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Gohlke J.,University of Wurzburg | Scholz C.-J.,University Hospital of Wuerzburg | Kneitz S.,University of Wurzburg | Weber D.,University of Wurzburg | And 3 more authors.
PLoS Genetics | Year: 2013

Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA-encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA) in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA-mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes regulate gene expression, physiological processes, and the development of crown gall tumors. © 2013 Gohlke et al. Source

Petter-Puchner A.H.,Visceral and Oncological Surgery | Dietz U.A.,University Hospital of Wuerzburg
British Journal of Surgery | Year: 2013

Research needed to find out how they work and why they fail © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. Source

Bornholz B.,Heinrich Heine University Dusseldorf | Roggenbuck D.,Sudan University of Science and Technology | Jahns R.,University Hospital of Wuerzburg | Boege F.,Heinrich Heine University Dusseldorf
Autoimmunity Reviews | Year: 2014

Growing evidence indicates a cardio-pathogenic role of autoantibodies against β1-adrenergic receptors (β1AR). In particular autoantibodies stimulating β1AR-mediated cAMP-production (i.e. agonistic β1AR autoantibodies) play a paramount role in chronic heart failure. When induced by immunisation, such autoantibodies cause heart failure in rodents; when present in patients they negatively affect survival in heart failure. However, the true prevalence and clinical impact of agonistic β1AR autoantibodies in human heart disease are still unclear, as are the events triggering their production, and the inter-relationship between autoantibody level and disease activity. β1AR autoantibodies can be removed by extracorporeal absorption or neutralised by systemic administration of synthetic epitope mimics. Only patients bearing agonistic β1AR autoantibodies in their bloodstream will benefit from these approaches. Therefore, reliable detection of agonistic β1AR autoantibodies is a key pre-requisite for the future implementation of these strategies. β1AR autoantibodies impact on conformation and down-stream signalling of the receptor by binding a conformational epitope, which is poorly represented by synthetic mimics and readily destroyed by fixation. Consequently, β1AR autoantibodies can reliably be detected only by assays utilising the native β1AR as a test antigen. To provide a sufficient basis for diagnostic predictions or therapeutic decisions, one must also determine whether β1AR autoantibodies stimulate the receptor, which again requires native, cell-based reporter systems. Translation of these procedures into versatile diagnostic tests fitting the requirements of general health care is a challenge for future development. Here, we will review the state of diagnostic and therapeutic efforts in the field of β1AR-directed autoimmunity, thereby aiming to furnish a conceptual frame for the further development of novel, more reliable diagnostic tools and more specific antibody-targeted therapeutic concepts. © 2014. Source

Van Den Heuvel I.,University Childrens Hospital Muenster | Wurmb T.E.,University Hospital of Wuerzburg | Bottiger B.W.,University of Cologne | Bernhard M.,University of Leipzig
Current Opinion in Anaesthesiology | Year: 2013

PURPOSE OF REVIEW: To evaluate the most recent publications in the long-lived debate over the use of etomidate in critically ill septic and trauma patients. RECENT FINDINGS: Virtually without controversy is the hemodynamic stability after its use for induction of anesthesia on the one hand, and its negative effect on steroid synthesis on the other. The rating of the relative importance of both phenomena for the outcome of patients is however a highly controversial issue. We will discuss the most recent publications for two patient groups: trauma and critically ill septic patients. New meta-analyses and smaller studies have been published and might help us to weigh pros and cons in our patients. Sufficiently powered randomized controlled trials remain absent. The question whether supplemented corticosteroids after etomidate improve outcome is answered negatively by two recent studies. SUMMARY: A single dose of etomidate supplies good intubation conditions with hemodynamic stability, but increases the risk for adrenal insufficiency. The relative importance of these characteristics for the patients' outcome remains controversial, as there is a lack of direct evidence. According to the principle 'nihil nocere', reasoning argues against its use, especially in septic patients or in those at major risk to develop septic complications (e.g. trauma patients). © 2013 Lippincott Williams & Wilkins. Source

Kleinert S.,University Hospital of Wuerzburg | Tony H.-P.,University Hospital of Wuerzburg | Krueger K.,Praxiszentrum St. Bonifatius Munich | Detert J.,Charite - Medical University of Berlin | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objectives: To characterise optimal screening strategies for latent tuberculosis infection (LTBI) prior to the initiation of anti-tumour necrosis factor therapy. Methods: Patients in 62 German rheumatology centres were evaluated for LTBI. Each patient was screened with a tuberculin skin test (TST) and one form of an interferon-γ release assay (IGRA), either TSPOT.TB (TSPOT) or Quantiferon TB Gold (QFT). Results: A total of 1529 patients with rheumatological disease were tested with a TST, 844 with TSPOT and 685 with QFT. TST was positive in 11.3% (n=173). The prevalence of LTBI was 8.0% when defined as a positive TST and no previous Bacille Calmette-Guérin (BCG) vaccination and 7.9% when based on a positive IGRA. Combining both estimates increased the prevalence of LTBI to 11.1%. Clinical risk factors for LTBI were found in 122 patients (34 with a history of prior TB, 81 close contacts and 27 with suggestive chest x-ray lesions). A compound risk factor (CRF) was defined as the presence of at least one of these three risk factors. Statistical analyses were conducted to examine the association between CRF and LTBI test outcomes. In multivariate analysis, TST was influenced by CRF (OR 6.2; CI 4.08 to 9.44, p<0.001) and BCG vaccination status (OR 2.9; CI 2.00 to 4.35, p<0.001). QFT and TSPOT were only influenced by CRF (QFT: OR 2.6; CI 1.15 to 5.98, p=0.021; TSPOT: OR 8.7; CI 4.83 to 15.82, p<0.001). ORs and the agreement of TST and IGRA test results varied by rheumatological disease. Conclusion: LTBI test results in an individual patient need to be considered in the context of prior BCG vaccination and clinical risk factors. In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity. Source

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