Baleeiro R.B.,ChariteUniversitatsmedizin Berlin |
Walden P.,ChariteUniversitatsmedizin Berlin
Molecular Immunology | Year: 2017
Cross-presentation of endocytosed antigen is essential for induction of CD8 effector T cell responses and a hallmark of dendritic cells (DCs). The mode of antigen processing in this context is controversial and some models imply translocation of the antigen from the endosomes into the cytosol. To test this hypothesis we made use of the pro-apoptotic properties of cytochrome c when in the cytosol, and confirmed that it indeed triggered apoptosis of human immature DCs but only at high concentrations. Proteasome inhibitors reduced the required concentration of cytochrome c thousand-fold, indicating that protein translocated into the cytosol is rapidly degraded by proteasomes. Mature DCs were also susceptible to cytochrome c-triggered apoptosis at high concentrations but proteasome inhibitors did not increase their sensitivity. Other cross-presenting cells such as B cells and monocytes were not sensitive to cytochrome c at all, indicating that they do not shuttle internalized antigen into the cytosol. Thus, processing of internalized antigens seems to follow different pathways depending on cell type and, in case of DCs, maturation state. Immature DCs appear to have a unique capacity to shuttle external antigen into the cytosol for proteasomal processing, which could explain their efficiency in antigen cross-presentation. © 2017 Elsevier Ltd
Muller S.,ChariteUniversitatsmedizin Berlin |
Riedmuller R.,ChariteUniversitatsmedizin Berlin |
Walter H.,ChariteUniversitatsmedizin Berlin |
Christen M.,University of Zürich
AJOB Neuroscience | Year: 2015
Anorexia nervosa (AN) is one of several neuropsychiatric disorders that are increasingly tackled experimentally using stereotactic neurosurgery (deep brain stimulation and ablative procedures). We analyze all 27 such cases published between 1990 and 2014. The majority of the patients benefitted significantly from neurosurgical treatments, in terms of both weight restoration and psychiatric morbidity. A remission of AN was reported in 61% of patients treated with DBS and 100% of patients treated with ablative surgery. Unfortunately, information on side effects is insufficient, and after DBS, severe side effects occurred in some cases. Altogether, the risk–benefit evaluation is positive, particularly for ablative stereotactic procedures. However, fundamental ethical issues are raised. We discuss whether neurosurgery can be justified for treating psychiatric disorders of the will that are seemingly self-inflicted, such as addiction or AN, and where cultural factors contribute significantly to their development. We suggest that although psychosocial factors determine the onset of AN, this is not a legitimate argument for banning neurosurgical treatments, since in AN, a vicious circle develops that deeply affects the brain, undermines the will, and prevents ceasing the self-destructive behavior. Three confounding issues provide ethical challenges for research in neurosurgery for AN: first, a scarce information base regarding risks and benefits of the intervention; second, doubtful capabilities for autonomous decision making; and third, the minor age of many patients. We recommend protective measures to ensure that stereotactic neurosurgery research can proceed with respect for the patients' autonomy and orientation to the beneficence principle. © 2015, Copyright © Taylor and Francis Group, LLC.
Wackerhagen C.,ChariteUniversitatsmedizin Berlin
Neuropsychopharmacology | Year: 2017
Imbalances in cortico-limbic activity and functional connectivity (FC) supposedly underlie biased emotional processing and present putative intermediate phenotypes (IPs) for major depressive disorder (MDD). To prove the validity of these IPs, we assessed them in familial risk. In 70 healthy first-degree relatives of MDD patients and 70 controls, brain activity and seed-based amygdala FC were assessed during an implicit emotional processing task for fMRI containing angry and fearful faces. Using the generalized psychophysiological interaction approach, amygdala FC was assessed (a) across conditions to provide comparable data to previous studies and (b) compared between conditions to elucidate its implications for emotional processing. Associations of amygdala FC with self-reported negative affect were explored post hoc. Groups did not differ in brain activation. In relatives, amygdala FC across conditions was decreased with superior and medial frontal gyrus (SFG, MFG) and increased with subgenual and perigenual anterior cingulate cortex (sgACC, pgACC). NA was inversely correlated with amygdala FC with MFG, pgACC and their interaction in relatives. Relatives showed aberrant condition-dependent modulations of amygdala FC with visual cortex, thalamus and orbitofrontal cortex. Our results do not support imbalanced cortico-limbic activity as IP for MDD. Diminished amygdala-dorsomedial prefrontal FC in relatives might indicate insufficient regulatory capacity, which appears to be compensated by ventromedial prefrontal regions. Differential task-dependent modulations of amygdala FC are discussed as a stronger involvement of automatic instead of voluntary emotional processing pathways. Reliability and etiological implications of these results should be investigated in future studies including longitudinal designs and patient–risk–control comparisons.Neuropsychopharmacology advance online publication, 5 April 2017; doi:10.1038/npp.2017.59. © 2017 American College of Neuropsychopharmacology
Vogt A.,ChariteUniversitatsmedizin Berlin |
Wischke C.,Helmholtz Center Geesthacht |
Neffe A.T.,Helmholtz Center Geesthacht |
Ma N.,Helmholtz Center Geesthacht |
And 2 more authors.
Journal of Controlled Release | Year: 2016
The topical application of drug-loaded particles has been explored extensively aiming at a dermal, follicular or transdermal drug delivery. This review summarizes the present state of the field of polymeric nanocarriers for skin application, also covering methodologies to clinically characterize their interaction and penetration in skin in vivo. Furthermore, with a focus on a clinical perspective, a number of questions are addressed: How well are existing nanoparticle systems penetrating the skin? Which functions of new carrier concepts may meet the clinical requirements? To which extend will instrumental imaging techniques provide information on the biological functions of nanocarriers? Which issues have to be addressed for translating experimental concepts into a future clinical application? © 2016 Elsevier B.V.
Luftner D.,ChariteUniversitatsmedizin Berlin |
Supportive Care in Cancer | Year: 2016
Purpose: The aim of this study is to provide an overview of the potential barriers to uptake of bone-targeted agents for the prevention of skeletal-related events (SREs) in patients with breast cancer and bone metastases. Methods: A top-line literature review was conducted to identify trends in and barriers to initiating bone-targeted therapy in patients with metastatic breast cancer. Results: The majority of patients with bone metastases that are secondary to breast cancer clearly benefit from treatment with a bone-targeted agent such as the RANK ligand inhibitor denosumab or the bisphosphonate zoledronic acid, because both delay the onset of SREs. Evidence suggests, however, that these agents are not being used in these patients as per European guideline recommendations. Conclusions: Adoption of a number of behavioral changes may help to overcome barriers to earlier initiation of treatment with bone-targeted agents in these patients. This includes raising awareness of the guidelines that are available for bone-targeted therapies, providing physician and patient education on the appropriate use of these agents, and highlighting to physicians the importance of early treatment and regular monitoring for adverse events. Earlier initiation of treatment should help to reduce the risk of SREs and thus lessen the burden that these debilitating skeletal complications place on patients and healthcare systems. © 2016, Springer-Verlag Berlin Heidelberg.
Knecht S.,Universitatsklinikum Munster |
Hesse S.,ChariteUniversitatsmedizin Berlin |
Oster P.,Geriatrisches Zentrum
Deutsches Arzteblatt | Year: 2011
Background: Stroke is becoming more common in Germany as the population ages. Its long-term sequelae can be alleviated by early reperfusion in stroke units and by complication management and functional restoration in early-rehabilitation and rehabilitation centers. Methods: Selective review of the literature. Results: Successful rehabilitation depends on systematic treatment by an interdisciplinary team of experienced specialists. In the area of functional restoration, there has been major progress in our understanding of the physiology of learning, relearning, training, and neuroenhancement. There have also been advances in supportive pharmacotherapy and robot technology. Conclusion: Well-organized acute and intermediate rehabilitation after stroke can provide patients with the best functional results attainable on the basis of our current scientific understanding. Further experimental and clinical studies will be needed to expand our knowledge and improve the efficacy of rehabilitation.
Christen M.,University of Zürich |
Muller S.,ChariteUniversitatsmedizin Berlin
Current Topics in Behavioral Neurosciences | Year: 2015
Understanding how the “brain produces behavior” is a guiding idea in neuroscience. It is thus of no surprise that establishing an interrelation between brain pathology and antisocial behavior has a long history in brain research. However, interrelating the brain with moral agency—the ability to act in reference to right and wrong—is tricky with respect to therapy and rehabilitation of patients affected by brain lesions. In this contribution, we outline the complexity of the relationship between the brain and moral behavior, and we discuss ethical issues of the neuroscience of ethics and of its clinical consequences. First, we introduce a theory of moral agency and apply it to the issue of behavioral changes caused by brain lesions. Second, we present a typology of brain lesions both with respect to their cause, their temporal development, and the potential for neural plasticity allowing for rehabilitation. We exemplify this scheme with case studies and outline major knowledge gaps that are relevant for clinical practice. Third, we analyze ethical pitfalls when trying to understand the brain–morality relation. In this way, our contribution addresses both researchers in neuroscience of ethics and clinicians who treat patients affected by brain lesions to better understand the complex ethical questions, which are raised by research and therapy of brain lesion patients. © Springer-Verlag Berlin Heidelberg 2014.
Savvatis K.,ChariteUniversitatsmedizin Berlin |
Pappritz K.,ChariteUniversitatsmedizin Berlin |
Becher P.M.,University of Hamburg |
Lindner D.,University of Hamburg |
And 6 more authors.
Circulation: Heart Failure | Year: 2014
Background - CD4+ cells are implicated in the healing process after myocardial infarction (MI). We sought to investigate the role of interleukin-23 (IL-23) deficiency, a cytokine important in differentiation of CD4+ cells, in scar formation of the ischemic heart. Methods and Results - MI was performed in wild-type and IL23p19./. mice. Thirty-day mortality, hemodynamic function 4 days after MI and myocardial inflammation, and remodeling 4 and 30 days after MI were examined. Differentiation of fibroblasts from infarcted and noninfarcted hearts into myofibroblasts was examined under basal conditions and after stimulation with interferon-ã, IL-17á and IL-23. Interleukin-23p19./. mice showed higher expression of proinflammatory cytokines and immune cell infiltration in the scar early after MI compared with wild-type mice. A stronger interferon- ã/ Th1 reaction seemed to be responsible for the increased inflammation under IL-23 deficiency. Expression of á-smooth muscle actin (á-SMA), collagen I and III was significantly higher in the heart tissue and isolated cardiac fibroblasts 4 days after MI in the wild-type mice. Interleukin-23p19./. mice showed impaired healing compared with wild-type mice, as seen by significantly higher mortality because of ventricular rupture (40% higher after 30 days) and stronger left ventricular dilation early after MI. Stimulation of cardiac fibroblasts with interferon-ã, the main Th1 cytokine, but not with IL-23 or IL-17á, led to a significant downregulation of á-smooth muscle actin, collagen I and III and decreased migration and differentiation to myofibroblasts. Conclusions - IL-23 deficiency leads to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired scar formation and adverse remodeling after MI. © 2013 American Heart Association, Inc.
Sinn M.,ChariteUniversitatsmedizin Berlin
British Journal of Cancer | Year: 2014
Background:Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods:CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results:High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions:Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.British Journal of Cancer advance online publication, 14 October 2014; doi:10.1038/bjc.2014.495 www.bjcancer.com. © 2014 Cancer Research UK
Audebert H.J.,ChariteUniversitatsmedizin Berlin |
Fiebach J.B.,ChariteUniversitatsmedizin Berlin
Current Neurology and Neuroscience Reports | Year: 2015
In acute stroke, imaging provides different technologies to demonstrate stroke subtype, tissue perfusion and vessel patency. In this review, we highlight recent clinical studies that are likely to guide therapeutic decisions. Clot length in computed tomography (CT) and clot burden in MR, imaging of leptomeningeal collaterals and indicators for active bleeding are illustrated. Imaging-based concepts for treatment of stroke at awakening and pre-hospital treatment in specialized ambulances offer new potentials to improve patient outcome. © 2015, Springer Science+Business Media New York.