-Induced Metabolic Crisis JF - Case Reports in Anesthesiology N2 - Malignant hyperthermia is a rare but life-threatening complication of general anesthesia in predisposed patients usually triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine. The authors present a case of delayed sevoflurane-induced malignant hyperthermia in a 21-year-old male patient that was sufficiently treated by discontinuation of trigger agent application and dantrolene infusion. After surviving an MH episode diagnostic procedures are indicated to increase patient safety. In the presented case, the use of a novel minimal-invasive metabolic test with intramuscular injection of halothane and caffeine successfully confirmed MH susceptibility and hence might be an alternative for invasive in vitro contracture testing in selected cases. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97080 ER - TY - JOUR A1 - Reichert, Johannes A1 - Schmalzl, Jonas A1 - Prager, Patrick A1 - Gilbert, Fabian A1 - Quent, Verena M. C. A1 - Steinert, Andre F. A1 - Rudert, Maximilian A1 - Nöth, Ulrich T1 - Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells JF - Stem Cell Research & Therapy N2 - Introduction To stimulate healing of large bone defects research has concentrated on the application of mesenchymal stem cells (MSCs). Methods In the present study, we induced the overexpression of the growth factors bone morphogenetic protein 2 (BMP-2) and/or Indian hedgehog (IHH) in human MSCs by adenoviral transduction to increase their osteogenic potential. GFP and nontransduced MSCs served as controls. The influence of the respective genetic modification on cell metabolic activity, proliferation, alkaline phosphatase (ALP) activity, mineralization in cell culture, and osteogenic marker gene expression was investigated. Results Transduction had no negative influence on cell metabolic activity or proliferation. ALP activity showed a typical rise-and-fall pattern with a maximal activity at day 14 and 21 after osteogenic induction. Enzyme activity was significantly higher in groups cultured with osteogenic media. The overexpression of BMP-2 and especially IHH + BMP-2 resulted in a significantly higher mineralization after 28 days. This was in line with obtained quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analyses, which showed a significant increase in osteopontin and osteocalcin expression for osteogenically induced BMP-2 and IHH + BMP-2 transduced cells when compared with the other groups. Moreover, an increase in runx2 expression was observed in all osteogenic groups toward day 21. It was again more pronounced for BMP-2 and IHH + BMP-2 transduced cells cultured in osteogenic media. Conclusions In summary, viral transduction did not negatively influence cell metabolic activity and proliferation. The overexpression of BMP-2 in combination with or without IHH resulted in an increased deposition of mineralized extracellular matrix, and expression of osteogenic marker genes. Viral transduction therefore represents a promising means to increase the osteogenic potential of MSCs and the combination of different transgenes may result in synergistic effects. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97010 UR - http://stemcellres.com/content/4/5/105 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Kunze, Ekkehard A1 - Willner, Nadine A1 - Raslan, Furat A1 - Vince, Giles H. A1 - Ernestus, Ralf-Ingo T1 - Magnesium treatment for neuroprotection in ischemic diseases of the brain JF - Experimental and Translational Stroke Medicine N2 - This article reviews experimental and clinical data on the use of magnesium as a neuroprotective agent in various conditions of cerebral ischemia. Whereas magnesium has shown neuroprotective properties in animal models of global and focal cerebral ischemia, this effect could not be reproduced in a large human stroke trial. These conflicting results may be explained by the timing of treatment. While treatment can be started before or early after ischemia in experimental studies, there is an inevitable delay of treatment in human stroke. Magnesium administration to women at risk for preterm birth has been investigated in several randomized controlled trials and was found to reduce the risk of neurological deficits for the premature infant. Postnatal administration of magnesium to babies after perinatal asphyxia has been studied in a number of controlled clinical trials. The results are promising but the trials have, so far, been underpowered. In aneurysmal subarachnoid hemorrhage (SAH), cerebral ischemia arises with the onset of delayed cerebral vasospasm several days after aneurysm rupture. Similar to perinatal asphyxia in impending preterm delivery, treatment can be started prior to ischemia. The results of clinical trials are conflicting. Several clinical trials did not show an additive effect of magnesium with nimodipine, another calcium antagonist which is routinely administered to SAH patients in many centers. Other trials found a protective effect after magnesium therapy. Thus, it may still be a promising substance in the treatment of secondary cerebral ischemia after aneurysmal SAH. Future prospects of magnesium therapy are discussed. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96729 UR - http://www.etsmjournal.com/content/5/1/6 ER - TY - JOUR A1 - Frey, Sönke Percy A1 - Jansen, Hendrik A1 - Doht, Stefanie A1 - Filgueira, Luis A1 - Zellweger, Rene T1 - Immunohistochemical and Molecular Characterization of the Human Periosteum JF - The Scientific World Journal N2 - Purpose. The aim of the present study was to characterize the cell of the human periosteum using immunohistological and molecular methods. Methods. Phenotypic properties and the distribution of the cells within the different layers were investigated with immunohistochemical staining techniques and RT-PCR, focussing on markers for stromal stem cells, osteoblasts, osteoclasts and immune cells. Results. Immunohistochemical results revealed that all stained cells were located in the cambium layer and that most cells were positive for vimentin. The majority of cells consisted of stromal stem cells and osteoblastic precursor cells. The density increased towards the deeper layers of the cambium. In addition, cells positive for markers of the osteoblast, chondrocyte, and osteoclast lineages were found. Interestingly, there were MHC class II-expressing immune cells suggesting the presence of dendritic cells. Using lineage-specific primer pairs RT-PCR confirmed the immunofluorescence microscopy results, supporting that human periosteum serves as a reservoir of stromal stem cells, as well as cells of the osteoblastic, and the chondroblastic lineage, osteoclasts, and dendritic cells. Conclusion. Our work elucidates the role of periosteum as a source of cells with a high regenerative capacity. Undifferentiated stromal stem cells as well as osteoblastic precursor cells are dominating in the cambium layer. A new outlook is given towards an immune response coming from the periosteum as MHC II positive immune cells were detected. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96623 ER - TY - JOUR A1 - Gunreben, Ignaz A1 - Geis, Christian A1 - Kleinschnitz, Christoph T1 - Acute tetraparesis secondary to bilateral precentral gyral cerebral ischemia: a case report JF - Journal of Medical Case Reports N2 - Introduction Sudden tetraparesis represents a neurological emergency and is most often caused by traumatic spinal cord injury, spinal epidural bleeding or brainstem ischemia and less frequently by medial disc herniation or spinal ischemia. Case presentation Here we report the rare case of an 82-year-old Caucasian man who developed severe tetraparesis four days after radical cystoprostatectomy. An emergency diagnostic study for spinal cord affection was normal. Brain magnetic resonance imaging revealed acute bilateral ischemic strokes in the precentral gyri as the underlying cause. Conclusions This case report underlines the need to also consider unusual causes of tetraparesis in an emergency situation apart from spinal cord or brain stem injury in order not to leave severe symptomatology unclear and possibly miss therapeutic options. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96179 UR - http://www.jmedicalcasereports.com/content/7/1/61 ER - TY - THES A1 - Kunkel, Sabine T1 - Veränderungen innerhalb der Schnittentbindung, ein Vergleich der Jahre 1995 und 2005. Eine retrospektive Analyse geburtshilflicher Parameter T1 - Developments in caesarean section, a comparison of the years 1995 and 2005. A retrospective analysis of obstetric parameters N2 - In der Abteilung für Gynäkologie und Geburtshilfe der Missionsärztlichen Klinik Würzburg wurden 1995 120 und 2005 312 Schnittentbindungen durchgeführt. In der vorliegenden retrospektiven Arbeit interessierte, ob sich zwischen 1995 und 2005 ein signifikanter Wandel der geburtshilflichen Parameter innerhalb dieser Schnittentbindungen abgezeichnet hat. Die Sectio-Frequenz stieg im untersuchten Zeitraum höchst signifikant von 11,4 % auf 24,7 %. Es wurden pro Schnittentbindung ein bis maximal fünf Indikationen, die zu einer Sectio führten, angegeben. 1995 gab es 31 und 2005 34 verschiedene Indikationen. Bezüglich der sieben häufigsten Indikationsangaben hat sich in diesen 10 Jahren nichts verändert. Statistisch signifikant waren nur zwei Veränderungen. Die Indikation Missverhältnis erfuhr eine signifikante Steigerung von 21,6 % auf 33,4 % und war damit 2005 die meistgenannte Indikation. Die Indikation frustrane Geburtseinleitung ging von 9,9 % auf 3,3 % zurück. Die häufigste Indikationsangabe 1995 war der Geburtsstillstand/protrahierte Eröffnungsperiode (33,3%). Höchst signifikante Unterschiede gab es bei den Anästhesieverfahren. 1995 wurde zu 67,7 % eine Intubationsnarkose durchgeführt, 2005 waren es nur noch 12,1 %. Im Gegensatz dazu stieg der Anteil an der Spinalanästhesie von 27 % auf 75,7 %. Das durchschnittliche Geburtsgewicht der Sectio-Geborenen lag 1995 bei 3235,6 Gramm gegenüber 3387,9 Gramm 2005. Dieser Unterschied war statistisch signifikant. Das niedrigere Geburtsgewicht 1995 liegt sicherlich auch daran, dass in diesem Jahr mehr Frühgeborene durch Kaiserschnitt zur Welt kamen. Bei der Betrachtung des Fetal Outcome der Sectiokinder zeigten sich folgende Ergebnisse. Der 1-Minuten-APGAR-Mittelwert war 2005 mit 8,9 statistisch höchst signifikant besser als 1995 mit 8,4. Der 5-Minuten- und 10 Minuten-APGAR-Mittelwert zeigte keine signifikanten Unterschiede. 1995 hatten weniger Neugeborene einen 1-Minuten-APGAR-Wert > 8 als 2005 und dafür mehr Kinder Werte < 7 (10,2 % 1995 zu 2,9 % 2005). Dies ist ebenfalls auf die höhere Frühgeburtenrate 1995 zurückzuführen. Beim Nabelarterien-pH-Mittelwert gab es keinen signifikanten Unterschied. 1995 gab es sechs Kinder mit einem pH-Wert kleiner 7,1 (dies entspricht 5,7 %) und 2005 fünf Kinder (1,7 %). Es wurde die Abhängigkeit der Indikationsstellung Missverhältnis/Geburtsstillstand von Geburtsgewicht, BMI und der untersuchten Jahre 1995 und 2005 untersucht. Hierbei zeigte sich, dass das Geburtsgewicht ein höchst signifikanter Risikofaktor für die Indikationsstellung Missverhältnis oder Geburtsstillstand darstellt. Ein Effekt des BMI oder der untersuchten Jahre konnte nicht nachgewiesen werden. Keine signifikanten Unterschiede gab es bei der Untersuchung der primären Sectiones, Re-Sectiones, Erstgebärenden, Alter der Mütter, BMI-Werte oder Komplikationen im Wochenbett. N2 - In the Department of Obstetrics and Gynecology at Medical Missionary Clinic in Würzburg (Missionsärztliche Klinik Würzburg) 120 caesarean sections took place in 1995 compared to 312 in 2005. Aim of this retrospective study is to find if there is a significant change in obstetric parameters of these caesarean sections in the years from 1995 to 2005. The sectio frequency increased highly significantly from 11.4% to 24.7% in the investigation period. Per caesarean section up to a maximum of five indications that led to a section have been specified. There were 31 different indications in 1995, in 2005 there were 34. No changes occurred regarding the seven most frequent indications in those ten years. Statistically significant were only two changes. The indication cephalopelvic disproportion rose significantly from 21.6% to 33.4% and as the most stated indication in 2005. The indication failure to induce labour fell from 9.9% to 3.3%. In 1995 the most common indication was failure to progress in labour (33.3%). Highly significant differences became apparent in the anaesthetic procedures. In 1995 an general anesthesia had been carried out in 67.7% of cases, in 2005 the number fell to only 12.1%. By contrast, the rate of spinal anesthesia rose from 27% to 75.7%. The average birth weight of the children born by caesarean section lay by 3235.6 gram in 1995 and 3387.9 gram in 2005. This difference is statistically significant. The lower 1995 birth weight is certainly down to the fact that more premature babies were delivered by caesarean section that year. The results of a consideration of the Fetal Outcome of the children born by caesarean section were as follows: the 1 minute APGAR score was 8.9 in 2005 and therefore statistically highly significantly better than in 1995 when the score was 8.4. The 5 and 10 minute APGAR score shows no significant difference. In 1995 fewer newborns had a 1 minute APGAR score of >8 than in 2005 and more children had scores <7 (10.2% in 1995 compared to 2.9% in 2005). This is also due to the higher preterm birth rate of 1995. There was no significant difference regarding the umbilical arteries pH score. In 1995 there were six children with a pH score below 7.1 (representing 5.7%) and five children (representing 1.7%) in 2005. The dependence of the indication cephalopelvic disproportion/failure to progress in labour on birth weight, BMI and the investigation years 1995 and 2005 was analysed. It showed that the birth weight is a highly significant risk factor for the indication cephalopelvic disproportion or failure to progress in labour. There has been no evidence for an effect of the BMI or the year in question. The study of primary sections, previous sections, nulliparous women, maternal age, BMI scores or complications in childbed resulted in no significant difference. KW - Medizin KW - Gynäkologie KW - Geburtshilfe KW - Schnittentbindung KW - Sectio caesarea KW - Kaiserschnitt KW - Indikationen KW - retrospektive Analyse KW - geburtshilflicher Parameter KW - caesarean section KW - retrospective analysis KW - obstetric parameters Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-82342 ER - TY - THES A1 - Schneider-Schaulies, Sibylle T1 - Molekularbiologische Charakterisierung der Masernvirusreplikation in zentralen Nervensystem von Lewis- und BN-Ratten N2 - Einleitung: Das Masernvirus (MV) ist ein hochkontagiöser, primatenpathogener Erreger, der für die bekannte Masernerkrankung verantwortlich ist... N2 - No abstract available. KW - Medizin KW - Masernvirus KW - Immunbiologie KW - Masern KW - Medicine Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78465 ER - TY - JOUR A1 - Stöber, Gerald A1 - Franzek, E. A1 - Beckmann, H. T1 - Die selbstquälerische Depression: eine Form monopolarer endogener Depression N2 - Anhand von drei exemplarischen fällen wird. das Krankheitsbild der selbstquälerischen Depression, eine Form der reinen Depressionen Leonhards, dargestellt. Im Zentrum stehen die Ideen der Selbsterniedrigung und Selbstentwertung und der sich daran entwickelnde ängstlich-depressive Affekt. Charakteristisch ist auch die Angst um die nächsten Angehörigen. In ihren Selbstanklagen erwarten und fordern die Patienten für sich die schrecklichsten Strafen. Diese wenigen Leitsymptome kehren in jeder Krankheitsphase gleichförmig wieder. Andere depressive Symptome wie Denkhemmung und psychomotorische Hemmung treten dagegen völlig in den Hintergrund. Der Krankheitsverlauf ist streng monopolar. Die Dauer der Krankheitsphasen wurde von Leonhard mit durchschnittlich 5,8 Monaten angegeben. Sie betrug bei unseren Patienten durchschnittlich 4,1 Monate. Das klinische Erscheinungsbild ist durch moderne Behandlungsstrategien nicht wesentlich zu beeinflussen. Eine familiäre Belastung mit affektiven Psychosen findet sich nur sehr selten. N2 - Three ease reports will be used to describe the self-torturing depression, one form of Leonhard's monopolar depressive disorders. The main symptomatology consists of marked feelings of guilt, as weil as ideas of self-abasement and self-depreciation. The severe anxious-depressive affect developes on the grounds of these symptoms. Worries of the patients about their family are also characteristic. Excessive self-reproach results in the expectation of and demand for heaviest punishment. These symptoms repeatedly occur during each episode. Other depressive symptoms like inhibited thinking and motor retardation are lacking. The course of the disease is strictly monopolar. In Leonhard's original description the mean duration of the episodes was found to be 5.8 months. We noticed a mean duration of 25 episodes of 4.1 months. The clinical manifestation of the episodes can only insignificantly be influenced by modern therapy. There is little evidence for familial loading with affective psychoses. KW - Medizin KW - Psychopathologie KW - monopolare endogene Depression KW - Leonhard-Klassifikation KW - Affective psychoses KW - psychopathology KW - monopolar depressive disorders KW - Leonhard classification Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78454 ER - TY - JOUR A1 - Stöber, Gerald T1 - Schwangerschaftsinfektionen bei Müttern von chronisch Schizophrenen: die Bedeutung einer differenzierten Nosologie N2 - In einer retrospektiven Untersuchung erinnerten 16 von 80 Müttern von chronisch Schizophrenen eine schwere Infektionserkrankung in der Schwangerschaft. Im zweiten Trimenon waren gehäuft Infektionen aufgetreten. Zehn von 80 Müttern von Kontrollpersonen erinnerten ebenfalls eine Infektion. Im Vergleich zu den Kontrollen halfen Mütter Schizophrener im 5. Schwangerschaftsmonat häufiger Infektionen als in den anderen Gestationsmonaten (p < 0,05). Bei "familiären" und "sporadischen" Schizophrenen gemäß DSM III-R kamen im Vergleich zu Kontrollen Infektionen in gleicher Häufigkeit vor. Wurden hingegen in der Diagnostik schizophrener Psychosen die Definitionen von Leonhard zugrunde gelegt, ergaben sich signifikante Unterschiede! Bei den systematischen Schizophrenen (denen nach Leonhard keine erbliche Disposition zugrunde liegt) waren Infektionen gehäuft im 2. Schwangerschaftsdrittel aufgetreten, sowohl im Vergleich zu Kontrollen (p < 0,01) als auch im Vergleich zu den unsystematischen Schizophrenen, die hauptsächlich genetisch bedingt zu sein scheinen (p < 0,001). Infektionserkrankungen im 5. Schwangerschaftsmonat waren ausschließlich bei den Müttern von systematischen Schizophrenen vorgekommen. Bei diesen Krankheitsformen scheinen Infektionen im 2. Schwangerschaftstrimenon und insbesondere im 5. Schwangerschaftsmonat wichtige ätiologische Faktoren zu sein und könnten mitursächlich sein für die beschriebenen zytoarchitektonischen Aberrationen im Zentralnervensystem von chronisch Schizophrenen. N2 - In a retrospective study, 16 of 80 mothers of chronic DSM III-R schizophrenics reported having had a serious infectious disease during pregnancy. Eleven of the infections had occurred during the second trimester. Influenza and the common cold with fever were frequent. Ten of 80 female controls also recalled having had an infectious illness during pregnancy. Compared to the controls, mothers of schizophrenics reported more infectious illness during pregnancy, particularly during the fifth month ofgestation (p < 0.05). Mothers of familial and of sporadic DSM III-R schizophrenics reported equal frequencies of infections in pregnancy. In contrast, when Leonhard's classification of psychoses was applied, significant differences appeared. Infections during pregnancy were scarcely found in unsystematic schizophrenics (mainly genetically determined according to Leonhard). In systematicschizophrenics (mainly exogenously determined according to Leonhard), a significantly higher frequency of infectious diseases was reported for the second trimester as compared both to controls (p < 0.01) and to unsystematic schizophrenics (p < 0.001). Infections during the fifth month of gestation were exclusively reported in systematic schizophrenics. Thus, in the systematic forms of schizophrenia infections during the second trimester and particularly during the fifth montb ofgestation seem to play an important role in the etiology and seem to be of causal importance for the various cytoarchitectural abnormalities detected in the central nervous system of schizophrenics. KW - Medizin KW - Psychologie KW - Schizophrenie KW - Schwangerschaftsinfektion KW - "Familiär-sporadisch"- Konzept KW - Leonhard-Klassifikation KW - Schizophrenia KW - Maternal infections KW - Pregnancy KW - Familial/sporadic concept KW - Leonhard classification Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78438 ER - TY - JOUR A1 - Becker, T. A1 - Schmidtke, A. A1 - Stöber, Gerald A1 - Franzek, E. A1 - Teichmann, E. A1 - Hofmann, E. T1 - Hyperintense Marklagerläsionen bei psychiatrischen Patienten: räumliche Verteilung und psychopathologische Symptome T1 - Hyperintense white matter lesions in psychiatrie patients: spatial distribution and psychopathological symptoms N2 - In einem Kollektiv von 130 MR-tomographisch untersuchten psychiatrischen Patienten (axiale T2-SE-Sequenz) wurden Zahl und räumliche Verteilung von hyperintensen Marklagerläsionen ("white matter lesions"; WM L) erfaßt und die Ventricle-to-brain-Ratio (VBR) bestimmt. Eine Konfigurationsfrequenzanalyse auf der Grundlage der räumlichen WMLVerteilung erlaubte die Abgrenzung von vier Patientengruppen: 1. keine WML (n = 35), 2. WML rechts frontotemporal (n = 23), 3. WML bifrontal (n = 12), 4. WML ubiquitär (n = 16). Die während 3 Jahren beobachteten psychopathologischen Symptome dieser Patienten wurden retrospektiv nach dem AMDP-Systemdokumentiert. In der Gruppe mit ubiquitären WML überwogen organisch-psychopathologische Ttems, die VER war größer als in den anderen Gruppen (ANOVA;p < 0,001). Die räumliche W M L- Verteilung erklärte 10,24 % der Gesamtvarianz psychopathologischer M erkmalsverteilung in den Gruppen. Das Patientenalter (MANCOVA; p < 0,021), nicht aber die VER hattesignifikanten Einfluß auf das psychopathologische Symptomprofil. Nach Ausblendung der Patientengruppe mit ubiquitären WMLblieb der Einfluß der WML-Verteilung auf die psychopathologische Symptomatiksignifikantc (p <0,05). Bifrontale WML waren mit Denkstörung, rechts frontotemporale WML mit affektiven Symptomen assoziiert. Die Befunde sprechen für einen Einfluß der räumlichen Verteilung unspezifischer Marklagerläsionen auf die psychopathologische Symptomatik. N2 - In a sampie of 130 patients who had undergone MRI (transverse TIweighted SE sequenee) patchywhite matter lesions (WML) were documented according to number and spatial distribution in the brain. Ventricle-to-Brain Ratio (VBR) was determined. Configural frequency analysis led to delineation of four patient groups on the basis of WML 10-cation: 1. no WML (n = 35), 2. right frontal-temporal WML (n = 23), 3. bifrontal WML (n = 12),4. WML in all/all but one brain region (n = 16). Psychopathological symptoms reported in the course of a maximum of 3 years were documen ted by chart review. In the 'pervasive WML' group psychopathological items characteristic of organic brain syndromes prevailed, mean VER exceeded values in all other groups (ANOVA, p < 0.001). WML spatial distribution accounted for 10.2 % oftotal psychopathological variance. Patient age, but not VER, had a significant impact on symptom profile (MANCOVA). When the 'pervasive WML' group was excluded, the finding of a significant effect of WML location on psychopathological symptom profiles was robust. Bifrontal WML were associated with thought incoherence, right frontal-temporal WML with affective symptoms. Findings support an impact of spatial distribution of unspecific WML on psychopathological symptoms in psychiatrie patients. KW - Medizin KW - Psychopathologie KW - MRT KW - Demyelinisierung KW - Periventrikuläre Hyperintensitäten KW - Hyperintense Marklagerläsionen KW - MRI KW - Demyelination KW - Periventricular hyperintensities KW - Hyperintense white matter lesions KW - Psychopathology Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78288 ER - TY - CHAP A1 - Herbert, M. K. T1 - Analgetikaeinsatz beim geriatrischen Patienten N2 - Nicht nur bei traumatologischen, sondern auch bei vielen internistischen und neurologischen Notfällen ist der Schmerz das oder eines der Leitsymptome. Neben der Wiederherstellung und Sicherung der Vitalfunktionen ist die rasche und effiziente Schmerzlinderung eine der wichtigsten Aufgaben des Notarztes. Eine erfolgreiche analgetische Therapie verbessert zum einen die subjektive Befindlichkeit des Patienten und unterbricht zum anderen die durch starke Schmerzen initiierten und unterhaltenen sympathiko-adrenergen und metabolisch-endokrinen Streßreaktionen, mit all ihren nachteiligen Auswirkungen auf die Hämodynamik und Respiration. Letzteres ist eine wichtige, positive Wirkung einer guten analgetischen Therapie, insbesondere beim kranken geriatrischen Patienten, der in den Kompensationsmöglichkeiten einzelner Organsysteme oft deutlich eingeschränkt ist. Länger fortbestehende starke Schmerzen würden gerade bei diesen Patienten eine Einschränkung der Hämodynamik und Respiration perpetuieren. KW - Medizin KW - Geriatrie KW - Analgetika Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78001 ER - TY - JOUR A1 - Schick, Martin Alexander A1 - Isbary, Jobst Tobias A1 - Stueber, Tanja A1 - Brugger, Juergen A1 - Stumpner, Jan A1 - Schlegel, Nicolas A1 - Roewer, Norbert A1 - Eichelbroenner, Otto A1 - Wunder, Christian T1 - Effects of crystalloids and colloids on liver and intestine microcirculation and function in cecal ligation and puncture induced septic rodents N2 - Background: Septic acute liver and intestinal failure is associated with a high mortality. We therefore investigated the influence of volume resuscitation with different crystalloid or colloid solutions on liver and intestine injury and microcirculation in septic rodents. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in 77 male rats. Animals were treated with different crystalloids (NaCl 0.9% (NaCl), Ringer’s acetate (RA)) or colloids (Gelafundin 4% (Gel), 6% HES 130/0.4 (HES)). After 24 h animals were re-anesthetized and intestinal (n = 6/group) and liver microcirculation (n = 6/group) were obtained using intravital microscopy, as well as macrohemodynamic parameters were measured. Blood assays and organs were harvested to determine organ function and injury. Results: HES improved liver microcirculation, cardiac index and DO2-I, but significantly increased IL-1β, IL-6 and TNF-α levels and resulted in a mortality rate of 33%. Gel infused animals revealed significant reduction of liver and intestine microcirculation with severe side effects on coagulation (significantly increased PTT and INR, decreased haemoglobin and platelet count). Furthermore Gel showed severe hypoglycemia, acidosis and significantly increased ALT and IL-6 with a lethality of 29%. RA exhibited no derangements in liver microcirculation when compared to sham and HES. RA showed no intestinal microcirculation disturbance compared to sham, but significantly improved the number of intestinal capillaries with flow compared to HES. All RA treated animals survided and showed no severe side effects on coagulation, liver, macrohemodynamic or metabolic state. Conclusions: Gelatine 4% revealed devastated hepatic and intestinal microcirculation and severe side effects in CLP induced septic rats, whereas the balanced crystalloid solution showed stabilization of macro- and microhemodynamics with improved survival. HES improved liver microcirculation, but exhibited significantly increased pro-inflammatory cytokine levels. Crystalloid infusion revealed best results in mortality and microcirculation, when compared with colloid infusion. KW - Medizin KW - Sepsis KW - Microcirculation KW - Colloids KW - HES KW - Crystalloids Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78151 ER - TY - JOUR A1 - Knies, Kerstin A1 - Schuster, Beatrice A1 - Ameziane, Najim A1 - Rooimans, Martin A1 - Bettecken, Thomas A1 - de Winter, Johan A1 - Schindler, Detlev T1 - Genotyping of Fanconi Anemia Patients by Whole Exome Sequencing: Advantages and Challenges N2 - Fanconi anemia (FA) is a rare genomic instability syndrome. Disease-causing are biallelic mutations in any one of at least 15 genes encoding members of the FA/BRCA pathway of DNA-interstrand crosslink repair. Patients are diagnosed based upon phenotypical manifestationsand the diagnosis of FA is confirmed by the hypersensitivity of cells to DNA interstrand crosslinking agents. Customary molecular diagnostics has become increasingly cumbersome, time-consuming and expensive the more FA genes have been identified. We performed Whole Exome Sequencing (WES) in four FA patients in order to investigate the potential of this method for FA genotyping. In search of an optimal WES methodology we explored different enrichment and sequencing techniques. In each case we were able to identify the pathogenic mutations so that WES provided both, complementation group assignment and mutation detection in a single approach. The mutations included homozygous and heterozygous single base pair substitutions and a two-base-pair duplication in FANCJ, -D1, or - D2. Different WES strategies had no critical influence on the individual outcome. However, database errors and in particular pseudogenes impose obstacles that may prevent correct data perception and interpretation, and thus cause pitfalls. With these difficulties in mind, our results show that WES is a valuable tool for the molecular diagnosis of FA and a sufficiently safe technique, capable of engaging increasingly in competition with classical genetic approaches. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77985 ER - TY - JOUR A1 - Riedel, Simone S. A1 - Mottok, Anja A1 - Brede, Christian A1 - Bäuerlein, Carina A. A1 - Jordán Garrote, Ana Laura A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Bogen, Bjarne A1 - Beilhack, Andreas T1 - Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma N2 - Background: Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy. Material and Methods: A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology. Results: Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and a4b1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells. Conclusions: This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77978 ER - TY - JOUR A1 - Fehrholz, Markus A1 - Bersani, Iliana A1 - Kramer, Boris W. A1 - Speer, Christian P. A1 - Kunzmann, Steffen T1 - Synergistic Effect of Caffeine and Glucocorticoids on Expression of Surfactant Protein B (SP-B) mRNA N2 - Administration of glucocorticoids and caffeine is a common therapeutic intervention in the neonatal period, but possible interactions between these substances are still unclear. The present study investigated the effect of caffeine and different glucocorticoids on expression of surfactant protein (SP)-B, crucial for the physiological function of pulmonary surfactant. We measured expression levels of SP-B, various SP-B transcription factors including erythroblastic leukemia viral oncogene homolog 4 (ErbB4) and thyroid transcription factor-1 (TTF-1), as well as the glucocorticoid receptor (GR) after administering different doses of glucocorticoids, caffeine, cAMP, or the phosphodiesterase-4 inhibitor rolipram in the human airway epithelial cell line NCI-H441. Administration of dexamethasone (1 mM) or caffeine (5 mM) stimulated SP-B mRNA expression with a maximal of 38.8611.1-fold and 5.261.4-fold increase, respectively. Synergistic induction was achieved after coadministration of dexamethasone (1 mM) in combination with caffeine (10 mM) (206659.7-fold increase, p,0.0001) or cAMP (1 mM) (2136111-fold increase, p = 0.0108). SP-B mRNA was synergistically induced also by administration of caffeine with hydrocortisone (87.9639.0), prednisolone (154666.8), and betamethasone (12366.4). Rolipram also induced SP-B mRNA (64.9621.0-fold increase). We detected a higher expression of ErbB4 and GR mRNA (7.0- and 1.7-fold increase, respectively), whereas TTF-1, Jun B, c-Jun, SP1, SP3, and HNF-3a mRNA expression was predominantly unchanged. In accordance with mRNA data, mature SP-B was induced significantly by dexamethasone with caffeine (13.869.0-fold increase, p = 0.0134). We found a synergistic upregulation of SP-B mRNA expression induced by co-administration of various glucocorticoids and caffeine, achieved by accumulation of intracellular cAMP. This effect was mediated by a caffeinedependent phosphodiesterase inhibition and by upregulation of both ErbB4 and the GR. These results suggested that caffeine is able to induce the expression of SP-transcription factors and affects the signaling pathways of glucocorticoids, amplifying their effects. Co-administration of caffeine and corticosteroids may therefore be of benefit in surfactant homeostasis. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77927 ER - TY - JOUR A1 - Benkert, Thomas F. A1 - Dietz, Lena A1 - Hartmann, Elena M. A1 - Leich, Ellen A1 - Rosenwald, Andreas A1 - Serfling, Edgar A1 - Buttmann, Mathias A1 - Berberich-Siebelt, Friederike T1 - Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis N2 - Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-c and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-c and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77905 ER - TY - RPRT A1 - Linker, Ralf, A. A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph T1 - Report on the 4'th scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report] N2 - From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year’s keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of Düsseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76407 ER - TY - JOUR A1 - Matlach, Juliane A1 - Slobodda, Joerg A1 - Grehn, Franz A1 - Klink, Thomas T1 - Pars plana vitrectomy for malignant glaucoma in non-glaucomatous and in filtered glaucomatous eyes N2 - Purpose: To assess the outcomes of pars plana vitrectomy for the treatment of malignant glaucoma in patients with and without previous filtration surgery. Patients and methods: Data of 15 patients developing malignant glaucoma after trabeculectomy (60%) or following ophthalmic interventions other than filtration surgery (40%) were recorded retrospectively. Pars plana vitrectomy was performed in case of failed medical or laser treatment recreating the normal pathway of aqueous humor. The main outcome measures were the postoperative intraocular pressure (IOP), the frequency of complications, and success rate based on the following criteria: IOP reduction by $20% and to #21 mmHg (definition one) or an IOP , 18 mmHg (definition two) with (qualified success) and without (complete success) glaucoma medication. Results: Vitrectomy reduced IOP from baseline in eyes with and without previous trabeculectomy during a median follow-up of 16.4 months (range 7 days to 58 months); although the majority of patients required glaucoma medication to reach desired IOP. The complete success rates were 11% (both definitions) for patients with filtering blebs and none of the patients without previous trabeculectomy had complete success at the 12-month visit. Complications were few and included transient shallowing of the anterior chamber, choroidal detachment, corneal decompensation, filtering bleb failure, and need for further IOP-lowering procedures. Conclusion: Pars plana vitrectomy is equally effective for malignant glaucoma caused by trabeculectomy or interventions other than filtration surgery, although IOP-lowering medication is necessary in nearly all cases to maintain target IOP. KW - Medizin KW - ciliolenticular block glaucoma KW - malignant glaucoma KW - pars plana vitrectomy KW - trabeculectomy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76375 ER - TY - JOUR A1 - Schulte, Leon N. A1 - Westermann, Alexander J. A1 - Vogel, Jörg T1 - Differential activation and functional specialization of miR-146 and miR-155 in innate immune sensing N2 - Many microRNAs (miRNAs) are co-regulated during the same physiological process but the underlying cellular logic is often little understood. The conserved, immunomodulatory miRNAs miR-146 and miR-155, for instance, are co-induced in many cell types in response to microbial lipopolysaccharide (LPS) to feedback-repress LPS signalling through Toll-like receptor TLR4. Here, we report that these seemingly co-induced regulatory RNAs dramatically differ in their induction behaviour under various stimuli strengths and act non-redundantly through functional specialization; although miR-146 expression saturates at sub-inflammatory doses of LPS that do not trigger the messengers of inflammation markers, miR-155 remains tightly associated with the pro-inflammatory transcriptional programmes. Consequently, we found that both miRNAs control distinct mRNA target profiles; although miR-146 targets the messengers of LPS signal transduction components and thus downregulates cellular LPS sensitivity, miR-155 targets the mRNAs of genes pervasively involved in pro-inflammatory transcriptional programmes. Thus, miR-155 acts as a broad limiter of pro-inflammatory gene expression once the miR-146 dependent barrier to LPS triggered inflammation has been breached. Importantly, we also report alternative miR-155 activation by the sensing of bacterial peptidoglycan through cytoplasmic NOD-like receptor, NOD2. We predict that dosedependent responses to environmental stimuli may involve functional specialization of seemingly coinduced miRNAs in other cellular circuitries as well. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76365 ET - Advance Access ER - TY - JOUR A1 - Zeller, Daniel A1 - Dang, Su-Yin A1 - Weise, David A1 - Rieckmann, Peter A1 - Toyka, Klaus V. A1 - Classen, Joseph T1 - Excitability decreasing central motor plasticity is retained in multiple sclerosis patients N2 - Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS. KW - Medizin KW - Multiple sclerosis KW - LTD KW - Motor plasticity KW - TMS KW - Motor cortex Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76333 ER - TY - JOUR A1 - Laug, Roderich A1 - Fehrholz, Markus A1 - Schütze, Norbert A1 - Kramer, Boris W. A1 - Krump-Konvalinkova, Vera A1 - Speer, Christian P. A1 - Kunzmann, Steffen T1 - IFN-gamma and TNF-alpha synergize to inhibit CTGF expression in human lung endothelial cells N2 - Connective tissue growth factor (CTGF/CCN2) is an angiogenetic and profibrotic factor, acting downstream of TGF-b, involved in both airway- and vascular remodeling. While the T-helper 1 (Th1) cytokine interferon-gamma (IFN-c) is well characterized as immune-modulatory and anti-fibrotic cytokine, the role of IFN-c in lung endothelial cells (LEC) is less defined. Tumour necrosis factor alpha (TNF-a) is another mediator that drives vascular remodeling in inflammation by influencing CTGF expression. In the present study we investigated the influence of IFN-c and TNF-a on CTGF expression in human LEC (HPMEC-ST1.6R) and the effect of CTGF knock down on human LEC. IFN-c and TNF-a down-regulated CTGF in human LEC at the promoter-, transcriptional- and translational-level in a dose- and time-dependent manner. The inhibitory effect of IFN-c on CTGF-expression could be almost completely compensated by the Jak inhibitor AG-490, showing the involvement of the Jak-Stat signaling pathway. Besides the inhibitory effect of IFN-c and TNF-a alone on CTGF expression and LEC proliferation, these cytokines had an additive inhibitory effect on proliferation as well as on CTGF expression when administered together. To study the functional role of CTGF in LEC, endogenous CTGF expression was down-regulated by a lentiviral system. CTGF silencing in LEC by transduction of CTGF shRNA reduced cell proliferation, but did not influence the anti-proliferative effect of IFN-c and TNF-a. In conclusion, our data demonstrated that CTGF was negatively regulated by IFN-c in LEC in a Jak/Stat signaling pathway-dependent manner. In addition, an additive effect of IFN-c and TNF-a on inhibition of CTGF expression and cell proliferation could be found. The inverse correlation between IFN-c and CTGF expression in LEC could mean that screwing the Th2 response to a Th1 response with an additional IFN-c production might be beneficial to avoid airway remodeling in asthma. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76253 ER - TY - JOUR A1 - Kunze, Ekkehard A1 - Pham, Mirko A1 - Raslan, Furat A1 - Stetter, Christian A1 - Lee, Jin-Yul A1 - Solymosi, Laszlo A1 - Ernestus, Ralf-Ingo A1 - Hamilton Vince, Giles A1 - Westermaier, Thomas T1 - Value of Perfusion CT, Transcranial Doppler Sonography and Neurological Examination to detect delayed Vasospasm after aneurysmal Subarachnoid Hemorrhage [Research Article] N2 - Background If detected in time, delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may be treated by balloon angioplasty or chemical vasospasmolysis in order to enhance cerebral blood flow (CBF) and protect the brain from ischemic damage. This study was conceived to compare the diagnostic accuracy of detailed neurological examination, Transcranial Doppler Sonography (TCD), and Perfusion-CT (PCT) to detect angiographic vasospasm. Methods The sensitivity, specificity, positive and negative predictive values of delayed ischemic neurological deterioration (DIND), pathological findings on PCT- maps, and accelerations of the mean flow velocity (MVF) were calculated. Results The accuracy of DIND to predict angiographic vasospasm was 0.88. An acceleration of MFV in TCD (>140 cm/s) had an accuracy of 0.64, positive PCT-findings of 0.69 with a higher sensitivity, and negative predictive value than TCD. Interpretation Neurological assessment at close intervals is the most sensitive and specific parameter for cerebral vasospasm. PCT has a higher accuracy, sensitivity and negative predictive value than TCD. If detailed neurological evaluation is possible, it should be the leading parameter in the management and treatment decisions. If patients are not amenable to detailed neurological examination, PCT at regular intervals is a helpful tool to diagnose secondary vasospasm after aneurysmal SAH. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76241 ER - TY - JOUR A1 - Li, Xiang A1 - Samnick, Samuel A1 - Lapa, Constantin A1 - Israel, Ina A1 - Buck, Andreas K. A1 - Kreissl, Michael C. A1 - Bauer, Wolfgang T1 - 68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with18F-FDG, calcium burden and risk factors N2 - Background: Ga-[1,4,7,10-tetraazacyclododecane-N,N0,N00,N000-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. Methods: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. Results: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2%) had a colocalized 68Ga-DOTATATE accumulation. Conclusions: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions. KW - Medizin KW - Atherosclerotic plaque KW - 68Ga-DOTATATE KW - Somatostatin receptor KW - Cardiovascular risk factors KW - Macrophage Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76231 ER - TY - JOUR A1 - Raslan, Furat A1 - Albert-Weißenberger, Christiane A1 - Westermaier, Thomas A1 - Saker, Saker A1 - Kleinschmitz, Christoph A1 - Lee, Jin-Yul T1 - A modified double injection model of cisterna magna for the study of delayed cerebral vasospasm following subarachnoid hemorrhage in rats N2 - Delayed cerebral vasospasm following subarachnoid hemorrhage (SAH) is a serious medical complication, characterized by constriction of cerebral arteries leading to varying degrees of cerebral ischemia. Numerous clinical and experimental studies have been performed in the last decades; however, the pathophysiologic mechanism of cerebral vasospasm after SAH still remains unclear. Among a variety of experimental SAH models, the double hemorrhage rat model involving direct injection of autologous arterial blood into the cisterna magna has been used most frequently for the study of delayed cerebral vasospasm following SAH in last years. Despite the simplicity of the technique, the second blood injection into the cisterna magna may result in brainstem injury leading to high mortality. Therefore, a modified double hemorrhage model of cisterna magna has been developed in rat recently. We describe here step by step the surgical technique to induce double SAH and compare the degree of vasospasm with other cisterna magna rat models using histological assessment of the diameter and cross-sectional area of the basilar artery KW - Medizin KW - Cerebral vasospasm KW - Cisterna magna KW - Double hemorrhage model KW - Rat KW - Subarachnoid Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76038 ER - TY - JOUR A1 - Langenhorst, Daniela A1 - Gogishvili, Tea A1 - Ribechini, Eliana A1 - Kneitz, Susanne A1 - McPherson, Kirsty A1 - Lutz, Manfred B. A1 - Hünig, Thomas T1 - Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells N2 - The ability of CD4+Foxp3+ regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7+CCR52 lymph node-seeking to a CCR72CCR5+ inflammationseeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76009 ER - TY - JOUR A1 - Kannen, Vinicius A1 - Hintzsche, Henning A1 - Zanette, Dalila L. A1 - Silva Jr., Wilson A. A1 - Garcia, Sergio B. A1 - Waaga-Gasser, Anna Maria A1 - Stopper, Helga T1 - Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model N2 - The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G0/G1 phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75879 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Hawkins, Maria A1 - Flentje, Michael A1 - Sweeney, Reinhart A. T1 - Fractionated radiosurgery for painful spinal metastases: DOSIS - a phase II trial N2 - Background One third of all cancer patients will develop bone metastases and the vertebral column is involved in approximately 70 % of these patients. Conventional radiotherapy with of 1–10 fractions and total doses of 8-30 Gy is the current standard for painful vertebral metastases; however, the median pain response is short with 3–6 months and local tumor control is limited with these rather low irradiation doses. Recent advances in radiotherapy technology – intensity modulated radiotherapy for generation of highly conformal dose distributions and image-guidance for precise treatment delivery – have made dose-escalated radiosurgery of spinal metastases possible and early results of pain and local tumor control are promising. The current study will investigate efficacy and safety of radiosurgery for painful vertebral metastases and three characteristics will distinguish this study. 1) A prognostic score for overall survival will be used for selection of patients with longer life expectancy to allow for analysis of long-term efficacy and safety. 2) Fractionated radiosurgery will be performed with the number of treatment fractions adjusted to either good (10 fractions) or intermediate (5 fractions) life expectancy. Fractionation will allow inclusion of tumors immediately abutting the spinal cord due to higher biological effective doses at the tumor - spinal cord interface compared to single fraction treatment. 3) Dose intensification will be performed in the involved parts of the vertebrae only, while uninvolved parts are treated with conventional doses using the simultaneous integrated boost concept. Methods / Design It is the study hypothesis that hypo-fractionated image-guided radiosurgery significantly improves pain relief compared to historic data of conventionally fractionated radiotherapy. Primary endpoint is pain response 3 months after radiosurgery, which is defined as pain reduction of ≥2 points at the treated vertebral site on the 0 to 10 Visual Analogue Scale. 60 patients will be included into this two-centre phase II trial. Conclusions Results of this study will refine the methods of patient selection, target volume definition, treatment planning and delivery as well as quality assurance for radiosurgery. It is the intention of this study to form the basis for a future randomized controlled trial comparing conventional radiotherapy with fractionated radiosurgery for palliation of painful vertebral metastases. Trial registration ClinicalTrials.gov Identifier: NCT01594892 KW - Medizin KW - Phase II trial KW - Spinal metastasis KW - Pain KW - Radiosurgery KW - Stereotactic body radiotherapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75853 ER - TY - JOUR A1 - Weber, Heike A1 - Scholz, Claus Jürgen A1 - Domschke, Katharina A1 - Baumann, Christian A1 - Klauke, Benedikt A1 - Jacob, Christian P. A1 - Maier, Wolfgang A1 - Fritze, Jürgen A1 - Bandelow, Borwin A1 - Zwanzger, Peter Michael A1 - Lang, Thomas A1 - Fehm, Lydia A1 - Ströhle, Andreas A1 - Hamm, Alfons A1 - Gerlach, Alexander L. A1 - Alpers, Georg W. A1 - Kircher, Tilo A1 - Wittchen, Hans-Ulrich A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Reif, Andreas T1 - Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder N2 - Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75830 ER - TY - JOUR A1 - Thein, Marcus A1 - Bonde, Mari A1 - Bunikis, Ignas A1 - Denker, Katrin A1 - Sickmann, Albert A1 - Bergström, Sven A1 - Benz, Roland T1 - DipA, a Pore-Forming Protein in the Outer Membrane of Lyme Disease Spirochetes Exhibits Specificity for the Permeation of Dicarboxylates N2 - Lyme disease Borreliae are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography from Borrelia burgdorferi B31 and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borreliae. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a singlechannel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl) were obtained among the 11 tested anions for oxaloacetate, 2-oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75809 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Raslan, Furat A1 - Vinc, Giles Hamilton A1 - Ernestus, Ralf-Ingo T1 - Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats N2 - Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH. KW - Medizin KW - Subarachnoid hemorrhage KW - Cerebral blood flow KW - Brain ischemia KW - Brain edema KW - Animal models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75765 ER - TY - JOUR A1 - Serfling, Edgar A1 - Avots, Andris A1 - Klein-Hessling, Stefan A1 - Rudolf, Ronald A1 - Vaeth, Martin A1 - Berberich-Siebelt, Friederike T1 - NFATc1/alphaA: The other Face of NFAT Factors in Lymphocytes N2 - In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin and the translocation of NFAT transcription factors from cytosol to nucleus. In addition to this first wave of NFAT activation, in a second step the occurrence of NFATc1/αA, a short isoform of NFATc1, is strongly induced. Upon primary stimulation of lymphocytes the induction of NFATc1/αA takes place during the G1 phase of cell cycle. Due to an auto-regulatory feedback circuit high levels of NFATc1/αA are kept constant during persistent immune receptor stimulation. Contrary to NFATc2 and further NFATc proteins which dampen lymphocyte proliferation, induce anergy and enhance activation induced cell death (AICD), NFATc1/αA supports antigenmediated proliferation and protects lymphocytes against rapid AICD. Whereas high concentrations of NFATc1/αA can also lead to apoptosis, in collaboration with NF-κB-inducing co-stimulatory signals they support the survival of mature lymphocytes in late phases after their activation. However, if dysregulated, NFATc1/αA appears to contribute to lymphoma genesis and – as we assume – to further disorders of the lymphoid system. While the molecular details of NFATc1/αA action and its contribution to lymphoid disorders have to be investigated, NFATc1/αA differs in its generation and function markedly from all the other NFAT proteins which are expressed in lymphoid cells. Therefore, it represents a prime target for causal therapies of immune disorders in future. KW - Medizin KW - Activation induced cell death/AICD KW - Anergy KW - Apoptosis KW - Calcineurin KW - NFATc KW - NFATc1/αA KW - NF-κB KW - Proliferation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75748 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Alexandrow, Nikolaus A1 - Flentje, Michael T1 - Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation N2 - Background: To analyze long-term results of radiotherapy alone for stage I-III low grade follicular lymphoma and to compare outcome after extended field irradiation (EFI) and total nodal irradiation (TNI). Methods and materials: Between 1982 and 2007, 107 patients were treated with radiotherapy alone for low grade follicular lymphoma at Ann Arbor stage I (n = 50), II (n = 36) and III (n = 21); 48 and 59 patients were treated with EFI and TNI, respectively. The median total dose in the first treatment series of the diaphragmatic side with larger lymphoma burden was 38 Gy (25 Gy – 50 Gy) and after an interval of median 30 days, a total dose of 28 Gy (12.6 Gy – 45 Gy) was given in the second treatment series completing TNI. Results: After a median follow-up of 14 years for living patients, 10-years and 15-years overall survival (OS) were 64% and 50%, respectively. Survival was not significantly different between stages I, II and III. TNI and EFI resulted in 15-years OS of 65% and 34% but patients treated with TNI were younger, had better performance status and higher stage of disease compared to patients treated with EFI. In multivariate analysis, only age at diagnosis (p<0.001, relative risk [RR] 1.06) and Karnofsky performance status (p = 0.04, RR = 0.96) were significantly correlated with OS. Freedom from progression (FFP) was 58% and 56% after 10-years and 15-years, respectively. Recurrences outside the irradiated volume were significantly reduced after TNI compared to EFI; however, increased rates of in-field recurrences and extra-nodal out-of-field recurrence counterbalanced this effect resulting in no significant difference in FFP between TNI and EFI. In univariate analysis, FFP was significantly improved in stage I compared to stage II but no differences were observed between stages I/II and stage III. In multivariate analysis no patient or treatment parameter was correlated with FFP. Acute toxicity was significantly increased after TNI compared to EFI with a trend to increased late toxicity as well. Conclusions: Radiotherapy alone for stage I and II follicular lymphoma resulted in long-term OS with high rates of disease control; no benefit of TNI over EFI was observed. For stage III follicular lymphoma, TNI achieved promising OS and FFP and should be considered as a potentially curative treatment option. KW - Medizin KW - Follicular lymphoma KW - Total nodal irradiation KW - Extended field irradiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75702 ER - TY - JOUR A1 - Sweeney, Reinhart A. A1 - Seubert, Benedikt A1 - Stark, Silke A1 - Homann, Vanessa A1 - Müller, Gerd A1 - Flentje, Michael A1 - Guckenbeger, Matthias T1 - Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors N2 - Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1–3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 % and 7.1 % observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability. KW - Medizin KW - Lung cancer KW - Image-guidance KW - Cone-beam CT KW - Inter-observer variability KW - Respiration correlated imaging Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75698 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Roesch, Johannes A1 - Baier, Kurt A1 - Sweeney, Reinhart A. A1 - Flentje, Michael T1 - Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery N2 - Background: To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery (IG-RS) for brain metastases. Methods and materials: Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- and posttreatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated. Results: Errors prior to IG were 3.9 mm± 1.7 mm (3D vector) and the maximum rotational error was 1.7° ± 0.8° on average. The post-treatment 3D error was 0.9 mm± 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7mm±0.5mm and 1.2mm±0.7mm for treatment times ≤23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image-guidance reduced target coverage and conformity to 75% ± 19% and 60% ± 25% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6% and 10% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion. Conclusions: IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra-fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins. KW - Medizin KW - Radiosurgery KW - Frame-less KW - Frame-based KW - Stereotactic KW - Image-guidance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75669 ER - TY - JOUR A1 - Wieching, Anna A1 - Benser, Jasmin A1 - Kohlhauser-Vollmuth, Christina A1 - Weisbrich, Bendikt A1 - Streng, Andrea A1 - Liese, Johannes G. T1 - Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza a (H1N1) in Northern Bavaria, Germany N2 - Background: The 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18 years of age. All hospitalized cases of children <18 years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications. Results: Between July 2009 and March 2010, 94 PIAH (62% males) occurred in children <18 years of age, with a median age of 7 years (IQR: 3–12 years). Underlying diseases and predisposing factors were documented in 40 (43%) children; obesity (n = 12, 30%), asthma (n = 10, 25%) and neurologic disorders (n = 8, 20%) were most frequently reported. Sixteen (17%) children received oxygen supplementation; three (3%) children required mechanical ventilation. Six (6%) children were admitted to an intensive care unit, four of them with underlying chronic diseases. Conclusions: Most PIAH demonstrated a benign course of disease. However, six children (6%) needed treatment at an intensive care unit for severe complications. KW - Medizin KW - Influenza KW - Pediatric KW - Infectious disease KW - Hospitalization Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75657 ER - TY - JOUR A1 - Kreissl, Michael C. A1 - Hänscheid, Heribert A1 - Löhr, Mario A1 - Verburg, Frederik A. A1 - Schiller, Markus A1 - Lassmann, Michael A1 - Reiners, Christoph A1 - Samnick, Samuel S. A1 - Buck, Andreas K. A1 - Flentje, Michael A1 - Sweeney, Reinhart A. T1 - Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma N2 - Background: External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. Methods: 10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5–6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3–6 months. Side effects were evaluated according to CTCAE 4.0. Results: Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects>CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUVmax in the meningiomas was 14.2 (range: 4.3–68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUVmax (median: 37%; range: 15%–46%) to a median value of 23.7 (range: 8.0–119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21% of the initial volume. Conclusions: The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated. KW - Medizin KW - PRRT KW - Peptide receptor radionuclide therapy KW - Meningioma KW - Radiotherapy KW - EBRT KW - Combination Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75540 ER - TY - JOUR A1 - Lutz, Manfred B. T1 - Therapeutic Potential of Semi-Mature Dendritic Cells for Tolerance Induction N2 - Dendritic cells (DCs) are major players in the control of adaptive tolerance and immunity. Therefore, their specific generation and adoptive transfer into patients or their in vivo targeting is attractive for clinical applications. While injections of mature immunogenic DCs are tested in clinical trials, tolerogenic DCs still are awaiting this step. Besides the tolerogenic potential of immature DCs, also semi-mature DCs can show tolerogenic activity but both types also bear unfavorable features. Optimal tolerogenic DCs, their molecular tool bar, and their use for specific diseases still have to be defined. Here, the usefulness of in vitro generated and adoptively transferred semi-mature DCs for tolerance induction is outlined. The in vivo targeting of semi-mature DCs as represented by steady state migratory DCs are discussed for treatment of autoimmune diseases and allergies. First clinical trials with transcutaneous allergen application may point to their therapeutic use in the future. KW - Medizin KW - dendritic cells KW - tolerance KW - epicutaneous KW - transcutaneous KW - steady state KW - migration Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75535 ER - TY - JOUR A1 - Neubauer, Henning A1 - Evangelista, Laura A1 - Morbach, Henner A1 - Girschick, Hermann A1 - Prelog, Martina A1 - Köstler, Herbert A1 - Hahn, Dietbert A1 - Beer, Meinrad T1 - Diffusion-weighted MRI of bone marrow oedema, soft tissue oedema and synovitis in paediatric patients: feasibility and initial experience N2 - Background: MRI has become the mainstay of diagnostic imaging in paediatric rheumatology for lesion detection, differential diagnosis and therapy surveillance. MR imaging of synovitis, in particular, is indispensable for early diagnosis and follow-up in arthritis patients. We used diffusion-weighted MRI (DWI) as a new imaging modality in comparison to standard MRI sequences to study bone marrow oedema, soft-tissue oedema and synovitis in paediatric patients. Methods: A total of 52 patients (mean age 11 ± 5 years) with bone marrow oedema (n = 31), soft-tissue oedema (n = 20) and synovitis (n = 15) were examined with transversal diffusion-weighted single-shot echoplanar imaging in addition to standard MR sequences (T2W TIRM, T1W pre- and post-contrast). Diffusion-weighted images were used for lesion detection and apparent diffusion coefficient (ADC, unit × 10-3 mm2/s) values were measured with ROI technique on ADC maps. Results: In 50 of 52 patients, DWI delineated the lesion of interest corresponding to pathological signal increase on standard sequences. Mean ADC was 1.60 ± 0.14 (range 1.38 - 1.99) in osseous lesions, 1.72 ± 0.31 (range 1.43 - 2.56) in soft tissue oedema and 2.82 ± 0.24 (range 2.47 - 3.18) for joint effusion (ANOVA p<0.001). No significant difference in mean ADC was seen for inflammatory vs. non-inflammatory lesions. Relative signal intensity of oedema was similar for DWI and T2W TIRM. DWI visualised synovial restricted diffusion with a mean ADC of 2.12 ± 0.45 in 12 of 15 patients with synovitis. Conclusions: Diffusion-weighted MRI reliably visualises osseous and soft tissue oedema, as compared to standard sequences. DWI of synovitis is feasible in large joints and presents a novel approach to contrast-free imaging of synovitis. Whole-body DWI for chronic non-bacterial osteomyelitis should be evaluated in future studies. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75521 ER - TY - JOUR A1 - Homola, György A. A1 - Jbabdi, Saad A1 - Beckmann, Christian F. A1 - Bartsch, Andreas J. T1 - A Brain Network Processing the Age of Faces N2 - Age is one of the most salient aspects in faces and of fundamental cognitive and social relevance. Although face processing has been studied extensively, brain regions responsive to age have yet to be localized. Using evocative face morphs and fMRI, we segregate two areas extending beyond the previously established face-sensitive core network, centered on the inferior temporal sulci and angular gyri bilaterally, both of which process changes of facial age. By means of probabilistic tractography, we compare their patterns of functional activation and structural connectivity. The ventral portion of Wernicke’s understudied perpendicular association fasciculus is shown to interconnect the two areas, and activation within these clusters is related to the probability of fiber connectivity between them. In addition, post-hoc age-rating competence is found to be associated with high response magnitudes in the left angular gyrus. Our results provide the first evidence that facial age has a distinct representation pattern in the posterior human brain. We propose that particular face-sensitive nodes interact with additional object-unselective quantification modules to obtain individual estimates of facial age. This brain network processing the age of faces differs from the cortical areas that have previously been linked to less developmental but instantly changeable face aspects. Our probabilistic method of associating activations with connectivity patterns reveals an exemplary link that can be used to further study, assess and quantify structure-function relationships. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75513 ER - TY - JOUR A1 - Steinert, Andre F. A1 - Weissenberger, Manuel A1 - Kunz, Manuela A1 - Gilbert, Fabian A1 - Ghivizzani, Steven C. A1 - Goebel, Sascha A1 - Jakob, Franz A1 - Nöth, Ulrich A1 - Rudert, Maximilian T1 - Indian hedgehog gene transfer is a chondrogenic inducer of human mesenchymal stem cells N2 - Introduction: To date, no single most-appropriate factor or delivery method has been identified for the purpose of mesenchymal stem cell (MSC)-based treatment of cartilage injury. Therefore, in this study we tested whether gene delivery of the growth factor Indian hedgehog (IHH) was able to induce chondrogenesis in human primary MSCs, and whether it was possible by such an approach to modulate the appearance of chondrogenic hypertrophy in pellet cultures in vitro. Methods: First-generation adenoviral vectors encoding the cDNA of the human IHH gene were created by cre-lox recombination and used alone or in combination with adenoviral vectors, bone morphogenetic protein-2 (Ad.BMP- 2), or transforming growth factor beta-1 (Ad.TGF-b1) to transduce human bone-marrow derived MSCs at 5 × 102 infectious particles/cell. Thereafter, 3 × 105 cells were seeded into aggregates and cultured for 3 weeks in serumfree medium, with untransduced or marker gene transduced cultures as controls. Transgene expressions were determined by ELISA, and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy. Results: IHH, TGF-b1 and BMP-2 genes were equipotent inducers of chondrogenesis in primary MSCs, as evidenced by strong staining for proteoglycans, collagen type II, increased levels of glycosaminoglycan synthesis, and expression of mRNAs associated with chondrogenesis. IHH-modified aggregates, alone or in combination, also showed a tendency to progress towards hypertrophy, as judged by the expression of alkaline phosphatase and stainings for collagen type X and Annexin 5. Conclusion: As this study provides evidence for chondrogenic induction of MSC aggregates in vitro via IHH gene delivery, this technology may be efficiently employed for generating cartilaginous repair tissues in vivo. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75425 ER - TY - JOUR A1 - Raslan, Furat A1 - Albert-Weißenberger, Christiane A1 - Ernestus, Ralf-Ingo A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - Focal brain trauma in the cryogenic lesion model in mice N2 - The method to induce unilateral cryogenic lesions was first described in 1958 by Klatzo. We describe here an adaptation of this model that allows reliable measurement of lesion volume and vasogenic edema by 2, 3, 5-triphenyltetrazolium chloride-staining and Evans blue extravasation in mice. A copper or aluminium cylinder with a tip diameter of 2.5 mm is cooled with liquid nitrogen and placed on the exposed skull bone over the parietal cortex (coordinates from bregma: 1.5 mm posterior, 1.5 mm lateral). The tip diameter and the contact time between the tip and the parietal skull determine the extent of cryolesion. Due to an early damage of the blood brain barrier, the cryogenic cortical injury is characterized by vasogenic edema, marked brain swelling, and inflammation. The lesion grows during the first 24 hours, a process involving complex interactions between endothelial cells, immune cells, cerebral blood flow, and the intracranial pressure. These contribute substantially to the damage from the initial injury. The major advantage of the cryogenic lesion model is the circumscribed and highly reproducible lesion size and location. KW - Medizin KW - Experimental brain trauma KW - Cryolesion KW - Secondary traumatic brain damage KW - Mice Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75419 ER -