TY - JOUR A1 - de Vreeze, Ronald S. A. A1 - Coevorden, Frits van A1 - Boerrigter, Lucie A1 - Nederlof, Petra M. A1 - Haas, Rick L. A1 - Bras, Johannes A1 - Rosenwald, Andreas A1 - Mentzel, Thomas A1 - de Jong, Daphne T1 - Delineation of Chondroid Lipoma: An Immunohistochemical and Molecular Biological Analysis JF - Sarcoma N2 - Aims Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocation (11;16). Here, we analyze CL and its histological mimics. Methods CL ( ) was compared to a variety of histological mimics ( ) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis, CCND1 and FUS were investigated as potential translocation partners. Results All CLs were strongly positive for CCND1. One of 4 myoepitheliomas, CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas, CCND1 was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement of CCND1 and FUS as translocation partners. Conclusions Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support. KW - Lipom Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135103 VL - 2011 IS - Article ID 638403 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stöffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - Parkinson’s disease KW - Disease-modifying therapies KW - Neuroprotection KW - Biomarkers KW - Surrogate endpoints KW - Drug development KW - Disease progression Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133856 VL - 119 IS - 1 ER - TY - JOUR A1 - Neugebauer, Hermann A1 - Heuschmann, Peter U. A1 - Jüttler, Eric T1 - DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY - Registry (DESTINY-R): design and protocols JF - BMC Neurology N2 - Background: Randomized controlled trials (RCT) on the treatment of severe space-occupying infarction of the middle cerebral artery (malignant MCA infarction) showed that early decompressive hemicraniectomy (DHC) is life saving and improves outcome without promoting most severe disablity in patients aged 18-60 years. It is, however, unknown whether the results obtained in the randomized trials are reproducible in a broader population in and apart from an academical setting and whether hemicraniectomy has been implemented in clinical practice as recommended by national and international guidelines. In addition, they were not powered to answer further relevant questions, e. g. concerning the selection of patients eligible for and the timing of hemicraniectomy. Other important issues such as the acceptance of disability following hemicraniectomy, the existence of specific prognostic factors, the value of conservative therapeutic measures, and the overall complication rate related to hemicraniectomy have not been sufficiently studied yet. Methods/Design: DESTINY-R is a prospective, multicenter, open, controlled registry including a 12 months follow-up. The only inclusion criteria is unilateral ischemic MCA stroke affecting more than 50% of the MCA-territory. The primary study hypothesis is to confirm the results of the RCT (76% mRS <= 4 after 12 months) in the subgroup of patients additionally fulfilling the inclusion cirteria of the RCT in daily routine. Assuming a calculated proportion of 0.76 for successes and a sample size of 300 for this subgroup, the width of the 95% CI, calculated using Wilson's method, will be 0.096 with the lower bound 0.709 and the upper bound 0.805. Discussion: The results of this study will provide information about the effectiveness of DHC in malignant MCA infarction in a broad population and a real-life situation in addition to and beyond RCT. Further prospectively obtained data will give crucial information on open questions and will be helpful in the plannig of upcomming treatment studies. KW - registry KW - quality of life KW - territory infaction KW - brain edema KW - hemicraniectomy KW - multicenter KW - crantiectomy KW - predictors KW - stroke KW - trial KW - decompressive surgery KW - ischaemic stroke KW - malignant MCA infarct Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133892 VL - 12 IS - 115 ER - TY - JOUR A1 - Steinmann, Diana A1 - Paelecke-Habermann, Yvonne A1 - Geinitz, Hans A1 - Aschoff, Raimund A1 - Bayerl, Anja A1 - Bölling, Tobias A1 - Bosch, Elisabeth A1 - Bruns, Frank A1 - Eichenseder-Seiss, Ute A1 - Gerstein, Johanna A1 - Gharbi, Nadine A1 - Hagg, Juliane A1 - Hipp, Matthias A1 - Kleff, Irmgard A1 - Müller, Axel A1 - Schäfer, Christof A1 - Schleicher, Ursula A1 - Sehlen, Susanne A1 - Theodorou, Marilena A1 - Wypior, Hans-Joachim A1 - Zehentmayr, Franz A1 - van Oorschot, Birgitt A1 - Vordermark, Dirk T1 - Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases JF - BMC Cancer N2 - Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information. KW - breast cancer KW - brain tumours KW - survival KW - validation KW - symptoms KW - EORTC-QLQ-C15-PAL KW - EORTC-BN20 KW - whole-brain radiotherapy KW - partitioning analysis RPA KW - cancer patients KW - lung cancer KW - prognostic index KW - radiation oncology KW - clinical trials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135254 VL - 12 IS - 283 ER - TY - JOUR A1 - Burlina, Alessandro P. A1 - Sims, Katherine B. A1 - Politei, Juan M. A1 - Bennett, Gary J. A1 - Baron, Ralf A1 - Sommer, Claudia A1 - Moller, Anette Torvin A1 - Hilz, Max J. T1 - Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel JF - BMC Neurology N2 - Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate. KW - Enzyme replacement therapy KW - Quality of life KW - Small-fiber neuropathy KW - Rochester diabetic neuropathy KW - Randomized controlled trial KW - Agalsidase beta therapy KW - Outcome survey KW - Pharmacological management KW - Clinical manifestations KW - Alpha galactosidase KW - Diagnosis KW - Fabry KW - Disease KW - Neuropathy KW - Pain KW - Treatment Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135309 VL - 11 IS - 61 ER - TY - JOUR A1 - Ntoukas, Vasileios A1 - Tappe, Dennis A1 - Pfütze, Daniel A1 - Simon, Michaela A1 - Holzmann, Thomas T1 - Cerebellar Cysticercosis Caused by Larval Taenia crassiceps Tapeworm in Immunocompetent Woman, Germany JF - Emerging Infectious Diseases N2 - Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing. KW - helminths KW - acquired immunodeficiency-syndrome KW - foxes vulpes-vulpes KW - invasive cysticerocsis KW - infection KW - patient KW - AIDS Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131686 N1 - Public Domain VL - 19 IS - 12 ER - TY - JOUR A1 - Palige, Katja A1 - Linde, Jörg A1 - Martin, Ronny A1 - Böttcher, Bettina A1 - Citiulo, Francesco A1 - Sullivan, Derek J. A1 - Weber, Johann A1 - Staib, Claudia A1 - Rupp, Steffen A1 - Hube, Bernhard A1 - Morschhäuser, Joachim A1 - Staib, Peter T1 - Global Transcriptome Sequencing Identifies Chlamydospore Specific Markers in Candida albicans and Candida dubliniensis JF - PLoS ONE N2 - Candida albicans and Candida dubliniensis are pathogenic fungi that are highly related but differ in virulence and in some phenotypic traits. During in vitro growth on certain nutrient-poor media, C. albicans and C. dubliniensis are the only yeast species which are able to produce chlamydospores, large thick-walled cells of unknown function. Interestingly, only C. dubliniensis forms pseudohyphae with abundant chlamydospores when grown on Staib medium, while C. albicans grows exclusively as a budding yeast. In order to further our understanding of chlamydospore development and assembly, we compared the global transcriptional profile of both species during growth in liquid Staib medium by RNA sequencing. We also included a C. albicans mutant in our study which lacks the morphogenetic transcriptional repressor Nrg1. This strain, which is characterized by its constitutive pseudohyphal growth, specifically produces masses of chlamydospores in Staib medium, similar to C. dubliniensis. This comparative approach identified a set of putatively chlamydospore-related genes. Two of the homologous C. albicans and C. dubliniensis genes (CSP1 and CSP2) which were most strongly upregulated during chlamydospore development were analysed in more detail. By use of the green fluorescent protein as a reporter, the encoded putative cell wall related proteins were found to exclusively localize to C. albicans and C. dubliniensis chlamydospores. Our findings uncover the first chlamydospore specific markers in Candida species and provide novel insights in the complex morphogenetic development of these important fungal pathogens. KW - NRG1 KW - staib agar KW - gene KW - morphogenesis KW - expression KW - regulator KW - virulence KW - growth KW - UME6 KW - epidemiology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131007 VL - 8 IS - 4 ER - TY - JOUR A1 - Hennings, Johannes M. A1 - Kohli, Martin A. A1 - Czamara, Darina A1 - Giese, Maria A1 - Eckert, Anne A1 - Wolf, Christiane A1 - Heck, Angela A1 - Domschke, Katharina A1 - Arolt, Volker A1 - Baune, Bernhard T. A1 - Horstmann, Sonja A1 - Brückl, Tanja A1 - Klengel, Torsten A1 - Menke, Andreas A1 - Müller-Myhsok, Bertram A1 - Ising, Marcus A1 - Uhr, Manfred A1 - Lucae, Susanne T1 - Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach JF - PLoS ONE N2 - Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies. KW - brain KW - bipolar disorder KW - mood disorder KW - treatment response KW - genome-wide association KW - major depressive disorder KW - neurotrophic factor gene KW - VAL66MET polymorphism KW - sequence variations KW - messenger RNA Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130924 VL - 8 IS - 6 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Kolleritz, Barbara A1 - Meinitzer, Andreas A1 - März, Winfried A1 - Ritz, Eberhard A1 - König, Paul A1 - Neyer, Ulrich A1 - Pilz, Stefan A1 - Wanner, Christoph A1 - Kronenberg, Florian T1 - Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study JF - PLoS ONE N2 - Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. KW - risk KW - alkaline phosphatase KW - cardiovascular events KW - nictric-oxide KW - induced insulin-release KW - creatine synthesis KW - renal function KW - heart failure KW - rat kidney KW - L-arginine Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130979 VL - 8 IS - 5 ER - TY - JOUR A1 - Rodrigues, Lénia A1 - Popov, Nikita A1 - Kaye, Kenneth M. A1 - Simas, J. Pedro T1 - Stabilization of Myc through Heterotypic Poly-Ubiquitination by mLANA Is Critical for \(\gamma\)-Herpesvirus Lymphoproliferation JF - PLoS PATHOGENS N2 - Host colonization by lymphotropic \(\gamma\)-herpesviruses depends critically on expansion of viral genomes in germinal center (GC) B-cells. Myc is essential for the formation and maintenance of GCs. Yet, the role of Myc in the pathogenesis of \(\gamma\)-cherpesviruses is still largely unknown. In this study, Myc was shown to be essential for the lymphotropic \(\gamma\)-herpesvirus MuHV- 4 biology as infected cells exhibited increased expression of Myc signature genes and the virus was unable to expand in Myc defficient GC B- cells. We describe a novel strategy of a viral protein activating Myc through increased protein stability resulting in increased progression through the cell cycle. This is acomplished by modulating a physiological posttranslational regulatory pathway of Myc. The molecular mechanism involves Myc heterotypic poly- ubiquitination mediated via the viral E3 ubiquitin- ligase mLANA protein. \(EC_5S^{mLANA}\) modulates cellular control of Myc turnover by antagonizing \(SCF^{Fbw7}\) mediated proteasomal degradation of Myc, mimicking \(SCF^{\beta-TrCP}\). The findings here reported reveal that modulation of Myc is essential for \(\gamma\)-herpesvirus persistent infection, establishing a link between virus induced lymphoproliferation and disease. KW - latency KW - murine gammaherpesvirus 68 KW - Epstein-Barr-virus KW - C-MYC KW - nuclear antigen KW - germinal center KW - B lymphocytes KW - protein KW - cells KW - beta-TRCP Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131227 VL - 9 IS - 8 ER - TY - JOUR A1 - Muranyi, Walter A1 - Malkusch, Sebastian A1 - Müller, Barbara A1 - Heilemann, Mike A1 - Kräusslich, Hans-Georg T1 - Super-Resolution Microscopy Reveals Specific Recruitment of HIV-1 Envelope Proteins to Viral Assembly Sites Dependent on the Envelope C-Terminal Tail JF - PLoS Pathogens N2 - The inner structural Gag proteins and the envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) traffic independently to the plasma membrane, where they assemble the nascent virion. HIV-1 carries a relatively low number of glycoproteins in its membrane, and the mechanism of Env recruitment and virus incorporation is incompletely understood. We employed dual-color super-resolution microscopy visualizing Gag assembly sites and HIV-1 Env proteins in virus-producing and in Env expressing cells. Distinctive HIV-1 Gag assembly sites were readily detected and were associated with Env clusters that always extended beyond the actual Gag assembly site and often showed enrichment at the periphery and surrounding the assembly site. Formation of these Env clusters depended on the presence of other HIV-1 proteins and on the long cytoplasmic tail (CT) of Env. CT deletion, a matrix mutation affecting Env incorporation or Env expression in the absence of other HIV-1 proteins led to much smaller Env clusters, which were not enriched at viral assembly sites. These results show that Env is recruited to HIV-1 assembly sites in a CT-dependent manner, while Env\((\Delta CT)\) appears to be randomly incorporated. The observed Env accumulation surrounding Gag assemblies, with a lower density on the actual bud, could facilitate viral spread in vivo. Keeping Env molecules on the nascent virus low may be important for escape from the humoral immune response, while cell-cell contacts mediated by surrounding Env molecules could promote HIV-1 transmission through the virological synapse. KW - ENV KW - fluorescent-probes KW - type-1 matrix KW - glycoprotein incorporation KW - GP41 cytoplasmic tail KW - human immunodeficiency virus KW - cellular proteins KW - plasma membrane KW - virions KW - particles Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131235 VL - 9 IS - 2 ER - TY - JOUR A1 - Kraft, Peter A1 - Fleischer, Anna A1 - Wiedmann, Silke A1 - Rücker, Viktoria A1 - Mackenrodt, Daniel A1 - Morbach, Caroline A1 - Malzahn, Uwe A1 - Kleinschnitz, Christoph A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study JF - BMC Neurology N2 - Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital Würzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95% confidence intervals (95% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71–0.89) to 0.93 (95% CI 0.87–0.96), and κ from 0.39 (−95% CI 0.14–0.92) to 0.79 (95% CI 0.67–0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96–1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95% CI 0.40–0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies. KW - ischemic stroke KW - systolic dysfunction KW - point-of-care echocardiography KW - ejection fraction KW - stroke unit KW - feasibility KW - accuracy Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158081 VL - 17 IS - 159 ER - TY - JOUR A1 - Morbach, Caroline A1 - Wagner, Martin A1 - Güntner, Stefan A1 - Malsch, Carolin A1 - Oezkur, Mehmet A1 - Wood, David A1 - Kotseva, Kornelia A1 - Leyh, Rainer A1 - Ertl, Georg A1 - Karmann, Wolfgang A1 - Heuschmann, Peter U A1 - Störk, Stefan T1 - Heart failure in patients with coronary heart disease: Prevalence, characteristics and guideline implementation - Results from the German EuroAspire IV cohort JF - BMC Cardiovascular Disorders N2 - Background: Adherence to pharmacotherapeutic treatment guidelines in patients with heart failure (HF) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Our aim was to investigate prevalence and characteristics of HF in patients with coronary heart disease (CHD), and to assess the adherence to current HF guidelines in patients with HF stage C, thus identifying potential targets for the optimization of guideline implementation. Methods: Patients from the German sample of the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EuroAspire) IV survey with a hospitalization for CHD within the previous six to 36 months providing valid data on echocardiography as well as on signs and symptoms of HF were categorized into stages of HF: A, prevalence of risk factors for developing HF; B, asymptomatic but with structural heart disease; C, symptomatic HF. A Guideline Adherence Indicator (GAI-3) was calculated for patients with reduced (≤40%) left ventricular ejection fraction (HFrEF) as number of drugs taken per number of drugs indicated; beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRA) were considered. Results: 509/536 patients entered analysis. HF stage A was prevalent in n = 20 (3.9%), stage B in n = 264 (51.9%), and stage C in n = 225 (44.2%) patients; 94/225 patients were diagnosed with HFrEF (42%). Stage C patients were older, had a longer duration of CHD, and a higher prevalence of arterial hypertension. Awareness of pre-diagnosed HF was low (19%). Overall GAI-3 of HFrEF patients was 96.4% with a trend towards lower GAI-3 in patients with lower LVEF due to less thorough MRA prescription. Conclusions: In our sample of CHD patients, prevalence of HF stage C was high and a sizable subgroup suffered from HFrEF. Overall, pharmacotherapy was fairly well implemented in HFrEF patients, although somewhat worse in patients with more reduced ejection fraction. Two major targets were identified possibly suited to further improve the implementation of HF guidelines: 1) increase patients´ awareness of diagnosis and importance of HF; and 2) disseminate knowledge about the importance of appropriately implementing the use of mineralocorticoid receptor antagonists. Trial registration: This is a cross-sectional analysis of a non-interventional study. Therefore, it was not registered as an interventional trial. KW - awareness KW - heart failure KW - pharmacotherapy KW - coronary artery disease KW - coronary heart disease KW - euroaspire KW - guideline adherence KW - guideline implementation KW - mineralocorticoid antagonist KW - preserved ejection fraction Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157738 VL - 17 IS - 108 ER - TY - JOUR A1 - Oder, Daniel A1 - Üceyler, Nurcan A1 - Liu, Dan A1 - Hu, Kai A1 - Petritsch, Bernhard A1 - Sommer, Claudia A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y JF - BMJ Open N2 - Objectives: The severity of Fabry disease is dependent on the type of mutation in the α-galactosidase A (AgalA) encoding gene (GLA). This study focused on the impact of the GLA haplotype D313Y on long-term organ involvement and function. Setting and participants: In this monocentric study, all participants presenting with the D313Y haplotype between 2001 and 2015 were comprehensively clinically investigated at baseline and during a 4-year follow-up if available. Five females and one male were included. Primary and secondary outcome measures: Cardiac, nephrological, neurological, laboratory and quality of life data. Results: AgalA enzyme activity in leucocytes (0.3±0.9 nmol/min/mg protein (mean±SD)) and serum lyso-Gb3 (0.6±0.3 ng/mL at baseline) were in normal range in all patients. Cardiac morphology and function were normal (left-ventricular (LV) ejection fraction 66±8%; interventricular septum 7.7±1.4 mm; LV posterior wall 7.5±1.4 mm; normalised LV mass in MRI 52±9 g/m2; LV global longitudinal strain −21.6±1.9%) and there were no signs of myocardial fibrosis in cardiac MRI. Cardiospecific biomarkers were also in normal range. Renal function was not impaired (estimated glomerular filtration rate MDRD 103±15 mL/min; serum-creatinine 0.75±0.07 mg/dL; cystatin-c 0.71±0.12 mg/L). One female patient (also carrying a Factor V Leiden mutation) had a transitory ischaemic attack. One patient showed white matter lesions in brain MRI, but none had Fabry-associated pain attacks, pain crises, evoked pain or permanent pain. Health-related quality of life analysis revealed a reduction in individual well-being. At long-term follow-up after 4 years, no significant change was seen in any parameter. Conclusions: The results of the current study suggest that the D313Y genotype does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD." KW - inherited metabolic disorders KW - Anderson-Fabry Disease KW - D313Y genotype KW - Fabry cardiomyopathy KW - Fabry nephropathy KW - Fabry-associated pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161210 VL - 6 ER - TY - JOUR A1 - Blein, Sophie A1 - Bardel, Claire A1 - Danjean, Vincent A1 - McGuffog, Lesley A1 - Healay, Sue A1 - Barrowdale, Daniel A1 - Lee, Andrew A1 - Dennis, Joe A1 - Kuchenbaecker, Karoline B. A1 - Soucy, Penny A1 - Terry, Mary Beth A1 - Chung, Wendy K. A1 - Goldgar, David E. A1 - Buys, Saundra S. A1 - Janavicius, Ramunas A1 - Tihomirova, Laima A1 - Tung, Nadine A1 - Dorfling, Cecilia M. A1 - van Rensburg, Elizabeth J. A1 - Neuhausen, Susan L. A1 - Ding, Yuan Chun A1 - Gerdes, Anne-Marie A1 - Ejlertsen, Bent A1 - Nielsen, Finn C. A1 - Hansen, Thomas V. O. A1 - Osorio, Ana A1 - Benitez, Javier A1 - Andreas Conejero, Raquel A1 - Segota, Ena A1 - Weitzel, Jeffrey N. A1 - Thelander, Margo A1 - Peterlongo, Paolo A1 - Radice, Paolo A1 - Pensotti, Valeria A1 - Dolcetti, Riccardo A1 - Bonanni, Bernardo A1 - Peissel, Bernard A1 - Zaffaroni, Daniela A1 - Scuvera, Giulietta A1 - Manoukian, Siranoush A1 - Varesco, Liliana A1 - Capone, Gabriele L. A1 - Papi, Laura A1 - Ottini, Laura A1 - Yannoukakos, Drakoulis A1 - Konstantopoulou, Irene A1 - Garber, Judy A1 - Hamann, Ute A1 - Donaldson, Alan A1 - Brady, Angela A1 - Brewer, Carole A1 - Foo, Claire A1 - Evans, D. Gareth A1 - Frost, Debra A1 - Eccles, Diana A1 - Douglas, Fiona A1 - Cook, Jackie A1 - Adlard, Julian A1 - Barwell, Julian A1 - Walker, Lisa A1 - Izatt, Louise A1 - Side, Lucy E. A1 - Kennedy, M. John A1 - Tischkowitz, Marc A1 - Rogers, Mark T. A1 - Porteous, Mary E. A1 - Morrison, Patrick J. A1 - Platte, Radka A1 - Eeles, Ros A1 - Davidson, Rosemarie A1 - Hodgson, Shirley A1 - Cole, Trevor A1 - Godwin, Andrew K A1 - Isaacs, Claudine A1 - Claes, Kathleen A1 - De Leeneer, Kim A1 - Meindl, Alfons A1 - Gehrig, Andrea A1 - Wappenschmidt, Barbara A1 - Sutter, Christian A1 - Engel, Christoph A1 - Niederacher, Dieter A1 - Steinemann, Doris A1 - Plendl, Hansjoerg A1 - Kast, Karin A1 - Rhiem, Kerstin A1 - Ditsch, Nina A1 - Arnold, Norbert A1 - Varon-Mateeva, Raymonda A1 - Schmutzler, Rita K. A1 - Preisler-Adams, Sabine A1 - Markov, Nadja Bogdanova A1 - Wang-Gohrke, Shan A1 - de Pauw, Antoine A1 - Lefol, Cedrick A1 - Lasset, Christine A1 - Leroux, Dominique A1 - Rouleau, Etienne A1 - Damiola, Francesca A1 - Dreyfus, Helene A1 - Barjhoux, Laure A1 - Golmard, Lisa A1 - Uhrhammer, Nancy A1 - Bonadona, Valerie A1 - Sornin, Valerie A1 - Bignon, Yves-Jean A1 - Carter, Jonathan A1 - Van Le, Linda A1 - Piedmonte, Marion A1 - DiSilvestro, Paul A. A1 - de la Hoya, Miguel A1 - Caldes, Trinidad A1 - Nevanlinna, Heli A1 - Aittomäki, Kristiina A1 - Jager, Agnes A1 - van den Ouweland, Ans M. W. A1 - Kets, Carolien M. A1 - Aalfs, Cora M. A1 - van Leeuwen, Flora E. A1 - Hogervorst, Frans B. L. A1 - Meijers-Heijboer, Hanne E. J. A1 - Oosterwijk, Jan C. A1 - van Roozendaal, Kees E. P. A1 - Rookus, Matti A. A1 - Devilee, Peter A1 - van der Luijt, Rob B. A1 - Olah, Edith A1 - Diez, Orland A1 - Teule, Alex A1 - Lazaro, Conxi A1 - Blanco, Ignacio A1 - Del Valle, Jesus A1 - Jakubowska, Anna A1 - Sukiennicki, Grzegorz A1 - Gronwald, Jacek A1 - Spurdle, Amanda B. A1 - Foulkes, William A1 - Olswold, Curtis A1 - Lindor, Noralene M. A1 - Pankratz, Vernon S. A1 - Szabo, Csilla I. A1 - Lincoln, Anne A1 - Jacobs, Lauren A1 - Corines, Marina A1 - Robson, Mark A1 - Vijai, Joseph A1 - Berger, Andreas A1 - Fink-Retter, Anneliese A1 - Singer, Christian F. A1 - Rappaport, Christine A1 - Geschwantler Kaulich, Daphne A1 - Pfeiler, Georg A1 - Tea, Muy-Kheng A1 - Greene, Mark H. A1 - Mai, Phuong L. A1 - Rennert, Gad A1 - Imyanitov, Evgeny N. A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Andrulis, Irene L. A1 - Tchatchou, Andrine A1 - Toland, Amanda Ewart A1 - Pedersen, Inge Sokilde A1 - Thomassen, Mads A1 - Kruse, Torben A. A1 - Jensen, Uffe Birk A1 - Caligo, Maria A. A1 - Friedman, Eitan A1 - Zidan, Jamal A1 - Laitman, Yael A1 - Lindblom, Annika A1 - Melin, Beatrice A1 - Arver, Brita A1 - Loman, Niklas A1 - Rosenquist, Richard A1 - Olopade, Olufunmilayo I. A1 - Nussbaum, Robert L. A1 - Ramus, Susan J. A1 - Nathanson, Katherine L. A1 - Domchek, Susan M. A1 - Rebbeck, Timothy R. A1 - Arun, Banu K. A1 - Mitchell, Gillian A1 - Karlan, Bethy Y. A1 - Lester, Jenny A1 - Orsulic, Sandra A1 - Stoppa-Lyonnet, Dominique A1 - Thomas, Gilles A1 - Simard, Jacques A1 - Couch, Fergus J. A1 - Offit, Kenenth A1 - Easton, Douglas F. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. A1 - Mazoyer, Sylvie A1 - Phelan, Catherine M. A1 - Sinilnikova, Olga M. A1 - Cox, David G. T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers JF - Breast Cancer Research N2 - Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. KW - single-nucleotide polymorphisms KW - genetic modifiers KW - oxidative stress KW - consortium KW - multiple diseases KW - DNA KW - haplogroups KW - susceptibility KW - Ovarian KW - variants Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145458 VL - 17 IS - 61 ER - TY - JOUR A1 - Jessberger, Steffen A1 - Högger, Petra A1 - Genest, Franca A1 - Salter, Donald M. A1 - Seefried, Lothar T1 - Cellular pharmacodynamic effects of Pycnogenol\(^{®}\) in patients with severe osteoarthritis: a randomized controlled pilot study JF - BMC Complementary and Alternative Medicine N2 - Background: The standardized maritime pine bark extract (Pycnogenol\(^{®}\)) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol\(^{®}\) and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol\(^{®}\) twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol\(^{®}\) downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol\(^{®}\) on symptom scores of patients suffering from OA. KW - maritime pine bark extract KW - qPCR KW - ADAMTS KW - cartilage KW - clinical study KW - osteoarthritis KW - Pycnogenol KW - serum KW - synovial fluid Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159532 VL - 17 IS - 537 ER - TY - JOUR A1 - Weigand, Isabel A1 - Ronchi, Cristina L. A1 - Rizk-Rabin, Marthe A1 - Dalmazi, Guido Di A1 - Wild, Vanessa A1 - Bathon, Kerstin A1 - Rubin, Beatrice A1 - Calebiro, Davide A1 - Beuschlein, Felix A1 - Bertherat, Jérôme A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas JF - Scientific Reports N2 - Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion. KW - kinases KW - immunohistochemistry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157952 VL - 7 IS - 49 ER - TY - JOUR A1 - Wang Ip, Chi A1 - Klaus, Laura-Christin A1 - Karikari, Akua A. A1 - Visanji, Naomi P. A1 - Brotchie, Jonathan M. A1 - Lang, Anthony E. A1 - Volkmann, Jens A1 - Koprich, James B. T1 - AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson’s disease JF - Acta Neuropathologica Communications N2 - α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson’s disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10\(^{12}\) gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33% reduction in TH+ dopaminergic nigral neurons (P < 0.001), 29% deficit in striatal DAT binding (P < 0.05), 38% and 33% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (P < 0.001; P < 0.05). These data show that unilateral injection of AAV1/2-A53T α-synuclein into the mouse SN leads to persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system and development of Lewy-like pathology, thereby reflecting clinical and pathological hallmarks of human PD. KW - Lewy-like pathology KW - Parkinson’s disease KW - α-synuclein KW - A53T KW - mutation KW - mouse model Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159429 VL - 5 IS - 11 ER - TY - JOUR A1 - Wilhelm, M. A1 - Smetak, M. A1 - Reimer, P. A1 - Geissinger, E. A1 - Ruediger, T. A1 - Metzner, B. A1 - Schmitz, N. A1 - Engert, A. A1 - Schaefer-Eckart, K. A1 - Birkmann, J. T1 - First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation JF - Blood Cancer Journal N2 - Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified (n=42) and angioimmunoblastic T-cell lymphoma (n=37). Seventy-five (68%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the complete response rate after myeloablative therapy was 59%. The estimated 5-year overall survival, disease-free survival and progression-free survival rates were 44%, 54% and 39%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible. KW - Chemotherapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164506 VL - 6 ER - TY - JOUR A1 - Weigand, Annika A1 - Boos, Anja M. A1 - Tasbihi, Kereshmeh A1 - Beier, Justus P. A1 - Dalton, Paul D. A1 - Schrauder, Michael A1 - Horch, Raymund E. A1 - Beckmann, Matthias W. A1 - Strissel, Pamela L. A1 - Strick, Reiner T1 - Selective isolation and characterization of primary cells from normal breast and tumors reveal plasticity of adipose derived stem cells JF - Breast Cancer Research N2 - Background There is a need to establish more cell lines from breast tumors in contrast to immortalized cell lines from metastatic effusions in order to represent the primary tumor and not principally metastatic biology of breast cancer. This investigation describes the simultaneous isolation, characterization, growth and function of primary mammary epithelial cells (MEC), mesenchymal cells (MES) and adipose derived stem cells (ADSC) from four normal breasts, one inflammatory and one triple-negative ductal breast tumors. Methods A total of 17 cell lines were established and gene expression was analyzed for MEC and MES (n = 42) and ADSC (n = 48) and MUC1, pan-KRT, CD90 and GATA-3 by immunofluorescence. DNA fingerprinting to track cell line identity was performed between original primary tissues and isolates. Functional studies included ADSC differentiation, tumor MES and MEC invasion co-cultured with ADSC-conditioned media (CM) and MES adhesion and growth on 3D-printed scaffolds. Results Comparative analysis showed higher gene expression of EPCAM, CD49f, CDH1 and KRTs for normal MEC lines; MES lines e.g. Vimentin, CD10, ACTA2 and MMP9; and ADSC lines e.g. CD105, CD90, CDH2 and CDH11. Compared to the mean of all four normal breast cell lines, both breast tumor cell lines demonstrated significantly lower ADSC marker gene expression, but higher expression of mesenchymal and invasion gene markers like SNAI1 and MMP2. When compared with four normal ADSC differentiated lineages, both tumor ADSC showed impaired osteogenic and chondrogenic but enhanced adipogenic differentiation and endothelial-like structures, possibly due to high PDGFRB and CD34. Addressing a functional role for overproduction of adipocytes, we initiated 3D-invasion studies including different cell types from the same patient. CM from ADSC differentiating into adipocytes induced tumor MEC 3D-invasion via EMT and amoeboid phenotypes. Normal MES breast cells adhered and proliferated on 3D-printed scaffolds containing 20 fibers, but not on 2.5D-printed scaffolds with single fiber layers, important for tissue engineering. Conclusion Expression analyses confirmed successful simultaneous cell isolations of three different phenotypes from normal and tumor primary breast tissues. Our cell culture studies support that breast-tumor environment differentially regulates tumor ADSC plasticity as well as cell invasion and demonstrates applications for regenerative medicine. KW - Normal breast KW - Breast cancer KW - Stem cells plasticity KW - Primary cell lines KW - Tissue engineering Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164759 VL - 18 IS - 32 ER - TY - JOUR A1 - Wunsch, Marie A1 - Zhang, Wenji A1 - Hanson, Jodi A1 - Caspell, Richard A1 - Karulin, Alexey Y. A1 - Recks, Mascha S. A1 - Kuerten, Stefanie A1 - Sundararaman, Srividya A1 - Lehmann, Paul V. T1 - Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity JF - Viruses N2 - Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospot\(^{®}\) assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)-\({\gamma}\) and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN-\({\gamma}\) and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails. KW - memory cells KW - hcv infection KW - signature KW - Enzyme-Linked Immunospot assay (ELISPOT) KW - cytokine secretion kinetics KW - chronic viral infection KW - HCMV infection KW - CD4 T cells KW - exhaustion KW - activation KW - human cytomegalovirus (HCMV) KW - B cells KW - cytomegalovirus KW - elispot Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151462 VL - 7 SP - 4414 EP - 4437 ER - TY - JOUR A1 - Biernacka, J. M. A1 - Sangkuhl, K. A1 - Jenkins, G. A1 - Whaley, R. M. A1 - Barman, P. A1 - Batzler, A. A1 - Altman, R. B. A1 - Arolt, V. A1 - Brockmöller, J. A1 - Chen, C. H. A1 - Domschke, K. A1 - Hall-Flavin, D. K. A1 - Hong, C. J. A1 - Illi, A. A1 - Ji, Y. A1 - Kampman, O. A1 - Kinoshita, T. A1 - Leinonen, E. A1 - Liou, Y. J. A1 - Mushiroda, T. A1 - Nonen, S. A1 - Skime, M. K. A1 - Wang, L. A1 - Baune, B. T. A1 - Kato, M. A1 - Liu, Y. L. A1 - Praphanphoj, V. A1 - Stingl, J. C. A1 - Tsai, S. J. A1 - Kubo, M. A1 - Klein, T. E. A1 - Weinshilboum, R. T1 - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response JF - Translational Psychiatry N2 - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. KW - major depressive disorder KW - genetic variation KW - schizophrenia KW - neuregulin-1 KW - population KW - microcephalin 1 KW - susceptibility KW - metaanalysis KW - MCPH1 KW - loci Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223 VL - 5 IS - e553 ER - TY - JOUR A1 - Boes, Alexander A1 - Spiegel, Holger A1 - Voepel, Nadja A1 - Edgue, Gueven A1 - Beiss, Veronique A1 - Kapelski, Stephanie A1 - Fendel, Rolf A1 - Scheuermayer, Matthias A1 - Pradel, Gabriele A1 - Bolscher, Judith M. A1 - Behet, Marije C. A1 - Dechering, Koen J. A1 - Hermsen, Cornelus C. A1 - Sauerwein, Robert W. A1 - Schillberg, Stefan A1 - Reimann, Andreas A1 - Fischer, Rainer T1 - Analysis of a multi-component multi-stage malaria vaccine candidate—tackling the cocktail challenge JF - PLoS ONE N2 - Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total) from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80%), blood (up to 90%) and sexual parasite stages (100%). Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17–25 μg/ml), the blood stage (40–60 μg/ml) and the sexual stage (1.75 μg/ml). While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy. KW - malaria KW - vaccines KW - antibodies KW - P. falciparum Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173092 VL - 10 IS - 7 ER - TY - JOUR A1 - Dipaola, Mariangela A1 - Pavan, Esteban E. A1 - Cattaneo, Andrea A1 - Frazzitta, Giuseppe A1 - Pezzoli, Gianni A1 - Cavallari, Paolo A1 - Frigo, Carlo A. A1 - Isaias, Ioannis U. T1 - Mechanical Energy Recovery during Walking in Patients with Parkinson Disease JF - PLoS ONE N2 - The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD). The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years) with bilateral symptoms (H&Y ≥II) if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs). Ten healthy subjects (mean age 62±3 years) walked both at their ‘preferred’ and ‘slow’ speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM) of hip, knee and ankle joint angles. We also measured kinetic (Wk), potential (W\(_{p}\)), total (W\(_{totCM}\)) energy variations and the energy recovery index (ER). Along with PD progression, we found a significant correlation of W\(_{totCM}\) and W\(_{p}\) with knee ROM and in particular with knee extension in terminal stance phase. W\(_{k}\) and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both W\(_{p}\) and W\(_{totCM}\). Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components. KW - Parkinson disease KW - mechanical energy KW - kinematics KW - velocity KW - hip KW - gait analysis KW - walking KW - knees Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179739 VL - 11 IS - 6 ER - TY - JOUR A1 - Kredel, Markus A1 - Kunzmann, Steffen A1 - Schlegel, Paul-Gerhardt A1 - Wölfl, Matthias A1 - Nordbeck, Peter A1 - Bühler, Christoph A1 - Lotz, Christopher A1 - Lepper, Philipp M. A1 - Wirbelauer, Johannes A1 - Roewer, Norbert A1 - Muellenbach, Ralf M. T1 - Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock JF - American Journal of Case Reports N2 - Background: The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. Case Report: A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. Conclusions: In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option. KW - extracorporeal membrane oxygenation KW - myeloid KW - leukemia KW - acute KW - shock KW - cardiogenic KW - septic Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158193 VL - 18 ER - TY - JOUR A1 - Baur, Johannes A1 - Büntemeyer, Tjark-Ole A1 - Megerle, Felix A1 - Deutschbein, Timo A1 - Spitzweg, Christine A1 - Quinkler, Marcus A1 - Nawroth, Peter A1 - Kroiss, Matthias A1 - Germer, Christoph-Thomas A1 - Fassnacht, Martin A1 - Steger, Ulrich T1 - Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study JF - BMC Cancer N2 - Background: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome. KW - Adrenocortical Carcinoma KW - liver resection KW - retrospective study KW - prognosis KW - survival analysis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159409 VL - 17 IS - 522 ER - TY - JOUR A1 - Wagner, Martin A1 - Wanner, Christoph A1 - Schich, Martin A1 - Kotseva, Kornelia A1 - Wood, David A1 - Hartmann, Katrin A1 - Fette, Georg A1 - Rücker, Viktoria A1 - Oezkur, Mehmet A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Patient’s and physician’s awareness of kidney disease in coronary heart disease patients – a cross-sectional analysis of the German subset of the EUROASPIRE IV survey JF - BMC Nephrology N2 - Background Chronic kidney disease (CKD) is a common comorbid condition in coronary heart disease (CHD). CKD predisposes the patient to acute kidney injury (AKI) during hospitalization. Data on awareness of kidney dysfunction among CHD patients and their treating physicians are lacking. In the current cross-sectional analysis of the German EUROASPIRE IV sample we aimed to investigate the physician’s awareness of kidney disease of patients hospitalized for CHD and also the patient’s awareness of CKD in a study visit following hospital discharge. Methods All serum creatinine (SCr) values measured during the hospital stay were used to describe impaired kidney function (eGFR\(_{CKD-EPI}\) < 60 ml/min/1.73m2) at admission, discharge and episodes of AKI (KDIGO definition). Information extracted from hospital discharge letters and correct ICD coding for kidney disease was studied as a surrogate of physician’s awareness of kidney disease. All patients were interrogated 0.5 to 3 years after hospital discharge, whether they had ever been told about kidney disease by a physician. Results Of the 536 patients, 32% had evidence for acute or chronic kidney disease during the index hospital stay. Either condition was mentioned in the discharge letter in 22%, and 72% were correctly coded according to ICD-10. At the study visit in the outpatient setting 35% had impaired kidney function. Of 158 patients with kidney disease, 54 (34%) were aware of CKD. Determinants of patient’s awareness were severity of CKD (OR\(_{eGFR}\) 0.94; 95%CI 0.92–0.96), obesity (OR 1.97; 1.07–3.64), history of heart failure (OR 1.99; 1.00–3.97), and mentioning of kidney disease in the index event’s hospital discharge letter (OR 5.51; 2.35–12.9). Conclusions Although CKD is frequent in CHD, only one third of patients is aware of this condition. Patient’s awareness was associated with kidney disease being mentioned in the hospital discharge letter. Future studies should examine how raising physician’s awareness for kidney dysfunction may improve patient’s awareness of CKD. KW - coronary heart disease KW - ICD-coding of CKD KW - chronic kidney disease KW - patients’ awareness KW - physicians’ awareness KW - EUROASPIRE survey Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158387 VL - 18 IS - 321 ER - TY - JOUR A1 - Lotz, Christian A1 - Schmid, Freia F. A1 - Rossi, Angela A1 - Kurdyn, Szymon A1 - Kampik, Daniel A1 - De Wever, Bart A1 - Walles, Heike A1 - Groeber, Florian K. T1 - Alternative Methods for the Replacement of Eye Irritation Testing JF - ALTEX - Alternatives to Animal Experimentation N2 - In the last decades significant regulatory attempts were made to replace, refine and reduce animal testing to assess the risk of consumer products for the human eye. As the original in vivo Draize eye test is criticized for limited predictivity, costs and ethical issues, several animal-free test methods have been developed to categorize substances according to the global harmonized system (GHS) for eye irritation. This review summarizes the progress of alternative test methods for the assessment of eye irritation. Based on the corneal anatomy and current knowledge of the mechanisms causing eye irritation, different ex vivo and in vitro methods will be presented and discussed with regard to possible limitations and status of regulatory acceptance. In addition to established in vitro models, this review will also highlight emerging, full thickness cornea models that might be suited to predict all GHS categories. KW - eye irritation testing KW - alternatives KW - Draize eye test KW - OECD guideline KW - corneal equivalent Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164444 VL - 33 IS - 1 ER - TY - JOUR A1 - Hillmann, Steffi A1 - Wiedmann, Silke A1 - Rücker, Viktoria A1 - Berger, Klaus A1 - Nabavi, Darius A1 - Bruder, Ingo A1 - Koennecke, Hans-Christian A1 - Seidel, Günter A1 - Misselwitz, Björn A1 - Janssen, Alfred A1 - Burmeister, Christoph A1 - Matthis, Christine A1 - Busse, Otto A1 - Hermanek, Peter A1 - Heuschmann, Peter Ulrich T1 - Stroke unit care in Germany: the German stroke registers study group (ADSR) JF - BMC Neurology N2 - Background: Factors influencing access to stroke unit (SU) care and data on quality of SU care in Germany are scarce. We investigated characteristics of patients directly admitted to a SU as well as patient-related and structural factors influencing adherence to predefined indicators of quality of acute stroke care across hospitals providing SU care. Methods: Data were derived from the German Stroke Registers Study Group (ADSR), a voluntary network of 9 regional registers for monitoring quality of acute stroke care in Germany. Multivariable logistic regression analyses were performed to investigate characteristics influencing direct admission to SU. Generalized Linear Mixed Models (GLMM) were used to estimate the influence of structural hospital characteristics (percentage of patients admitted to SU, year of SU-certification, and number of stroke and TIA patients treated per year) on adherence to predefined quality indicators. Results: In 2012 180,887 patients were treated in 255 hospitals providing certified SU care participating within the ADSR were included in the analysis; of those 82.4% were directly admitted to a SU. Ischemic stroke patients without disturbances of consciousness (p < .0001), an interval onset to admission time ≤3 h (p < .0001), and weekend admission (p < .0001) were more likely to be directly admitted to a SU. A higher proportion of quality indicators within predefined target ranges were achieved in hospitals with a higher proportion of SU admission (p = 0.0002). Quality of stroke care could be maintained even if certification was several years ago. Conclusions: Differences in demographical and clinical characteristics regarding the probability of SU admission were observed. The influence of structural characteristics on adherence to evidence-based quality indicators was low. KW - stroke register KW - stroke unit care KW - quality of health care KW - quality indicators Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159447 VL - 17 IS - 49 ER - TY - JOUR A1 - Lilla, Nadine A1 - Füllgraf, Hannah A1 - Stetter, Christian A1 - Köhler, Stefan A1 - Ernestus, Ralf-Ingo A1 - Westermaier, Thomas T1 - First Description of Reduced Pyruvate Dehydrogenase Enzyme Activity Following Subarachnoid Hemorrhage (SAH) JF - Frontiers in Neuroscience N2 - Object: Several previous studies reported metabolic derangements and an accumulation of metabolic products in the early phase of experimental subarachnoid hemorrhage (SAH), which may contribute to secondary brain damage. This may be a result of deranged oxygen utilization due to enzymatic dysfunction in aerobic glucose metabolism. This study was performed to investigate, if pyruvate dehydrogenase enzyme (PDH) is affected in its activity giving further hints for a derangement of oxidative metabolism. Methods: Eighteen male Sprague-Dawley rats were randomly assigned to one of two experimental groups (n = 9): (1) SAH induced by the endovascular filament model and (2) sham-operated controls. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local cerebral blood flow (LCBF; laser-Doppler flowmetry) were continuously monitored from 30 min before until 3 h after SAH. Thereafter, the animals were sacrificed and PDH activity was measured by ELISA. Results: PDH activity was significantly reduced in animals subjected to SAH compared to controls. Conclusion: The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage. KW - secondary brain damage KW - aerobic glycolysis KW - CBF KW - metabolism KW - PDH KW - SAH Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157636 VL - 11 IS - 37 ER - TY - JOUR A1 - Wollborn, Jakob A1 - Wunder, Christian A1 - Stix, Jana A1 - Neuhaus, Winfried A1 - Bruno, Rapahel R. A1 - Baar, Wolfgang A1 - Flemming, Sven A1 - Roewer, Norbert A1 - Schlegel, Nicolas A1 - Schick, Martin A. T1 - Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression JF - Journal of Pharmacology and Pharmacotherapeutics N2 - Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation. KW - acute liver failure KW - endotoxemia KW - phosphodiesterase KW - rolipram KW - sepsis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149336 VL - 6 IS - 1 ER - TY - JOUR A1 - Hagemann, Christine A1 - Streng, Andrea A1 - Kraemer, Alexander A1 - Liese, Johannes G. T1 - Heterogeneity in coverage for measles and varicella vaccination in toddlers – analysis of factors influencing parental acceptance JF - BMC Public Health N2 - Background: In 2004, routine varicella vaccination was introduced in Germany for children aged 11–14 months. Routine measles vaccination had already been introduced in 1973 for the same age group, but coverage is still too low (<95%) in some areas to eliminate measles. The present study assessed varicella and measles vaccination coverage and determinants of parental acceptance in two study regions, situated in Northern and Southern Bavaria (Germany). Methods: From 2009 to 2011, annual cross-sectional parent surveys were performed on random samples of 600 children aged 18–36 months in the Bavarian regions of both Munich and Würzburg. Logistic regression models were used to identify factors associated with varicella and measles vaccination. Results: In 2009, 2010 and 2011, vaccination coverage was lower in Munich than in Würzburg, for both varicella (Munich 53%, 67%, 69% vs. Würzburg 72%, 81%, 83%) and for measles (Munich 88%, 89%, 91% vs. Würzburg 92%, 93%, 95%). Recommendation by the physician was the main independent factor associated with varicella vaccination in both regions (adjusted odd ratios (OR) with 95% confidence interval (CI): Munich OR 19.7, CI 13.6–28.6; Würzburg OR 34.7, CI 22.6–53.2). Attendance at a childcare unit was positively associated with a higher acceptance of varicella vaccination in Munich (OR 1.5, CI 1.1–2.2). Regarding measles vaccination, attendance at a childcare unit was positively associated in both regions (Munich OR 2.0; CI 1.3–3.0; Würzburg OR 1.8; CI 1.1–3.1), and a higher level of parental school education was negatively associated in Würzburg (OR 0.5, CI 0.3–0.9). Conclusions: Vaccination rates differed between regions, with rates constantly higher in Würzburg. Within each region, vaccination rates were lower for varicella than for measles. Measles vaccination status was mainly dependent upon socio-demographic factors (attendance at a childcare unit, parental school education), whereas for the more recently introduced varicella vaccination recommendation by the physician had the strongest impact. Hence, different strategies are needed to further improve vaccination rates for both diseases. KW - varicella KW - measles KW - vaccination KW - coverage KW - surveillance KW - pediatric Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157827 VL - 17 IS - 724 ER - TY - JOUR A1 - Weismann, Dirk A1 - Schneider, Andreas A1 - Höybye, Charlotte T1 - Clinical aspects of symptomatic hyponatremia JF - Endocrine Connections N2 - Hyponatremia (HN) is a common condition, with a large number of etiologies and a complicated treatment. Although chronic HN has been shown to be a predictor of poor outcome, sodium-increasing treatments in chronic stable and asymptomatic HN have not proven to increase life expectancy. For symptomatic HN, in contrast, the necessity for urgent treatment has broadly been accepted to avoid the development of fatal cerebral edema. On the other hand, a too rapid increase of serum sodium in chronic HN may result in cerebral damage due to osmotic demyelinisation. Recently, administration of hypertonic saline bolus has been recommended as first-line treatment in patients with moderate-to-severe symptomatic HN. This approach is easy to memorize and holds the potential to greatly facilitate the initial treatment of symptomatic HN. First-line treatment of chronic HN is fluid restriction and if ineffective treatment with tolvaptan or in some patients other agents should be considered. A number of recommendations and guidelines have been published on HN. In the present review, the management of patients with HN in relation to everyday clinical practice is summarized with focus on the acute management. KW - hyponatremia KW - clinical Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162936 VL - 5 IS - 5 ER - TY - JOUR A1 - Vona, Barbara A1 - Nanda, Indrajit A1 - Shehata-Dieler, Wafaa A1 - Haaf, Thomas T1 - Genetics of Tinnitus: Still in its Infancy JF - Frontiers in Neuroscience N2 - Tinnitus is the perception of a phantom sound that affects between 10 and 15% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention. KW - twin study KW - complex disorders KW - genetics KW - genetic heterogeneity KW - genome-wide association study (GWAS) KW - hearing loss KW - tinnitus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170926 VL - 11 IS - 236 ER - TY - JOUR A1 - Mülek, Melanie A1 - Seefried, Lothar A1 - Genest, Franca A1 - Högger, Petra T1 - Distribution of constituents and metabolites of maritime pine bark extract (Pycnogenol\(^{®}\)) into serum, blood cells, and synovial fluid of patients with severe osteoarthritis: a randomized controlled trial JF - Nutrients N2 - The present randomized controlled study aimed to investigate the in vivo distribution of constituents or metabolites of the standardized maritime pine bark extract Pycnogenol\(^{®}\). Thirty-three patients with severe osteoarthritis scheduled for a knee arthroplasty were randomized to receive either 200 mg per day Pycnogenol\(^{®}\) (P+) or no treatment (Co) over three weeks before surgery. Serum, blood cells, and synovial fluid samples were analyzed using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization (LC-ESI/MS/MS). Considerable interindividual differences were observed indicating pronounced variability of the polyphenol pharmacokinetics. Notably, the highest polyphenol concentrations were not detected in serum. Catechin and taxifolin primarily resided within the blood cells while the microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone, ferulic, and caffeic acid were mainly present in synovial fluid samples. Taxifolin was detected in serum and synovial fluid exclusively in the P+ group. Likewise, no ferulic acid was found in serum samples of the Co group. Calculating ratios of analyte distribution in individual patients revealed a simultaneous presence of some polyphenols in serum, blood cells, and/or synovial fluid only in the P+ group. This is the first evidence that polyphenols distribute into the synovial fluid of patients with osteoarthritis which supports rationalizing the results of clinical efficacy studies. KW - osteoarthritis KW - randomized controlled study KW - LC-ESI/MS/MS KW - human KW - pine bark extract KW - polyphenols Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159862 VL - 9 IS - 5 ER - TY - JOUR A1 - Lee, Marcel A1 - Eyer, Florian A1 - Felgenhauer, Norbert A1 - Klinker, Hartwig H. F. A1 - Spinner, Christoph D. T1 - Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient JF - AIDS Research and Therapy N2 - A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay\(^{®}\)) and tenofovir disaproxil fumarate/emtricitabine (Truvada\(^{®}\)) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments. KW - integrase inhibitor KW - HIV KW - AIDS KW - suicide attempt KW - dolutegravir KW - tenofovir disaproxil fumarate KW - emtricitabine KW - overdose Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151994 VL - 12 IS - 18 ER - TY - JOUR A1 - Völker, Hans-Ullrich A1 - Weigel, Michael A1 - Strehl, Annette A1 - Frey, Lea T1 - Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array JF - Diagnostic Pathology N2 - Background: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods: The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised). KW - breast cancer KW - OncotypeDX\(^{®}\) KW - uPA KW - multigene-array KW - PAI-1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176960 VL - 13 IS - 67 ER - TY - JOUR A1 - Akhrif, Atae A1 - Romanos, Marcel A1 - Domschke, Katharina A1 - Schmitt-Boehrer, Angelika A1 - Neufang, Susanne T1 - Fractal Analysis of BOLD Time Series in a Network Associated With Waiting Impulsivity JF - Frontiers in Physiology N2 - Fractal phenomena can be found in numerous scientific areas including neuroscience. Fractals are structures, in which the whole has the same shape as its parts. A specific structure known as pink noise (also called fractal or 1/f noise) is one key fractal manifestation, exhibits both stability and adaptability, and can be addressed via the Hurst exponent (H). FMRI studies using H on regional fMRI time courses used fractality as an important characteristic to unravel neural networks from artificial noise. In this fMRI-study, we examined 103 healthy male students at rest and while performing the 5-choice serial reaction time task. We addressed fractality in a network associated with waiting impulsivity using the adaptive fractal analysis (AFA) approach to determine H. We revealed the fractal nature of the impulsivity network. Furthermore, fractality was influenced by individual impulsivity in terms of decreasing fractality with higher impulsivity in regions of top-down control (left middle frontal gyrus) as well as reward processing (nucleus accumbens and anterior cingulate cortex). We conclude that fractality as determined via H is a promising marker to quantify deviations in network functions at an early stage and, thus, to be able to inform preventive interventions before the manifestation of a disorder. KW - fMRI KW - Hurst Exponent KW - frontal cortex KW - nucleus accumbens KW - biomarker KW - impulse control disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189191 SN - 1664-042X VL - 9 ER - TY - JOUR A1 - Awad, Eman A1 - Othman, Eman M. A1 - Stopper, Helga T1 - Effects of resveratrol, lovastatin and the mTOR-inhibitor RAD-001 on insulin-induced genomic damage in vitro JF - Molecules N2 - Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy. KW - genomic damage KW - insulin KW - resveratrol KW - lovastatin KW - mTOR-inhibitor RAD-001 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159260 VL - 22 IS - 12 ER - TY - JOUR A1 - Da Vià, Matteo Claudio A1 - Solimando, Antonio Giovanni A1 - Garitano-Trojaola, Andoni A1 - Barrio, Santiago A1 - Munawar, Umair A1 - Strifler, Susanne A1 - Haertle, Larissa A1 - Rhodes, Nadine A1 - Vogt, Cornelia A1 - Lapa, Constantin A1 - Beilhack, Andreas A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Kortüm, K. Martin T1 - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement JF - The Oncologist N2 - Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KW - Multiple myeloma KW - Extramedullary disease KW - Capicua transcriptional repressor KW - Drug resistance KW - BRAF mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549 VL - 25 IS - 2 ER - TY - JOUR A1 - Kramer, Susanne T1 - The ApaH-like phosphatase TbALPH1 is the major mRNA decapping enzyme of trypanosomes JF - PLoS Pathogens N2 - 5’-3’ decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5’-3’ exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5’-3’ degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5’-3’ exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5’-3’ decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5’ polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA’s 5’ end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap. KW - eukaryota KW - Trypanosoma KW - RNA interference KW - messenger RNA Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158482 VL - 13 IS - 6 ER - TY - JOUR A1 - Kunz, Meik A1 - Göttlich, Claudia A1 - Walles, Thorsten A1 - Nietzer, Sarah A1 - Dandekar, Gudrun A1 - Dandekar, Thomas T1 - MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact JF - Tumor Biology N2 - MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic. KW - biomarker KW - microRNA–target interaction KW - microRNAs KW - lung cancer KW - therapeutic strategy KW - bioinformatics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158399 VL - 39 IS - 7 ER - TY - JOUR A1 - Kim, Jae Ho A1 - Franck, Julien A1 - Kang, Taewook A1 - Heinsen, Helmut A1 - Ravid, Rivka A1 - Ferrer, Isidro A1 - Cheon, Mi Hee A1 - Lee, Joo-Yong A1 - Yoo, Jong Shin A1 - Steinbusch, Harry W. A1 - Salzet, Michel A1 - Fournier, Isabelle A1 - Park, Young Mok T1 - Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer's disease JF - Scientific Reports N2 - Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post-mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross-validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis. KW - imaging mass spectrometry KW - neuron navigator 3 KW - dentate gyrus KW - growth factor KW - mouse model KW - neurotrophic factor KW - entorhinal cortex KW - factor expression KW - oxidative stress KW - memory deficits Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151727 VL - 5 IS - 11138 ER - TY - JOUR A1 - Kleikers, Pamela W. M. A1 - Hooijmans, Carlijn A1 - Göb, Eva A1 - Langhauser, Friederike A1 - Rewell, Sarah S. J. A1 - Radermacher, Kim A1 - Ritskes-Hoitinga, Merel A1 - Howells, David W. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation JF - Scientific Reports N2 - Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX\(_{2}\) to be a major therapeutic target in stroke. Systematic review and MA of all available NOX\(_{2}\)\(^{-/y}\) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX\(_{2}\) as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias. KW - focal cerebral ischemia KW - darbepoetin alpha KW - mice KW - translational stroke research KW - colony-stimulating factor KW - NADPH oxidase inhibitors KW - chronic kidney disease KW - diabetes mellitus KW - oxidative stress KW - search filter Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151401 VL - 5 IS - 13428 ER - TY - JOUR A1 - Erlbeck, Helena A1 - Mochty, Ursula A1 - Kübler, Andrea A1 - Real, Ruben G. L. T1 - Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI) JF - BMC Neurology N2 - Background: Accidents or neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) can lead to progressing, extensive, and complete paralysis leaving patients aware but unable to communicate (locked-in state). Brain-computer interfaces (BCI) based on electroencephalography represent an important approach to establish communication with these patients. The most common BCI for communication rely on the P300, a positive deflection arising in response to rare events. To foster broader application of BCIs for restoring lost function, also for end-users with impaired vision, we explored whether there were specific time windows during the day in which a P300 driven BCI should be preferably applied. Methods: The present study investigated the influence of time of the day and modality (visual vs. auditory) on P300 amplitude and latency. A sample of 14 patients (end-users) with ALS and 14 healthy age matched volunteers participated in the study and P300 event-related potentials (ERP) were recorded at four different times (10, 12 am, 2, & 4 pm) during the day. Results: Results indicated no differences in P300 amplitudes or latencies between groups (ALS patients v. healthy participants) or time of measurement. In the auditory condition, latencies were shorter and amplitudes smaller as compared to the visual condition. Conclusion: Our findings suggest applicability of EEG/BCI sessions in patients with ALS throughout normal waking hours. Future studies using actual BCI systems are needed to generalize these findings with regard to BCI effectiveness/efficiency and other times of day. KW - brain computer interface KW - amyotrophic lateral sclerosis KW - ALS KW - P300 KW - auditory KW - visual KW - BCI Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157423 VL - 17 IS - 3 ER - TY - JOUR A1 - Gulve, Nitish A1 - Frank, Celina A1 - Klepsch, Maximilian A1 - Prusty, Bhupesh K. T1 - Chromosomal integration of HHV-6A during non-productive viral infection JF - Scientific Reports N2 - Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two different species of betaherpesviruses that integrate into sub-telomeric ends of human chromosomes, for which different prevalence rates of integration have been reported. It has been demonstrated that integrated viral genome is stable and is fully retained. However, study of chromosomally integrated viral genome in individuals carrying inherited HHV-6 (iciHHV-6) showed unexpected number of viral DR copies. Hence, we created an in vitro infection model and studied retention of full or partial viral genome over a period of time. We observed an exceptional event where cells retained viral direct repeats (DRs) alone in the absence of the full viral genome. Finally, we found evidence for non-telomeric integration of HHV-6A DR in both cultured cells and in an iciHHV-6 individual. Our results shed light on several novel features of HHV-6A chromosomal integration and provide valuable information for future screening techniques. KW - herpes virus KW - infectious-disease diagnostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158117 VL - 7 IS - 512 ER - TY - JOUR A1 - Herold, Volker A1 - Herz, Stefan A1 - Winter, Patrick A1 - Gutjahr, Fabian Tobias A1 - Andelovic, Kristina A1 - Bauer, Wolfgang Rudolf A1 - Jakob, Peter Michael T1 - Assessment of local pulse wave velocity distribution in mice using k-t BLAST PC-CMR with semi-automatic area segmentation. JF - Journal of Cardiovascular Magnetic Resonance N2 - Background: Local aortic pulse wave velocity (PWV) is a measure for vascular stiffness and has a predictive value for cardiovascular events. Ultra high field CMR scanners allow the quantification of local PWV in mice, however these systems are yet unable to monitor the distribution of local elasticities. Methods: In the present study we provide a new accelerated method to quantify local aortic PWV in mice with phase-contrast cardiovascular magnetic resonance imaging (PC-CMR) at 17.6 T. Based on a k-t BLAST (Broad-use Linear Acquisition Speed-up Technique) undersampling scheme, total measurement time could be reduced by a factor of 6. The fast data acquisition enables to quantify the local PWV at several locations along the aortic blood vessel based on the evaluation of local temporal changes in blood flow and vessel cross sectional area. To speed up post processing and to eliminate operator bias, we introduce a new semi-automatic segmentation algorithm to quantify cross-sectional areas of the aortic vessel. The new methods were applied in 10 eight-month-old mice (4 C57BL/6J-mice and 6 ApoE\(^{(-/-)}\)-mice) at 12 adjacent locations along the abdominal aorta. Results: Accelerated data acquisition and semi-automatic post-processing delivered reliable measures for the local PWV, similiar to those obtained with full data sampling and manual segmentation. No statistically significant differences of the mean values could be detected for the different measurement approaches. Mean PWV values were elevated for the ApoE\(^{(-/-)}\)-group compared to the C57BL/6J-group (3.5 ± 0.7 m/s vs. 2.2 ± 0.4 m/s, p < 0.01). A more heterogeneous PWV-distribution in the ApoE \(^{(-/-)}\)-animals could be observed compared to the C57BL/6J-mice, representing the local character of lesion development in atherosclerosis. Conclusion: In the present work, we showed that k-t BLAST PC-MRI enables the measurement of the local PWV distribution in the mouse aorta. The semi-automatic segmentation method based on PC-CMR data allowed rapid determination of local PWV. The findings of this study demonstrate the ability of the proposed methods to non-invasively quantify the spatial variations in local PWV along the aorta of ApoE\(^{(-/-)}\)-mice as a relevant model of atherosclerosis. KW - pulse wave velocity KW - ApoE\(^{(-/-)}\) KW - magnetic resonance imaging KW - phase contrast Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157696 VL - 19 IS - 77 ER - TY - JOUR A1 - Oezkur, Mehmet A1 - Magyar, Attila A1 - Thomas, Phillip A1 - Stork, Tabea A1 - Schneider, Reinhard A1 - Bening, Constanze A1 - Störk, Stefan A1 - Heuschmann, Peter U. A1 - Leyh, Rainer G. A1 - Wagner, Martin T1 - TIMP-2*IGFBP7 (Nephrocheck®) Measurements at Intensive Care Unit Admission After Cardiac Surgery are Predictive for Acute Kidney Injury Within 48 Hours JF - Kidney & Blood Pressure Research N2 - Background/Aims: Acute kidney injury (AKI) is a postoperative complication after cardiac surgery with a high impact on mortality and morbidity. Nephrocheck® [TIMP-2*IGFBP7] determines markers of tubular stress, which occurs prior to tubular damage. It is unknown at which time-point [TIMP-2*IGFBP7] measurement should be performed to ideally predict AKI. We investigated the association of [TIMP-2*IGFBP7] at various time-points with the incidence of AKI in patients undergoing elective cardiac surgery including cardio-pulmonary bypass. Methods: In a prospective cohort study, serial blood and urine samples were collected from 150 patients: pre-operative, at ICU-admission, 24h and 48h post-surgery. AKI was defined as Serum-Creatinine rise >0.3 mg/dl within 48hrs. Urinary [TIMP-2*IGFBP7] was measured at pre-operative, ICU-admission and 24h post-surgery; medical staff was kept blinded to these results. Results: A total of 35 patients (23.5%) experienced AKI, with a higher incidence in those with high [TIMP-2*IGFBP7] values at ICU admission (57.1% vs. 10.1%, p<0.001). In logistic regression [TIMP-2*IGFBP7] at ICU admission was independently associated with the occurrence of AKI (Odds Ratio 11.83; p<0.001, C-statistic= 0.74) after adjustment for EuroSCORE II and CBP-time. Conclusions: Early detection of elevated [TIMP-2*IGFBP7] at ICU admission was strongly predictive for postoperative AKI and appeared to be more precise as compared to subsequent measurements. KW - postoperativ KW - Akutes Nierenversagen Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157988 VL - 42 ER - TY - JOUR A1 - Sauer, Alexander A1 - Li, Mengxia A1 - Holl-Wieden, Annette A1 - Pabst, Thomas A1 - Neubauer, Henning T1 - Readout-segmented multi-shot diffusion-weighted MRI of the knee joint in patients with juvenile idiopathic arthritis JF - Pediatric Rheumatology N2 - Background: Diffusion-weighted MRI has been proposed as a new technique for imaging synovitis without intravenous contrast application. We investigated diagnostic utility of multi-shot readout-segmented diffusion-weighted MRI (multi-shot DWI) for synovial imaging of the knee joint in patients with juvenile idiopathic arthritis (JIA). Methods: Thirty-two consecutive patients with confirmed or suspected JIA (21 girls, median age 13 years) underwent routine 1.5 T MRI with contrast-enhanced T1w imaging (contrast-enhanced MRI) and with multi-shot DWI (RESOLVE, b-values 0–50 and 800 s/mm\(^2\)). Contrast-enhanced MRI, representing the diagnostic standard, and diffusion-weighted images at b = 800 s/mm\(^2\) were separately rated by three independent blinded readers at different levels of expertise for the presence and the degree of synovitis on a modified 5-item Likert scale along with the level of subjective diagnostic confidence. Results: Fourteen (44%) patients had active synovitis and joint effusion, nine (28%) patients showed mild synovial enhancement not qualifying for arthritis and another nine (28%) patients had no synovial signal alterations on contrast-enhanced imaging. Ratings by the 1st reader on contrast-enhanced MRI and on DWI showed substantial agreement (κ = 0.74). Inter-observer-agreement was high for diagnosing, or ruling out, active arthritis of the knee joint on contrast-enhanced MRI and on DWI, showing full agreement between 1st and 2nd reader and disagreement in one case (3%) between 1st and 3rd reader. In contrast, ratings in cases of absent vs. little synovial inflammation were markedly inconsistent on DWI. Diagnostic confidence was lower on DWI, compared to contrast-enhanced imaging. Conclusion: Multi-shot DWI of the knee joint is feasible in routine imaging and reliably diagnoses, or rules out, active arthritis of the knee joint in paediatric patients without the need of gadolinium-based i.v. contrast injection. Possibly due to “T2w shine-through” artifacts, DWI does not reliably differentiate non-inflamed joints from knee joints with mild synovial irritation. KW - diffusion-weighted MRI KW - juvenile idiopathic arthritis KW - synovitis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158095 VL - 15 IS - 73 ER - TY - JOUR A1 - Baur, Johannes A1 - Mathe, Katrin A1 - Gesierich, Anja A1 - Weyandt, Gerhard A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Gasser, Martin A1 - Pelz, Jörg O. W. T1 - Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients JF - World Journal of Surgical Oncology N2 - Background: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. Methods: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. Results: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. Conclusions: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional. KW - malignant melanoma KW - inguinal lymph node dissection KW - regional recurrence KW - V. saphena magna Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157687 VL - 15 IS - 99 ER -