Charite University Medicine

Berlin, Germany

Charite University Medicine

Berlin, Germany
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Horn A.,Charite University Medicine | Horn A.,Max Planck Institute for Human Development | Blankenburg F.,Max Planck Institute for Human Development | Blankenburg F.,Free University of Berlin
NeuroImage | Year: 2016

The analysis of the structural architecture of the human brain in terms of connectivity between its subregions has provided profound insights into its underlying functional organization and has coined the concept of the "connectome", a structural description of the elements forming the human brain and the connections among them. Here, as a proof of concept, we introduce a novel group connectome in standard space based on a large sample of 169 subjects from the Enhanced Nathan Kline Institute-Rockland Sample (eNKI-RS). Whole brain structural connectomes of each subject were estimated with a global tracking approach, and the resulting fiber tracts were warped into standard stereotactic (MNI) space using DARTEL. Employing this group connectome, the results of published tracking studies (i.e., the JHU white matter and Oxford thalamic connectivity atlas) could be largely reproduced directly within MNI space. In a second analysis, a study that examined structural connectivity between regions of a functional network, namely the default mode network, was reproduced. Voxel-wise structural centrality was then calculated and compared to others' findings. Furthermore, including additional resting-state fMRI data from the same subjects, structural and functional connectivity matrices between approximately forty thousand nodes of the brain were calculated. This was done to estimate structure-function agreement indices of voxel-wise whole brain connectivity. Taken together, the combination of a novel whole brain fiber tracking approach and an advanced normalization method led to a group connectome that allowed (at least heuristically) performing fiber tracking directly within MNI space. Such an approach may be used for various purposes like the analysis of structural connectivity and modeling experiments that aim at studying the structure-function relationship of the human connectome. Moreover, it may even represent a first step toward a standard DTI template of the human brain in stereotactic space. The standardized group connectome might thus be a promising new resource to better understand and further analyze the anatomical architecture of the human brain on a population level. © 2015 Elsevier Inc.

Hess V.,Charite University Medicine | Mendelsohn J.A.,Queen Mary, University of London
Early Science and Medicine | Year: 2014

What was classification as it first took modern form in the eighteenth century, and how did it relate to earlier ways of describing and ordering? We offer new answers to these questions by examining medicine rather than botany and by reconstructing practice on paper. First among disease classifications was the 'nosology' of the Montpellier physician François Boissier de Sauvages de Lacroix. Analysis of his hitherto unstudied notebooks and of the nosology's many editions (1731-1772) shows that Boissier de Sauvages broke with earlier physicians' humanistic ordering of disease while sustaining the paper practices they had used. Scientific method was scholarly method. Classification arose through an incomplete break with, and intensified practice of, a past library-based way of ordering the described world. A new empiricism of generalizations (species) arose out of an older one of particulars (observationes). This happened through the rewriting - not the replacement - of the canon of disease knowledge since antiquity and its reordering on the printed page. © koninklijke brill nv, leiden, 2014.

Norman K.,Charite University Medicine | Pirlich M.,Charite University Medicine | Smoliner C.,Charite University Medicine | Kilbert A.,Charite University Medicine | And 4 more authors.
European Journal of Clinical Nutrition | Year: 2011

Background/Objectives: Nutritional intervention with oral nutritional supplements (ONS) has been shown to increase quality of life in malnourished patients. We investigated whether post-hospital supplementation with ONS is cost-effective according to international benchmarks in malnourished patients. Subjects/Methods: In total, 114 malnourished patients (50.6±16.1 years, 57 female) with benign gastrointestinal disease were included and randomised to receive either ONS for 3 months and dietary counselling at discharge (intervention, n=60) or only dietary counselling at discharge (control group, n=54). Nutritional status was assessed with Subjective Global Assessment. Intervention patients documented daily intake of ONS; quality of life was assessed with Short-Form (SF)-36 Health Survey and SF-36 values were transformed into health-status utilities. Quality-adjusted life years (QALYs) were calculated by adopting the area under the curve method. We used two different pricing scenarios for ONS (minimum price: €2.30 and maximum: €2.93/tetrapack). The incremental cost-effectiveness ratio (ICER) of supplementation with ONS was calculated for both price scenarios. All analyses were corrected for age and gender. Results: Intervention patients consumed 2.4±0.8 ONS per day. Intervention and control patients did not differ in their health status utilities at baseline (0.594±0.017 vs 0.619±0.018), but after 3 months, the health status utilities were significantly higher in intervention patients than in control patients (0.731±0.015 vs 0.671±0.016, P=0.028). Intervention was associated with significantly higher costs (ICER: €9497 and €12 099/additional QALY, respectively) but deemed cost-effective according to international thresholds (<€50 000/QALY). Conclusions: A 3-month intervention with ONS increases quality of life in malnourished patients. This treatment appears to be cost-effective according to international benchmarks. © 2011 Macmillan Publishers Limited All rights reserved.

Avouac J.,University of Paris Descartes | Avouac J.,French National Center for Scientific Research | Riemekasten G.,Charite University Medicine | Meune C.,University of Paris 13 | And 5 more authors.
Journal of Rheumatology | Year: 2015

Objective. To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc). Methods. Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) auto-antibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup. Results. Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional auto-antibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoanti-bodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU. Conclusion.Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoanti-bodies may allow for earlier management and therapeutic intervention. Copyright © 2015. All rights reserved.

Horn A.,Charite University Medicine | Horn A.,Max Planck Institute for Human Development | Kuhn A.A.,Charite University Medicine
NeuroImage | Year: 2015

To determine placement of electrodes after deep brain stimulation (DBS) surgery, a novel toolbox that facilitates both reconstruction of the lead electrode trajectory and the contact placement is introduced. Using the toolbox, electrode placement can be reconstructed and visualized based on the electrode-induced artifacts on post-operative magnetic resonance (MR) or computed tomography (CT) images.Correct electrode placement is essential for efficacious treatment with DBS. Post-operative knowledge about the placement of DBS electrode contacts and trajectories is a promising tool for clinical evaluation of DBS effects and adverse effects. It may help clinicians in identifying the best stimulation contacts based on anatomical target areas and may even shorten test stimulation protocols in the future.Fifty patients that underwent DBS surgery were analyzed in this study. After normalizing the post-operative MR/CT volumes into standard Montreal Neurological Institute (MNI)-stereotactic space, electrode leads (n = 104) were detected by a novel algorithm that iteratively thresholds each axial slice and isolates the centroids of the electrode artifacts within the MR/CT-images (MR only n = 32, CT only n = 10, MR and CT n = 8). Two patients received four, the others received two quadripolar DBS leads bilaterally, summing up to a total of 120 lead localizations. In a second reconstruction step, electrode contacts along the lead trajectories were reconstructed by using templates of electrode tips that had been manually created beforehand. Reconstructions that were made by the algorithm were finally compared to manual surveys of contact localizations.The algorithm was able to robustly accomplish lead reconstructions in an automated manner in 98% of electrodes and contact reconstructions in 69% of electrodes. Using additional subsequent manual refinement of the reconstructed contact positions, 118 of 120 electrode lead and contact reconstructions could be localized using the toolbox.Taken together, the toolbox presented here allows for a precise and fast reconstruction of DBS contacts by proposing a semi-automated procedure. Reconstruction results can be directly exported to two- and three-dimensional views that show the relationship between DBS contacts and anatomical target regions. The toolbox is made available to the public in form of an open-source MATLAB repository. © 2014 Elsevier Inc.

Wend P.,University of California at Los Angeles | Runke S.,University of California at Los Angeles | Anchondo B.,University of California at Los Angeles | Yesayan M.,University of California at Los Angeles | And 15 more authors.
EMBO Molecular Medicine | Year: 2013

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients. WNT10B specifically activates the canonical Wnt/i-catenin pathway and functions as a ligand-based model of triple-negative mammary gland tumours that is conserved between mouse and human. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Kociok N.,Heinrich Heine University Düsseldorf | Kociok N.,Charite University Medicine | Joussen A.M.,Heinrich Heine University Düsseldorf | Joussen A.M.,Charite University Medicine
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2010

Background: RPE cells are a major player in various diseases of the retina and choroid. Proliferating RPE cells are thought to be an initiating factor in proliferative vitreoretinopathy (PVR); the aging RPE cells are important in age-related macular degeneration (AMD). Early passages of cultured human retinal pigment epithelial cells were used as a model system to identify differentially expressed genes in proliferating retinal pigment epithelial (RPE) cells. Methods: A differential expression analysis (DEmRNA-PCR) was used to find differentially expressed mRNA in early passages of cultured human RPE cells. The detected mRNAs were identified by sequencing. Their differential expression was verified by semi-quantitative RT-PCR. The expression of the identified protein in vitro and its presence in surgically removed epiretinal membranes was demonstrated by western blotting and immunocytochemical analysis. Results: DEmRNA-PCR detected a decreased expression of a band at approximately 530 bp in human RPE cells of passage 3 (P3) compared to P0. This band was identified as part of the human complement regulatory factor H, a cofactor to complement factor I. The mRNA expression of both regulatory proteins of the complement system was confirmed in freshly prepared human RPE cells and in cultured cells from P0 to P8. The protein expression was verified in cultured RPE cells. The expression of both proteins in surgically removed epiretinal membranes was demonstrated by immunohistochemistry. Conclusion: The identification of the differential expression of the regulatory factors H and I of the complement system in cultured RPE cells by a technique without any prerequisites demonstrates and confirms the importance of these factors in RPE cells. In addition to its known role in age-related macular degeneration, the presence of these complement factors in epiretinal membranes may also indicate a role of the complement system in proliferative retinopathy. © 2010 Springer-Verlag.

PubMed | University of Turku, Medical University of Bialystok, Polish Academy of Sciences, China Agricultural University and Charite University Medicine
Type: | Journal: Scientific reports | Year: 2016

Expression of follicle-stimulation hormone receptor (FSHR) is confined to gonads and at low levels to some extragonadal tissues like human umbilical vein endothelial cells (HUVEC). FSH-FSHR signaling was shown to promote HUVEC angiogenesis and thereafter suggested to have an influential role in pregnancy. We revisited hereby the expression and functionality of FSHR in HUVECs angiogenesis, and were unable to reproduce the FSHR expression in human umbilical cord, HUVECs or immortalized HUVECs (HUV-ST). Positive controls as granulosa cells and HEK293 cells stably transfected with human FSHR cDNA expressed FSHR signal. In contrast to positive control VEGF, FSH treatment showed no effects on tube formation, nitric oxide production, wound healing or cell proliferation in HUVEC/HUV-ST. Thus, it remains open whether the FSH-FSHR activation has a direct regulatory role in the angiogenesis of HUVECs.

PubMed | Heinrich Heine University Düsseldorf, University of Regensburg, Jena University Hospital, University of Tübingen and 20 more.
Type: Journal Article | Journal: Annals of neurology | Year: 2016

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuks 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach.A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n=810), plasma exchange (PE; n=192), immunoadsorption (IA; n=38), other (n=80), and unknown (n=33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p<0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p<0.001), and for unilateral versus bilateral optic neuritis (p=0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p=0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR]=0.97, p=0.011), presence of myelitis (OR=0.38, p=0.002), CR from previous attack (OR=6.85, p<0.001), and first-line PE/IA versus HD-S (OR=4.38, p=0.006).Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.

PubMed | Charité - Medical University of Berlin, University of Turku, China Agricultural University and Charite University Medicine
Type: Journal Article | Journal: Cancer immunology, immunotherapy : CII | Year: 2015

The efficacy of immunotherapy in cancer patients is influenced by differences in their immune status. An evaluation of immunocompetence before therapy may help to predict therapeutic success and guide the selection of appropriate regimens. We assessed the preexisting cellular immunity against prostate-specific antigen (PSA) in untreated prostate cancer patients and healthy controls through measurement of the phenotype and function of CD8(+) T cells. Our data show that the majority of healthy men possess functional PSA-specific CD8(+) T cells in contrast to cancer patients, where <50 % showed a CD8(+) T cell response. PSA146-154-specific CD8(+) T cells of these patients had a higher expression of the activation marker CD38 and the exhaustion marker Tim-3, indicating that PSA-specific cells are exhausted. The heterogeneity of the CD8(+) T cell response against PSA in prostate cancer patients may influence their response to therapy and is a factor to be taken into account while designing and selecting treatment regimens.

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