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Siepert A.,University of Rostock | Brosel S.,Charité - Medical University of Berlin | Vogt K.,Charité - Medical University of Berlin | Ahrlich S.,Charité - Medical University of Berlin | And 14 more authors.
American Journal of Transplantation | Year: 2013

To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs (IS). But IS such as calcineurin inhibitors (CNI), for example, cyclosporin A (CsA), can interfere with tolerance induction. We investigated the effect of an additional transient CsA treatment on anti-CD4mAb-induced tolerance induction upon rat kidney transplantation. Additional CsA treatment induced deteriorated graft function, resulting in chronic rejection characterized by glomerulosclerosis, interstitial fibrosis, tubular atrophy and vascular changes. Microarray analysis revealed enhanced intragraft expression of the B cell attracting chemokine CXCL13 early during CsA treatment. Increase in CXCL13 expression is accompanied by enhanced B cell infiltration with local and systemic IgG production and C3d deposition as early as 5 days upon CsA withdrawal. Adding different CNIs to cultures of primary mesangial cells isolated from glomeruli resulted in a concentration-dependent increase in CXCL13 transcription. CsA in synergy with TNF-α can enhance the B cell attracting and activating potential of mesangial cells. Transient B cell depletion or transfer of splenocytes from tolerant recipients 3 weeks after transplantation could rescue tolerance induction and did inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection. Transient coapplication of cyclosporine A abrogates CD4-specific monoclonal antibody-mediated transplant tolerance by inducing intragraft CXCL13 expression leading to B cell attraction, alloantibody production and complement-mediated tissue destruction. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Kremer S.,CNRS Computer Science and Engineering Laboratory | Kremer S.,Hopitaux Universitaires Of Strasbourg | Renard F.,French National Center for Scientific Research | Achard S.,French National Center for Scientific Research | And 52 more authors.
JAMA Neurology | Year: 2015

Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than gray matter degradation. These findings could be confirmed by ultrahigh-field MRI. The use of nonconventional MRI techniques may further our understanding of the pathogenic processes in NMO spectrum disorders and may help us identify the distinct radiographic features corresponding to specific phenotypic manifestations of this disease. Copyright 2015 American Medical Association. All rights reserved.

Lal D.,University of Cologne | Steinbrucker S.,University of Bern | Schubert J.,University of Tübingen | Sander T.,University of Cologne | And 71 more authors.
Epilepsy Research | Year: 2015

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40. kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. © 2015 Elsevier B.V.

Benson S.,University of Duisburg - Essen | Arck P.C.,ChariteUniversity Medicine | Blois S.,ChariteUniversity Medicine | Blois S.,University College London | And 2 more authors.
Stress | Year: 2011

Subclinical depressive symptoms constitute a primary risk factor for major depression as well as for cardiovascular conditions, which may be mediated by endocrine or immune alterations. The aim of this study was to assess the association between the extent of subclinical depressive symptoms and neuroendocrine and immune cell responses to acute psychosocial stress in healthy females. In N 33 healthy premenopausal women, state anxiety, plasma adrenocorticotropic hormone and serum cortisol, and interleukin-6 (IL-6) concentration responses to public speaking stress were assessed. Beck depression inventory (BDI) scores were entered as a covariate in the analyses. The IL-6 response was significantly associated with BDI scores (p < 0.05). Secondary analyses revealed that women with more subclinical depressive symptoms demonstrated a reduced stress-induced increase in circulating IL-6 level (p < 0.05). By contrast, stress-induced neuroendocrine activation was not associated with depressive symptoms. Hence, subclinical depressive symptoms were associated with IL-6 responses to stress in young, healthy women. Unexpectedly, there was a reduced increase of serum IL-6 level in response to stress. Effects of depressive symptoms on the IL-6 response to stress may differ between subclinical and major depression. © 2010 Informa Healthcare USA, Inc.

Schmidt A.F.,Medical School Hamburg | Babchishin K.M.,University of Ottawa | Lehmann R.J.B.,ChariteUniversity Medicine
Archives of Sexual Behavior | Year: 2016

Due to unobtrusiveness and ease of implementation, viewing time (VT) measures of sexual interest in children have sparked increasing research interest in forensic contexts over the last two decades. The current study presents two meta-analyses of VT measures adapted to assess pedophilic interest to determine their discrimination between sexual offenders against children (SOC) and non-SOC groups as well as convergent validity (associations with other measures of sexual interest in children). On average, VT measures showed moderate discrimination between criterion groups (fixed-effect d = 0.60, 95 % CI [0.51, 0.68], N = 2705, k = 14) and significant convergent validity with self-reports, penile plethysmography, Implicit Association Tests, and offence behavioral measures ranging from r = .18 to r = .38. VT measures, however, provided better discrimination for adults (fixed-effect d = 0.78, 95 % CI [0.64, 0.92]) than adolescent samples (fixed-effect d = 0.50, 95 % CI [0.40, 0.61]), Qbetween = 9.37, p = .002. Moreover, compared to absolute scores, using pedophilic difference scores within adult samples substantially increased VT measures’ validity (fixed-effect d = 1.03, 95 % CI [0.82, 1.25], N = 414, k = 7). Results are discussed in terms of their theoretical and applied implications for forensic contexts. © 2016 Springer Science+Business Media New York

Seidel C.,University of Hamburg | Busch J.,ChariteUniversity Medicine | Weikert S.,Vivantes Humboldt Klinikum | Steffens S.,Hannover Medical School | And 2 more authors.
British Journal of Cancer | Year: 2013

Background:The aim of our analysis is to further characterise the prognostic relevance of early tumour shrinkage (TS) during VEGF-targeted therapy in mRCC, in order to explore whether this could define a group of patients with long-term survivorship.Methods:A hundred patients were stratified into five subgroups according to their change of tumour size with first treatment evaluation:-100% to-60%;-59% to-30% and-29% to 0% TS or gain of tumour size from 1% to 19% and ≥20% or occurrence of new lesions (i.e., progressive disease).Results:The median PFS and OS were 10.4 months and 28.2 months, respectively. The median OS stratified according to the subgroups as described above was 77.4, 33.5, 26.9, 30.0 and 14.3 months, respectively. Multivariate analysis revealed early TS as a prognostic marker (P=0.021; HR 1.624).Conclusion:The extent of TS defines a small proportion of patients with an excellent prognosis. Larger studies are warranted to define the relationship of long-term survivorship and extent of TS with targeted therapies. © 2013 Cancer Research UK.

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