Bauer S.,Charit Universitatsmedizin Berlin |
Kohler S.,Charit Universitatsmedizin Berlin |
Schulz M.H.,Max Planck Institute for Molecular Genetics |
Schulz M.H.,Carnegie Mellon University |
And 2 more authors.
Bioinformatics | Year: 2012
Motivation: Ontologies provide a structured representation of the concepts of a domain of knowledge as well as the relations between them. Attribute ontologies are used to describe the characteristics of the items of a domain, such as the functions of proteins or the signs and symptoms of disease, which opens the possibility of searching a database of items for the best match to a list of observed or desired attributes. However, naive search methods do not perform well on realistic data because of noise in the data, imprecision in typical queries and because individual items may not display all attributes of the category they belong to. Results:: We present a method for combining ontological analysis with Bayesian networks to deal with noise, imprecision and attribute frequencies and demonstrate an application of our method as a differential diagnostic support system for human genetics. © The Author 2012. Published by Oxford University Press. All rights reserved.
Papageorgiou A.-P.,Maastricht University |
Papageorgiou A.-P.,Catholic University of Leuven |
Swinnen M.,Catholic University of Leuven |
Vanhoutte D.,Catholic University of Leuven |
And 16 more authors.
Cardiovascular Research | Year: 2012
Aims: Thrombospondin-2 (TSP-2) modulates matrix integrity and myocyte survival in the hypertensive or ageing heart. Whether TSP-2 may affect cardiac inflammation and injury, in particular during acute viral myocarditis, is completely unknown. Methods and results: Therefore, mortality, cardiac inflammation, and function were assessed in TSP-2-null (KO) and wild-type (WT) mice in human Coxsackie virus B3 (CVB3)-induced myocarditis. TSP-2 KO had an increased mortality when compared with WT mice during viral myocarditis. The absence of TSP-2 resulted in increased cardiac inflammation and injury at 14 days, which resulted in depressed systolic function [fractional shortening (FS); 34 ± 2.6 in WT vs. 24 ± 1.8 in KO mice, P< 0.05] and increased cardiac dilatation (end-diastolic dimensions, mm; 3.7 ± 0.09 in WT vs. 4.8 ± 0.06 in KO mice, P< 0.05) 35 days post-infection. Lack of TSP-2 resulted in a decreased activation of the anti-inflammatory T-regulatory cells, as indicated by a lower number of CD25-positive T-cells, and significantly decreased gene expression of regulatory T-cell markers, Foxp3 and CTLA-4. Finally, overexpression of TSP-2 in WT hearts using cardiotropic vectors derived from adeno-associated virus serotype 9 (AAV9) inhibited cardiac inflammation and injury at 14 days and improved cardiac function at 35 days post-CVB3 infection when compared with control AAV9. Conclusion: TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.
Scheerer P.,Charit Universitatsmedizin Berlin |
Michael N.,TU Berlin |
Park J.H.,Charit Universitatsmedizin Berlin |
Nagano S.,Queen Mary, University of London |
And 5 more authors.
ChemPhysChem | Year: 2010
Recombinant phytochromes Agp1 and Agp2 from Agrobacterium tumefaciens are used as model phytochromes for biochemical and biophysical studies. In biliverdin binding phytochromes the site for covalent attachment of the chromophore lies in the N-terminal region of the protein, different from plant phytochromes. The issue which stereochemistry the chromophore adopts in the so-called Pr and Pfr forms is ad-dressed by using a series of locked chromophores which form spectrally characteristic adducts with Agp1 and Agp2. Studies on light-induced conformational changes of Agp1 give an insight into how the intrinsic histidine kinase is modulated by light. Comparison of the crystal structure of an Agp1 fragment with other phytochrome crystal structures supports the idea that a light induced rearrangement of subunits within the homodimer modulates the activity of the kinase. © 2010 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim.
Kanti V.,Charit Universitatsmedizin Berlin |
Bonzel A.,University of Duisburg - Essen |
Stroux A.,Charit Universitatsmedizin Berlin |
Proquitte H.,Charit Universitatsmedizin Berlin |
And 3 more authors.
Skin Pharmacology and Physiology | Year: 2014
Background: In preterm infants, skin barrier maturation entails regional variability. Objectives: To characterize postnatal skin barrier development in covered, uncovered and diapered regions in healthy premature infants over a longitudinal observation period. Methods: Transepidermal water loss (TEWL), stratum corneum hydration (SCH), pH and sebum were measured at postnatal ages of 1-7 days and 2-7 weeks on the forehead, abdomen, thigh and buttock of preterm infants (gestational age 30-37 weeks; n = 48) under monitored ambient conditions. A standard minimal skin care regimen was practised. Results: TEWL increased significantly on the buttock (p = 0.007), while remaining stable on the forehead, abdomen and thigh. SCH and sebum remained stable in all studied body regions with increasing age. On the buttock, pH increased (p = 0.049), while other body regions exhibited a significant decrease (p ≤ 0.019). TEWL (p < 0.001) and SCH (p ≤ 0.002) revealed significantly higher values on the buttock, compared to other body regions. Conclusions: Stable TEWL, SCH and sebum values may indicate a lack of skin barrier maturation. Postnatal decrease in skin pH suggests an adaptation process with acid mantle formation. Differences in skin barrier development were observed between anatomical regions. SCH, TEWL and pH values demonstrated a distinct course in the diaper area, indicating an impaired skin barrier function in this region. © 2014 S. Karger AG, Basel.
Assaf C.,Dermatologische Klinik |
Assaf C.,Charit Universitatsmedizin Berlin
Aktuelle Dermatologie | Year: 2012
Transcription factors are DNA-binding proteins involved in transcription processes in eukaryotes, by binding parts of promoters or enhancers with high specificity. They can thus regulate genes or complex networks by themselves. On this basis, alteration of a solitary transcription factor may lead to various cellular changes and also to neoplasia. A network of transcription factors, such as E2a, ID-2, NOTCH and PAX5 regulates lymphocytic development into B-, T-, NK- or plasmocytoid dendritic cells. Alterations of these genes via mutation or activation of inhibitors my lead to developmental disorders and also to malignant transformation. In our own investigations we have shown that in Sezary's syndrome genomic deletion of transcription factor E2A may be detected in 70% of the cases, resulting in deregulation of a series of oncogenes and other transcription factors responsible for cell proliferation and transformation. © Georg Thieme Verlag KG Stuttgart.
Recommendations for therapy, chemoprevention and chemoprophylaxis of tuberculosis in adults and children: German Central Committee against Tuberculosis (DZK), German Respiratory Society (DGP) [Empfehlungen zur Therapie, Chemoprävention und Chemoprophylaxe der Tuberkulose im Erwachsenen- und Kindesalter: Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose (DZK), Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)]
Schaberg T.,Zentrum fur Pneumologie |
Bauer T.,Deutsches Zentralkomitee Zur Bekampfung der Tuberkulose DZK |
Castell S.,Deutsches Zentralkomitee Zur Bekampfung der Tuberkulose DZK |
Dalhoff K.,Universitatsklinikum Schleswig Holstein |
And 7 more authors.
Pneumologie | Year: 2012
Several new international recommendations have been published since the German Central Committee against Tuberculosis (DZK) published its recommendations for drug treatment of tuberculosis (TB) in 2001 and for chemoprevention of latent tuberculosis infection (LTBI) in 2004. These international publications have been integrated in the present new recommendations which describe both the treatment of active TB and preventive treatment, pointing out specific adaptations for Germany. Separate sections deal with the current management of mono-, poly-, and multiresistance or drug intolerance, of TB in children, of different forms of extrapulmonary TB, of LTBI and of special situations such as HIV infection, renal or hepatic insufficiency, infection following BCG instillation in bladder cancer or in case of adverse drug reactions. The following aspects differ from the previous recommendations: A three-drug regimen for the so-called fully susceptible minimal TB is no longer recommended in adults. A dosage of 15 mg/kg body weight of ethambutol for adults is regarded as sufficient. Four secondline drugs (supplemented by pyrazinamide, where appropriate) are recommended for multidrug-resistant tuberculosis (MDR-TB). MDR-TB should be treated over a period of at least 20 months, with an injectable drug administered for a minimum of 8 months (initial phase). Ciprofloxacine and ofloxacine are no longer used to treat TB. It is also recommended to offer an HIV test to all TB patients to complement antiretroviral therapy, if necessary, and to adapt the antituberculous therapy accordingly. © Georg Thieme Verlag KG Stuttgart - New York.
Kreutz R.,Charit Universitatsmedizin Berlin
Klinikarzt | Year: 2012
New oral anticoagulants (NOACs) such as the direct factor IIa inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban demonstrate pharmacological characteristics that result in desirable and significant advantages in comparison to previous available antithrombotic treatment strategies. Thus, they allow oral application and show a rapid onset and offset of action. Amajor advantage results from their predictable pharmacokinetic and pharmacodynamic profile. Consequently, these NOACs can be administered at fixed doses without the need for routine coagulation monitoring. Nevertheless, when using these drugs some restrictions have to be considered, e.g. in patients with renal impairment and with regard to co-medications. Moreover, some aspects of their use in daily practice are not (well) established, such as monitoring of anticoagulatory effects in specific clinical situations, reversal of their effects and the potential use of antidotes in patients with major bleedings. In this regard, knowledge of the pharmacological characteristics of NOACs can provide an important and necessary basis for clinical decision making. © Georg Thieme Verlag KG Stuttgart · New York.
Kadmon M.,Universitatsklinik Heidelberg |
Busemann A.,Universitatsmedizin Greifswald |
Euteneier A.,Klinik fur Unfallchirurgie und Orthopadie |
Gawad K.,Hospital Zum Heiligen Geist |
And 2 more authors.
Zentralblatt fur Chirurgie - Zeitschrift fur Allgemeine, Viszeral- und Gefasschirurgie | Year: 2012
Background: The quality of postgraduate training is an important motivating factor for the career decisions of young doctors and has an impact on the satisfaction of postgraduate trainees. In Germany, we still lack a postgraduate training programme in surgery that defines the competency profile at the time of certification. This article describes the development of a national modular competency-based core curriculum for postgraduate surgery training as well as first experience and evaluation data from the initial period of implementation. Methods: The curriculum was developed in a group of highly motivated surgeons according to the "Kern-cycleo", a conceptual framework for curriculum development in medicine, and includs considerations from the "CanMEDSo"-competency framework for physicians. The curriculum follows a "blended learningo" concept with modular attendance courses and associated preparatory online courses. The didactics follows the principles of adult learning and are characterised by learner-centred, self-directed learning processes in small groups with feedback. The initial implementation phase was accompanied by a detailed evaluation of the general concept as well as the quality of content and didactics of the attendance courses. Results: Seven of the planned 12attendance courses have been designed, 6courses have been implemented2q1. Altogether 562participants from hospitals of all levels of patient care took part in the attendance courses, some of them in several courses. The gender distribution was almost balanced with a slight female surplus. The majority of participants were supported by their clinics through exemption from clinical work or financial sponsoring. 80 % of the participants completed the evaluation of the attendance courses. The data show a high degree of participant satisfaction with the content and didactic concept of the courses, as well as with the surrounding conditions and the commitment of the trainers. Conclusions: The evaluation data on the attendance courses implemented reveal a high acceptance among participants concerning the overall concept of the modular postgraduate training programme as well as the support of the programme by surgeons responsible for postgraduate training. © 2012 Georg Thieme Verlag KG Stuttgart • New York.
Dreger H.,Charit Universitatsmedizin Berlin |
Antonow G.,Charit Universitatsmedizin Berlin |
Spethmann S.,Charit Universitatsmedizin Berlin |
Bondke H.,Charit Universitatsmedizin Berlin |
And 2 more authors.
Europace | Year: 2012
Aims: Interventricular (VV) delay optimization for cardiac resynchronization therapy (CRT) is recommended by current guidelines and several algorithms have been proposed. So far, however, no gold standard has been established in the clinical routine. We hypothesized that dyssynchrony parameter assessment might guide VV delay optimization and investigated whether dyssynchrony parameter changes induced by sequential biventricular pacing follow a predictable pattern. Methods and results: We determined intra- and interventricular dyssynchrony in 80 CRT patients by echocardiographic quantification of the interventricular mechanical delay and the septal-lateral time to peak systolic velocity delay. Dyssynchrony parameters were assessed during simultaneous biventricular pacing as well as during sequential biventricular pacing with a right ventricular (RV) or left ventricular (LV) preactivation of 40 ms. Simultaneous biventricular pacing significantly improved inter- and intraventricular dyssynchrony parameters compared with preoperative baseline measurements. In general, dyssynchrony parameter changes induced by sequential biventricular pacing showed high interindividual variance and did not follow a predictable pattern. Intra- or interventricular dyssynchrony persisted during simultaneous biventricular pacing in 39 and 19% of our patients, respectively. Neither RV nor LV preactivation significantly decreased the number of patients with persistent intraventricular dyssynchrony. In contrast, LV preactivation significantly reduced the prevalence of interventricular dyssynchrony by 80%. Conclusions: Left ventricular preactivation effectively ameliorates interventricular dyssynchrony, which persists in almost one in five CRT patients. Assessment of interventricular dyssynchrony and consecutive programming of LV preactivation in patients with persistent interventricular dyssynchrony may represent a pragmatic and time-effective approach to improve CRT in patients with inferior response. © 2011 The Author.
Paneni F.,University of Zürich |
Paneni F.,Karolinska University Hospital |
Costantino S.,University of Zürich |
Costantino S.,Karolinska University Hospital |
And 3 more authors.
European Heart Journal | Year: 2016
Aims Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66Shc and the AP-1 transcription factor JunD, contribute to age-related EOCs dysfunction in humans. Methods and results Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66Shc gene up-regulation and reduced JunD expression. Deregulation of p66Shc and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 - generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66Shc silencing or JunD overexpression blunted age-related O2 - production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs. Conclusion Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly. © The Author 2016.