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Meta-analysis identifies seven susceptibility loci involved in the atopic march (2015)
Marenholz, Ingo ; Esparza-Gordillo, Jorge ; Rüschendorf, Franz ; Bauerfeind, Anja ; Strachan, David P. ; Spycher, Ben D. ; Baurecht, Hansjörg ; Magaritte-Jeannin, Patricia ; Sääf, Annika ; Kerkhof, Marjan ; Ege, Markus ; Baltic, Svetlana ; Matheson, Melanie C. ; Li, Jin ; Michel, Sven ; Ang, Wei Q. ; McArdle, Wendy ; Arnold, Andreas ; Homuth, Georg ; Demenais, Florence ; Bouzigon, Emmanuelle ; Söderhäll, Cilla ; Pershagen, Göran ; de Jongste, Johan C. ; Postma, Dirkje S. ; Braun-Fahrländer, Charlotte ; Horak, Elisabeth ; Ogorodova, Ludmila M. ; Puzyrev, Valery P. ; Bragina, Elena Yu ; Hudson, Thomas J. ; Morin, Charles ; Duffy, David L. ; Marks, Guy B. ; Robertson, Colin F. ; Montgomery, Grant W. ; Musk, Bill ; Thompson, Philip J. ; Martin, Nicholas G. ; James, Alan ; Sleiman, Patrick ; Toskala, Elina ; Rodriguez, Elke ; Fölster-Holst, Regina ; Franke, Andre ; Lieb, Wolfgang ; Gieger, Christian ; Heinzmann, Andrea ; Rietschel, Ernst ; Keil, Thomas ; Cichon, Sven ; Nöthen, Markus M. ; Pennel, Craig E. ; Sly, Peter D. ; Schmidt, Carsten O. ; Matanovic, Anja ; Schneider, Valentin ; Heinig, Matthias ; Hübner, Norbert ; Holt, Patrick G. ; Lau, Susanne ; Kabesch, Michael ; Weidinger, Stefan ; Hakonarson, Hakon ; Ferreira, Manuel A. R. ; Laprise, Catherine ; Freidin, Maxim B. ; Genuneit, Jon ; Koppelman, Gerard H. ; Melén, Erik ; Dizier, Marie-Hélène ; Henderson, A. John ; Lee, Young Ae
Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016 (2016)
Ullmann, Andrew J. ; Schmidt-Hieber, Martin ; Bertz, Hartmut ; Heinz, Werner J. ; Kiehl, Michael ; Krüger, William ; Mousset, Sabine ; Neuburger, Stefan ; Neumann, Silke ; Penack, Olaf ; Silling, Gerda ; Vehreschild, Jörg Janne ; Einsele, Hermann ; Maschmeyer, Georg
Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.
Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 (2016)
Schoffer, Olaf ; Schülein, Stefanie ; Arand, Gerlinde ; Arnholdt, Hans ; Baaske, Dieter ; Bargou, Ralf C. ; Becker, Nikolaus ; Beckmann, Matthias W. ; Bodack, Yves ; Böhme, Beatrix ; Bozkurt, Tayfun ; Breitsprecher, Regine ; Buchali, Andre ; Burger, Elke ; Burger, Ulrike ; Dommisch, Klaus ; Elsner, Gudrun ; Fernschild, Karin ; Flintzer, Ulrike ; Funke, Uwe ; Gerken, Michael ; Göbel, Hubert ; Grobe, Norbert ; Gumpp, Vera ; Heinzerling, Lucie ; Kempfer, Lana Raffaela ; Kiani, Alexander ; Klinkhammer-Schalke, Monika ; Klöcking, Sabine ; Kreibich, Ute ; Knabner, Katrin ; Kuhn, Peter ; Lutze, Stine ; Mäder, Uwe ; Maisel, Tanja ; Maschke, Jan ; Middeke, Martin ; Neubauer, Andreas ; Niedostatek, Antje ; Opazo-Saez, Anabelle ; Peters, Christoph ; Schell, Beatrice ; Schenkirsch, Gerhard ; Schmalenberg, Harald ; Schmidt, Peter ; Schneider, Constanze ; Schubotz, Birgit ; Seide, Anika ; Strecker, Paul ; Taubenheim, Sabine ; Wackes, Matthias ; Weiß, Steffen ; Welke, Claudia ; Werner, Carmen ; Wittekind, Christian ; Wulff, Jörg ; Zettl, Heike ; Klug, Stefanie J.
Background Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. Methods Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. Results The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%). Conclusions No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008. "
Quantitation of Glucocorticoid Receptor DNA-Binding Dynamics by Single-Molecule Microscopy and FRAP (2014)
Groeneweg, Femke L. ; van Royen, Martin E. ; Fenz, Susanne ; Keizer, Veer I. P. ; Geverts, Bart ; Prins, Jurrien ; de Kloet, E. Ron ; Houtsmuller, Adriaan B. ; Schmidt, Thomas S. ; Schaaf, Marcel J. M.
Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (similar to 0.7 s) and the other half for longer time periods (similar to 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (<= 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences.
Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model (2015)
Boivin, Valérie ; Beyersdorf, Niklas ; Palm, Dieter ; Nikolaev, Viacheslav O. ; Schlipp, Angela ; Müller, Justus ; Schmidt, Doris ; Kocoski, Vladimir ; Kerkau, Thomas ; Hünig, Thomas ; Ertl, Georg ; Lohse, Martin J. ; Jahns, Roland
Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure.
Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) (2014)
Mousset, Sabine ; Buchheidt, Dieter ; Heinz, Werner ; Ruhnke, Markus ; Cornely, Oliver A. ; Egerer, Gerlinde ; Krüger, William ; Link, Hartmut ; Neumann, Silke ; Ostermann, Helmut ; Panse, Jens ; Penack, Olaf ; Rieger, Christina ; Schmidt-Hieber, Martin ; Silling, Gerda ; Südhoff, Thomas ; Ullmann, Andrew J. ; Wolf, Hans-Heinrich ; Maschmeyer, Georg ; Böhme, Angelika
Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection.
Neuroanatomy of the equine brain as revealed by high-field (3Tesla) magnetic-resonance-imaging (2018)
Schmidt, Martin J. ; Knemeyer, Carola ; Heinsen, Helmut
In this study, the morphology of the horse brain (Equus caballus) is decribed in detail using high field MRI. The study includes sagittal, dorsal, and transverse T2-weighted images at 0.25 mm resolution at 3 Tesla and 3D models of the brain presenting the external morphology of the brain. Representative gallocyanin stained histological slides of the same brain are presented. The images represent a useful tool for MR image interpretation in horses and may serve as a starting point for further research aiming at in vivo analysis in this species.
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