TY - JOUR A1 - Güder, Gülmisal A1 - Brenner, Susanne A1 - Angermann, Christiane E. A1 - Ertl, Georg A1 - Held, Matthias A1 - Sachs, Alfred P. A1 - Lammers, Jan Willem A1 - Zanen, Peter A1 - Hoes, Arno W. A1 - Störk, Stefan A1 - Rutten, Frans H. T1 - "GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study" N2 - Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice. KW - Medizin KW - COPD diagnosis KW - lower limit of normal KW - GOLD KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75193 ER - TY - JOUR A1 - Klotz, Barbara A1 - Mentrup, Birgit A1 - Regensburger, Martina A1 - Zeck, Sabine A1 - Schneidereit, Jutta A1 - Schupp, Nicole A1 - Linden, Christian A1 - Merz, Cornelia A1 - Ebert, Regina A1 - Jakob, Franz T1 - 1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity JF - PLoS ONE N2 - 1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence-and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging. KW - perspectives KW - bone marrow KW - mutant mice KW - oxidative stress KW - transcription factors KW - vitamin-D-receptor KW - differentiation KW - tissue KW - 2',7'-dichlorofluorescin KW - homeostasis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133392 VL - 7 IS - 1 ER - TY - JOUR A1 - Finze, Maik A1 - Reiss, Guido J. A1 - Frohn, Hermann-Josef T1 - 2,3,5,6-Tetrafluoro-1,4-bis(trimethylsilyl)benzene N2 - no abstract available KW - Chemie KW - single-crystal X-ray study KW - T = 199 K KW - R factor = 0.027 KW - wR factor = 0.068 KW - data-to-parameter ratio = 14.0. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75401 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 - 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 - Hagemann, Carsten A1 - Anacker, Jelena A1 - Ernestus, Ralf-Ingo A1 - Vince, Giles H. T1 - A complete compilation of matrix metalloproteinase expression in human malignant gliomas JF - World Journal of Clinical Oncology N2 - Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy. KW - glioblastoma cell-lines KW - matrix metalloproteinase KW - glioblastoma multiforme KW - astrocytic tumor KW - expression pattern Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123982 VL - 3 IS - 5 ER - TY - JOUR A1 - Fröhlich, Kathrin S. A1 - Papenfort, Kai A1 - Berger, Allison A. A1 - Vogel, Jörg T1 - A conserved RpoS-dependent small RNA controls the synthesis of major porin OmpD JF - Nucleic Acids Research N2 - A remarkable feature of many small non-coding RNAs (sRNAs) of Escherichia coli and Salmonella is their accumulation in the stationary phase of bacterial growth. Several stress response regulators and sigma factors have been reported to direct the transcription of stationary phase-specific sRNAs, but a widely conserved sRNA gene that is controlled by the major stationary phase and stress sigma factor, Sigma(S) (RpoS), has remained elusive. We have studied in Salmonella the conserved SdsR sRNA, previously known as RyeB, one of the most abundant stationary phase-specific sRNAs in E. coli. Alignments of the sdsR promoter region and genetic analysis strongly suggest that this sRNA gene is selectively transcribed by Sigma(S). We show that SdsR down-regulates the synthesis of the major Salmonella porin OmpD by Hfq-dependent base pairing; SdsR thus represents the fourth sRNA to regulate this major outer membrane porin. Similar to the InvR, MicC and RybB sRNAs, SdsR recognizes the ompD mRNA in the coding sequence, suggesting that this mRNA may be primarily targeted downstream of the start codon. The SdsR-binding site in ompD was localized by 3'-RACE, an experimental approach that promises to be of use in predicting other sRNA-target interactions in bacteria. KW - shock sigma factor KW - general stress response KW - down regulation KW - stationary phase KW - salmonella enterica KW - messenger RNA KW - escherichia coli KW - enterica serovar typhimurium KW - outer-membrane proteins KW - small noncoding RNAs Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134230 VL - 40 IS - 8 ER - TY - JOUR A1 - Jain, M. A1 - Vélez, J. I. A1 - Acosta, M. T. A1 - Palacio, L. G. A1 - Balog, J. A1 - Roessler, E. A1 - Pineda, D. A1 - Londoño, A. C. A1 - Palacio, J. D. A1 - Arbelaez, A. A1 - Lopera, F. A1 - Elia, J. A1 - Hakonarson, H. A1 - Seitz, C. A1 - Freitag, C. M. A1 - Palmason, H. A1 - Meyer, J. A1 - Romanos, M. A1 - Walitza, S. A1 - Hemminger, U. A1 - Warnke, A. A1 - Romanos, J. A1 - Renner, T. A1 - Jacob, C. A1 - Lesch, K.-P. A1 - Swanson, J. A1 - Castellanos, F. X. A1 - Bailey-Wilson, J. E. A1 - Arcos-Burgos, M. A1 - Muenke, M. T1 - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD JF - Molecular Psychiatry N2 - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome. KW - ADHD KW - genetic interaction KW - LPHN3 KW - NCAM1 KW - DRD2 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125128 VL - 17 ER - TY - JOUR A1 - Staiger, Christine A1 - Cadot, Sidney A1 - Kooter, Raul A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Klau, Gunnar W. A1 - Wessels, Lodewyk F. A. T1 - A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer JF - PLoS One N2 - Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer. KW - modules KW - protein-interaction networks KW - expression signature KW - classification KW - set KW - metastasis KW - stability KW - survival KW - database KW - markers Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131323 VL - 7 IS - 4 ER - TY - JOUR A1 - Reuss, Heiko A1 - Kiesel, Andrea A1 - Kunde, Wilfried A1 - Wühr, Peter T1 - A cue from the unconscious - masked symbols prompt spatial anticipation JF - Frontiers in Psychology N2 - Anticipating where an event will occur enables us to instantaneously respond to events that occur at the expected location. Here we investigated if such spatial anticipations can be triggered by symbolic information that participants cannot consciously see. In two experiments involving a Posner cueing task and a visual search task, a central cue informed participants about the likely location of the next target stimulus. In half of the trials, this cue was rendered invisible by pattern masking. In both experiments, visible cues led to cueing effects, that is, faster responses after valid compared to invalid cues. Importantly, even masked cues caused cueing effects, though to a lesser extent. Additionally, we analyzed effects on attention that persist from one trial to the subsequent trial. We found that spatial anticipations are able to interfere with newly formed spatial anticipations and influence orienting of attention in the subsequent trial. When the preceding cue was visible, the corresponding spatial anticipation persisted to an extent that prevented a noticeable effect of masked cues. The effects of visible cues were likewise modulated by previous spatial anticipations, but were strong enough to also exert an impact on attention themselves. Altogether, the results suggest that spatial anticipations can be formed on the basis of unconscious stimuli, but that interfering influences like still active spatial anticipations can suppress this effect. KW - masked priming KW - unconscious processing KW - anticipation KW - endogenous shifts of attention KW - spatial cueing Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123971 VL - 3 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 - Molochnikov, Leonid A1 - Rabey, Jose M. A1 - Dobronevsky, Evgenya A1 - Bonuccelli, Ubaldo A1 - Ceravolo, Roberto A1 - Frosini, Daniela A1 - Grünblatt, Edna A1 - Riederer, Peter A1 - Jacob, Christian A1 - Aharon-Peretz, Judith A1 - Bashenko, Yulia A1 - Youdim, Moussa B. H. A1 - Mandel, Silvia A. T1 - A molecular signature in blood identifies early Parkinson's disease JF - Molecular Neurodegeneration N2 - Background: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. Results: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). Conclusions: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder. KW - cerebrospina KW - magnetic-resonance-spectroscopy KW - protein KW - biomarkers KW - E3 ubiquitin ligase KW - SCF KW - SKP1 KW - heat shock protein Hsc-70 KW - early diagnosis KW - fluid KW - alpha-synuclein KW - dehydrogenases KW - Alzheimer's disease KW - sporadic Parkinson's disease KW - blood biomarker KW - CSF KW - multiple system atrophy KW - clinical diagnosis KW - substantia nigra KW - gene expression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134508 VL - 7 IS - 26 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study JF - BMC Nephrology N2 - Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23-6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8.15.7 +/- 14.3% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - XA KW - low molecular weight KW - severe renal insufficiency KW - unfractionated heparin KW - standard heparin KW - enoxaparin KW - metaanalysis KW - coagulation KW - fragmin KW - sodium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134845 VL - 13 IS - 50 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis – the membrane study JF - BMC Nephrology N2 - Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26–90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23–6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters’ visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400–6000) and 4200 (3000–6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21–0.27], 0.33 [0.27–0.40] and 0.38 [0.33–0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01–0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19–3.24] and 3.66 [3.00–4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - hemodialysis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124052 VL - 13 IS - 50 ER - TY - JOUR A1 - Hardcastle, Nicholas A1 - Tomé, Wolfgang A. A1 - Cannon, Donald M. A1 - Brouwer, Charlotte L. A1 - Wittendorp, Paul W. H. A1 - Dogan, Nesrin A1 - Guckenberger, Matthias A1 - Allaire, Stéphane A1 - Mallya, Yogish A1 - Kumar, Prashant A1 - Oechsner, Markus A1 - Richter, Anne A1 - Song, Shiyu A1 - Myers, Michael A1 - Polat, Bülent A1 - Bzdusek, Karl T1 - A multi-institution evaluation of deformable image registration algorithms for automatic organ delineation in adaptive head and neck radiotherapy JF - Radiation Oncology N2 - Background: Adaptive Radiotherapy aims to identify anatomical deviations during a radiotherapy course and modify the treatment plan to maintain treatment objectives. This requires regions of interest (ROIs) to be defined using the most recent imaging data. This study investigates the clinical utility of using deformable image registration (DIR) to automatically propagate ROIs. Methods: Target (GTV) and organ-at-risk (OAR) ROIs were non-rigidly propagated from a planning CT scan to a per-treatment CT scan for 22 patients. Propagated ROIs were quantitatively compared with expert physician-drawn ROIs on the per-treatment scan using Dice scores and mean slicewise Hausdorff distances, and center of mass distances for GTVs. The propagated ROIs were qualitatively examined by experts and scored based on their clinical utility. Results: Good agreement between the DIR-propagated ROIs and expert-drawn ROIs was observed based on the metrics used. 94% of all ROIs generated using DIR were scored as being clinically useful, requiring minimal or no edits. However, 27% (12/44) of the GTVs required major edits. Conclusion: DIR was successfully used on 22 patients to propagate target and OAR structures for ART with good anatomical agreement for OARs. It is recommended that propagated target structures be thoroughly reviewed by the treating physician. KW - intensity-modulated radiotherapy KW - megavoltage computed-tomography KW - cancer KW - variability KW - strategies KW - risk Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134756 VL - 7 IS - 90 ER - TY - JOUR A1 - Gavvovidis, Ioannis A1 - Rost, Isabell A1 - Trimborn, Marc A1 - Kaiser, Frank J. A1 - Purps, Josephine A1 - Wiek, Konstanze A1 - Haneberg, Helmut A1 - Neitzel, Heidemarie A1 - Schindler, Detlev T1 - A Novel MCPH1 Isoform Complements the Defective Chromosome Condensation of Human MCPH1-Deficient Cells N2 - Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 39 exons (MCPH1De9–14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1De9–14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level. KW - MCPH1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75050 ER - TY - JOUR A1 - Hofgaard, Peter O. A1 - Jodal, Henriette C. A1 - Bommert, Kurt A1 - Huard, Bertrand A1 - Caers, Jo A1 - Carlsen, Harald A1 - Schwarzer, Rolf A1 - Schünemann, Nicole A1 - Jundt, Franziska A1 - Lindeberg, Mona M. A1 - Bogen, Bjarne T1 - A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease JF - PLoS One N2 - Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10\(^4\) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM. KW - resistance KW - CD4(+) T-cells KW - tumor specific antigen KW - plasma cells KW - B cell KW - C57BL/KALWRIJ mouse KW - bone disease KW - scid mice KW - idiotype KW - differentiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131117 VL - 7 IS - 12 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity JF - Psychopharmacology N2 - RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - endocannabinoid KW - FAAH KW - genetics KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126845 VL - 224 IS - 4 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity JF - Psychopharmacology N2 - Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional–motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional–motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional–motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system’s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - FAAH KW - genetics KW - endocannabinoid KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129936 VL - 224 IS - 4 ER - TY - JOUR A1 - Weiße, Sebastian A1 - Heddergott, Niko A1 - Heydt, Matthias A1 - Pflästerer, Daniel A1 - Maier, Timo A1 - Haraszti, Tamas A1 - Grunze, Michael A1 - Engstler, Markus A1 - Rosenhahn, Axel T1 - A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy JF - PLoS One N2 - We present a quantitative 3D analysis of the motility of the blood parasite Trypanosoma brucei. Digital in-line holographic microscopy has been used to track single cells with high temporal and spatial accuracy to obtain quantitative data on their behavior. Comparing bloodstream form and insect form trypanosomes as well as mutant and wildtype cells under varying external conditions we were able to derive a general two-state-run-and-tumble-model for trypanosome motility. Differences in the motility of distinct strains indicate that adaption of the trypanosomes to their natural environments involves a change in their mode of swimming. KW - african trypanosomes KW - actin cortex KW - flagellum KW - tracking KW - surface KW - models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130666 VL - 7 IS - 5 ER - TY - JOUR A1 - Dupuis, Luc A1 - Dengler, Reinhard A1 - Heneka, Michael T. A1 - Meyer, Thomas A1 - Zierz, Stephan A1 - Kassubek, Jan A1 - Fischer, Wilhelm A1 - Steiner, Franziska A1 - Lindauer, Eva A1 - Otto, Markus A1 - Dreyhaupt, Jens A1 - Grehl, Torsten A1 - Hermann, Andreas A1 - Winkler, Andrea S. A1 - Bogdahn, Ulrich A1 - Benecke, Reiner A1 - Schrank, Bertold A1 - Wessig, Carsten A1 - Grosskreutz, Julian A1 - Ludolph, Albert C. T1 - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis JF - PLoS One N2 - Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. KW - ALS KW - transgenic mouse model KW - central nervous system KW - nonalcoholic steatohepatitis KW - PPAR-gamme KW - hexanucleotide repeat KW - disease progression KW - delays progression KW - SOD1 mutations KW - monocycline Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255 VL - 7 IS - 6 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Marzegan, Alberto A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Canesi, Margherita A1 - Biella, Gabriele E. M. A1 - Volkmann, Jens A1 - Cavallari, Paolo T1 - A role for locus coeruleus in Parkinson tremor JF - Frontiers in Human Neuroscience N2 - We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease(PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [\(^{123}\)I] N-\(\omega\)-fluoropropyl-2 \(\beta\)-carbomethoxy-3 \(\beta\)-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor. KW - locus coeruleus KW - disease KW - basal ganglia KW - resting tremor KW - functional neuroanatomy KW - dopamine KW - norepinephrine KW - progression KW - binding KW - rat KW - noradrenalin KW - parkinson disease KW - tremor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133955 VL - 5 IS - 179 ER - TY - JOUR T1 - A search for \(t\overline t\) resonances in lepton+jets events with highly boosted top quarks collected in pp collisions at √s=7 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - A search for resonant production of high-mass top-quark pairs is performed on 2.05 fb\(^{−1}\) of proton-proton collisions at √s=7 TeV collected in 2011 with the ATLAS experiment at the Large Hadron Collider. This analysis of the lepton+jets final state is specifically designed for the particular topology that arises from the decay of highly boosted top quarks. The observed \(t\overline t\) invariant mass spectrum is found to be compatible with the Standard Model prediction and 95% credibility level upper limits are derived on the \(t\overline t\) production rate through new massive states. An upper limit of 0.7 pb is set on the production cross section times branching fraction of a narrow 1 TeV resonance. A Kaluza-Klein gluon with a mass smaller than 1.5 TeV is excluded. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129555 VL - 09 IS - 41 ER - TY - JOUR T1 - A search for \(t\overline t\) resonances with the ATLAS detector in 2.05 fb\(^{−1}\) of proton-proton collisions at √s=7 TeV JF - European Physical Journal C N2 - A search for top quark pair resonances in final states containing at least one electron or muon has been performed with the ATLAS experiment at the CERN Large Hadron Collider. The search uses a data sample corresponding to an integrated luminosity of 2.05 fb\(^{−1}\), which was recorded in 2011 at a proton-proton centre-of-mass energy of 7 TeV. No evidence for a resonance is found and limits are set on the production cross-section times branching ratio to \(t\overline t\) for narrow and wide resonances. For narrow Z′ bosons, the observed 95 % Bayesian credibility level limits range from 9.3 pb to 0.95 pb for masses in the range of m Z′=500 GeV to m\(_{Z′}\)=1300 GeV. The corresponding excluded mass region for a leptophobic topcolour Z′ boson (Kaluza-Klein gluon excitation in the Randall-Sundrum model) is m\(_{Z′}\)<880 GeV (m\(_{gKK}\)<1130 GeV). KW - dilepton invariant mass KW - dilepton channel KW - jet channel KW - top quark mass KW - heavy flavour quark KW - reconstructed mass spectrum KW - muon channel KW - single top production KW - electron energy deposition KW - multijet background KW - non-prompt lepton KW - light quark jet KW - jet sample KW - pair invariant mass KW - event selcetion cut Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127959 VL - 72 IS - 2083 ER - TY - JOUR T1 - A search for flavour changing neutral currents in top-quark decays in pp collision data collected with the ATLAS detector at √s=7 TeV JF - Journal of High Energy Physics N2 - A search for flavour changing neutral current (FCNC) processes in top-quark decays by the ATLAS Collaboration is presented. Data collected from pp collisions at the LHC at a centre-of-mass energy of √s=7TeV during 2011, corresponding to an integrated luminosity of 2.1 fb\(^{−1}\), were used. A search was performed for top-quark pair-production events, with one top quark decaying through the t → Zq FCNC (q = u, c) channel, and the other through the Standard Model dominant mode t → W b. Only the decays of the Z boson to charged leptons and leptonic W -boson decays were considered as signal. Consequently, the final-state topology is characterised by the presence of three isolated charged leptons, at least two jets and missing transverse momentum from the undetected neutrino. No evidence for an FCNC signal was found. An upper limit on the t → Zq branching ratio of BR(t → Zq) < 0.73% is set at the 95% confidence level. KW - neutral currents KW - rare decays KW - top physics KW - hadron hadron scattering KW - flavour changing Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129152 VL - 9 IS - 139 ER - TY - JOUR A1 - Weisschuh, Nicole A1 - Wissinger, Bernd A1 - Gramer, Eugen T1 - A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia JF - Molecular Vision N2 - Purpose: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. Methods: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. Results: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a ‘run on’ translation past the normal translational stop codon. Conclusions: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124379 VL - 18 ER - TY - JOUR A1 - Jahn, Daniel A1 - Schramm, Sabine A1 - Schnölzer, Martina A1 - Heilmann, Clemens J. A1 - de Koster, Chris G. A1 - Schütz, Wolfgang A1 - Benavente, Ricardo A1 - Alsheimer, Manfred T1 - A truncated lamin A in the Lmna\(^{−/−}\) mouse line: Implications for the understanding of laminopathies JF - Nucleus N2 - During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna\(^{−/−}\)) by Sullivan and others,1 which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna\(^{−/−}\) mice and the concept of human laminopathies. KW - nuclear organization KW - A-type lamins KW - LMNA mutations KW - laminopathies KW - nuclear envelope KW - nuclear lamina Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127281 VL - 3 IS - 5 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 - Stolpmann, K. A1 - Brinkmann, J. A1 - Salzmann, S. A1 - Genkinger, D. A1 - Fritsche, E. A1 - Hutzler, C. A1 - Wajant, H. A1 - Luch, A. A1 - Henkler, F. T1 - Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis JF - Cell Death & Disease N2 - In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[ a] pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by beta-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure. KW - CD95 KW - HaCaT cells KW - growth-factor receptor KW - cell death KW - mitochondrial dysfunction KW - mediated apoptosis KW - FAS KW - dermatitis KW - pathways KW - skin KW - progression KW - aryl hydrocarbon receptor (AhR) KW - apoptosis KW - benzo[a]pyrene KW - human keratinocytes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133501 VL - 3 IS - e388 ER - TY - JOUR A1 - Hafner, Christian A1 - Houben, Roland A1 - Baeurle, Anne A1 - Ritter, Cathrin A1 - Schrama, David A1 - Landthaler, Michael A1 - Becker, Jürgen C. T1 - Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma JF - PLoS One N2 - Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients. KW - rare KW - T-antigen KW - PIK3CA mutations KW - squamous cell KW - melanoma KW - polymavirus KW - cancer KW - tumors KW - akt KW - expression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131398 VL - 7 IS - 2 ER - TY - JOUR A1 - Neubauer, Henning A1 - Wirth, Clemens A1 - Ruf, Katharina A1 - Hebestreit, Helge A1 - Beer, Meinrad T1 - Acute Muscle Trauma due to Overexercise in an Otherwise Healthy Patient with Cystic Fibrosis JF - Case Reports in Pediatrics N2 - Cystic fibrosis (CF) is one of the most common inherited diseases and is caused by mutations in the CFTR gene. Although the pulmonary and gastrointestinal manifestations of the disease remain in the focus of treatment, recent studies have shown expression of the CFTR gene product in skeletal muscle cells and observed altered intramuscular \(Ca^{2+}\) release dynamics in CFTR-deficient animal models. Physical exercise is beneficial for maintaining fitness and well-being in CF patients and constitutes one aspect of modern multimodal treatment, which has considerably increased life span and reduced morbidity. We report on a case of acute muscle trauma resulting from excessive dumbbell exercise in a young adult with cystic fibrosis and describe clinical, laboratory and imaging characteristics of acute exercise-induced muscle injury. KW - Cystic fibrosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123967 VL - 2012 IS - 527989 ER - TY - JOUR A1 - Neuhaus, Winfried A1 - Burek, Malgorzata A1 - Djuzenova, Cholpon C A1 - Thal, Serge C A1 - Koepsell, Hermann A1 - Roewer, Norbert A1 - Förster, Carola Y T1 - Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells N2 - During stroke the blood–brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907% after 6 h OGD and was still higher (210%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells. KW - Blut-Hirn-Schranke KW - Schlaganfall KW - Glucosetransportproteine KW - NMDA-Antagonist KW - NMDA-Rezeptor KW - blood-brain barrier KW - MK801 KW - NMDAR KW - stroke KW - glut1 KW - sglt1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67241 ER - TY - JOUR A1 - Müller, P.A. A1 - Bröcker, E.B. A1 - Klinker, E. A1 - Stoevesandt, J. A1 - Benoit, S. T1 - Adjuvant treatment of recalcitrant Bullous pemphigoid with immunoadsorption JF - Dermatology N2 - Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP. KW - Bullous pemphigoid KW - Immunoadsorption KW - Immunoapheresis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196620 SN - 1018-8665 SN - 1421-9832 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 224 IS - 3 SP - 224 EP - 227 ER - TY - JOUR A1 - Klauke, Benedikt A1 - Winter, Bernward A1 - Gajewska, Agnes A1 - Zwanzger, Peter A1 - Reif, Andreas A1 - Herrmann, Martin J. A1 - Dlugos, Andrea A1 - Warrings, Bodo A1 - Jacob, Christian A1 - Mühlberger, Andreas A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Domschke, Katharina T1 - Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma JF - PLoS One N2 - The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. KW - COMT VAL(158)MET polymorphism KW - serotonin transporter gene KW - life events KW - community sample KW - acoustic startle KW - prepulse inhibition KW - panic disorder KW - caffeine-induced anxiety KW - fear-potentiated startle KW - posttraumatic-stress-disorder Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132184 VL - 7 IS - 6 ER - TY - JOUR A1 - Jäger, Dominik A1 - Pernitzsch, Sandy R. A1 - Richter, Andreas S. A1 - Backofen, Rolf A1 - Sharma, Cynthia M. A1 - Schmitz, Ruth A. T1 - An archaeal sRNA targeting cis- and trans-encoded mRNAs via two distinct domains JF - Nucleic Acids Research N2 - We report on the characterization and target analysis of the small (s) RNA\(_{162}\) in the methanoarchaeon Methanosarcina mazei. Using a combination of genetic approaches, transcriptome analysis and computational predictions, the bicistronic MM2441-MM2440 mRNA encoding the transcription factor MM2441 and a protein of unknown function was identified as a potential target of this sRNA, which due to processing accumulates as three stabile 5' fragments in late exponential growth. Mobility shift assays using various mutants verified that the non-structured single-stranded linker region of sRNA\(_{162}\) (SLR) base-pairs with the MM2440-MM2441 mRNA internally, thereby masking the predicted ribosome binding site of MM2441. This most likely leads to translational repression of the second cistron resulting in dis-coordinated operon expression. Analysis of mutant RNAs in vivo confirmed that the SLR of sRNA\(_{162}\) is crucial for target interactions. Furthermore, our results indicate that sRNA\(_{162}\)-controlled MM2441 is involved in regulating the metabolic switch between the carbon sources methanol and methylamine. Moreover, biochemical studies demonstrated that the 50 end of sRNA\(_{162}\) targets the 5'-untranslated region of the cis-encoded MM2442 mRNA. Overall, this first study of archaeal sRNA/mRNA-target interactions unraveled that sRNA\(_{162}\) acts as an antisense (as) RNA on cis- and trans-encoded mRNAs via two distinct domains, indicating that cis-encoded asRNAs can have larger target regulons than previously anticipated. KW - strain KW - escherichia coli KW - methanosarcina mazei GO1 KW - methanol methyltransferase isozymes KW - small nucleolar RNAs KW - acetivorans C2A KW - antisense RNAs KW - GO1 KW - transcriptional regulator KW - translational initiation KW - pyrococcus furiosus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134972 VL - 40 IS - 21 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER - TY - JOUR A1 - Fernández-Rodríguez, Juana A1 - Quiles, Francisco A1 - Blanco, Ignacio A1 - Teulé, Alex A1 - Feliubadaló, Lídia A1 - del Valle, Jesús A1 - Salinas, Mónica A1 - Izquierdo, Ángel A1 - Darder, Esther A1 - Schindler, Detlev A1 - Capellá, Gabriel A1 - Brunet, Joan A1 - Lázaro, Conxi A1 - Angel Pujana, Miguel T1 - Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families JF - BMC Cancer N2 - Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease. KW - SLX4 KW - Holliday junction reolvass KW - Fanconi-anemia subtype KW - susceptibility gene KW - helicase BRIP1 KW - ovarian cancer KW - DNA repair KW - mutations KW - protein KW - RAD51C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131772 VL - 12 IS - 84 ER - TY - JOUR A1 - Zirkel, J. A1 - Cecil, A. A1 - Schäfer, F. A1 - Rahlfs, S. A1 - Ouedraogo, A. A1 - Xiao, K. A1 - Sawadogo, S. A1 - Coulibaly, B. A1 - Becker, K. A1 - Dandekar, T. T1 - Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling JF - Bioinformatics and Biology Insights N2 - BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data. RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs. CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas. KW - methylene blue KW - malaria KW - elementary mode analysis KW - drug KW - resistance KW - combination therapy KW - pathway KW - metabolic flux Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123751 N1 - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. VL - 6 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Szesny, Matthias A1 - Othman, Eman Maher A1 - Schirmeister, Tanja A1 - Grond, Stepanie A1 - Stopper, Helga A1 - Hentschel, Ute T1 - Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115 N2 - Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70–90 μM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 μM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate. KW - Biologie KW - diazepinomicin KW - anti-protease KW - antioxidant KW - actinomycetes KW - Micromonospora Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76279 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 - Jazbutyte, Virginija A1 - Stumpner, Jan A1 - Redel, Andreas A1 - Lorenzen, Johan M. A1 - Roewer, Norbert A1 - Thum, Thomas A1 - Kehl, Franz T1 - Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo JF - PLoS One N2 - The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17b- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94615.5% vs. 17.163.62%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model. KW - smooth muscle cells KW - estrogens KW - heart KW - anesthetics KW - immunostaining KW - endothelial cells KW - gene expression KW - myocardial infarction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151258 VL - 7 IS - 8 ER - TY - JOUR A1 - Schreiber, Ulrich A1 - Klughammer, Christof A1 - Kolbowski, Jörg T1 - Assessment of wavelength-dependent parameters of photosynthetic electron transport with a new type of multi-color PAM chlorophyll fluorometer JF - Photosynthesis Research N2 - Technical features of a novel multi-color pulse amplitude modulation (PAM) chlorophyll fluorometer as well as the applied methodology and some typical examples of its practical application with suspensions of Chlorella vulgaris and Synechocystis PCC 6803 are presented. The multi-color PAM provides six colors of pulse-modulated measuring light (peak-wavelengths at 400, 440, 480, 540, 590, and 625 nm) and six colors of actinic light (AL), peaking at 440, 480, 540, 590, 625 and 420–640 nm (white). The AL can be used for continuous illumination, maximal intensity single-turnover pulses, high intensity multiple-turnover pulses, and saturation pulses. In addition, far-red light (peaking at 725 nm) is provided for preferential excitation of PS I. Analysis of the fast fluorescence rise kinetics in saturating light allows determination of the wavelength- and sample-specific functional absorption cross section of PS II, Sigma(II)λ, with which the PS II turnover rate at a given incident photosynthetically active radiation (PAR) can be calculated. Sigma(II)λ is defined for a quasi-dark reference state, thus differing from σPSII used in limnology and oceanography. Vastly different light response curves for Chlorella are obtained with light of different colors, when the usual PAR-scale is used. Based on Sigma(II)λ the PAR, in units of μmol quanta/(m2 s), can be converted into PAR(II) (in units of PS II effective quanta/s) and a fluorescence-based electron transport rate ETR(II) = PAR(II) · Y(II)/Y(II)max can be defined. ETR(II) in contrast to rel.ETR qualifies for quantifying the absolute rate of electron transport in optically thin suspensions of unicellular algae and cyanobacteria. Plots of ETR(II) versus PAR(II) for Chlorella are almost identical using either 440 or 625 nm light. Photoinhibition data are presented suggesting that a lower value of ETR(II)max with 440 nm possibly reflects photodamage via absorption by the Mn-cluster of the oxygen-evolving complex. KW - synechocystis KW - O–I 1 fluorescence rise KW - functional absorption cross section of PS II KW - ETR KW - chlorella KW - PAR KW - photoinhibition Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127003 VL - 113 IS - 1 ER - TY - JOUR A1 - Zwink, Nadine A1 - Jenetzky, Ekkehart A1 - Schmiedeke, Eberhard A1 - Schmidt, Dominik A1 - Märzheuser, Schmidt A1 - Grasshoff-Derr, Sabine A1 - Holland-Cunz, Stefan A1 - Weih, Sandra A1 - Hosie, Stuart A1 - Reifferscheid, Peter A1 - Ameis, Helen A1 - Kujath, Christina A1 - Rissmann, Anke A1 - Obermayr, Florian A1 - Schwarzer, Nicole A1 - Bartels, Enrika A1 - Reutter, Heiko A1 - Brenner, Hermann T1 - Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study JF - Orphanet Journal of Rare Diseases N2 - Background: The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results: In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births. Conclusions: There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births. KW - metaanalysis KW - in-vitro fertilization KW - reproductive medicine KW - anal atresia KW - imperforate anus KW - anorectal malformation KW - birth defects KW - prevalence KW - assisted reproductive techniques KW - congenital malformations KW - descriptive epidemiology KW - infants born KW - children born KW - IVF-methods KW - technology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134036 VL - 7 IS - 65 ER - TY - JOUR A1 - Tomei, Sara A1 - Adams, Sharon A1 - Uccellini, Lorenzo A1 - Bedognetti, Davide A1 - De Giorgi, Valeria A1 - Erdenebileg, Narnygerel A1 - Libera Ascierto, Maria A1 - Reinboth, Jennifer A1 - Liu, Qiuzhen A1 - Bevilacqua, Generoso A1 - Wang, Ena A1 - Mazzanti, Chiara A1 - Marincola, Francesco M. T1 - Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population JF - Medical Oncology N2 - HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690. KW - HRAS KW - polymorphism KW - melanoma KW - rs12628 KW - rs112587690 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126834 VL - 29 IS - 5 ER - TY - JOUR T1 - ATLAS search for a heavy gauge boson decaying to a charged lepton and a neutrino in pp collisions at √s=7 TeV JF - The European Physical Journal C N2 - The ATLAS detector at the LHC is used to search for high-mass states, such as heavy charged gauge bosons (W′), decaying to a charged lepton (electron or muon) and a neutrino. Results are presented based on the analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.7 fb\(^{−1}\). No excess beyond Standard Model expectations is observed. A W′ with Sequential Standard Model couplings is excluded at the 95 % credibility level for masses up to 2.55 TeV. Excited chiral bosons (W∗) with equivalent coupling strength are excluded for masses up to 2.42 TeV. KW - systematic uncertainty KW - muon decay channel KW - partial decay width KW - simulated signal event KW - background cross section KW - primary vertex KW - sequential standard model KW - muon spectrometer KW - Cl Lowe limit KW - QCD background KW - coupling strength KW - isolation requirement KW - chiral boson KW - experimental systematic uncertainty Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128888 VL - 72 IS - 2241 ER - TY - JOUR A1 - Chen, Wen A1 - Gaßner, Birgit A1 - Börner, Sebastian A1 - Nikolaev, Viacheslav O. A1 - Schlegel, Nicolas A1 - Waschke, Jens A1 - Steinbronn, Nadine A1 - Strasser, Ruth A1 - Kuhn, Michaela T1 - Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway JF - Cardiovascular Research N2 - Aims Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP. Methods and results Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1−/− mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains. Conclusion ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume. KW - caveolin-1 KW - microvessel permeability KW - atrial natriuretic peptide Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126562 N1 - Lizenzhinweis: The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for noncommercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. VL - 93 IS - 1 ER - TY - JOUR A1 - Wolff, Alexander A1 - Rutter, Iganz T1 - Augmenting the Connectivity of Planar and Geometric Graphs JF - Journal of Graph Algorithms and Applications N2 - In this paper we study connectivity augmentation problems. Given a connected graph G with some desirable property, we want to make G 2-vertex connected (or 2-edge connected) by adding edges such that the resulting graph keeps the property. The aim is to add as few edges as possible. The property that we consider is planarity, both in an abstract graph-theoretic and in a geometric setting, where vertices correspond to points in the plane and edges to straight-line segments. We show that it is NP-hard to � nd a minimum-cardinality augmentation that makes a planar graph 2-edge connected. For making a planar graph 2-vertex connected this was known. We further show that both problems are hard in the geometric setting, even when restricted to trees. The problems remain hard for higher degrees of connectivity. On the other hand we give polynomial-time algorithms for the special case of convex geometric graphs. We also study the following related problem. Given a planar (plane geometric) graph G, two vertices s and t of G, and an integer c, how many edges have to be added to G such that G is still planar (plane geometric) and contains c edge- (or vertex-) disjoint s{t paths? For the planar case we give a linear-time algorithm for c = 2. For the plane geometric case we give optimal worst-case bounds for c = 2; for c = 3 we characterize the cases that have a solution. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97587 ER - TY - JOUR A1 - El-Keredy, Amira A1 - Schleyer, Michael A1 - König, Christian A1 - Ekim, Aslihan A1 - Gerber, Bertram T1 - Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila JF - PLoS One N2 - Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant. KW - honeybees KW - chemosensory system KW - bitter taste KW - melanogaster KW - receptor KW - reward KW - brain KW - organization KW - architecture KW - perception Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130811 VL - 7 IS - 7 ER - TY - JOUR A1 - Gross, Henrik A1 - Hennard, Christine A1 - Masouris, Ilias A1 - Cassel, Christian A1 - Barth, Stephanie A1 - Stober-Grässer, Ute A1 - Mamiani, Alfredo A1 - Moritz, Bodo A1 - Ostareck, Dirk A1 - Ostareck-Lederer, Antje A1 - Neuenkirchen, Nils A1 - Fischer, Utz A1 - Deng, Wen A1 - Leonhardt, Heinrich A1 - Noessner, Elfriede A1 - Kremmer, Elisabeth A1 - Grässer, Friedrich A. T1 - Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression JF - PLoS One N2 - The Epstein-Barr Virus (EBV) -encoded EBNA2 protein, which is essential for the in vitro transformation of B-lymphocytes, interferes with cellular processes by binding to proteins via conserved sequence motifs. Its Arginine-Glycine (RG) repeat element contains either symmetrically or asymmetrically di-methylated arginine residues (SDMA and ADMA, respectively). EBNA2 binds via its SDMA-modified RG-repeat to the survival motor neurons protein (SMN) and via the ADMA-RG-repeat to the NP9 protein of the human endogenous retrovirus K (HERV-K (HML-2) Type 1). The hypothesis of this work was that the methylated RG-repeat mimics an epitope shared with cellular proteins that is used for interaction with target structures. With monoclonal antibodies against the modified RG-repeat, we indeed identified cellular homologues that apparently have the same surface structure as methylated EBNA2. With the SDMA-specific antibodies, we precipitated the Sm protein D3 (SmD3) which, like EBNA2, binds via its SDMA-modified RG-repeat to SMN. With the ADMA-specific antibodies, we precipitated the heterogeneous ribonucleoprotein K (hnRNP K). Specific binding of the ADMA-antibody to hnRNP K was demonstrated using E. coli expressed/ADMA-methylated hnRNP K. In addition, we show that EBNA2 and hnRNP K form a complex in EBV-infected B-cells. Finally, hnRNP K, when co-expressed with EBNA2, strongly enhances viral latent membrane protein 2A (LMP2A) expression by an unknown mechanism as we did not detect a direct association of hnRNP K with DNA-bound EBNA2 in gel shift experiments. Our data support the notion that the methylated surface of EBNA2 mimics the surface structure of cellular proteins to interfere with or co-opt their functional properties. KW - SM proteins KW - protein argentine methyltranserase KW - motor-neuron protein KW - RNA-polymerase-II KW - messenger RNA KW - C-MYC KW - gene expression KW - splicing factor KW - down regulation KW - living cells Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133707 VL - 7 IS - 8 ER - TY - JOUR A1 - Berendzen, Kenneth W. A1 - Weiste, Christoph A1 - Wanke, Dierk A1 - Kilian, Joachim A1 - Harter, Klaus A1 - Dröge-Laser, Wolfgang T1 - Bioinformatic cis-element analyses performed in Arabidopsis and rice disclose bZIP- and MYB-related binding sites as potential AuxRE-coupling elements in auxin-mediated transcription N2 - Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation. KW - Arabidopsis KW - Cis-elements KW - cis-element modules KW - Auxin-regulated transcription KW - AuxRE KW - bZIP KW - MYB KW - MYC Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75138 ER -