@article{BoltzeKleinschnitzReymannetal.2012, author = {Boltze, Johannes and Kleinschnitz, Christoph and Reymann, Klaus G. and Reiser, Georg and Wagner, Daniel-Christoph and Kranz, Alexander and Michalski, Dominik}, title = {Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain - current trends in basic, translational and clinical research}, series = {Experimental \& Translational Stroke Medicine}, volume = {4}, journal = {Experimental \& Translational Stroke Medicine}, number = {14}, doi = {doi:10.1186/2040-7378-4-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126679}, year = {2012}, abstract = {The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood-brain barrier, recent findings regarding the pathomechanism of Alzheimer's disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.}, language = {en} } @article{PanduranganPajakMolnaretal.2012, author = {Pandurangan, Sudhakar and Pajak, Agnieszka and Molnar, Stephen J. and Cober, Elroy R. and Dhaubhadel, Sangeeta and Hern{\´a}ndez-Sebasti{\`a}, Cinta and Kaiser, Werner M. and Nelson, Randall L. and Huber, Steven C. and Marsolais, Fr{\´e}d{\´e}ric}, title = {Relationship between asparagine metabolism and protein concentration in soybean seed}, series = {Journal of Experimental Botany}, volume = {63}, journal = {Journal of Experimental Botany}, number = {8}, doi = {10.1093/jxb/ers039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126900}, pages = {3173-3184}, year = {2012}, abstract = {The relationship between asparagine metabolism and protein concentration was investigated in soybean seed. Phenotyping of a population of recombinant inbred lines adapted to Illinois confirmed a positive correlation between free asparagine levels in developing seeds and protein concentration at maturity. Analysis of a second population of recombinant inbred lines adapted to Ontario associated the elevated free asparagine trait with two of four quantitative trait loci determining population variation for protein concentration, including a major one on chromosome 20 (linkage group I) which has been reported in multiple populations. In the seed coat, levels of asparagine synthetase were high at 50 mg and progressively declined until 150 mg seed weight, suggesting that nitrogenous assimilates are pre-conditioned at early developmental stages to enable a high concentration of asparagine in the embryo. The levels of asparaginase B1 showed an opposite pattern, being low at 50 mg and progressively increased until 150 mg, coinciding with an active phase of storage reserve accumulation. In a pair of genetically related cultivars, ∼2-fold higher levels of asparaginase B1 protein and activity in seed coat, were associated with high protein concentration, reflecting enhanced flux of nitrogen. Transcript expression analyses attributed this difference to a specific asparaginase gene, ASPGB1a. These results contribute to our understanding of the processes determining protein concentration in soybean seed.}, language = {en} } @article{YamakawaFukushimaItohetal.2012, author = {Yamakawa, Hisanori and Fukushima, Yoshimasa and Itoh, Shigeru and Heber, Ulrich}, title = {Three different mechanisms of energy dissipation of a desiccation-tolerant moss serve one common purpose: to protect reaction centres against photo-oxidation}, series = {Journal of Experimental Botany}, volume = {63}, journal = {Journal of Experimental Botany}, number = {10}, doi = {10.1093/jxb/ers062}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126897}, pages = {3765-3775}, year = {2012}, abstract = {Three different types of non-photochemical de-excitation of absorbed light energy protect photosystem II of the sun- and desiccation-tolerant moss Rhytidium rugosum against photo-oxidation. The first mechanism, which is light-induced in hydrated thalli, is sensitive to inhibition by dithiothreitol. It is controlled by the protonation of a thylakoid protein. Other mechanisms are activated by desiccation. One of them permits exciton migration towards a far-red band in the antenna pigments where fast thermal deactivation takes place. This mechanism appears to be similar to a mechanism detected before in desiccated lichens. A third mechanism is based on the reversible photo-accumulation of a radical that acts as a quencher of excitation energy in reaction centres of photosystem II. On the basis of absorption changes around 800 nm, the quencher is suggested to be an oxidized chlorophyll. The data show that desiccated moss is better protected against photo-oxidative damage than hydrated moss. Slow drying of moss thalli in the light increases photo-protection more than slow drying in darkness.}, language = {en} } @article{AzzamiRitterTautzetal.2012, author = {Azzami, Klara and Ritter, Wolfgang and Tautz, J{\"u}rgen and Beier, Hildburg}, title = {Infection of honey bees with acute bee paralysis virus does not trigger humoral or cellular immune responses}, series = {Archives of Virology}, volume = {157}, journal = {Archives of Virology}, number = {4}, doi = {10.1007/s00705-012-1223-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126863}, pages = {689-702}, year = {2012}, abstract = {We have studied the responses of honey bees at different life stages (Apis mellifera) to controlled infection with acute bee paralysis virus and have identified the haemolymph of infected larvae and adult worker bees as the compartment where massive propagation of ABPV occurs. Insects respond with a broad spectrum of induced innate immune reactions to bacterial infections, whereas defence mechanisms based on RNA interference play a major role in antiviral immunity. In this study, we have determined that honey bee larvae and adult workers do not produce a humoral immune reaction upon artificial infection with ABPV, in contrast to control individuals challenged with Escherichia coli. ABPV-infected bees produced neither elevated levels of specific antimicrobial peptides (AMPs), such as hymenoptaecin and defensin, nor any general antimicrobial activity, as revealed by inhibition-zone assays. Additionally, adult bees did not generate melanised nodules upon ABPV infection, an important cellular immune function activated by bacteria and viruses in some insects. Challenge of bees with both ABPV and E. coli showed that innate humoral and cellular immune reactions are induced in mixed infections, albeit at a reduced level.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126845}, pages = {573-579}, year = {2012}, abstract = {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.}, language = {en} } @article{MuysomsCampanelliChampaultetal.2012, author = {Muysoms, F. and Campanelli, G. and Champault, G. and DeBeaux, A. C. and Dietz, U. A. and Jeekel, J. and Klinge, U. and K{\"a}ckerling, F. and Mandala, M. and Montgomery, A. and Morales Conde, S. and Puppe, F. and Simmermacher, R. K. J. and Asmieta Aski, M. and Miserez, M.}, title = {EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair}, series = {Hernia}, volume = {16}, journal = {Hernia}, number = {3}, doi = {10.1007/s10029-012-0912-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126691}, pages = {239-250}, year = {2012}, abstract = {BACKGROUND: Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult. MATERIALS AND METHODS: Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry. RESULTS: A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co-morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database. CONCLUSION: An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques.}, language = {en} } @article{ChenGassnerBoerneretal.2012, author = {Chen, Wen and Gaßner, Birgit and B{\"o}rner, Sebastian and Nikolaev, Viacheslav O. and Schlegel, Nicolas and Waschke, Jens and Steinbronn, Nadine and Strasser, Ruth and Kuhn, Michaela}, title = {Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway}, series = {Cardiovascular Research}, volume = {93}, journal = {Cardiovascular Research}, number = {1}, doi = {10.1093/cvr/cvr279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126562}, pages = {141-151}, year = {2012}, abstract = {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.}, language = {en} } @article{KraftDeMeyerKleinschnitz2012, author = {Kraft, Peter and De Meyer, Simon F. and Kleinschnitz, Christoph}, title = {Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on 'Bleeding-Free Antithrombosis'}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {10}, doi = {10.1038/jcbfm.2012.108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126538}, pages = {1831-1840}, year = {2012}, abstract = {The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.}, language = {en} } @article{KleinertTonyKrauseetal.2012, author = {Kleinert, Stefan and Tony, Hans-Peter and Krause, Andreas and Feuchtenberger, Martin and Wassenberg, Siegfried and Richter, Constanze and R{\"o}ther, Ekkehard and Spieler, Wolfgang and Gnann, Holger and Wittig, Bianca M.}, title = {Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German}, series = {Rheumatology International}, volume = {32}, journal = {Rheumatology International}, number = {9}, doi = {10.1007/s00296-011-2033-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126220}, pages = {2759-2767}, year = {2012}, abstract = {The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9-3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy.}, language = {en} } @article{BeckerAndersenHofmeisterMuelleretal.2012, author = {Becker, J{\"u}rgen C. and Andersen, Mads H. and Hofmeister-M{\"u}ller, Valeska and Wobser, Marion and Frey, Lidia and Sandig, Christiane and Walter, Steffen and Singh-Jasuja, Harpreet and K{\"a}mpgen, Eckhart and Opitz, Andreas and Zapatka, Marc and Br{\"o}cker, Eva-B. and thor Straten, Per and Schrama, David and Ugurel, Selma}, title = {Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {11}, doi = {10.1007/s00262-012-1266-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126215}, pages = {2091-2103}, year = {2012}, abstract = {Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.}, language = {en} } @article{BandyraSaidPfeifferetal.2012, author = {Bandyra, Katarzyna J. and Said, Nelly and Pfeiffer, Verena and G{\´o}rna, Maria W. and Vogel, J{\"o}rg and Luisi, Ben F.}, title = {The Seed Region of a Small RNA Drives the Controlled Destruction of the Target mRNA by the Endoribonuclease RNase E}, series = {Molecular Cell}, volume = {47}, journal = {Molecular Cell}, number = {6}, doi = {10.1016/j.molcel.2012.07.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126202}, pages = {943-953}, year = {2012}, abstract = {Numerous small non-coding RNAs (sRNAs) in bacteria modulate rates of translation initiation and degradation of target mRNAs, which they recognize through base-pairing facilitated by the RNA chaperone Hfq. Recent evidence indicates that the ternary complex of Hfq, sRNA and mRNA guides endoribonuclease RNase E to initiate turnover of both the RNAs. We show that a sRNA not only guides RNase E to a defined site in a target RNA, but also allosterically activates the enzyme by presenting a monophosphate group at the 5′-end of the cognate-pairing "seed." Moreover, in the absence of the target the 5′-monophosphate makes the sRNA seed region vulnerable to an attack by RNase E against which Hfq confers no protection. These results suggest that the chemical signature and pairing status of the sRNA seed region may help to both 'proofread' recognition and activate mRNA cleavage, as part of a dynamic process involving cooperation of RNA, Hfq and RNase E.}, language = {en} } @article{ParkerAdriaenssensRogersetal.2012, author = {Parker, H. E. and Adriaenssens, A. and Rogers, G. and Richards, P. and Koepsell, H. and Reimann, F. and Gribble, F. M.}, title = {Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion}, series = {Diabetologia}, volume = {55}, journal = {Diabetologia}, number = {9}, doi = {10.1007/s00125-012-2585-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125927}, pages = {2445-2455}, year = {2012}, abstract = {Aims/hypothesis Several glucose-sensing pathways have been implicated in glucose-triggered secretion of glucagon-like peptide-1 (GLP-1) from intestinal L cells. One involves glucose metabolism and closure of ATP-sensitive K\(^+\) channels, and another exploits the electrogenic nature of Na\(^+\)-coupled glucose transporters (SGLTs). This study aimed to elucidate the role of these distinct mechanisms in glucose-stimulated GLP-1 secretion. Methods Glucose uptake into L cells (either GLUTag cells or cells in primary cultures, using a new transgenic mouse model combining proglucagon promoter-driven Cre recombinase with a ROSA26tdRFP reporter) was monitored with the FLII\(_{12}\)Pglu-700μδ6 glucose sensor. Effects of pharmacological and genetic interference with SGLT1 or facilitative glucose transport (GLUT) on intracellular glucose accumulation and metabolism (measured by NAD(P)H autofluorescence), cytosolic Ca\(^{2+}\) (monitored with Fura2) and GLP-1 secretion (assayed by ELISA) were assessed. Results L cell glucose uptake was dominated by GLUT-mediated transport, being abolished by phloretin but not phloridzin. NAD(P)H autofluorescence was glucose dependent and enhanced by a glucokinase activator. In GLUTag cells, but not primary L cells, phloretin partially impaired glucose-dependent secretion, and suppressed an amplifying effect of glucose under depolarising high K\(^+\) conditions. The key importance of SGLT1 in GLUTag and primary cells was evident from the impairment of secretion by phloridzin or Sglt1 knockdown and failure of glucose to trigger cytosolic Ca\(^{2+}\) elevation in primary L cells from Sglt1 knockout mice. Conclusions/interpretation SGLT1 acts as the luminal glucose sensor in L cells, but intracellular glucose concentrations are largely determined by GLUT activity. Although L cell glucose metabolism depends partially on glucokinase activity, this plays only a minor role in glucose-stimulated GLP-1 secretion.}, language = {en} } @article{HansmannPliushchLeubneretal.2012, author = {Hansmann, Tamara and Pliushch, Galyna and Leubner, Monika and Kroll, Patricia and Endt, Daniela and Gehrig, Andrea and Preisler-Adams, Sabine and Wieacker, Peter and Haaf, Thomas}, title = {Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer}, series = {Human Molecular Genetics}, volume = {21}, journal = {Human Molecular Genetics}, number = {21}, doi = {10.1093/hmg/dds308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125673}, pages = {4669-4679}, year = {2012}, abstract = {Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40\% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6\% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4\%) patients with constitutive BRCA1 and three (0.5\%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5\%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10\%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40\%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.}, language = {en} } @article{JaschkeChungHesseetal.2012, author = {Jaschke, Alexander and Chung, Bomee and Hesse, Deike and Kluge, Reinhart and Zahn, Claudia and Moser, Markus and Petzke, Klaus-J{\"u}rgen and Brigelius-Floh{\´e}, Regina and Puchkov, Dmytro and Koepsell, Hermann and Heeren, Joerg and Joost, Hans-Georg and Sch{\"u}rmann, Annette}, title = {The GTPase ARFRP1 controls the lipidation of chylomicrons in the Golgi of the intestinal epithelium}, series = {Human Molecular Genetics}, volume = {21}, journal = {Human Molecular Genetics}, number = {14}, doi = {10.1093/hmg/dds140}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125658}, pages = {3128-3142}, year = {2012}, abstract = {The uptake and processing of dietary lipids by the small intestine is a multistep process that involves several steps including vesicular and protein transport. The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) controls the ARF-like 1 (ARL1)-mediated Golgi recruitment of GRIP domain proteins which in turn bind several Rab-GTPases. Here, we describe the essential role of ARFRP1 and its interaction with Rab2 in the assembly and lipidation of chylomicrons in the intestinal epithelium. Mice lacking Arfrp1 specifically in the intestine \((Arfrp1^{vil-/-})\) exhibit an early post-natal growth retardation with reduced plasma triacylglycerol and free fatty acid concentrations. \(Arfrp1^{vil-/-}\) enterocytes as well as Arfrp1 mRNA depleted Caco-2 cells absorbed fatty acids normally but secreted chylomicrons with a markedly reduced triacylglycerol content. In addition, the release of apolipoprotein A-I (ApoA-I) was dramatically decreased, and ApoA-I accumulated in the \(Arfrp1^{vil-/-}\) epithelium, where it predominantly co-localized with Rab2. The release of chylomicrons from Caco-2 was markedly reduced after the suppression of Rab2, ARL1 and Golgin-245. Thus, the GTPase ARFRP1 and its downstream proteins are required for the lipidation of chylo­microns and the assembly of ApoA-I to these particles in the Golgi of intestinal epithelial cells.}, language = {en} } @article{MaidenFrosch2012, author = {Maiden, Martin C. J. and Frosch, Matthias}, title = {Can we, should we, eradicate the meningococcus?}, series = {Vaccine}, volume = {30}, journal = {Vaccine}, number = {Suppl. 2}, doi = {10.1016/j.vaccine.2011.12.068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125646}, pages = {B52-B56}, year = {2012}, abstract = {The eradication of infectious agents is an attractive means of disease control that, to date, has been achieved for only one human pathogen, the smallpox virus. The introduction of vaccines against Neisseria meningitidis into immunisation schedules, and particularly the conjugate polysaccharide vaccines which can interrupt transmission, raises the question of whether disease caused by this obligate human bacterium can be controlled, eliminated, or even eradicated. The limited number of meningococcal serogroups, lack of an animal reservoir, and importance of meningococcal disease are considerations in favour of eradication; however, the commensal nature of most infections, the high diversity of meningococcal populations, and the lack of comprehensive vaccines are all factors that suggest that this is not feasible. Indeed, any such attempt might be harmful by perturbing the human microbiome and its interaction with the immune system. On balance, the control and possible elimination of disease caused by particular disease-associated meningococcal genotypes is a more achievable and worthwhile goal.}, language = {en} } @article{NordbeckBeerKoestleretal.2012, author = {Nordbeck, Peter and Beer, Meinrad and K{\"o}stler, Herbert and Ladd, Mark E. and Quick, Harald H. and Bauer, Wolfgang R. and Ritter, Oliver}, title = {Cardiac catheter ablation under real-time magnetic resonance guidance}, series = {European Heart Journal}, volume = {33}, journal = {European Heart Journal}, number = {15}, doi = {10.1093/eurheartj/ehs139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125638}, year = {2012}, abstract = {One of the main shortcomings of interventional electrophysiology (EP) is its inability to generate sufficient soft tissue contrast for intra-procedural visualization of the myocardium and the surrounding tissue, using conventional imaging techniques. Interventional cardiovascular magnetic resonance imaging (MRI) aims at bringing about significant improvements to the complex and decisive EP interventions far beyond the capabilities of currently available supportive imaging techniques used to surmount the drawbacks of fluoroscopy, as MRI not only allows of precise three-dimensional exposure of the cardiovascular morphology, but also proves to be a promising technique exclusively suitable for direct visualization of arrhythmogenic substrate and therapeutic effects. The major challenge posed by clinical …}, language = {en} } @article{HornBaumannPereiraetal.2012, author = {Horn, Michael and Baumann, Reto and Pereira, Jorge A. and Sidiropoulos, P{\´a}ris N. M. and Somandin, Christian and Welzl, Hans and Stendel, Claudia and L{\"u}hmann, Tessa and Wessig, Carsten and Toyka, Klaus V. and Relvas, Jo{\~a}o B. and Senderek, Jan and Suter, Ueli}, title = {Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells}, series = {Brain}, volume = {135}, journal = {Brain}, doi = {10.1093/brain/aws275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125390}, pages = {3567-3583}, year = {2012}, abstract = {Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.}, language = {en} } @article{GaletzkaHansmannElHajjetal.2012, author = {Galetzka, Danuta and Hansmann, Tamara and El Hajj, Nady and Weis, Eva and Irmscher, Benjamin and Ludwig, Marco and Schneider-R{\"a}tzke, Brigitte and Kohlschmidt, Nicolai and Beyer, Vera and Bartsch, Oliver and Zechner, Ulrich and Spix, Claudia and Haaf, Thomas}, title = {Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer}, series = {Epigenetics}, volume = {7}, journal = {Epigenetics}, number = {1}, doi = {10.4161/epi.7.1.18814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125386}, pages = {47-54}, year = {2012}, abstract = {We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12\%), compared with her sister (3\%). Subsequent bisulfite plasmid sequencing demonstrated that 13\% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25\% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.}, language = {en} } @article{GerlachMaetzlerBroichetal.2012, author = {Gerlach, Manfred and Maetzler, Walter and Broich, Karl and Hampel, Harald and Rems, Lucas and Reum, Torsten and Riederer, Peter and St{\"a}ffler, Albrecht and Streffer, Johannes and Berg, Daniela}, title = {Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics}, series = {Journal of Neural Transmission}, volume = {119}, journal = {Journal of Neural Transmission}, number = {1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125375}, pages = {39-52}, year = {2012}, abstract = {Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.}, language = {en} } @article{JainVelezAcostaetal.2012, author = {Jain, M. and V{\´e}lez, J. I. and Acosta, M. T. and Palacio, L. G. and Balog, J. and Roessler, E. and Pineda, D. and Londo{\~n}o, A. C. and Palacio, J. D. and Arbelaez, A. and Lopera, F. and Elia, J. and Hakonarson, H. and Seitz, C. and Freitag, C. M. and Palmason, H. and Meyer, J. and Romanos, M. and Walitza, S. and Hemminger, U. and Warnke, A. and Romanos, J. and Renner, T. and Jacob, C. and Lesch, K.-P. and Swanson, J. and Castellanos, F. X. and Bailey-Wilson, J. E. and Arcos-Burgos, M. and Muenke, M.}, title = {A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD}, series = {Molecular Psychiatry}, volume = {17}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2011.59}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125128}, pages = {741-747}, year = {2012}, abstract = {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.}, language = {en} } @article{KleinertTonyKrauseetal.2012, author = {Kleinert, Stefan and Tony, Hans-Peter and Krause, Andreas and Feuchtenberger, Martin and Wassenberg, Siegfried and Richter, Constanze and R{\"a}ther, Ekkehard and Spieler, Wolfgang and Gnann, Holger and Wittig, Bianca M.}, title = {Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study}, series = {Rheumatology International}, volume = {32}, journal = {Rheumatology International}, number = {9}, doi = {10.1007/s00296-011-2033-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125118}, pages = {2759-2767}, year = {2012}, abstract = {The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9-3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy.}, language = {en} } @article{AlbSieAdametal.2012, author = {Alb, Miriam and Sie, Christopher and Adam, Christian and Chen, Suzie and Becker, J{\"u}rgen C. and Schrama, David}, title = {Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {12}, doi = {10.1007/s00262-012-1290-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125096}, pages = {2239-2249}, year = {2012}, abstract = {Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.}, language = {en} } @article{BeckerAndersenHofmeisterMuelleretal.2012, author = {Becker, J{\"u}rgen C. and Andersen, Mads H. and Hofmeister-M{\"u}ller, Valeska and Wobser, Marion and Frey, Lidia and Sandig, Christiane and Walter, Steffen and Singh-Jasuja, Harpreet and K{\"a}mpgen, Eckhart and Opitz, Andreas and Zapatka, Marc and Br{\"o}cker, Eva-B. and thor Straten, Per and Schrama, David and Ugurel, Selma}, title = {Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {11}, doi = {10.1007/s00262-012-1266-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124830}, pages = {2091-2103}, year = {2012}, abstract = {Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.}, language = {en} } @article{TomeiAdamsUccellinietal.2012, author = {Tomei, Sara and Adams, Sharon and Uccellini, Lorenzo and Bedognetti, Davide and De Giorgi, Valeria and Erdenebileg, Narnygerel and Libera Ascierto, Maria and Reinboth, Jennifer and Liu, Qiuzhen and Bevilacqua, Generoso and Wang, Ena and Mazzanti, Chiara and Marincola, Francesco M.}, title = {Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population}, series = {Medical Oncology}, volume = {29}, journal = {Medical Oncology}, number = {5}, doi = {dx.doi.org/10.1007/s12032-012-0255-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126834}, pages = {3456-3461}, year = {2012}, abstract = {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.}, language = {en} } @article{BurekSalvadorFoerster2012, author = {Burek, Malgorzata and Salvador, Ellaine and F{\"o}rster, Carola Y.}, title = {Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an In Vitro Blood Brain Barrier Model}, series = {Journal of Visualized Experiments}, volume = {66}, journal = {Journal of Visualized Experiments}, number = {e4022}, doi = {10.3791/4022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126702}, year = {2012}, abstract = {Epithelial and endothelial cells (EC) are building paracellular barriers which protect the tissue from the external and internal environment. The blood-brain barrier (BBB) consisting of EC, astrocyte end-feet, pericytes and the basal membrane is responsible for the protection and homeostasis of the brain parenchyma. In vitro BBB models are common tools to study the structure and function of the BBB at the cellular level. A considerable number of different in vitro BBB models have been established for research in different laboratories to date. Usually, the cells are obtained from bovine, porcine, rat or mouse brain tissue (discussed in detail in the review by Wilhelm et al. 1). Human tissue samples are available only in a restricted number of laboratories or companies 2,3. While primary cell preparations are time consuming and the EC cultures can differ from batch to batch, the establishment of immortalized EC lines is the focus of scientific interest. Here, we present a method for establishing an immortalized brain microvascular EC line from neonatal mouse brain. We describe the procedure step-by-step listing the reagents and solutions used. The method established by our lab allows the isolation of a homogenous immortalized endothelial cell line within four to five weeks. The brain microvascular endothelial cell lines termed cEND 4 (from cerebral cortex) and cerebEND 5 (from cerebellar cortex), were isolated according to this procedure in the F{\"o}rster laboratory and have been effectively used for explanation of different physiological and pathological processes at the BBB. Using cEND and cerebEND we have demonstrated that these cells respond to glucocorticoid- 4,6-9 and estrogen-treatment 10 as well as to pro-infammatory mediators, such as TNFalpha 5,8. Moreover, we have studied the pathology of multiple sclerosis 11 and hypoxia 12,13 on the EC-level. The cEND and cerebEND lines can be considered as a good tool for studying the structure and function of the BBB, cellular responses of ECs to different stimuli or interaction of the EC with lymphocytes or cancer cells.}, language = {en} } @article{BonnSchmittAsan2012, author = {Bonn, Maria and Schmitt, Angelika and Asan, Esther}, title = {Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels}, series = {Histochemistry and Cell Biology}, volume = {137}, journal = {Histochemistry and Cell Biology}, number = {1}, doi = {10.1007/s00418-011-0882-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126720}, pages = {11-24}, year = {2012}, abstract = {Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection.}, language = {en} } @article{DietzWichelmannWunderetal.2012, author = {Dietz, U. A. and Wichelmann, C. and Wunder, C. and Kauczok, J. and Spor, L. and Strauß, A. and Wildenauer, R. and Jurowich, C. and Germer, C. T.}, title = {Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia}, series = {Hernia}, volume = {16}, journal = {Hernia}, number = {4}, doi = {10.1007/s10029-012-0919-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126732}, pages = {451-460}, year = {2012}, abstract = {Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3-4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60-100 \% granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 \%) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 \%) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result.}, language = {en} } @article{JazbutyteFiedlerKneitzetal.2012, author = {Jazbutyte, Virginija and Fiedler, Jan and Kneitz, Susanne and Galuppo, Paolo and Just, Annette and Holzmann, Angelika and Bauersachs, Johann and Thum, Thomas}, title = {MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart}, series = {AGE}, volume = {35}, journal = {AGE}, number = {3}, doi = {10.1007/s11357-012-9407-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126745}, pages = {747-762}, year = {2012}, abstract = {MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA-mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. Rescue experiments revealed that the effects of miR-22 on cardiac fibroblasts were only partially mediated by mimecan. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. Our results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis.}, language = {en} } @phdthesis{Lueker2012, author = {L{\"u}ker, Anna-Lena}, title = {Funktionelle Ergebnisse der zweizeitigen H{\"u}ftendoprothesenrevision bei periprothetischer Infektion}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123829}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Diese retrospektive Studie analysierte die Ergebnisse der zweizeitigen, unzementierten Revision bei periprothetischer Infektion der H{\"u}ftendoprothese. Dabei wurde besonders auf die Eradikationsrate, die Rate septischer und aseptischer Rezidive, die Standzeit des Spacers, die Art der lokalen Antibiotikatherapie und die postoperativen funktionellen Ergebnisse eingegangen. Die Studie umfasst die klinische Nachuntersuchung der Patienten unter Verwendung des Harris Hip Scores, sowie die radiologische Kontrolle des Sitzes der H{\"u}ftendoprothese und die laborchemische {\"U}berpr{\"u}fung der Entz{\"u}ndungsparameter. Insgesamt wurden 52 Patienten von 2000 bis 2007 in der Orthop{\"a}dischen Klinik K{\"o}nig Ludwig Haus in W{\"u}rzburg mit einer zweizeitigen Revision der H{\"u}ftendoprothese bei periprothetischer Infektion versorgt. 36 dieser 52 Patiente konnten 2008 im Rahmen dieser Studie nachuntersucht werden. Dabei betrug die mittlere Nachuntersuchungszeit 42 Monate. Das mittlere Patientenalter war 66,3 Jahre. 81\% der Patienten hatten zum Zeitpunkt der Infektion internistische oder orthop{\"a}dische Grunderkrankungen, oftmals auch multiple, welche das Risiko f{\"u}r die Entstehung einer periprothetischen Infektion erh{\"o}hten. 47\% der Patienten waren zum Zeitpunkt der zweizeitigen Revision bereits mehr als einmal an der H{\"u}fte voroperiert, die H{\"a}lfte davon mussten aufgrund von septischen Komplikationen bereits revidiert werden. 10\% der Patienten hatten eine akute Fr{\"u}hinfektion, 90\% ein chronisches Geschehen (51\% low-grade Infekt, 39\% Sp{\"a}tinfekt). Die h{\"a}ufigsten bakteriellen Erreger waren Staphylococcus epidermidis (39\%), Staphylococcus aureus (14\%), Streptococcus agalactiae (14\%) und weitere koagulase negative Staphylokokken (11\%). Bei zwei Patienten konnten Methicillin-resistente Keime isoliert werden. Insgesamt waren 25\% der Infektionen Mischinfektionen. Bei drei Patienten konnte kein Keim nachgewiesen werden. Diese Patienten wurden anhand ihrer eindeutigen klinischen Symptome bei gleichzeitiger Erh{\"o}hung der Entz{\"u}ndungsparameter behandelt. Zur besseren Eradikation der chronischen, persistierenden und komplizierten Infektionen wurden die Patienten mit einer zweizeitigen Revision der H{\"u}ftendoprothese behandelt. Hierbei wurde nach Explantation der infizierten Prothese mit ausf{\"u}hrlichem chirurgischen Debridement ein - soweit m{\"o}glich - patientenspezifischer antibiotikaimpr{\"a}gnierter Spacer vor Implantation der Zweitprothese eingesetzt. Diese Methode dient einerseits der Vermeidung einer Girdlestone-Situation und der damit verbundenen Komplikationen, andererseits erm{\"o}glicht der Spacer eine kalkulierte und hoch dosierte lokale, weitreichende und patientenspezifische Antibiotikatherapie (Kombinationstherapie) zur sicheren Eradikation der Infektion. Die Standzeit (zwischen vier und neunzehn Wochen, Mittelwert von 9 Wochen) des Spacers wurde individuell anhand des klinischen Bildes und dem R{\"u}ckgang der laborchemischen Entz{\"u}ndungsparameter entschieden. Die Eradiaktionsrate durch die zweizeitige Revision lag in dieser Studie bei 94\%. Lediglich zwei Patienten zeigten eine persistierende bzw. wiederkehrende Infektion im Verlauf und mussten erneut revidiert werden. Es konnten keine aseptische Komplikationen, insbesondere keine Prothesenlockerung oder -sinterung nachgewiesen werden. Sechs Patienten mussten aufgrund anderer, nicht Infekt-assoziierter Komplikationen im Verlauf erneut operiert werden. Die funktionellen Ergebnisse wurden anhand des Harris Hip Scores untersucht. Der Median lag bei 74 Punkten. Somit l{\"a}sst sich auch funktionell ein insgesamt zufriedenstellendes Ergebnis pr{\"a}sentieren. Schlussfolgernd ist die Aussage m{\"o}glich, dass die zweizeitige, unzementierte Revision unter Verwendung eines antibiotikabeladenen Spacers eine zuverl{\"a}ssige Methode zur Behandlung auch chronischer und komplizierter periprothetischer Infektionen der H{\"u}ftendoprothese ist. Insgesamt konnten mit einer Eradikationsrate von 94\% und keinen aseptischen Rezidiven gute Ergebnisse erzielt werden. Bez{\"u}glich der Antibiotikatherapie l{\"a}sst sich eine kalkulierte, lokale Kombinationstherapie zur optimalen Eradikation der Infektion empfehlen. Des Weiteren empfiehlt es sich, die Standzeit des Spacers ebenfalls individuell bis zum klinischen und laborchemischen Nachweis der Infektfreiheit festzulegen. Dadurch wird eine ausreichende Dauer der lokalen Antibiotikatherapie gew{\"a}hrleistet, und gleichzeitig die Standzeit des Spacers auf eine m{\"o}glichst kurze Zeit beschr{\"a}nkt um eine fr{\"u}he Mobilisation und gute Funktionalit{\"a}t und Zufriedenheit des Patienten zu erreichen.}, subject = {periprothetische Infektion}, language = {de} } @article{WalshLemsKarrasetal.2012, author = {Walsh, J. Bernard and Lems, Willem F. and Karras, Dimitrios and Langdahl, Bente L. and Ljunggren, Osten and Fahrleitner-Pammer, Astrid and Barrett, Annabel and Rajzbaum, Gerald and Jakob, Franz and Marin, Fernando}, title = {Effectiveness of Teriparatide in Women Over 75 Years of Age with Severe Osteoporosis: 36-Month Results from the European Forsteo Observational Study (EFOS)}, series = {Calcified Tissue International}, volume = {90}, journal = {Calcified Tissue International}, number = {5}, doi = {10.1007/s00223-012-9590-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124746}, pages = {373-383}, year = {2012}, abstract = {This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged ≥75 years. Data on clinical fractures, back pain (visual analogue scale, VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 \%) women aged ≥75 years sustained a total of 111 new fractures: 37 (33.3 \%) vertebral fractures and 74 (66.7 \%) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 \% in the 30 to <36-month interval compared with the first 6-month interval (P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged ≥75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study.}, language = {en} } @article{JakobEbertRudertetal.2012, author = {Jakob, Franz and Ebert, Regina and Rudert, Maximilian and N{\"o}th, Ulrich and Walles, Heike and Docheva, Denitsa and Schieker, Matthias and Meinel, Lorenz and Groll, J{\"u}rgen}, title = {In situ guided tissue regeneration in musculoskeletal diseases and aging}, series = {Cell and Tissue Research}, volume = {347}, journal = {Cell and Tissue Research}, number = {3}, doi = {10.1007/s00441-011-1237-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124738}, pages = {725-735}, year = {2012}, abstract = {In situ guided tissue regeneration, also addressed as in situ tissue engineering or endogenous regeneration, has a great potential for population-wide "minimal invasive" applications. During the last two decades, tissue engineering has been developed with remarkable in vitro and preclinical success but still the number of applications in clinical routine is extremely small. Moreover, the vision of population-wide applications of ex vivo tissue engineered constructs based on cells, growth and differentiation factors and scaffolds, must probably be deemed unrealistic for economic and regulation-related issues. Hence, the progress made in this respect will be mostly applicable to a fraction of post-traumatic or post-surgery situations such as big tissue defects due to tumor manifestation. Minimally invasive procedures would probably qualify for a broader application and ideally would only require off the shelf standardized products without cells. Such products should mimic the microenvironment of regenerating tissues and make use of the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. This is especially important because the main target populations for such applications are the elderly and diseased. The quality of regenerative cells is impaired in such organisms and high levels of inhibitors also interfere with regeneration and healing. In metabolic bone diseases like osteoporosis, it is already known that antagonists for inhibitors such as activin and sclerostin enhance bone formation. Implementing such strategies into applications for in situ guided tissue regeneration should greatly enhance the efficacy of tailored procedures in the future.}, language = {en} } @article{MuysomsCampanelliChampaultetal.2012, author = {Muysoms, F. and Campanelli, G. and Champault, G. G. and DeBeaux, A. C. and Dietz, U. A. and Jeekel, J. and Klinge, U. and K{\"o}ckerling, F. and Mandala, V. and Montgomery, A. and Morales Conde, S. and Puppe, F. and Simmermacher, R. K. J. and Śmietański, M. and Miserez, M.}, title = {EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair}, series = {Hernia}, volume = {16}, journal = {Hernia}, number = {3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124728}, pages = {239-250}, year = {2012}, abstract = {Background Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult. Materials and methods Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry. Results A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co-morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database. Conclusion An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques.}, language = {en} } @article{WarnockOrtizMaueretal.2012, author = {Warnock, David G. and Ortiz, Alberto and Mauer, Michael and Linthorst, Gabor E. and Oliveira, Jo{\~a}o P. and Serra, Andreas L. and Mar{\´o}di, L{\´a}szl{\´o} and Mignani, Renzo and Vujkovac, Bojan and Beitner-Johnson, Dana and Lemay, Roberta and Cole, J. Alexander and Svarstad, Einar and Waldek, Stephen and Germain, Dominique P. and Wanner, Christoph}, title = {Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation}, series = {Nephrology Dialysis Transplantation}, volume = {27}, journal = {Nephrology Dialysis Transplantation}, number = {3}, organization = {Fabry Registry}, doi = {10.1093/ndt/gfr420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124697}, pages = {1042-1049}, year = {2012}, abstract = {Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95\% confidence interval (95\% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95\% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.}, language = {en} } @article{DietzWichelmannWunderetal.2012, author = {Dietz, U. A. and Wichelmann, C. and Wunder, C. and Kauczok, J. and Spor, L. and Strauß, A. and Wildenauer, R. and Jurowich, C. and Germer, C. T.}, title = {Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia}, series = {Hernia}, volume = {16}, journal = {Hernia}, number = {4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124686}, pages = {451-460}, year = {2012}, abstract = {Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3-4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60-100 \% granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 \%) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 \%) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result.}, language = {en} } @article{FrankeFaraoneAshersonetal.2012, author = {Franke, B. and Faraone, S. V. and Asherson, P. and Buitelaar, J. and Bau, C. H. D. and Ramos-Quiroga, J. A. and Mick, E. and Grevet, E. H. and Johansson, S. and Haavik, J. and Lesch, K.-P. and Cormand, B. and Reif, A.}, title = {The genetics of attention deficit/hyperactivity disorder in adults, a review}, series = {Molecular Psychiatry}, volume = {17}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2011.138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124677}, pages = {960-987}, year = {2012}, abstract = {The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5\% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40\%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.}, language = {en} } @article{BuchinBuchinByrkaetal.2012, author = {Buchin, Kevin and Buchin, Maike and Byrka, Jaroslaw and N{\"o}llenburg, Martin and Okamoto, Yoshio and Silveira, Rodrigo I. and Wolff, Alexander}, title = {Drawing (Complete) Binary Tanglegrams}, series = {Algorithmica}, volume = {62}, journal = {Algorithmica}, doi = {10.1007/s00453-010-9456-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124622}, pages = {309-332}, year = {2012}, abstract = {A binary tanglegram is a drawing of a pair of rooted binary trees whose leaf sets are in one-to-one correspondence; matching leaves are connected by inter-tree edges. For applications, for example, in phylogenetics, it is essential that both trees are drawn without edge crossings and that the inter-tree edges have as few crossings as possible. It is known that finding a tanglegram with the minimum number of crossings is NP-hard and that the problem is fixed-parameter tractable with respect to that number. We prove that under the Unique Games Conjecture there is no constant-factor approximation for binary trees. We show that the problem is NP-hard even if both trees are complete binary trees. For this case we give an O(n 3)-time 2-approximation and a new, simple fixed-parameter algorithm. We show that the maximization version of the dual problem for binary trees can be reduced to a version of MaxCut for which the algorithm of Goemans and Williamson yields a 0.878-approximation.}, language = {en} } @article{MergetKoetschanHackletal.2012, author = {Merget, Benjamin and Koetschan, Christian and Hackl, Thomas and F{\"o}rster, Frank and Dandekar, Thomas and M{\"u}ller, Tobias and Schultz, J{\"o}rg and Wolf, Matthias}, title = {The ITS2 Database}, series = {Journal of Visual Expression}, volume = {61}, journal = {Journal of Visual Expression}, number = {e3806}, doi = {10.3791/3806}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124600}, year = {2012}, abstract = {The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation. The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold. The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure. In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses.}, language = {en} } @article{VottelerCarvajalBerrioPudlasetal.2012, author = {Votteler, Miriam and Carvajal Berrio, Daniel A. and Pudlas, Marieke and Walles, Heike and Schenke-Layland, Katja}, title = {Non-contact, Label-free Monitoring of Cells and Extracellular Matrix using Raman Spectroscopy}, series = {Journal of Visual Expression}, volume = {63}, journal = {Journal of Visual Expression}, number = {e3977}, doi = {10.3791/3977}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124569}, year = {2012}, abstract = {Non-destructive, non-contact and label-free technologies to monitor cell and tissue cultures are needed in the field of biomedical research.1-5 However, currently available routine methods require processing steps and alter sample integrity. Raman spectroscopy is a fast method that enables the measurement of biological samples without the need for further processing steps. This laser-based technology detects the inelastic scattering of monochromatic light.6 As every chemical vibration is assigned to a specific Raman band (wavenumber in cm-1), each biological sample features a typical spectral pattern due to their inherent biochemical composition.7-9 Within Raman spectra, the peak intensities correlate with the amount of the present molecular bonds.1 Similarities and differences of the spectral data sets can be detected by employing a multivariate analysis (e.g. principal component analysis (PCA)).10 Here, we perform Raman spectroscopy of living cells and native tissues. Cells are either seeded on glass bottom dishes or kept in suspension under normal cell culture conditions (37 °C, 5\% CO2) before measurement. Native tissues are dissected and stored in phosphate buffered saline (PBS) at 4 °C prior measurements. Depending on our experimental set up, we then either focused on the cell nucleus or extracellular matrix (ECM) proteins such as elastin and collagen. For all studies, a minimum of 30 cells or 30 random points of interest within the ECM are measured. Data processing steps included background subtraction and normalization.}, language = {en} } @article{OwenSauerGaus2012, author = {Owen, Dylan M. and Sauer, Markus and Gaus, Katharina}, title = {Fluorescence localization microscopy}, series = {Communicative \& Integrative Biology}, volume = {5}, journal = {Communicative \& Integrative Biology}, number = {4}, doi = {10.4161/cib.20348}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124416}, pages = {345-349}, year = {2012}, abstract = {Localization microscopy techniques are super-resolution fluorescence imaging methods based on the detection of individual molecules. Despite the relative simplicity of the microscope setups and the availability of commercial instruments, localization microscopy faces unique challenges. While achieving super-resolution is now routine, issues concerning data analysis and interpretation mean that revealing novel biological insights is not. Here, we outline why data analysis and the design of robust test samples may hold the key to harness the full potential of localization microscopy.}, language = {en} } @article{RallGrimm2012, author = {Rall, Susanne and Grimm, Tiemo}, title = {Survival in Duchenne muscular dystrophy}, series = {Acta Myologica}, volume = {31}, journal = {Acta Myologica}, number = {2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124404}, pages = {117-120}, year = {2012}, abstract = {Objective: To determine the survival in a population of German patients with Duchenne muscular dystrophy. Patients and methods: Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected. Results: 67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 \% to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years. Conclusion and clinical relevance: our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.}, language = {en} } @article{StippekohlWinklerWalteretal.2012, author = {Stippekohl, Bastian and Winkler, Markus H. and Walter, Bertram and Kagerer, Sabine and Mucha, Ronald F. and Pauli, Paul and Vaitl, Dieter and Stark, Rudolf}, title = {Neural Responses to Smoking Stimuli Are Influenced by Smokers' Attitudes towards Their Own Smoking Behaviour}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0046782}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124393}, year = {2012}, abstract = {An important feature of addiction is the high drug craving that may promote the continuation of consumption. Environmental stimuli classically conditioned to drug-intake have a strong motivational power for addicts and can elicit craving. However, addicts differ in the attitudes towards their own consumption behavior: some are content with drug taking (consonant users) whereas others are discontent (dissonant users). Such differences may be important for clinical practice because the experience of dissonance might enhance the likelihood to consider treatment. This fMRI study investigated in smokers whether these different attitudes influence subjective and neural responses to smoking stimuli. Based on self-characterization, smokers were divided into consonant and dissonant smokers. These two groups were presented smoking stimuli and neutral stimuli. Former studies have suggested differences in the impact of smoking stimuli depending on the temporal stage of the smoking ritual they are associated with. Therefore, we used stimuli associated with the beginning (BEGIN-smoking-stimuli) and stimuli associated with the terminal stage (END-smoking-stimuli) of the smoking ritual as distinct stimulus categories. Stimulus ratings did not differ between both groups. Brain data showed that BEGIN-smoking-stimuli led to enhanced mesolimbic responses (amygdala, hippocampus, insula) in dissonant compared to consonant smokers. In response to END-smoking-stimuli, dissonant smokers showed reduced mesocortical responses (orbitofrontal cortex, subcallosal cortex) compared to consonant smokers. These results suggest that smoking stimuli with a high incentive value (BEGIN-smoking-stimuli) are more appetitive for dissonant than consonant smokers at least on the neural level. To the contrary, smoking stimuli with low incentive value (END-smoking-stimuli) seem to be less appetitive for dissonant smokers than consonant smokers. These differences might be one reason why dissonant smokers experience difficulties in translating their attitudes into an actual behavior change.}, language = {en} } @article{DurrenbergerGruenblattFernandoetal.2012, author = {Durrenberger, Pascal F. and Gr{\"u}nblatt, Edna and Fernando, Francesca S. and Monoranu, Camelia Maria and Evans, Jordan and Riederer, Peter and Reynolds, Richard and Dexter, David T.}, title = {Inflammatory Pathways in Parkinson's Disease; A BNE Microarray Study}, series = {Parkinson's Disease}, volume = {2012}, journal = {Parkinson's Disease}, number = {214714}, doi = {10.1155/2012/214714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124380}, year = {2012}, abstract = {The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth.}, language = {en} } @article{WeisschuhWissingerGramer2012, author = {Weisschuh, Nicole and Wissinger, Bernd and Gramer, Eugen}, title = {A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia}, series = {Molecular Vision}, volume = {18}, journal = {Molecular Vision}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124379}, pages = {751-757}, year = {2012}, abstract = {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.}, language = {en} } @article{NeuschKuhlmannKressetal.2012, author = {Neusch, Clemens and Kuhlmann, Tanja and Kress, Wolfram and Schneider-Gold, Christiane}, title = {Late-onset myopathy of the posterior calf muscles mimicking Miyoshi myopathy unrelated to dysferlin mutation: a case report}, series = {Journal of Medical Case Reports}, volume = {6}, journal = {Journal of Medical Case Reports}, number = {345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124365}, year = {2012}, abstract = {Introduction Miyoshi myopathy, a type of distal myopathy with predominant involvement of the posterior calf muscles, has been assigned to mutations in the dysferlin gene. However, many of the late-onset limb-girdle and distal myopathies that resemble dysferlinopathy or Miyoshi myopathy remain unclassified, even after extensive immunohistological and genetic analysis. Case presentation We report the case of a 59-year-old Caucasian man with distal myopathy and exercise-induced myalgia, preferentially of the leg muscles, closely resembling the Miyoshi phenotype. Magnetic resonance imaging of his calf muscles showed typical fatty replacement of the medial heads of the gastrocnemius muscles and soleus muscles, with progression to the adductor longus muscles over a time course of two years. However, genetic analysis revealed that the phenotype of our patient was not related to a mutation in the dysferlin gene but to a novel homozygous splice mutation in the anoctamin 5 gene. Mutations in the anoctamin 5 gene have so far been identified only in some cases of limb-girdle and distal myopathy. Mutations in the anoctamin 5 gene have been assigned to limb-girdle muscular dystrophy type 2L, while distal Miyoshi-like phenotypes have been classified as Miyoshi myopathy type 3. Conclusion The case presented in this report further strengthens the underlying genetic heterogeneity in Miyoshi myopathy-like phenotypes and adds another family to non-dysferlin, Miyoshi myopathy type 3 of late-onset. Furthermore, our case supports the recent observation that anoctamin 5 mutations are a primary cause of distal non-dysferlin myopathies. Therefore, given the increasing number of anoctamin 5 mutations in Miyoshi-like phenotypes, genetic analysis should include an anoctamin 5 screen in late-onset limb-girdle and distal myopathies.}, language = {en} } @article{SuetterlinPaapBabicetal.2012, author = {S{\"u}tterlin, Stefan and Paap, Muirne C. S. and Babic, Stana and K{\"u}bler, Andrea and V{\"o}gele, Claus}, title = {Rumination and Age: Some Things Get Better}, series = {Journal of Aging Research}, volume = {2012}, journal = {Journal of Aging Research}, number = {267327}, doi = {10.1155/2012/267327}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124356}, year = {2012}, abstract = {Rumination has been defined as a mode of responding to distress that involves passively focusing one's attention on symptoms of distress without taking action. This dysfunctional response style intensifies depressed mood, impairs interpersonal problem solving, and leads to more pessimistic future perspectives and less social support. As most of these results were obtained from younger people, it remains unclear how age affects ruminative thinking. Three hundred members of the general public ranging in age from 15 to 87 years were asked about their ruminative styles using the Response Styles Questionnaire (RSQ), depression and satisfaction with life. A Mokken Scale analysis confirmed the two-factor structure of the RSQ with brooding and reflective pondering as subcomponents of rumination. Older participants (63 years and older) reported less ruminative thinking than other age groups. Life satisfaction was associated with brooding and highest for the earlier and latest life stages investigated in this study.}, language = {en} } @article{BiedererMirsadraeeBeeretal.2012, author = {Biederer, J{\"u}rgen and Mirsadraee, S. and Beer, M. and Molinari, F. and Hintze, C. and Bauman, G. and Both, M. and Van Beek, E. J. R. and Wild, J. and Puderbach, M.}, title = {MRI of the lung (3/3)—current applications and future perspectives}, series = {Insights into Imaging}, volume = {3}, journal = {Insights into Imaging}, number = {4}, doi = {10.1007/s13244-011-0142-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124348}, pages = {373-386}, year = {2012}, abstract = {Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations.}, language = {en} } @article{BiedererBeerHirschetal.2012, author = {Biederer, J. and Beer, M. and Hirsch, W. and Wild, J. and Fabel, M. and Puderbach, M. and Van Beek, E. J. R.}, title = {MRI of the lung (2/3). Why … when … how?}, series = {Insights into Imaging}, volume = {3}, journal = {Insights into Imaging}, number = {4}, doi = {10.1007/s13244-011-0146-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124268}, pages = {355-371}, year = {2012}, abstract = {Background Among the modalities for lung imaging, proton magnetic resonance imaging (MRI) has been the latest to be introduced into clinical practice. Its value to replace X-ray and computed tomography (CT) when radiation exposure or iodinated contrast material is contra-indicated is well acknowledged: i.e. for paediatric patients and pregnant women or for scientific use. One of the reasons why MRI of the lung is still rarely used, except in a few centres, is the lack of consistent protocols customised to clinical needs. Methods This article makes non-vendor-specific protocol suggestions for general use with state-of-the-art MRI scanners, based on the available literature and a consensus discussion within a panel of experts experienced in lung MRI. Results Various sequences have been successfully tested within scientific or clinical environments. MRI of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination. It serves in difficult clinical problems encountered in daily routine, such as assessment of the mediastinum and chest wall, and even might challenge molecular imaging techniques in the near future. Conclusion This article helps new users to implement appropriate protocols on their own MRI platforms. Main Messages • MRI of the lung can be readily performed on state-of-the-art 1.5-T MRI scanners. • Protocol suggestions based on the available literature facilitate its use for routine • MRI offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. • MRI is an option for paediatrics and science when CT is contra-indicated}, language = {en} } @article{WildMarshallBocketal.2012, author = {Wild, J. M. and Marshall, H. and Bock, M. and Schad, L. R. and Jakob, P. M. and Puderbach, M. and Molinari, F. and Van Beek, E. J. R. and Biederer, J.}, title = {MRI of the lung (1/3): methods}, series = {Insights into Imaging}, volume = {3}, journal = {Insights into Imaging}, number = {4}, doi = {10.1007/s13244-012-0176-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124238}, pages = {345-353}, year = {2012}, abstract = {Proton magnetic resonance imaging (MRI) has recently emerged as a clinical tool to image the lungs. This paper outlines the current technical aspects of MRI pulse sequences, radiofrequency (RF) coils and MRI system requirements needed for imaging the pulmonary parenchyma and vasculature. Lung MRI techniques are presented as a "technical toolkit", from which MR protocols will be composed in the subsequent papers for comprehensive imaging of lung disease and function (parts 2 and 3). This paper is pitched at MR scientists, technicians and radiologists who are interested in understanding and establishing lung MRI methods. Images from a 1.5 T scanner are used for illustration of the sequences and methods that are highlighted. Main Messages • Outline of the hardware and pulse sequence requirements for proton lung MRI • Overview of pulse sequences for lung parenchyma, vascular and functional imaging with protons • Demonstration of the pulse-sequence building blocks for clinical lung MRI protocols}, language = {en} } @article{ZhangSiPahl2012, author = {Zhang, Shaowu and Si, Aung and Pahl, Mario}, title = {Visually guided decision making in foraging honeybees}, series = {Frontiers in Neuroscience}, volume = {6}, journal = {Frontiers in Neuroscience}, number = {88}, doi = {10.3389/fnins.2012.00088}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124228}, year = {2012}, abstract = {Honeybees can easily be trained to perform different types of discrimination tasks under controlled laboratory conditions. This review describes a range of experiments carried out with free-flying forager honeybees under such conditions. The research done over the past 30 or so years suggests that cognitive abilities (learning and perception) in insects are more intricate and flexible than was originally imagined. It has become apparent that honeybees are capable of a variety of visually guided tasks, involving decision making under challenging situations: this includes simultaneously making use of different sensory modalities, such as vision and olfaction, and learning to use abstract concepts such as "sameness" and "difference." Many studies have shown that decision making in foraging honeybees is highly flexible. The trained animals learn how to solve a task, and do so with a high accuracy, but when they are presented with a new variation of the task, they apply the learnt rules from the earlier setup to the new situation, and solve the new task as well. Honeybees therefore not only feature a rich behavioral repertoire to choose from, but also make decisions most apt to the current situation. The experiments in this review give an insight into the environmental cues and cognitive resources that are probably highly significant for a forager bee that must continually make decisions regarding patches of resources to be exploited.}, language = {en} } @article{LanghauserHeilerGrudzenskietal.2012, author = {Langhauser, Friederike L. and Heiler, Patrick M. and Grudzenski, Saskia and Lemke, Andreas and Alonso, Angelika and Schad, Lothar R. and Hennerici, Michael G. and Meairs, Stephen and Fata, Marc}, title = {Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe}, series = {Experimental and Translational Stroke Medicine}, volume = {4}, journal = {Experimental and Translational Stroke Medicine}, number = {18}, doi = {10.1186/2040-7378-4-18}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124218}, year = {2012}, abstract = {Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8\% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice.}, language = {en} } @article{RadermacherWinglerKleikersetal.2012, author = {Radermacher, Kim A. and Wingler, Kirstin and Kleikers, Pamela and Altenh{\"o}fer, Sebastian and Hermans, Johannes J. R. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.}, title = {The 1027th target candidate in stroke: Will NADPH oxidase hold up?}, series = {Experimental and Translational Stroke Medicine}, volume = {4}, journal = {Experimental and Translational Stroke Medicine}, number = {11}, doi = {10.1186/2040-7378-4-11}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124197}, year = {2012}, abstract = {As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.}, language = {en} } @article{NolteZadehKhorasaniSafarovetal.2012, author = {Nolte, Thomas and Zadeh-Khorasani, Maryam and Safarov, Orkhan and Rueff, Franziska and Varga, Rita and Herbach, Nadja and Wanke, R{\"u}diger and Wollenberg, Andreas and Mueller, Thomas and Gropp, Roswitha and Wolf, Eckhard and Siebeck, Matthias}, title = {Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid \(IL2Rγ^{null}\) mice engrafted with human peripheral blood mononuclear cells}, series = {Disease Models and Mechanisms}, volume = {6}, journal = {Disease Models and Mechanisms}, doi = {10.1242/dmm.009167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124150}, pages = {125-134}, year = {2012}, abstract = {Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2Rγnull mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease.}, language = {en} } @article{NassWeissbrichHuberetal.2012, author = {Nass, Maximilian and Weissbrich, Benedikt and Huber, Moritz and Schneider, Elisabeth Marion and Weiss, Manfred}, title = {BK viremia in critically ill surgical patients with hemorrhagic or septic shock}, series = {BMC Research Notes}, volume = {5}, journal = {BMC Research Notes}, number = {100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124136}, year = {2012}, abstract = {Background Infections with polyomavirus BK virus (BKV) are a common cause of renal dysfunction after renal transplantation and may also be harmful in surgical patients with shock. The aim of the present study was to determine the frequency of BKV viremia in critically ill surgical patients with septic or hemorrhagic shock, and, if viremia is detectable, whether viremia may be associated with renal dysfunction. Findings A total of 125 plasma samples from 44 critically ill surgical patients with septic or hemorrhagic shock were tested by real-time polymerase chain reaction (PCR) for BKV DNA during their stay on the intensive care unit (ICU). BKV viremia occurred in four patients, i.e. in three of the septic and in one of the hemorrhagic shock group. There was no association between viremia and renal dysfunction. All positive samples contained a low viral load (< 500 copies/ml). Conclusions Since BK viremia was rarely found and with low viral load only in critically ill surgical patients with shock, it is very unlikely that BK viremia results in BK nephropathy later on.}, language = {en} } @article{SangesScheuermannZahedietal.2012, author = {Sanges, C. and Scheuermann, C. and Zahedi, R. P. and Sickmann, A. and Lamberti, A. and Migliaccio, N. and Baljuls, A. and Marra, M. and Zappavigna, S. and Reinders, J. and Rapp, U. and Abbruzzese, A. and Caraglia, M. and Arcari, P.}, title = {Raf kinases mediate the phosphorylation of eukaryotic translation elongation factor 1A and regulate its stability in eukaryotic cells}, series = {Cell Death and Disease}, volume = {3}, journal = {Cell Death and Disease}, number = {e276}, doi = {10.1038/cddis.2012.16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124149}, year = {2012}, abstract = {We identified eukaryotic translation elongation factor 1A (eEF1A) Raf-mediated phosphorylation sites and defined their role in the regulation of eEF1A half-life and of apoptosis of human cancer cells. Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. Interestingly, S21 belongs to the first eEF1A GTP/GDP-binding consensus sequence. Phosphorylation of S21 was strongly enhanced when both eEF1A isoforms were preincubated prior the assay with C-Raf, suggesting that the eEF1A isoforms can heterodimerize thus increasing the accessibility of S21 to the phosphate. Overexpression of eEF1A1 in COS 7 cells confirmed the phosphorylation of T88 also in vivo. Compared with wt, in COS 7 cells overexpressed phosphodeficient (A) and phospho-mimicking (D) mutants of eEF1A1 (S21A/D and T88A/D) and of eEF1A2 (S21A/D), resulted less stable and more rapidly proteasome degraded. Transfection of S21 A/D eEF1A mutants in H1355 cells increased apoptosis in comparison with the wt isoforms. It indicates that the blockage of S21 interferes with or even supports C-Raf induced apoptosis rather than cell survival. Raf-mediated regulation of this site could be a crucial mechanism involved in the functional switching of eEF1A between its role in protein biosynthesis and its participation in other cellular processes.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124052}, year = {2012}, abstract = {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.}, language = {en} } @article{MonteliusLjungbergHornetal.2012, author = {Montelius, Mikael and Ljungberg, Maria and Horn, Michael and Forssell-Aronsson, Eva}, title = {Tumour size measurement in a mouse model using high resolution MRI}, series = {BMC Medical Imaging}, volume = {12}, journal = {BMC Medical Imaging}, number = {12}, doi = {10.1186/1471-2342-12-12}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124049}, year = {2012}, abstract = {Background Animal models are frequently used to assess new treatment methods in cancer research. MRI offers a non-invasive in vivo monitoring of tumour tissue and thus allows longitudinal measurements of treatment effects, without the need for large cohorts of animals. Tumour size is an important biomarker of the disease development, but to our knowledge, MRI based size measurements have not yet been verified for small tumours (10-2-10-1 g). The aim of this study was to assess the accuracy of MRI based tumour size measurements of small tumours on mice. Methods 2D and 3D T2-weighted RARE images of tumour bearing mice were acquired in vivo using a 7 T dedicated animal MR system. For the 3D images the acquired image resolution was varied. The images were exported to a PC workstation where the tumour mass was determined assuming a density of 1 g/cm3, using an in-house developed tool for segmentation and delineation. The resulting data were compared to the weight of the resected tumours after sacrifice of the animal using regression analysis. Results Strong correlations were demonstrated between MRI- and necropsy determined masses. In general, 3D acquisition was not a prerequisite for high accuracy. However, it was slightly more accurate than 2D when small (<0.2 g) tumours were assessed for inter- and intraobserver variation. In 3D images, the voxel sizes could be increased from 1603 μm3 to 2403 μm3 without affecting the results significantly, thus reducing acquisition time substantially. Conclusions 2D MRI was sufficient for accurate tumour size measurement, except for small tumours (<0.2 g) where 3D acquisition was necessary to reduce interobserver variation. Acquisition times between 15 and 50 minutes, depending on tumour size, were sufficient for accurate tumour volume measurement. Hence, it is possible to include further MR investigations of the tumour, such as tissue perfusion, diffusion or metabolic composition in the same MR session.}, language = {en} } @article{SchmittBackesNourkamiTutdibietal.2012, author = {Schmitt, Jana and Backes, Christina and Nourkami-Tutdibi, Nasenien and Leidinger, Petra and Deutscher, Stephanie and Beier, Markus and Gessler, Manfred and Graf, Norbert and Lenhof, Hans-Peter and Keller, Andreas and Meese, Eckart}, title = {Treatment-independent miRNA signature in blood of wilms tumor patients}, series = {BMC Genomics}, volume = {13}, journal = {BMC Genomics}, number = {379}, doi = {10.1186/1471-2164-13-379}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124034}, year = {2012}, abstract = {Background Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001. Results We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5\% and of patients after chemotherapy an accuracy of 97.0\%, each as compared to healthy controls. Conclusion Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.}, language = {en} } @article{VanBaelenMottetSpahnetal.2012, author = {Van Baelen, Anthony and Mottet, Nicolas and Spahn, Martin and Briganti, Alberto and Gontero, Paolo and Joniau, Steven}, title = {Sense and Nonsense of an Extended Pelvic Lymph Node Dissection in Prostate Cancer}, series = {Advances in Urology}, volume = {2012}, journal = {Advances in Urology}, number = {983058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123990}, year = {2012}, abstract = {Lymph node metastases associated with prostate cancer (PCa) has been shown to be a poor prognostic factor. The role of pelvic lymph node dissection (PLND) itself in relation to survival remains unclear, however. A Medline search was conducted to address this issue. The following conclusions were drawn. Only recently, improved survival due to completion of radical prostatectomy (RP) (compared to abandoning RP) in known or presumed lymph-node-positive patients has been shown. Lymph node sampling can only be considered representative if an adequate number of nodes is removed. While several authors have suggested that a therapeutic benefit in patients undergoing RP is not provided by PLND, the reliability of these studies is uncertain. Contrary to this, several studies have indicated the possibility of long-term survival even in the presence of limited lymph node metastases. The role and timing of initiation of adjuvant androgen deprivation therapy (ADT) in patients who have node-positive disease after RP is controversial. Recent studies suggest that delaying ADT may not adversely impact survival.}, language = {en} } @article{HagemannAnackerErnestusetal.2012, author = {Hagemann, Carsten and Anacker, Jelena and Ernestus, Ralf-Ingo and Vince, Giles H.}, title = {A complete compilation of matrix metalloproteinase expression in human malignant gliomas}, series = {World Journal of Clinical Oncology}, volume = {3}, journal = {World Journal of Clinical Oncology}, number = {5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123982}, pages = {67-79}, year = {2012}, abstract = {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.}, language = {en} } @article{ReussKieselKundeetal.2012, author = {Reuss, Heiko and Kiesel, Andrea and Kunde, Wilfried and W{\"u}hr, Peter}, title = {A cue from the unconscious - masked symbols prompt spatial anticipation}, series = {Frontiers in Psychology}, volume = {3}, journal = {Frontiers in Psychology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123971}, pages = {397}, year = {2012}, abstract = {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.}, language = {en} } @article{NeubauerWirthRufetal.2012, author = {Neubauer, Henning and Wirth, Clemens and Ruf, Katharina and Hebestreit, Helge and Beer, Meinrad}, title = {Acute Muscle Trauma due to Overexercise in an Otherwise Healthy Patient with Cystic Fibrosis}, series = {Case Reports in Pediatrics}, volume = {2012}, journal = {Case Reports in Pediatrics}, number = {527989}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123967}, year = {2012}, abstract = {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.}, language = {en} } @article{SchaeferVogelVillmann2012, author = {Schaefer, Natscha and Vogel, Nicolas and Villmann, Carmen}, title = {Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?}, series = {Frontiers in Molecular Neuroscience}, volume = {5}, journal = {Frontiers in Molecular Neuroscience}, number = {98}, doi = {10.3389/fnmol.2012.00098}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123839}, year = {2012}, abstract = {Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the (spasmodic, oscillator, cincinnati, Nmf11) or the (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABA(A) receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.}, language = {en} } @article{ZirkelCecilSchaeferetal.2012, author = {Zirkel, J. and Cecil, A. and Sch{\"a}fer, F. and Rahlfs, S. and Ouedraogo, A. and Xiao, K. and Sawadogo, S. and Coulibaly, B. and Becker, K. and Dandekar, T.}, title = {Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling}, series = {Bioinformatics and Biology Insights}, volume = {6}, journal = {Bioinformatics and Biology Insights}, doi = {10.4137/BBI.S10193}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123751}, pages = {287-302}, year = {2012}, abstract = {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.}, language = {en} } @article{ArnoldBraunschweigDamme2012, author = {Arnold, Nicole and Braunschweig, Holger and Damme, Alexander}, title = {Bis(μ-diisopropyl-phosphanido-\(κ^2\)P:P)bis-[hydrido(triisopropyl-phosphane-κP)platinum(II)]}, series = {Acta crystallographica. Section E, Structure reports online}, volume = {E68}, journal = {Acta crystallographica. Section E, Structure reports online}, doi = {http://dx.doi.org/10.1107/S1600536812022829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123723}, pages = {m808}, year = {2012}, abstract = {In the centrosymmetric molecular structure of the title compound \([Pt_2(C_6H_{14}P)_2H_2)(C_9H_{21}P)_2]\), each \(Pt^{II}\) atom is bound on one side to a phosphane ligand \((PiPr_3)\) and a hydrido ligand. On the other side, it is bound to two phosphanide ligands \((μ-PiPr_2)\), which engage a bridging position between the two \(Pt^{II}\) atoms, forming a distorted square-planar structure motif. The PtPt distance is 3.6755(2){\AA}. A comparable molecular structure was observed for bis-(μ-di-tert-butyl-phosphanido)bis-[hydrido(triethyl-phosphane)platinum(II)] [Itazaki et al. (2004 ). Organometallics, 23, 1610-1621].}, language = {en} } @article{MatlachHoffmannFreibergetal.2012, author = {Matlach, Juliane and Hoffmann, Niels and Freiberg, Florentina J. and Grehn, Franz and Klink, Thomas}, title = {Comparative study of trabeculectomy using single sutures versus releasable sutures}, series = {Clinical ophthalmology}, volume = {6}, journal = {Clinical ophthalmology}, doi = {http://dx.doi.org/10.2147/OPTH.S32503}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123715}, pages = {1019-1027}, year = {2012}, abstract = {BACKGROUND: The purpose of this study was to compare the outcomes of trabeculectomy using single sutures or releasable sutures. METHODS: This retrospective study analyzed the medical records of 61 patients who had undergone trabeculectomy using single sutures (n = 33, 54.1\%) or releasable sutures (n = 28, 45.9\%). The scleral flap was secured with a mean 3.9 (range 3-5) single sutures in 33 patients and with three releasable sutures in 28 patients. Primary outcomes were the success rate, based on intraocular pressure and medication usage, and the frequency of complications and post-surgical interventions. The criteria used to determine complete success were, first, intraocular pressure < 18 mmHg and, second, <=21 mmHg and >=20\% intraocular pressure reduction without glaucoma medication. RESULTS: All patients had an intraocular pressure <= 21 mmHg; 87.5\% in the single suture group and 92.6\% in the releasable suture group had an intraocular pressure < 18 mmHg at 24 months. There was a highly significant reduction in intraocular pressure to baseline values in both groups at the last visit. Applying the first criterion, complete success was achieved in 57.6\% of patients with single sutures and 71.4\% with releasable sutures, and based on the second criterion, 66.7\% and 71.4\%, respectively. No significant difference was found between the groups with regard to intraocular pressure, or success or complication rates. CONCLUSION: The results of trabeculectomy using single sutures or releasable sutures are equivalent. Therefore, the choice of suture technique should be based on individual patient requirements and surgeon experience.}, language = {en} } @article{AmichKrappmann2012, author = {Amich, Jorge and Krappmann, Sven}, title = {Deciphering metabolic traits of the fungal pathogen Aspergillus fumigatus: redundancy vs. essentiality}, series = {Frontiers in Microbiology}, volume = {3}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2012.00414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123669}, pages = {414}, year = {2012}, abstract = {Incidence rates of infections caused by environmental opportunistic fungi have risen over recent decades. Aspergillus species have emerged as serious threat for the immunecompromised, and detailed knowledge about virulence-determining traits is crucial for drug target identification. As a prime saprobe, A. fumigatus has evolved to efficiently adapt to various stresses and to sustain nutritional supply by osmotrophy, which is characterized by extracellular substrate digestion followed by efficient uptake of breakdown products that are then fed into the fungal primary metabolism. These intrinsic metabolic features are believed to be related with its virulence ability. The plethora of genes that encode underlying effectors has hampered their in-depth analysis with respect to pathogenesis. Recent developments in Aspergillus molecular biology allow conditional gene expression or comprehensive targeting of gene families to cope with redundancy. Furthermore, identification of essential genes that are intrinsically connected to virulence opens accurate perspectives for novel targets in antifungal therapy.}, language = {en} } @article{KruegerFriedrichFoersteretal.2012, author = {Krueger, Beate and Friedrich, Torben and F{\"o}rster, Frank and Bernhardt, J{\"o}rg and Gross, Roy and Dandekar, Thomas}, title = {Different evolutionary modifications as a guide to rewire two-component systems}, series = {Bioinformatics and Biology Insights}, volume = {6}, journal = {Bioinformatics and Biology Insights}, doi = {10.4137/BBI.S9356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123647}, pages = {97-128}, year = {2012}, abstract = {Two-component systems (TCS) are short signalling pathways generally occurring in prokaryotes. They frequently regulate prokaryotic stimulus responses and thus are also of interest for engineering in biotechnology and synthetic biology. The aim of this study is to better understand and describe rewiring of TCS while investigating different evolutionary scenarios. Based on large-scale screens of TCS in different organisms, this study gives detailed data, concrete alignments, and structure analysis on three general modification scenarios, where TCS were rewired for new responses and functions: (i) exchanges in the sequence within single TCS domains, (ii) exchange of whole TCS domains; (iii) addition of new components modulating TCS function. As a result, the replacement of stimulus and promotor cassettes to rewire TCS is well defined exploiting the alignments given here. The diverged TCS examples are non-trivial and the design is challenging. Designed connector proteins may also be useful to modify TCS in selected cases.}, language = {en} } @article{Gessner2012, author = {Gessner, Viktoria H.}, title = {Diphenyl[2-(phenyl-sulfon-yl)propan-2-yl]-\(\lambda^5\)-phosphanethione}, series = {Acta crystallographica. Section E, Structure reports online}, volume = {E68}, journal = {Acta crystallographica. Section E, Structure reports online}, number = {o1045}, doi = {10.1107/S1600536812010082}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123635}, year = {2012}, abstract = {The title compound, \(C_{21}H_{21}O_2PS_2\), was obtained from the corresponding dilithio methandiide by treatment with iodo-methane. The bond lengths and angles deviate considerably from those in the dimetallated compound. These differences are most pronounced in the PCS backbone. While the title compound features C-P and C-S distances of 1.9082(17) and 1.8348(17){\AA}, respectively, the dianion showed \(C-P_{av}\) distances shortened by 11\% [1.710(4){\AA}] and C-S distances shortened by 12\% [1.614(3){\AA}]. Additionally, the P-C-S angle experiences a contraction by methyl-ation of the dianion from 121.4(2) to 111.96(9)° in the title compound.}, language = {en} } @article{KittelSchneiderKenisScheketal.2012, author = {Kittel-Schneider, Sarah and Kenis, Gunter and Schek, Julia and van den Hove, Daniel and Prickaerts, Jos and Lesch, Klaus-Peter and Steinbusch, Harry and Reif, Andreas}, title = {Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes}, series = {Frontiers in Psychiatry}, volume = {3}, journal = {Frontiers in Psychiatry}, doi = {10.3389/fpsyt.2012.00033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123627}, pages = {33}, year = {2012}, abstract = {Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. Conclusion: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants.}, language = {en} } @article{RauBaurGeier2012, author = {Rau, Monika and Baur, Katharina and Geier, Andreas}, title = {Host Genetic Variants in the Pathogenesis of Hepatitis C.}, series = {Viruses}, volume = {4}, journal = {Viruses}, number = {12}, doi = {10.3390/v4123281}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123611}, pages = {3281-302}, year = {2012}, abstract = {Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.}, language = {en} } @article{HansenSeilerRumpfetal.2012, author = {Hansen, Niels and Seiler, Carola and Rumpf, Julian and Kraft, Peter and Dlaske, Henry and Abele-Horn, Marianne and Muellges, Wolfgang}, title = {Human Tuberculous Meningitis Caused by \(Mycobacterium\) \(caprae\)}, series = {Case Reports in Neurology}, volume = {4}, journal = {Case Reports in Neurology}, number = {1}, doi = {10.1159/000337299}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123425}, pages = {54-60}, year = {2012}, abstract = {INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM.}, language = {en} } @article{SchusterWessigSchimmeretal.2012, author = {Schuster, Frank and Wessig, Carsten and Schimmer, Christoph and Johannsen, Stephan and Lazarus, Marc and Aleksic, Ivan and Leyh, Rainer and Roewer, Norbert}, title = {In vitro contracture test results and anaesthetic management of a patient with emery-dreifuss muscular dystrophy for cardiac transplantation}, series = {Case Reports in Anesthesiology}, volume = {2012}, journal = {Case Reports in Anesthesiology}, number = {349046}, doi = {10.1155/2012/349046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123413}, year = {2012}, abstract = {Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.}, language = {en} } @article{SaidPolatSteinetal.2012, author = {Said, Harun M. and Polat, Buelent and Stein, Susanne and Guckenberger, Mathias and Hagemann, Carsten and Staab, Adrian and Katzer, Astrid and Anacker, Jelena and Flentje, Michael and Vordermark, Dirk}, title = {Inhibition of N-Myc down regulated gene 1 in in vitro cultured human glioblastoma cells}, series = {World Journal of Clinical Oncology}, volume = {3}, journal = {World Journal of Clinical Oncology}, number = {7}, doi = {10.5306/wjco.v3.i7.104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123385}, pages = {104-110}, year = {2012}, abstract = {AIM: To study short dsRNA oligonucleotides (siRNA) as a potent tool for artificially modulating gene expression of N-Myc down regulated gene 1 (NDRG1) gene induced under different physiological conditions (Normoxia and hypoxia) modulating NDRG1 transcription, mRNA stability and translation. METHODS: A cell line established from a patient with glioblastoma multiforme. Plasmid DNA for transfections was prepared with the Endofree Plasmid Maxi kit. From plates containing 5 x 10(7) cells, nuclear extracts were prepared according to previous protocols. The pSUPER-NDRG1 vectors were designed, two sequences were selected from the human NDRG1 cDNA (5'-GCATTATTGGCATGGGAAC-3' and 5'-ATGCAGAGTAACGTGGAAG-3'. reverse transcription polymerase chain reaction was performed using primers designed using published information on -actin and hypoxia-inducible factor (HIF)-1 mRNA sequences in GenBank. NDRG1 mRNA and protein level expression results under different conditions of hypoxia or reoxygenation were compared to aerobic control conditions using the Mann-Whitney U test. Reoxygenation values were also compared to the NDRG1 levels after 24 h of hypoxia (P < 0.05 was considered significant). RESULTS: siRNA- and iodoacetate (IAA)-mediated downregulation of NDRG1 mRNA and protein expression in vitro in human glioblastoma cell lines showed a nearly complete inhibition of NDRG1 expression when compared to the results obtained due to the inhibitory role of glycolysis inhibitor IAA. Hypoxia responsive elements bound by nuclear HIF-1 in human glioblastoma cells in vitro under different oxygenation conditions and the clearly enhanced binding of nuclear extracts from glioblastoma cell samples exposed to extreme hypoxic conditions confirmed the HIF-1 Western blotting results. CONCLUSION: NDRG1 represents an additional diagnostic marker for brain tumor detection, due to the role of hypoxia in regulating this gene, and it can represent a potential target for tumor treatment in human glioblastoma. The siRNA method can represent an elegant alternative to modulate the expression of the hypoxia induced NDRG1 gene and can help to monitor the development of the cancer disease treatment outcome through monitoring the expression of this gene in the patients undergoing the different therapeutic treatment alternatives available nowadays.}, language = {en} } @article{FraunholzSinha2012, author = {Fraunholz, Martin and Sinha, Bhanu}, title = {Intracellular staphylococcus aureus: Live-in and let die}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {2}, journal = {Frontiers in Cellular and Infection Microbiology}, number = {43}, doi = {10.3389/fcimb.2012.00043}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123374}, year = {2012}, abstract = {Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells. The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti-apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus.}, language = {en} } @article{WeiseStoll2012, author = {Weise, Gesa and Stoll, Guido}, title = {Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant?}, series = {Frontiers in Neurology}, volume = {3}, journal = {Frontiers in Neurology}, number = {178}, doi = {10.3389/fneur.2012.00178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123359}, year = {2012}, abstract = {Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate. We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients.}, language = {en} } @article{ReiterRitterNordbecketal.2012, author = {Reiter, Theresa and Ritter, Oliver and Nordbeck, Peter and Beer, Meinrad and Bauer, Wolfgang Rudolf}, title = {MRI-guided ablation of wide complex tachycardia in a univentricular heart}, series = {World Journal of Cardiology}, volume = {4}, journal = {World Journal of Cardiology}, number = {8}, doi = {10.4330/wjc.v4.i8.260}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123165}, pages = {260-263}, year = {2012}, abstract = {Magnetic resonance imaging can be used for preprocedural assessment of complex anatomy for radiofrequency (RF) ablations, e.g., in a univentricular heart. This case report features the treatment of a young patient with a functionally univentricular heart who suffered from persistent sudden onset tachycardia with wide complexes that required RF ablation as treatment.}, language = {en} } @article{WuPuAllenetal.2012, author = {Wu, Lingdan and Pu, Jie and Allen, John J. B. and Pauli, Paul}, title = {Recognition of facial expressions in individuals with elevated levels of depressive symptoms: an eye-movement study}, series = {Depression Research and Treatment}, volume = {2012}, journal = {Depression Research and Treatment}, number = {249030}, doi = {10.1155/2012/249030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123153}, year = {2012}, abstract = {Previous studies consistently reported abnormal recognition of facial expressions in depression. However, it is still not clear whether this abnormality is due to an enhanced or impaired ability to recognize facial expressions, and what underlying cognitive systems are involved. The present study aimed to examine how individuals with elevated levels of depressive symptoms differ from controls on facial expression recognition and to assess attention and information processing using eye tracking. Forty participants (18 with elevated depressive symptoms) were instructed to label facial expressions depicting one of seven emotions. Results showed that the high-depression group, in comparison with the low-depression group, recognized facial expressions faster and with comparable accuracy. Furthermore, the high-depression group demonstrated greater leftwards attention bias which has been argued to be an indicator of hyperactivation of right hemisphere during facial expression recognition.}, language = {en} } @article{DandekarFieselmannPoppetal.2012, author = {Dandekar, Thomas and Fieselmann, Astrid and Popp, Jasmin and Hensel, Michael}, title = {Salmonella enterica: a surprisingly well-adapted intracellular lifestyle}, series = {Frontiers in Microbiology}, journal = {Frontiers in Microbiology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123135}, year = {2012}, abstract = {The infectious intracellular lifestyle of Salmonella enterica relies on the adaptation to nutritional conditions within the Salmonella-containing vacuole (SCV) in host cells. We summarize latest results on metabolic requirements for Salmonella during infection. This includes intracellular phenotypes of mutant strains based on metabolic modeling and experimental tests, isotopolog profiling using (13)C-compounds in intracellular Salmonella, and complementation of metabolic defects for attenuated mutant strains towards a comprehensive understanding of the metabolic requirements of the intracellular lifestyle of Salmonella. Helpful for this are also genomic comparisons. We outline further recent studies and which analyses of intracellular phenotypes and improved metabolic simulations were done and comment on technical required steps as well as progress involved in the iterative refinement of metabolic flux models, analyses of mutant phenotypes, and isotopolog analyses. Salmonella lifestyle is well-adapted to the SCV and its specific metabolic requirements. Salmonella metabolism adapts rapidly to SCV conditions, the metabolic generalist Salmonella is quite successful in host infection.}, language = {en} } @article{MeuleKuebler2012, author = {Meule, Adrian and K{\"u}bler, Andrea}, title = {The translation of substance dependence criteria to food-related behaviors: different views and interpretations.}, series = {Frontiers in psychiatry}, journal = {Frontiers in psychiatry}, doi = {10.3389/fpsyt.2012.00064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123092}, year = {2012}, abstract = {No abstract available.}, language = {en} } @article{FoersterBeisserGrohmeetal.2012, author = {F{\"o}rster, Frank and Beisser, Daniela and Grohme, Markus A. and Liang, Chunguang and Mali, Brahim and Siegl, Alexander Matthias and Engelmann, Julia C. and Shkumatov, Alexander V. and Schokraie, Elham and M{\"u}ller, Tobias and Schn{\"o}lzer, Martina and Schill, Ralph O. and Frohme, Marcus and Dandekar, Thomas}, title = {Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations}, series = {Bioinformatics and biology insights}, volume = {6}, journal = {Bioinformatics and biology insights}, doi = {10.4137/BBI.S9150}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123089}, pages = {69-96}, year = {2012}, abstract = {Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant.}, language = {en} } @phdthesis{Hirschbeck2012, author = {Hirschbeck, Maria Wenefriede}, title = {Structure-based drug design on the enoyl-ACP reductases of Yersinia pestis and Burkholderia pseudomallei}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70869}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Spreading drug resistances among Gram-negative pathogens and the paucity of new agents on the antibacterial drug market against these tenacious bacteria create a pressing need for the development of new antibiotics. The bacterial fatty acid biosynthesis pathway FAS-II, especially the enoyl-ACP reductase catalyzing the last step of the elongation cycle, is an established drug target against tuberculosis but has not been extensively exploited for drug design against other bacterial pathogens. In this thesis the enoyl-ACP reductases of the Gram-negative biothreat organisms Burkholderia pseudomallei and Yersinia pestis were targeted in a structure-based drug design approach. The structure of the most recently identified enoyl-ACP isoenzyme FabV was characterized by X-ray crystallography and could be determined in three different states. FabV from B. pseudomallei was obtained in the apo-form of the enzyme, whereas FabV from Y. pestis was characterized in a binary complex with the cofactor NADH as well as in a ternary complex with NADH and the triclosan-based 2-pyridone inhibitors PT172 and PT173. Analysis of the FabV structure revealed the typical fold of the short chain dehydrogenase/reductase superfamily with the NADH-binding Rossmann fold and a substrate-binding pocket with a conserved active site geometry compared to the related isoenzyme FabI. Additional structural elements of FabV are located around the active site. The monomeric form of the enzyme is thereby stabilized and the substrate-binding loop is kept in a closed, helical conformation. The ternary complexes of FabV exhibited a similar inhibitor-binding mode as observed for triclosan inhibition in FabI and point to a potential substrate-binding mechanism. B. pseudomallei possesses FabI as an additional enoyl-ACP reductase isoenzyme, which was structurally characterized in the apo form and in ternary complexes with NAD+ and the diphenyl ether inhibitors triclosan, PT02, PT12 or PT404 as well as the 4-pyridone inhibitor PT155. The structural data of the ternary enoyl-ACP reductases complexes of B. pseudomallei and Y. pestis hold the promise for the possibility to develop antibacterials targeting FabV or even both isoenzymes, FabI and FabV, based on the triclosan scaffold.}, subject = {Yersinia}, language = {en} } @phdthesis{Baltrusch2012, author = {Baltrusch, Stefanie}, title = {Retrospektive Analyse von Amputationen im Fußbereich infolge peripherer arterieller Verschlußkrankheit}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113975}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Die Auswertung des Patientenkollektivs von 2000 bis 2004 an der Chirurgischen Universit{\"a}tsklinik W{\"u}rzburg ergab 63 Patienten (Gruppe 1), die einer Minoramputation und 59 Patienten die einer Minor- mit konsekutiver Majoramputation (Gruppe 2) infolge pAVK unterzogen wurden. Eine Abh{\"a}ngigkeit zwischen Alter und Majornachamputationsrate konnte nicht festgestellt werden, jedoch eine Tendenz beim Einfluss von Comorbidit{\"a}ten wie Diabetes mellitus und dialysepflichtiger Niereninsuffizienz auf die Wundheilung und Liegedauer. Die Anzahl an durchgef{\"u}hrten gef{\"a}ßchirurgischen Eingriffen wie PTA und Bypass-Operation lag in beiden Gruppen mit 65\% bzw. 72\% im Vergleich zur Literatur im Standardbereich. Eine hohe Rate an gef{\"a}ßmedizinischer Diagnostik und Therapie scheint auch bei fortgeschrittener pAVK (Grad IV) erforderlich, um die Notwendigkeit von Amputationen insbesondere die Anzahl an Majoramputationen zu verringern. Bei hoher und mit Gruppe 1 vergleichbarer Interventionsrate in Gruppe 2 l{\"a}sst sich allerdings auch erkennen, dass trotz Aussch{\"o}pfung dieser Massnahmen die Rate an Majoramputationen und damit des Beinverlustes hoch ist. Positiv zu werten ist, dass es bei {\"u}ber 50\% der Amputierten ausgereicht hat, eine Amputation im Fussbereich (Minoramputation) durchzuf{\"u}hren. Bei diesen 63 Patienten, war bei 58 Patienten sogar nur ein Eingriff n{\"o}tig. Ferner handelte es sich bei den Majoramputationen in der Mehrzahl um Unterschenkelamputation, und somit um einen nur partiellen Beinverlust . 76\% der durchgef{\"u}hrten ersten Majoramputationen erfolgten in den ersten beiden Monaten nach vorausgegangener Minoramputation, die gr{\"o}ßte Anzahl innerhalb des ersten Monats. Auch die letzte Amputation, die definitive Versorgung, erfolgte in den meisten F{\"a}llen innerhalb der ersten beiden Monate nach Prim{\"a}reingriff. Somit ist ein nur unwesentlicher Aufschub bis zur definitiven Versorgung ersichtlich. Der Versuch einer Konsolidierung der Isch{\"a}miefolgen (Gangr{\"a}n) mittels Minoramputation scheint bei fortgeschrittener pAVK im Stadium IV nach Aussch{\"o}pfung der gef{\"a}ßmedizinischen Diagnostika und Interventionen somit immer gerechtfertigt, und sollte wenn m{\"o}glich einer Majoramputation vorgezogen werden. Die durchschnittliche Krankenhausverweildauer in der Gruppe der Minoramputationen lag bei 28 Tagen, in der Gruppe 2 der Majoramputationen bei 39 Tagen. Die Mortalit{\"a}tsrate ergibt einen deutlich erh{\"o}hten Wert in der Gruppe der Majoramputationen. Die Dreijahresmortalit{\"a}t betrug in der Gruppe der Minoramputationen 20\% und der Majoramputationen 58\%. Es zeigte sich eine Zunahme der Mortalit{\"a}t mit zunehmender Amputationsh{\"o}he und zunehmender Zahl der Amputationen. Diese Daten lassen sich mit 52 aktuellen Literaturangaben durchaus vergleichen und beweisen die schlechte Prognose f{\"u}r AVK-Patienten, bei denen eine Majoramputation unausweichlich ist. Insgesamt ist es wichtig, dass ein Team aus Chirurgen, Gef{\"a}ßchirurgen, Radiologen und Angiologen kooperativ zusammen arbeitet, um dem Patienten, eine f{\"u}r ihn beste Versorgung anbieten zu k{\"o}nnen. Hier sollte auch nicht vor einem oft h{\"o}heren Patientenalter zur{\"u}ckgeschreckt werden, denn h{\"a}ufig konnte gerade bei diesen Patienten durch eine Bypass-Operation eine sonst vermutlich unumg{\"a}ngliche Amputation im Unter- bzw. Oberschenkelbereich verhindert werden.}, subject = {PAVK}, language = {de} } @phdthesis{Bischofberger2012, author = {Bischofberger, Simon}, title = {Entwicklung und biomechanische Untersuchungen eines Kreuzbandkonstrukts aus biomaterialbasiertem Kollagen I}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85648}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Das ACL ist eine der am h{\"a}ufigsten verletzten Strukturen des menschlichen K{\"o}rpers bei Sportunf{\"a}llen und die Anzahl der Rekonstruktionen wird weiterhin zunehmen. In den letzten Jahren wurden große Fortschritte in der Charakterisierung der biomechanischen Eigenschaften von Sehnen und B{\"a}ndern erzielt und neue Ans{\"a}tze auf dem Gebiet des Tissue Engineering er{\"o}ffnen neue M{\"o}glichkeiten. In dieser Arbeit wurde ein ACL-Konstrukt aus biomaterialbasiertem Kollagen I entwickelt und getestet. Die gewonnenen Ergebnisse k{\"o}nnen als Grundlage f{\"u}r die Herstellung eines Kreuzbandkonstruktes verwendet werden.}, subject = {Kreuzband}, language = {de} } @phdthesis{Hu2012, author = {Hu, Wanning}, title = {Organometal half-sandwich complexes and their bioconjugates: Biological activity on cancer cells and potential applications in biolabelling}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-87899}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {In summary, structure-activity relationships in peptide and dendrimer carriers modified with different organometal complexes were studied on a human breast cancer cell line. Variation of the organometal cargo and carrier can significantly influence their biological properties and might open the way to new approaches in chemotherapy. Furthermore, the incorporation of complexes with different C≡O vibrational signatures in a model peptide was explored to examine information encoding in biomolecules in a barcoding strategy for potential imaging applications. In particular for the latter, additional stable metal-carbonyl markers need to be prepared in future work to expand the pool of vibrational labels available.}, subject = {Konjugate}, language = {en} } @phdthesis{Schmidt2012, author = {Schmidt, Traudel}, title = {Establishment of Hey-triple-KO-ES cells and characterisation of Bre, a Hey binding partner}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85459}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Hey1, Hey2 and HeyL are downstream effectors of the Notch signalling pathway. Hey genes play decisive roles during embryonic development for example in cardiovascular development. However, the precise transcriptional programmes and genes, which are affected by each single Hey gene, are still poorly understood. One drawback for the analysis of Hey1, Hey2 or HeyL single gene function is that these genes are co-expressed in many tissues and share a high degree of functional redundancy. Thus, it was necessary to establish a system, which is either devoid of Hey expression, or just comprises one single Hey gene family member. For this, Hey1(fl/fl)/Hey2(-/-)/HeyL(-/-)- as well as Hey-triple- knock out (KO)-ES cells (embryonic stem cells) were generated in this work, because ES cells and their differentiation as EBs (embryoid bodies) represent a valuable tool for the in vitro analysis of embryonic developmental processes. After the establishment of Hey1(fl/fl)/Hey2(-/-)/HeyL(-/-)- and Hey-triple- KO-ES cells, it could be seen by ALP staining and pluripotency marker expression that loss of Hey expression did not affect ES cell pluripotency features. Thus, these ES cells represent bona fide ES cells and could be further used for the differentiation as EBs. Here, differences in gene expression between Hey1(fl/fl)/Hey2(-/-)/HeyL(-/-)- and Hey-triple- KO-ES cells (after the loss of Hey1) could be observed in realtime-RT-PCR analysis for the endodermal marker AFP as well as for neural and myogenic markers in d10 EBs. However, the establishment of inducible Hey1, Hey2 or HeyL ES cell lines will be essential to confirm these findings and to search for novel Hey target genes. To get further insight into the mode of Hey action, the analysis of Hey interaction partners is necessary. One such binding partner, the Bre protein, has previously been found in a yeast-two-hybrid screen. Bre has been described to be a member of two distinct complexes (i.e. the nuclear BRCA1-A complex with a function in DNA damage response and the cytoplasmic BRISC complex), to directly interact with the TNF-receptor and Fas and to interfere with apoptotic signalling. The Hey-Bre interaction could be further corroborated in this work; yet, it was not possible to narrow down the interaction site of Bre with Hey1. It rather seems that non-overlapping parts of the Bre protein may bind to Hey. This interaction may be direct- pointing to more than one interaction site inside the Bre protein - or via a common binding partner such as the endogenous Bre protein itself. Besides the interaction studies, functional assays were performed for a more detailed characterisation of Hey1 and Bre interaction. Here, it could be shown that Hey1 over-expression did not have any influence on Bre sub-cellular localisation. Interestingly, it could be demonstrated that Bre positively interfered with Hey1 repressive function in luciferase assays at three of four promoters analysed. Moreover, interaction with Bre seems to lead to a stabilisation of Hey1. As Bre has been described to modulate the E3-ligase activity intrinsic to the BRCC complex it was analysed whether Bre over-expression results in an ubiquitination of Hey1. Yet, this could not be observed in the present work. Furthermore, an interaction of Bre with ubiquitinated proteins could not be demonstrated in an ubiquitin binding assay. To obtain a better insight into Bre function, Bre LacZ gene trap-ES cells and animals were generated. However, realtime-RT-analyses revealed that these cells and mice did not show a loss of Bre expression on mRNA level indicating that insertion mutagenesis did not occur as expected. However, embryos derived from these mice could nevertheless be used for the detection of tissues with Bre expression by β-galactosidase staining. Bre deficiency on mRNA levels was only achieved after the deletion of the floxed exon 3 resulting in the generation of Bre del-mice. Bre del-mice were fertile and without any obvious phenotype and they were used for the generation of Bre del- and wt-MEFs (murine embryonic fibroblasts). Characterisation of these cells showed that proliferation was not affected after loss of Bre (neither under normal nor under stress conditions). However, loss of Bre notably resulted in a reduction in the BRCA1 DNA damage response, in a slightly increased sensitivity towards apoptosis induction by FasL treatment and in an increase in the K63-poly-ubiquitin content in Bre del-cytoplasmic fractions, probably linked to a change in the BRISC de-ubiquitinase activity. Even though these results have the same tendencies as observed in former studies, the effects in the present work are less striking. Further studies as well as intercrossing of Bre del- to Hey KO-animals will be necessary to further understand the functional relevance of Hey and Bre interaction.}, subject = {Embryonale Stammzelle}, language = {en} } @phdthesis{Ratzka2012, author = {Ratzka, Carolin}, title = {Immune responses of the ant Camponotus floridanus towards pathogens and its obligate mutualistic endosymbiont Blochmannia floridanus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69350}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Ants of the species Camponotus floridanus live in huge colonies composed of genetically identical or closely related animals, which should predispose them to an increased vulnerability towards infection by pathogens (Cremer et al. 2007). Therefore the question is how ants (or social insects in general) can nevertheless efficiently combat infections. In order to investigate the immune response of the ant C. floridanus, the present study initially focused on the identification of possible immune factors, encoded by the ant´s genome. By using the method "suppression subtractive hybridization" as well as by Illumnia sequencing technology, several immune-related genes could be identified. Among these were genes encoding proteins involved in pathogen recognition, signal transduction, antimicrobial activity, or general stress response. In accordance with the ant´s genome sequence (Bonasio et al. 2010), only three antimicrobial peptide (AMP) genes could be identified in C. floridanus. The gene and cDNA sequences of these AMPs were established and their expression was shown to be induced by microbial challenge. Two different defensin genes (type 1 and 2) were characterized. A detailed characterization of the mRNA and gene sequence of the other AMP, a hymenoptaecin, revealed a special repeat structure. The C. floridanus hymenoptaecin has a signal and a pro-sequence followed by a hymenoptaecin-like domain and six directly repeated hymenoptaecin domains (HDs). Since each HD is flanked by two known processing sites, proteolytic processing of the precursor protein may generate several mature AMPs. Bioinformatical analyses revealed the presence of hymenoptaecin genes with similar multipeptide precursor structure in genomes of other ant species suggesting an evolutionary conserved important role of this gene in ant immunity. C. floridanus ants harbor the obligate intracellular bacterium, Blochmannia floridanus, in specialized cells (so-called bacteriocytes), which are intercalated between midgut cells as well as in ovaries of females (Blochmann 1882; Sauer et al. 2002; Schr{\"o}der et al. 1996). Ant hosts face the problem that on the one hand they have to maintain the beneficial symbiotic bacteria and on the other hand they need to raise an immune response against harmful pathogenic bacteria during an infection. It was investigated, if endosymbionts are actually detected by the host immune system. Injection of B. floridanus induced an immune response of its host C. floridanus, which was comparable to the one towards pathogens. This means that, despite the evolutionary established cooperation of the endosymbionts and their hosts, these bacteria are still recognized as „non-self" by the host immune system. This finding led to the question, if the ant immune system might be involved in regulation of the endosymbiont number in the midgut tissue in order to avoid their uncontrolled replication. During the holometabolous life cycle of the ant hosts the distribution of bacteriocytes and of Blochmannia endosymbionts is remarkably dynamic and peaks in late pupal stages, in which the entire midgut is transformed into a symbiotic organ (Stoll et al. 2010). It was hypothesized that hosts could regulate the number of endosymbionts present in their tissues via the innate immune system. A quantitative gene expression analysis of assumed symbiosis-relevant candidate genes revealed distinct expression patterns of some genes according to developmental stage and tissue. Moreover, the immune gene expression in response to bacterial challenge was investigated in the pupal stage. By an artificial immune-challenge of pupae it was confirmed that in fact the immune response of the endosymbiont-bearing midgut tissue differs from that of other body parts. The data support a key role for amidase peptidoglycan recognition proteins (PGRPs), especially PGRP-LB, in endosymbiont tolerance and suggest an involvement of the lysosomal system in control of Blochmannia endosymbionts. In sum, this thesis provides a first description of the immune response of the ant C. floridanus. A comprehensive set of immune-relevant genes was determined. Especially, the identification and molecular characterization of the hymenoptaecin gene delivered new insights into the immune competence of ants in general. Moreover, first indications could be gathered for the involvement of the immune system in controlling the endosymbiont B. floridanus.}, subject = {Humorale Immunit{\"a}t}, language = {en} } @misc{OPUS4-11038, title = {Campus Uni W{\"u}rzburg Oktober 2012}, volume = {10/2012}, organization = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110384}, year = {2012}, abstract = {Theorie und Praxis in Balance: Projekte, Aktionen und Labors an der Uni W{\"u}rzburg}, language = {de} } @misc{OPUS4-11037, title = {Campus Uni W{\"u}rzburg Juni 2012}, volume = {06/2012}, organization = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110370}, year = {2012}, abstract = {Viel Raum f{\"u}r Forschung: die Uni W{\"u}rzburg w{\"a}chst und wandelt sich stetig}, language = {de} } @misc{OPUS4-11029, title = {Campus Uni W{\"u}rzburg Februar 2012}, volume = {02/2012}, organization = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110291}, year = {2012}, abstract = {Von Grad zu Grad: Vom Bachelor zum Doktor - Wie man die Etappen am besten schafft, erz{\"a}hlen sechs Nachwuchsforscher und ihre Betreuer}, language = {de} } @incollection{Schmitz2012, author = {Schmitz, Barbara}, title = {" ... der Schuld, Vergehen und S{\"u}nde vergibt" (Ex 34,7): S{\"u}nde und Schuld in der Hebr{\"a}ischen Bibel}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-109698}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {No abstract available.}, language = {de} } @incollection{Schmitz2012, author = {Schmitz, Barbara}, title = {Antiochus Epiphanes und der epiphane Gott. Gef{\"u}hle, Emotionen und Affekte im Zweiten Makkab{\"a}erbuch}, doi = {10.1515/dcly.2012.2011.1.253}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108916}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Das Zweite Makkab{\"a}erbuch ist eine absichtsvoll komponierte Erz{\"a}hlung, die ihr Erz{\"a}hlinteresse in der Vorrede (2Makk 2,19-32) und im Epilog (2Makk 15,37-39) benennt. Die Erz{\"a}hlung soll - so die Selbstauskunft der Erz{\"a}hlung im Vorwort - den Leserinnen und Lesern zur Psnchagogia, „Seelenf{\"u}hrung, Vergn{\"u}gung, Lockung", zur eukopia, „Leichtigkeit" sowie zur opheleia, „Vorteil, Nutzen, n{\"u}tzlichen Kenntnis" dienen (2Makk 2,25). Damit pr{\"a}sentiert sich das Zweite Makkab{\"a}erbuch als eine absichtsvolle literarische Erz{\"a}hlung, die ganz bewusst bei den Leserinnen und Lesern emotionale Wirkung, Gef{\"u}hle und Affekte hervorrufen will. Dieses Ziel wird gleich zu Beginn der Erz{\"a}hlung auf der Kommunikationsebene zwischen Erz{\"a}hlstimme und Lesenden benannt. Das auf diese Weise offengelegte Vorhaben der Erz{\"a}hlung l{\"a}sst zun{\"a}chst fragen, wie die emotionale Wirkung bei den Leserinnen und Lesern erzielt werden soll. Dar{\"u}ber hinaus ist die viel grundlegendere Frage zu stellen, warum es f{\"u}r das Zweite Makkab{\"a}erbuch von so zentralem Interesse ist, Emotionen bei den Rezipienten hervorzurufen.}, subject = {Makkab{\"a}er }, language = {de} } @unpublished{Schmitz2012, author = {Schmitz, Barbara}, title = {ΙΟΥΔΙΘ und IUDITH: {\"U}berlegungen zum Verh{\"a}tlnis der Judit-Erz{\"a}hlung in der LXX und der Vulgata}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108938}, year = {2012}, abstract = {"Das Buch Judit ist in zwei wesentlich voneinander unterschiedenen Textformen {\"u}berliefert: einerseits in der griechischen Fassung und den sich daran anschließenden alten {\"U}bersetzungen (vetus latina, syr., aeth., sah., arm.), zum anderen in der Fassung der lateinischen Vulgata und, mit dieser durchweg parallel laufend, in mittelalterlichen hebr{\"a}ischen Hss." - so fasst Helmut Engel die Textsituation des Buches Judit pr{\"a}gnant zusammen. Damit liegen heute zwei unterschiedliche Textformen der Juditerz{\"a}hlung vor: Die griechische Juditerz{\"a}hlung in der Septuaginta und die lateinische Iuditherz{\"a}hlung in der Vulgata. Beide Textfassungen unterscheiden sich deutlich voneinander: Die Vulgata-Fassung ist gegen{\"u}ber der LXX-Fassung um 20 Prozent k{\"u}rzer; weil die Vulgata-Fassung aber auch umfangreiche Erweiterungen aufweist, teilen LXX und Vulgata nur ungef{\"a}hr die H{\"a}lfte des Textbestandes. Lange ist man davon ausgegangen, dass hinter der Septuaginta- und der Vulgata-Fassung der Juditerz{\"a}hlung ein hebr{\"a}ischer "Ur"-Text gestanden habe. Diese Annahme, die die Forschung seit dem 19. Jh. pr{\"a}gt, gr{\"u}ndet sich im Wesentlichen auf zwei Argumenten: Erstens sei der griechische Text der Septuaginta so durchgehend von einem hebr{\"a}ischen Sprachduktus gepr{\"a}gt, dass man hier von einem hebr{\"a}ischen Originaltext, der recht w{\"o}rtlich ins Griechische {\"u}bertragen worden sei, ausgehen m{\"u}sse. Zweitens spreche Hieronymus (ca. 347-420) in seiner praefatio zu seiner lateinischen {\"U}bertragung von einem ihm vorliegenden "chald{\"a}ischen" Text, der ihm als Vorlage gedient habe. Beide Argumente werden im Folgenden diskutiert: Im ersten Teil wird auf die in den letzten Jahren neu aufgerollte Frage nach der Originalsprache der LXX-Fassung der Juditerz{\"a}hlung eingegangen; der zweite Teil ist der Analyse der praefatio des Hieronymus gewidmet.}, subject = {Judit }, language = {de} } @phdthesis{Boyanova2012, author = {Boyanova, Desislava Veselinova}, title = {Systems biological analysis of the platelet proteome and applications of functional module search in proteome networks}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72165}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Recent development of proteomic approaches and generation of large-scale proteomic datasets calls for new methods for biological interpretation of the obtained results. Systems biological approaches such as integrated network analysis and functional module search have become an essential part of proteomic investigation. Proteomics is especially applied in anucleate cells such as platelets. The underlying molecular mechanisms of platelet activation and their pharmacological modulation are of immense importance for clinical research. Advances in platelet proteomics have provided a large amount of proteomic data, which has not yet been comprehensively investigated in a systems biological perspective. To this end, I assembled platelet specific data from proteomic and transcriptomic studies by detailed manual curation and worked on the generation of a comprehensive human platelet repository for systems biological analysis of platelets in the functional context of integrated networks (PlateletWeb) (http:/PlateletWeb.bioapps.biozentrum.uni-wuerzburg.de). I also added platelet-specific experimentally validated phosphorylation data and generated kinase predictions for 80\% of the newly identified platelet phosphosites. The combination of drug, disease and pathway information with phosphorylation and interaction data makes this database the first integrative platelet platform available for platelet research. PlateletWeb contains more than 5000 platelet proteins, which can also be analyzed and visualized in a network context, allowing identification of all major signaling modules involved in platelet activation and inhibition. Using the wealth of integrated data I performed a series of platelet-specific analyses regarding the platelet proteome, pathways, drug targets and novel platelet phosphorylation events involved in crucial signaling events. I analyzed the statistical enrichment of known pathways for platelet proteins and identified endocytosis as a highly represented pathway in platelets. Further results revealed that highly connected platelet proteins are more often targeted by drugs. Using integrated network analysis offered by PlateletWeb, I analyzed the crucial activation signaling pathway of adenosine diphosphate (ADP), visualizing how the signal flow from receptors to effectors is maintained. My work on integrin inside-out signaling was also based on the integrated network approach and examined new platelet-specific phosphorylation sites and their regulation using kinase predictions. I generated hypothesis on integrin signaling, by investigating the regulation of Ser269 phosphorylation site on the docking protein 1 (DOK1). This phosphorylation site may influence the inhibiting effect of DOK1 on integrin a2bb3. Extending the integrated network approach to further cell lines, I used the assembled human interactome information for the analysis of functional modules in cellular networks. The investigation was performed with a previously developed module detection algorithm, which finds maximum-scoring subgraphs in transcriptomic datasets by using assigned values to the network nodes. We extended the algorithm to qualitative proteomic datasets and enhanced the module search by adding functional information to the network edges to concentrate the solution onto modules with high functional similarity. I performed a series of analyses to validate its performance in small-sized (virus-infected gastric cells) and medium-sized networks (human lymphocytes). In both cases the algorithm extracted characteristic modules of sample proteins with high functional similarity. The functional module search is especially useful in site-specific phosphoproteomic datasets, where kinase regulation of the detected sites is often sparse or lacking. Therefore, I used the module detection algorithm in quantitative phosphoproteomic datasets. In a platelet phosphorylation dataset, I presented a pipeline for network analysis of detected phosphorylation sites. In a second approach, the functional module detecting algorithm was used on a phosphoproteome network of human embryonic stem cells, in which nodes represented the maximally changing phosphorylation sites in the experiment. Additional kinases from the human phosphoproteome in PlateletWeb were included to the network to investigate the regulation of the signal flow. Results indicated important phosphorylation sites and their upstream kinases and explained changes observed in embryonic stem cells during differentiation. This work presents novel approaches for integrated network analysis in cells and introduces for the first time a systematic biological investigation of the human platelet proteome based on the platelet-specific knowledge base PlateletWeb. The extended methods for optimized functional module detection offer an invaluable tool for exploring proteomic datasets and covering gaps in complex large-scale data analysis. By combining exact module detection approaches with functional information data between interacting proteins, characteristic functional modules with high functional resemblance can be extracted from complex datasets, thereby focusing on important changes in the observed networks.}, subject = {Netzwerkanalyse}, language = {en} } @phdthesis{Schlereth2012, author = {Schlereth, Bernd Johannes}, title = {Das Petitionswesen im K{\"o}nigreich Bayern - Eine Studie zu den Grundlagen, dem politischen Stellenwert und der parlamentarischen Praxis unter besonderer Ber{\"u}cksichtigung der Erschließung der einschl{\"a}gigen parlamentarischen Quellen mittels einer EDV-Datenbank}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108508}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Die vorliegende Arbeit besch{\"a}ftigt sich mit der historischen Genese des Gewohnheitsrechts des Einzelnen, Petitionen an die Obrigkeit bzw. an die Staatsregierung einzureichen. Der besondere Fokus liegt hierbei auf den Zusammenh{\"a}ngen im modernen Bayern. Die Bedeutung des Petitionswesens f{\"u}r die parlamentarische Entwicklung im K{\"o}nigreich Bayern stellt den zentralen Forschunggegenstand dar. Die dieser Studie zugrundeliegende Sichtung umfangreicher Archivalien des Hauptstaatsarchivs M{\"u}nchen geht einher mit der Auswertung und der kritischen Beleuchtung eines Forschungsprojekts zum vorliegenden Thema, welches an der Universit{\"a}t W{\"u}rzburg durchgef{\"u}hrt wurde.}, subject = {Petitionswesen}, language = {de} } @phdthesis{AlbersgebOttmers2012, author = {Albers [geb. Ottmers], Hannah Maike}, title = {Lebensbedingungen und psychische Gesundheit der Bewohner der W{\"u}rzburger Gemeinschaftsunterkunft f{\"u}r Asylbewerber}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70131}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Hintergrund: {\"U}ber die psychische Gesundheit von Asylsuchenden in Deutschland ist wenig bekannt. Ziel dieser Studie ist, (1) die psychische Gesundheit der Asylsuchenden in der W{\"u}rzburger Gemeinschaftsunterkunft zu beschreiben, (2) ihre Wahrnehmung der aktuellen Lebensbedingungen zu erfassen, sowie (3) m{\"o}gliche Zusammenh{\"a}nge zwischen beiden Bereichen zu untersuchen. Methoden: Alle Bewohner der W{\"u}rzburger Gemeinschaftsunterkunft, welche zum Zeitpunkt der Befragung mindestens 16 Jahre alt waren und den Studienfragebogen in einer der Sprachen Arabisch, Amharisch, Farsi, Russich, Somali, Deutsch oder Englisch ausf{\"u}llen konnten, konnten an dieser Querschnittbefragung teilnehmen. Das Vorhandensein von psychischen Erkrankungen (Somatoformes Syndrom, Depressive Syndrome, Angstsyndrome, Alkoholsyndrom und eine Screeningfrage f{\"u}r PTBS), sowie das Ausmaß an psychosozialem Stress wurden mittels des PRIME-MD Patient Health Questionnaire (PHQ) gemessen. Die subjektive Einsch{\"a}tzung der Lebensbedingungen durch die Teilnehmer wurde mit einem f{\"u}r die spezifischen Bedingungen entwickelten Fragebogen erfasst. Die Ergebnisse wurden deskriptiv dargestellt und Korrelationen zwischen der Bewertung der Lebensbedingungen und ausgew{\"a}hlten Parametern der psychischen Gesundheit wurden mittels Chi-Quadrat-Tests und des Spearman Rangkorrelationskoeffizienten berechnet. Ergebnisse: Insgesamt nahmen 183 Bewohner an der Befragung teil. Der PHQ konnte f{\"u}r 140 Teilnehmer ausgewertet werden, der Fragebogen zu aktuellen Lebensbedingungen f{\"u}r 113 Teilnehmer. Die h{\"a}ufigsten PHQ-Syndrome waren das Somatoforme Syndrom (38,6\%; n=54), Depressive Syndrome (25,7\% (n=36) Major Depressives Syndrom; 22,8\% (n=32) andere depressive Syndrome) und Angstsyndrome (11,4\% (n=16) Paniksyndrom, 9,3\% (n=13) andere Angstsyndrome). Bei 38,6\% (n=54) ergab der PHQ f{\"u}r mehr als ein Syndrom ein positives Ergebnis. Die Lebensbedingungen in der Gemeinschaftsunterkunft wurden gr{\"o}ßtenteils negativ bewertet und ihre Auswirkungen auf die eigene Gesundheit wurden im Mittel als „ziemlich stark" beurteilt. Eine schlechtere Bewertung der Lebensbedingungen und eine l{\"a}ngere Aufenthaltsdauer in der Gemeinschaftsunterkunft waren in univariaten Analysen mit einem schlechteren Ergebnis bez{\"u}glich verschiedener Parameter der psychischen Gesundheit assoziiert (z.B. depressive Syndrome, psychosoziale Belastung). Schlussfolgerung: Verschiedene Limitationen der Studie m{\"u}ssen ber{\"u}cksichtigt werden (z.B. Querschnittdesign, mangelnde Validierung der Fragebogen{\"u}bersetzungen). Dennoch zeigen diese Ergebnisse eine deutliche Unzufriedenheit der Studienteilnehmer mit den Lebensbedingungen in der Gemeinschaftsunterkunft auf und lassen eine hohe Pr{\"a}valenz psychischer Erkrankungen in der Studienpopulation vermuten.}, subject = {Asylbewerber}, language = {de} } @phdthesis{Adelfinger2012, author = {Adelfinger, Marion}, title = {Pr{\"a}klinische Verwendung verschiedener onkolytischer Vaccinia-Viren zur Therapie von Human- und Hundetumoren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70688}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Nach Einsch{\"a}tzung der Weltgesundheitsorganisation WHO wird Krebs im Jahr 2013 die weltweit h{\"a}ufigste Todesursache bei Menschen und Haustieren sein. Diese Situation erfordert die Entwicklung neuer therapeutischer Ans{\"a}tze. Hauptziel einer Tumortherapie ist es, sowohl den Prim{\"a}rtumor als auch die Metastasen m{\"o}glichst vollst{\"a}ndig zu entfernen. Dabei wird nach Methoden gesucht, die im Gegensatz zu den meisten gegenw{\"a}rtigen therapeutischen Eins{\"a}tzen, wie der chirurgischen Entfernung b{\"o}sartiger Neubildungen, Chemotherapie und Strahlentherapie, selektiv die b{\"o}sartigen Zellen erkennen und zerst{\"o}ren k{\"o}nnen. Eine faszinierende M{\"o}glichkeit in dieser Hinsicht ist die Verwendung von onkolytischen Viren, die die F{\"a}higkeit besitzen, sich selektiv sowohl in Prim{\"a}rtumoren als auch in Metastasen anzusiedeln und die Krebszellen dort zu zerst{\"o}ren. Das Konzept, dass Viren n{\"u}tzlich f{\"u}r die Bek{\"a}mpfung von Krebs sein k{\"o}nnten, ist nicht neu. Allerdings konnte erst in den letzten Jahren durch zahlreiche Studien best{\"a}tigt werden, dass verschiedene Viren in der Lage sind, eine signifikante Antitumorwirkung in vivo auszu{\"u}ben. Zu den erfolgversprechenden onkolytischen Viren z{\"a}hlen insbesondere Adenovirus, Herpes simplex Virus, Reovirus und Vaccinia-Virus, die sich bereits in Phase III der klinischen Studien befinden oder kurz davor sind. Die therapeutische Nutzung von tumorspezifischen onkolytischen Viren beim Menschen hat bereits begonnen. Im Rahmen der vorliegenden Doktorarbeit wurden verschiedene Aspekte der Wirkungsweise von Vaccinia-Virus-St{\"a}mmen bei der Therapie verschiedener Tumore aus Mensch und Hund im Xenotransplantat-Mausmodell bearbeitet: die Onkolyse der Krebszellen und Inhibition des Tumorwachstums sowie die Effekte der Virusinfektion auf das Tumormikromilieu und die Mitwirkung des angeborenen Immunsystems bei der Virotherapie. Das Tumormikromilieu (Stroma) setzt sich aus einer Vielzahl verschiedener Zellen und Komponenten der extrazellul{\"a}ren Matrix zusammen. Die Krebszellen bilden unter anderem mit Endothelzellen des Blut- und Lymphsystems und verschiedenen Immunzellen eine komplexe Organ-{\"a}hnliche Struktur. Weitere wichtige Bestandteile des Stromas sind Wachstumsfaktoren, Chemokine und Zytokine und die Tumorvaskulatur. Diese ist durch zahlreiche strukturelle und funktionelle Abnormalit{\"a}ten charakterisiert, wodurch die Effektivit{\"a}t von Strahlen- und Chemotherapie herabgesetzt wird. Weiterhin ist das Tumormikromilieu durch seine {\"A}hnlichkeit mit einer chronischen Entz{\"u}ndungsreaktion gekennzeichnet und wirkt immunsupprimierend auf rekrutierte Leukozyten, die wiederum die Inflammation verst{\"a}rken und die Angiogenese und das Tumorwachstum weiter f{\"o}rdern. Aufgrund dieser vielen Komponenten ist die Zusammensetzung jedes Tumors einzigartig, weswegen Standardtherapien h{\"a}ufig nicht zu einer Heilung f{\"u}hren. Die Wirkung der Viren bei der Virotherapie beruht vermutlich auf 4 Mechanismen, die einzeln oder in Kombination auftreten k{\"o}nnen: die direkte Onkolyse der Krebszellen, die Zerst{\"o}rung des Tumorblutgef{\"a}ßsystems, die Aktivierung des Immunsystems des Wirts und die Suppression der microRNA-Expression des Wirtes. Zus{\"a}tzlich kann die Expression therapeutischer Gene die onkolytische Wirkung verst{\"a}rken. Zum Nachweis der Onkolyse der Krebszellen und Inhibition des Tumorwachstums wurde zuerst das Virus GLV-1h68 in einem autologen humanen Melanomzellpaar, 888-MEL und 1936-MEL, eingesetzt. Das GLV-1h68-Virus wurde auf Basis des Wildtyp Vaccinia-Virus LIVP durch die Insertion von 3 Expressionskassetten in den drei Genloci F14.5L, J2R und A56 genetisch konstruiert. 888-MEL, eine zu einem fr{\"u}hen Zeitpunkt der Krebserkrankung aus einer Metastase isolierte Zelllinie, zeigt nach Infektion mit GLV-1h68 im Mausmodell Tumornekrose („Responder"), w{\"a}hrend 1936-MEL aus einer sp{\"a}ten Metastasierungsphase kaum mit Onkolyse auf eine Virusinfektion reagiert („Poor-Responder"). Die onkolytische Wirkung konnte mittels Durchflusszytometrie in Tumoren beider Zelllinien zu einem fr{\"u}hen Zeitpunkt nach Virusinfektion nachgewiesen werden. In 888-MEL-Tumoren wurde hierbei eine große Zahl infizierter und toter Zellen nach Virusinfektion gefunden. Gleichzeitig wurde eine hohe Zahl an Immunzellen detektiert, die nach Virusinfektion reduziert war. In den schw{\"a}cher reagierenden 1936-MEL-Tumoren konnte eine Onkolyse bei Infektion mit h{\"o}herer Virusmenge und zu einem fr{\"u}heren Zeitpunkt demonstriert werden, wodurch mehr Zellen infiziert wurden. Zus{\"a}tzlich wurde eine Steigerung der nur in geringer Zahl vorhandenen Immunzellen nachgewiesen. Trotz des unterschiedlichen Tumormikromilieus konnte somit ein onkolytischer Effekt in beiden Tumormodellen erzielt werden. ...}, subject = {Vaccinia-Virus}, language = {de} } @phdthesis{Haydn2012, author = {Haydn, Johannes}, title = {Regulation of ERK1/2 signaling in melanoma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85727}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Die Mechanismen in einer Zelle, die die Genexpression und somit den Stoffwechsel, das Wachstum und das gesamte Zellverhalten steuern, sind ebenso bedeutsam f{\"u}r das Verst{\"a}ndnis der grundlegenden Biologie einer lebenden Zelle wie f{\"u}r die Vorg{\"a}nge der Krebsentstehung. Dabei bilden hochvernetzte, und strikt regulierte Signaltransduktionswege die Basis f{\"u}r ein belastbares und zugleich hochflexibles regulatorisches Netzwerk. Die St{\"o}rung solcher Signalkaskaden kann zum einen urs{\"a}chlich aber auch modifizierend auf die Bildung von Tumoren wirken. Die von Rezeptortyrosinkinasen (RTK) und RAS abh{\"a}ngigen Signalwege, die zur Aktivierung von AKT und ERK1/2 f{\"u}hren, sind hierbei von besonderem Interesse f{\"u}r die Entstehung des malignen Melanoms. Mutationen in Komponenten dieser Wege (z.B. NRAS, BRAF oder PTEN), die die Signalst{\"a}rke erh{\"o}hen kommen in Melanomen sehr h{\"a}ufig vor. Im ersten Teil dieser Arbeit wurden die unterschiedlichen und vielf{\"a}ltigen Funktionen von MKP2, einem Feedbackregulator des ERK1/2-Weges, unter verschiedenen zellul{\"a}ren Rahmenbedingungen, untersucht. Des Weiteren wird eine Funktion des zum AP1-Komplex geh{\"o}renden FOSL1, einem unter transkriptioneller Kontrolle des ERK1/2-Weges stehendem Transkriptionsfaktors, hinsichtlich der Steuerung der Zell-Proliferation gezeigt. Weiterhin habe ich Aspekte der direkten pharmakologischen Inhibition des ERK1/2-Weges hinsichtlich ihres Effekts auf die Ausl{\"o}sung von Apoptose untersucht. Aufgrund der H{\"a}ufigkeit von Mutationen in Genen, die f{\"u}r Proteine des ERK1/2-Weges kodieren (z.B. NRASQ61K, BRAFV600E), gilt die Inhibition dieses Signalwegs als vielversprechende Strategie zur Behandlung des Melanoms. Auch wenn klinische Studien, die Inhibitoren f{\"u}r MEK oder RAF als Einzelmedikamente verwenden, bei mehrmonatiger Behandlung sehr erfolgreich sind, konnten so keine langfristigen Erfolge erzielt werden. Aus diesem Grund werden nun Kombinationstherapien, die einen Inhibitor des ERK1/2-Weges und eine weitere Form der Therapie kombinieren, untersucht. Der zweite Teil dieser Arbeit beschreibt, dass der spezifische MEK Inhibitor PD184352 Melanomzellen vor der Apoptosewirkung von Cisplatin sch{\"u}tzen kann. Einzelbehandlung mit Cisplatin f{\"u}hrt hierbei zur Akkumulation von DNA Sch{\"a}den, die wiederum Caspase-abh{\"a}ngig Apoptose induzieren. Zus{\"a}tzliche Anwendung des MEK Inhibitors verringerte jedoch in einigen Zelllinien das Potential von Cisplatin, Apoptose auszul{\"o}sen. Diese Zellen zeigten eine verst{\"a}rkte Aktivierung der Serin/Threonin-KInase AKT nach MEK Inhibition. Diese AKT Aktivierung f{\"u}hrte zur Inaktivierung der FOXO Transkriptionsfaktoren, was wiederum die Expression des pro-apoptotischen BH3-only Proteins PUMA verringerte. PUMA selbst ist ein wichtiger Bestandteil der Apoptose Maschinerie, die durch Cisplatin aktiviert wird. Die im Rahmen dieser Arbeit erhaltenen Befunde deuten darauf hin, dass RTKs, im besonderen EGFR, bei diesem Crosstalk eine Rolle spielen. Diese Ergebnisse zeigen, dass die Inhibition des RAS/RAF/MEK/ERK Signalweges im Melanom nicht zwangsl{\"a}ufig von Vorteil sein muss, falls die Zellen gleichzeitig mit einem genotoxischen Medikament behandelt werden. Hier kann sie sogar die {\"U}berlebensf{\"a}higkeit von Melanomzellen unter Apoptose induzierenden Bedingungen verbessern.}, subject = {Melanom}, language = {en} } @phdthesis{Nilla2012, author = {Nilla, Jaya Santosh Chakravarthy}, title = {An Integrated Knowledgebase and Network Analysis Applied on Platelets and Other Cell Types}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Systems biology looks for emergent system effects from large scale assemblies of molecules and data, for instance in the human platelets. However, the computational efforts in all steps before such insights are possible can hardly be under estimated. In practice this involves numerous programming tasks, the establishment of new database systems but as well their maintenance, curation and data validation. Furthermore, network insights are only possible if strong algorithms decipher the interactions, decoding the hidden system effects. This thesis and my work are all about these challenges. To answer this requirement, an integrated platelet network, PlateletWeb, was assembled from different sources and further analyzed for signaling in a systems biological manner including multilevel data integration and visualization. PlateletWeb is an integrated network database and was established by combining the data from recent platelet proteome and transcriptome (SAGE) studies. The information on protein-protein interactions and kinase-substrate relationships extracted from bioinformatical databases as well as published literature were added to this resource. Moreover, the mass spectrometry-based platelet phosphoproteome was combined with site-specific phosphorylation/ dephosphorylation information and then enhanced with data from Phosphosite and complemented by bioinformatical sequence analysis for site-specific kinase predictions. The number of catalogued platelet proteins was increased by over 80\% as compared to the previous version. The integration of annotations on kinases, protein domains, transmembrane regions, Gene Ontology, disease associations and drug targets provides ample functional tools for platelet signaling analysis. The PlateletWeb resource provides a novel systems biological workbench for the analysis of platelet signaling in the functional context of protein networks. By comprehensive exploration, over 15000 phosphorylation sites were found, out of which 2500 have the corresponding kinase associations. The network motifs were also investigated in this anucleate cell and characterize signaling modules based on integrated information on phosphorylation and protein-protein interactions. Furthermore, many algorithmic approaches have been introduced, including an exact approach (heinz) based on integer linear programming. At the same time, the concept of semantic similarities between two genes using Gene Ontology (GO) annotations has become an important basis for many analytical approaches in bioinformatics. Assuming that a higher number of semantically similar gene functional annotations reflect biologically more relevant interactions, an edge score was devised for functional network analysis. Bringing these two approaches together, the edge score, based on the GO similarity, and the node score, based on the expression of the proteins in the analyzed cell type (e.g. data from proteomic studies), the functional module as a maximum-scoring sub network in large protein-protein interaction networks was identified. This method was applied to various proteome datasets (different types of blood cells, embryonic stem cells) to identify protein modules that functionally characterize the respective cell type. This scalable method allows a smooth integration of data from various sources and retrieves biologically relevant signaling modules.}, subject = {Systembiologie}, language = {en} } @phdthesis{Schwab2012, author = {Schwab, Julia}, title = {Antimikrobielle Aktivit{\"a}t humaner Kolonepithelzellen gegen{\"u}ber E. coli Nissle unter besonderer Ber{\"u}cksichtigung des Cathelicidins LL-37}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-105563}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Antimikrobielle Peptide und Proteine spielen eine wichtige Rolle bei der angeborenen Immunabwehr. Sie sind auf verschiedenen Schleimhautoberfl{\"a}chen des K{\"o}rpers zu finden, zum Beispiel auch in der Schleimschicht des Gastrointestinaltraktes. Beim Menschen sind drei Familien antimikrobiell wirksamer Peptide bekannt: die Defensine, die Cathelicidine und die Histatine. LL-37 ist das einzige Cathelicidin, das bisher beim Menschen gefunden wurde. Das Ziel der vorliegenden Arbeit war, den Effekt des probiotischen Bakteriums E. coli Nissle auf die LL-37-Genexpression in Kolonepithelzellen zu analysieren. Zun{\"a}chst wurde hierf{\"u}r die bakterizide Wirksamkeit von synthetischem LL-37 auf E. coli Nissle in vitro nachgewiesen. Anschließend wurde die antimikrobielle Aktivit{\"a}t verschiedener Kolonepithelzelllinien gegen{\"u}ber E. coli Nissle untersucht und die LL-37-Genexpression in den Zelllinien bestimmt. Zwei der vier untersuchten Zelllinien (SW 620 und Geki-2) zeigten eine signifikante antimikrobielle Aktivit{\"a}t gegen{\"u}ber E. coli Nissle. Die LL-37-Genexpression wurde in den Zelllinien T84 und Geki-2 gesteigert. Aus diesen Ergebnissen kann man folgern, dass die antimikrobielle Aktivit{\"a}t der Zelllinie Geki-2 auf eine erh{\"o}hte LL-37-Expression zur{\"u}ckzuf{\"u}hren ist, w{\"a}hrend die antimikrobielle Aktivit{\"a}t der Zelllinie SW 620 unabh{\"a}ngig von der LL-37-Expression ist. Die probiotische Wirksamkeit des Bakteriums E. coli Nissle k{\"o}nnte somit unter anderem durch eine Induktion der LL-37-Genexpression in differenzierten Kolonepithelzellen erkl{\"a}rt werden.}, subject = {Escherichia Coli}, language = {de} } @phdthesis{Meierhofer2012, author = {Meierhofer, Julia Theresa}, title = {Vergleichende Untersuchung der axill{\"a}ren Plexusblockade: Ultraschall gegen Nervenstimulation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85536}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Es handelt sich um eine randomisierte, kontrollierte und einfach verblindete Studie, um Ultraschall und Nervenstimulation bei der axill{\"a}ren Plexusblockade (Multiinjektionstechnik) bez{\"u}glich Anschlagszeiten, Durchf{\"u}hrungszeit, Blockadeerfolg, Komplikationsraten und Patientenkomfort zu vergleichen. Es ergaben sich nur kleine bzw. keine signifikanten Unterschiede in den Zeiten, Erfolgsraten, Komplikationsraten und beim Patientenkomfort. Bei gleicher klinischer Eignung ist die sonographische Methode zu favorisieren.}, subject = {Ultraschall}, language = {de} }