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Schachtner T.,ChariteUniversity Medicine Berlin | Mu ller K.,ChariteUniversity Medicine Berlin | Stein M.,ChariteUniversity Medicine Berlin | Diezemann C.,ChariteUniversity Medicine Berlin | And 3 more authors.
American Journal of Transplantation | Year: 2011

Impaired BKV-specific immunity is associated with development of BKV-associated nephropathy. Suitable immunological parameters to identify patients at risk, however, are still debated. We monitored 18 kidney-transplant recipients through the course of selflimited BKV-reactivation (n = 11) and BKV-associated nephropathy (n = 7). BKV-specific cellular immunity directed to nonstructural small and Large T-antigen, and structural VP1-3 was analyzed in an interferon-c Elispot assay. BKV-specific IgM and IgGweremeasured using an enzyme-linked immunosorbent assay simultaneously. BKV-specific cellular immunity directed to five BKV-proteins increased significantly from diagnosis to resolution of BKV-reactivation (p < 0.001). Patients with self-limited BKV-reactivation developed BKV-specific T cells without therapeutic interventions, and cleared BKV-reactivation within a median period of 1 month. Patients with BKV-associated nephropathy, however, showed BKV-specific T cells after a median period of 5 months after therapeutic interventions only, and cleared BKV-reactivation after a median period of 8 months. Anti-structural T cells were detected earlier than anti-nonstructural T cells, which coincided with BKV-clearance. Patients with BKV-associated nephropathy showed the highest frequencies of BKV-specific T cells at recovery, the highest increase in BKV-specific IgG and persistence of increased IgM levels (p < 0.05). Our results suggest prognostic values of BKV-specific immune monitoring to identify those patients at risk of BKV-associated nephropathy and to aid in the management of therapeutic interventions. © Copyright 2011 The American Society of Transplantation.


Busch J.,ChariteUniversity Medicine Berlin | Stephan C.,ChariteUniversity Medicine Berlin | Stephan C.,Berlin Institute for Urological Research | Herold A.,ChariteUniversity Medicine Berlin | And 9 more authors.
BJU International | Year: 2012

OBJECTIVE • To investigate biochemical recurrence (BCR) rates and data on postoperative incontinence in a large laparoscopic radical prostatectomy (LRP) cohort with extended follow-up. MATERIALS AND METHODS • BCR and independent predictors of BCR were identified using Kaplan-Meier and Cox regression analysis of 1845 patients who underwent LRP from 1999 to 2007. • Urinary incontinence was evaluated by pads per day and stratified as follows: 0-1 pad: no incontinence; 2-3 pads: mild incontinence; and ≥ 3 pads: severe incontinence. RESULTS • Organ-confined disease, extraprostatic extension, seminal vesicle invasion and lymph node metastasis were present in 71.3%, 20.5%, 6.7% and 3.2% of patients, respectively. The positive surgical margin rate was 29.2%. • Postoperatively, 74.9% of the patients were continent, while 9.2% had mild and 15.9% severe incontinence. • The mean follow-up was 5 years with a maximum follow-up of 11.3 years. • There were 51 overall deaths and six deaths from prostate cancer. The 5-year, 8-year and 10-year BCR-free survival rates were 83.9%, 78.6% and 75.6%, respectively. • On univariate analyses preoperative D'Amico risk classification, pathological tumour stage, postoperative Gleason sum and surgical margin status were predictors of BCR ( P < 0.001). • On multivariable analysis, D'Amico classification, Gleason sum ( P < 0.001), postoperative tumour stage ( P < 0.001), nodal status ( P < 0.001) and surgical margin status ( P =0.002) were independent predictors of BCR. CONCLUSIONS • LRP offers excellent long-term functional and oncological results with a low incidence of BCR for patients with localized disease. • These results could be used for patient counselling before robot-assisted laparascopic prostatectomy (RALP) until long-term follow-up data for RALP is available. © 2012 THE AUTHORS.


Sturm I.,Humboldt University of Berlin | Sturm I.,TU Berlin | Sturm I.,ChariteUniversity Medicine Berlin | Biankertz B.,TU Berlin | And 9 more authors.
Frontiers in Human Neuroscience | Year: 2014

Listening to music moves our minds and moods, stirring interest in its neural underpinnings. A multitude of compositional features drives the appeal of natural music. How such original music, where a composer's opus is not manipulated for experimental purposes, engages a listener's brain has not been studied until recently. Here, we report an in-depth analysis of two electrocorticographic (ECoG) data sets obtained over the left hemisphere in ten patients during presentation of either a rock song or a read-out narrative. First, the time courses of five acoustic features (intensity, presence/absence of vocals with lyrics, spectral centroid, harmonic change, and pulse clarity) were extracted from the audio tracks and found to be correlated with each other to varying degrees. In a second step, we uncovered the specific impact of each musical feature on ECoG high-gamma power (70-170 Hz) by calculating partial correlations to remove the influence of the other four features. In the music condition, the onset and offset of vocal lyrics in ongoing instrumental music was consistently identified within the group as the dominant driver for ECoG high-gamma power changes over temporal auditory areas, while concurrently subject-individual activation spots were identified for sound intensity, timbral, and harmonic features. The distinct cortical activations to vocal speech-related content embedded in instrumental music directly demonstrate that song integrated in instrumental music represents a distinct dimension in complex music. In contrast, in the speech condition, the full sound envelope was reflected in the high gamma response rather than the onset or offset of the vocal lyrics. This demonstrates how the contributions of stimulus features that modulate the brain response differ across the two examples of a full-length natural stimulus, which suggests a context-dependent feature selection in the processing of complex auditory stimuli. © 2014 Sturm, Blankertz, Potes, Schalk and Curio.


Heinz A.,ChariteUniversity Medicine Berlin | Muller D.J.,University of Toronto | Krach S.,University of Marburg | Cabanis M.,Center for Mental Health | Kluge U.P.,ChariteUniversity Medicine Berlin
Frontiers in Human Neuroscience | Year: 2014

The aim of this Hypothesis and Theory is to question the recently increasing use of the “race” concept in contemporary genetic, psychiatric, neuroscience as well as social studies. We discuss “race” and related terms used to assign individuals to distinct groups and caution that also concepts such as “ethnicity” or “culture” unduly neglect diversity. We suggest that one factor contributing to the dangerous nature of the “race” concept is that it is based on a mixture of traditional stereotypes about “physiognomy”, which are deeply imbued by colonial traditions. Furthermore, the social impact of “race classifications” will be critically reflected. We then examine current ways to apply the term “culture” and caution that while originally derived from a fundamentally different background, “culture” is all too often used as a proxy for “race”, particularly when referring to the population of a certain national state or wider region. When used in such contexts, suggesting that all inhabitants of a geographical or political unit belong to a certain “culture” tends to ignore diversity and to suggest a homogeneity, which consciously or unconsciously appears to extend into the realm of biological similarities and differences. Finally, we discuss alternative approaches and their respective relevance to biological and cultural studies. © 2014 Heinz, Müller, Krach, Cabanis and Kluge.


Strangfeld A.,German Rheumatism Research Center | Richter A.,German Rheumatism Research Center | Siegmund B.,ChariteUniversity Medicine Berlin | Herzer P.,Scientific Advisory Board | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2016

Objective To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). Methods In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. Results 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/ cumulative glucocorticoids and non-steroidal antiinflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) diseasemodifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-a inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. Conclusions The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation. © 2016 BMJ Publishing Group Ltd & European League Against Rheumatism.


Dorner T.,ChariteUniversity Medicine Berlin | Lipsky P.E.,RILITE Foundation
Nature Reviews Rheumatology | Year: 2016

New insights into the mechanisms of autoimmune diseases have been obtained not only from preclinical studies, but also from clinical trials of pan-B-cell-directed therapy. Overall, the results of these clinical trials suggest that more-specific approaches focusing on pathogenic B-cell functions, and perhaps sparing or even enhancing regulatory B-cell activity, might be attractive alternatives. Importantly, pathogenic B-cell subpopulations function within a network of cellular interactions, many of which might require additional interventions to restore immunologic balance and suppress autoimmune disease. Thus, approaches that simultaneously target innate immune cells as well as multiple nodes of T-cell and B-cell interactions might hold the promise of improved therapeutic efficacy. Interfering with B-cell intracellular signalling pathways, altering their intracellular metabolic pathways and perturbing transcription factors are additional options. This Review critically analyses these approaches, examines the role of cytokines and other functions of B-lineage cells separate from antibody secretion, and provides insights into the potential next generation of therapies targeting B-lineage cells. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Funke-Kaiser H.,ChariteUniversity Medicine Berlin | Zollmann F.S.,ChariteUniversity Medicine Berlin | Schefe J.H.,ChariteUniversity Medicine Berlin | Unger T.,ChariteUniversity Medicine Berlin
Hypertension Research | Year: 2010

The (pro)renin receptor ((P)RR) not only represents a novel component of the renin-angiotensin system but is also a promising novel drug target because of its crucial involvement in the pathogenesis of renal and cardiac end-organ damage. This review discusses the signal transduction of the (P)RR with its adapter protein promyelocytic zinc-finger protein, the impact of this receptor, especially on cardiovascular disease, and its putative interaction with renin inhibitors such as aliskiren. Furthermore, the increasing complexity regarding the cellular function of the (P)RR is addressed, which arises by the intimate link with proton pumps and the phosphatase PRL-1, as well as by the presence of different subcellular localizations and of a soluble isoform of the (P)RR. Finally, the rationale and strategy for the development of small-molecule antagonists of the (P)RR, called renin/prorenin receptor blockers, are presented. © 2010 The Japanese Society of Hypertension All rights reserved.


Eckstein J.,ChariteUniversity Medicine Berlin | Berndt N.,ChariteUniversity Medicine Berlin | Holzhutter H.-G.,ChariteUniversity Medicine Berlin
PLoS Computational Biology | Year: 2015

The bile fluid contains various lipids that are secreted at the canalicular membrane of hepatocytes. As the secretion mechanism is still a matter of debate and a direct experimental observation of the secretion process is not possible so far, we used a mathematical model to simulate the extraction of the major bile lipids cholesterol, phosphatidylcholine and sphingomyelin from the outer leaflet of the canalicular membrane. Lipid diffusion was modeled as random movement on a triangular lattice governed by next-neighbor interaction energies. Phase separation in liquid-ordered and liquid-disordered domains was modeled by assigning two alternative ordering states to each lipid species and minimization of next-neighbor ordering energies. Parameterization of the model was performed such that experimentally determined diffusion rates and phases in ternary lipid mixtures of model membranes were correctly recapitulated. The model describes the spontaneous formation of nanodomains in the external leaflet of the canalicular membrane in a time window between 0.1 ms to 10 ms at varying lipid proportions. The extraction of lipid patches from the bile salt soluble nanodomain into the bile reproduced observed biliary phospholipid compositions for a physiologi-cal membrane composition. Comparing the outcome of model simulations with available experi-mental observations clearly favors the extraction of tiny membrane patches composed of about 100–400 lipids as the likely mechanism of biliary lipid secretion. © 2015 Eckstein et al.


Schwabe P.,ChariteUniversity Medicine Berlin | Altintas B.,ChariteUniversity Medicine Berlin | Schaser K.-D.,ChariteUniversity Medicine Berlin | Druschel C.,ChariteUniversity Medicine Berlin | And 3 more authors.
Journal of Orthopaedic Trauma | Year: 2014

Objective: Anatomic reduction and articular restoration after acetabular fractures occur (Ac-Fxs) are accepted predictors for good function and slow progression of posttraumatic osteoarthritis of the hip. The aim of this study was to retrospectively analyze Ac-Fxs, which were treated with closed reduction and percutaneous (threedimensional) fluoroscopy-based navigated screw fixation.Design: Level 4, retrospective clinical and radiographic assessment.\r\nSetting: Level 1 trauma center.\r\nPatients: Twelve patients (male/female: 9/3; mean age: 60 years; range: 16-80 years) with moderately displaced Ac-Fxs were included. Intervention: In enrolled patients, the treatment involved percutaneous three-dimensional fluoroscopy-based navigated lag screw positioning. Closed reduction was achieved by lag screws, or reduction was aided by the insertion of percutaneous Schanz pins. Main Outcome Measurements: The quality of the reduction and screw positions were assessed using intraoperative and postoperative computed tomography scans. Functional outcome was assessed using the Harris hip score, the visual analog scale for pain, and the Tegener activity scale.\r\nResults: A total of 22 periacetabular screws were placed (mean: 1.8 ± 1.1 screws/patient, range: 1-5). The mean follow-up was done for 30 (16-72) months. The postoperative reduction was anatomical in all patients, and the mean fracture displacement was significantly reduced (gap: 4.1 ± 1.8 mm to 0.4 ± 0.7 mm/step: 1.4 ± 0.6 mm to 0.2 ± 0.4 mm). No secondary dislocations or malunions/nonunions were found. All screws correctly addressed the fracture morphology and corresponded to preoperative planning. The Harris hip score, the visual analog scale (motion), and Tegener activity scale showed excellent to very good results (92.4 ± 6.8, 1.9 ± 1.3, and 3.8 ± 1.6, respectively).\r\nConclusions: The navigated, percutaneous screw fixation of selected Ac-Fxs is a promising method that allows for closed reduction and fixation while obtaining a very good radiographic and functional outcome. © 2014 Lippincott Williams & Wilkins.


PubMed | ChariteUniversity Medicine Berlin
Type: Journal Article | Journal: Alcohol and alcoholism (Oxford, Oxfordshire) | Year: 2012

To examine the influence of country-level characteristics and individual socio-economic status (SES) on individual alcohol-related consequences.Data from 42,655 men and women collected by cross-sectional surveys in 25 countries of the Gender, Alcohol and Culture: An International Study study were used. The individual SES was measured by the highest attained educational level. Alcohol-related consequences were defined as the self-report of at least one internal or one external consequence in the last year. The relationship between individuals education and alcohol-related consequences was examined by meta-analysis. In a second step, the individual level data and country data were combined in multilevel models. As country-level indicators, we used the purchasing power parity of the gross national income (GNI), the Gini coefficient and the Gender Gap Index.Lower educated men and women were more likely to report consequences than higher educated men and women even after controlling for drinking patterns. For men, this relation was significant for both internal and external problems. For women, it was only significant for external problems. The GNI was significantly associated with reporting external consequences for men such that in lower income countries men were more likely to report social problems.The fact that problems accrue more quickly for lower educated persons even if they drink in the same manner can be linked to the social or environmental dimension surrounding problems. That is, those of fewer resources are less protected from the experience of a problem or the impact of a stressful life event.

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