TY - JOUR A1 - Kirsch, Anna Dalal A1 - Hassin-Baer, Sharon A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Steigerwald, Frank T1 - Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects JF - Parkinsonism and Related Disorders N2 - Introduction Stimulation settings of deep brain stimulation (DBS) have evolved empirically within a limited parameter space dictated by first generation devices. There is a need for controlled clinical studies, which evaluate efficacy and safety of established programming practice against novel programming options provided by modern neurostimulation devices. Methods Here, we tested a polarity reversal from conventional monopolar cathodic to anodic stimulation in an acute double-blind, randomized, cross-over study in patients with PD implanted with bilateral STN DBS. The primary outcome measure was the difference between efficacy and side-effect thresholds (current amplitude, mA) in a monopolar review and the severity of motor symptoms (as assessed by MDS-UPDRS III ratings) after 30 min of continuous stimulation in the medication off-state. Results Effect and side effect thresholds were significantly higher with anodic compared to cathodic stimulation (3.36 ± 1.58 mA vs. 1.99 ± 1.37 mA; 6.05 ± 1.52 mA vs. 4.15 ± 1.13 mA; both p < 0.0001). However, using a predefined amplitude of 0.5 mA below the respective adverse effect threshold, blinded MDS-UPDRS-III-ratings were significantly lower with anodic stimulation (anodic: median 17 [min: 12, max: 25]; cathodic: 23 [12, 37]; p < 0.005). Conclusion Effective anodic stimulation requires a higher charge injection into the tissue, but may provide a better reduction of off-period motor symptoms within the individual therapeutic window. Therefore, a programming change to anodic stimulation may be considered in patients suffering from residual off-period motor symptoms of PD despite reaching the adverse effect threshold of cathodic stimulation in the subthalamic nucleus. KW - deep brain stimulation KW - subthalamic nucleus KW - Parkinson's disease KW - anodic stimulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325820 VL - 55 ER - TY - JOUR A1 - Godel, Tim A1 - Pham, Mirko A1 - Kele, Henrich A1 - Kronlage, Moritz A1 - Schwarz, Daniel A1 - Brunée, Merle A1 - Heiland, Sabine A1 - Bendszus, Martin A1 - Bäumer, Philipp T1 - Diffusion tensor imaging in anterior interosseous nerve syndrome – functional MR Neurography on a fascicular level JF - NeuroImage: Clinical N2 - Purpose By applying diffusor tensor imaging (DTI) in patients with anterior interosseous nerve syndrome (AINS), this proof of principle study aims to quantify the extent of structural damage of a peripheral nerve at the anatomical level of individual fascicles. Methods In this institutional review board approved prospective study 13 patients with spontaneous AINS were examined at 3 Tesla including a transversal T2-weighted turbo-spin-echo and a spin-echo echo-planar-imaging pulse sequence of the upper arm level. Calculations of quantitative DTI parameters including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for median nerve lesion and non-lesion fascicles as well as ulnar and radial nerve were obtained. DTI values were compared to each other and to a previously published dataset of 58 healthy controls using one-way Analysis of Variance with Bonferroni correction and p-values <.05 were considered significant. Receiver operating characteristic (ROC) curves were performed to assess diagnostic accuracy. Results FA of median nerve lesion fascicles was decreased compared to median nerve non-lesion fascicles, ulnar nerve and radial nerve while MD, RD, and AD was increased (p < .001 for all parameters). Compared to median nerve values of healthy controls, lesion fascicles showed a significant decrease in FA while MD, RD, and AD was increased (p < .001 for all parameters). FA of median nerve non-lesion fascicles showed a weak significant decrease compared to healthy controls (p < .01) while there was no difference in MD, RD, and AD. ROC analyses revealed an excellent diagnostic accuracy of FA, MD and RD in the discrimination of median nerve lesion and non-lesion fascicles in AINS patients as well as in the discrimination of lesion fascicles and normative median nerve values of healthy controls. Conclusion By applying this functional MR Neurography technique in patients with AINS, this proof of principle study demonstrates that diffusion tensor imaging is feasible to quantify structural nerve injury at the anatomical level of individual fascicles. KW - anterior interosseous nerve syndrome KW - diffusion tensor imaging KW - functional MR Neurography Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233061 VL - 21 ER - TY - JOUR A1 - Counsell, John R. A1 - Karda, Rajvinder A1 - Diaz, Juan Antiano A1 - Carey, Louise A1 - Wiktorowicz, Tatiana A1 - Buckley, Suzanne M. K. A1 - Ameri, Shima A1 - Ng, Joanne A1 - Baruteau, Julien A1 - Almeida, Filipa A1 - de Silva, Rohan A1 - Simone, Roberto A1 - Lugarà, Eleonora A1 - Lignani, Gabriele A1 - Lindemann, Dirk A1 - Rethwilm, Axel A1 - Rahim, Ahad A. A1 - Waddington, Simon N. A1 - Howe, Steven J. T1 - Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice JF - Molecular Therapy: Nucleic Acids N2 - Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders. KW - foamy virus KW - spumavirus KW - viral vector KW - gene therapy KW - vector tropism KW - bioimaging KW - hippocampus Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223379 VL - 12 ER - TY - JOUR A1 - Griemert, Eva-Verena A1 - Schwarzmaier, Susanne M. A1 - Hummel, Regina A1 - Gölz, Christina A1 - Yang, Dong A1 - Neuhaus, Winfried A1 - Burek, Malgorzata A1 - Förster, Carola Y. A1 - Petkovic, Ivan A1 - Trabold, Raimund A1 - Plesnila, Nikolaus A1 - Engelhard, Kristin A1 - Schäfer, Michael K. A1 - Thal, Serge C. T1 - Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury JF - Annals of Neurology N2 - Objective Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma. Methods We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1–deficient animals. Results PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1–deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. Interpretation This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667–680 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228682 VL - 85 ER - TY - JOUR A1 - Figel, Benedikt A1 - Brinkmann, Leonie A1 - Buff, Christine A1 - Heitmann, Carina Y. A1 - Hofmann, David A1 - Bruchmann, Maximilian A1 - Becker, Michael P. I. A1 - Herrmann, Martin J. A1 - Straube, Thomas T1 - Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients JF - NeuroImage: Clinical N2 - Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC. KW - FMRI KW - threat anticipation KW - social anxiety disorder KW - bed nucleus of stria terminalis KW - amygdala Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228071 VL - 22 ER - TY - JOUR A1 - Fazzini, Federica A1 - Lamina, Claudia A1 - Fendt, Liane A1 - Schultheiss, Ulla T. A1 - Kotsis, Fruzsina A1 - Hicks, Andrew A. A1 - Meiselbach, Heike A1 - Weissensteiner, Hansi A1 - Forer, Lukas A1 - Krane, Vera A1 - Eckardt, Kai-Uwe A1 - Köttgen, Anna A1 - Kronenberg, Florian T1 - Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease JF - Kidney International N2 - Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD. KW - chronic kidney disease KW - infections KW - mitochondrial DNA copy number KW - mortality Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227662 VL - 96 ER - TY - JOUR A1 - Kiser, Dominik P. A1 - Popp, Sandy A1 - Schmitt-Böhrer, Angelika G. A1 - Strekalova, Tatyana A1 - van den Hove, Daniel L. A1 - Lesch, Klaus-Peter A1 - Rivero, Olga T1 - Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice JF - Progress in Neuropsychopharmacology & Biological Psychiatry N2 - Objective Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice. Methods Male and female wild-type (Cdh13+/+), heterozygous (Cdh13+/−) and homozygous (Cdh13−/−) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naïve for behavioural testing. Results MS lead to increased anxiety-like behaviour in Cdh13−/− mice compared to the other two MS groups. Cdh13−/− mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13−/− mice, but unaltered impulsivity and activity in male Cdh13−/− mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function. Conclusion MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13+/+ and Cdh13+/− mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13−/− mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity. KW - Cadherin-13 (CDH13) KW - T-cadherin KW - neurodevelopment KW - autism KW - ADHD KW - depression KW - psychiatric disorders KW - early-life stress KW - mouse KW - RNA sequencing KW - endoplasmic reticulum stress KW - adhesion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325859 VL - 89 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Fomin, Victor V. A1 - Hilz, Max J. A1 - Jovanovic, Ana A1 - Kantola, Ilkka A1 - Linhart, Aleš A1 - Renzo, Mignani A1 - Namdar, Mehdi A1 - Nowak, Albina A1 - Oliveira, João-Paulo A1 - Pieroni, Maurizio A1 - Viana-Baptista, Miguel A1 - Wanner, Christoph A1 - Spada, Marco T1 - The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism Reports N2 - Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment. KW - Fabry disease KW - systematic literature review KW - agalsidase beta KW - agalsidase alfa KW - enzyme replacement therapy KW - adult male patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232987 VL - 19 ER - TY - JOUR A1 - Flunkert, Julia A1 - Maierhofer, Anna A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Horvath, Steve A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts JF - Experimental Cell Research N2 - To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for variation in radiation sensitivity, all experiments were performed with two different fibroblast strains. After a single X-ray dose of 2 Gy more than half of the irradiated clones exhibited radiation-induced genome instability (RIGI). Irradiated clones displayed an increased rate of loss of chromosome Y (LOY) and copy number variations (CNVs), compared to controls. CNV breakpoints clustered in specific chromosome regions, in particular 3p14.2 and 7q11.21, coinciding with common fragile sites. CNVs affecting the FHIT gene in FRA3B were observed in independent unstable clones and may drive RIGI. Bisulfite pyrosequencing of control clones and the respective primary culture revealed global hypomethylation of ALU, LINE-1, and alpha-satellite repeats as well as rDNA hypermethylation during in vitro ageing. Irradiated clones showed further reduced ALU and alpha-satellite methylation and increased rDNA methylation, compared to controls. Methylation arrays identified several hundred differentially methylated genes and several enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic (LOY and CNVs) and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis. We did not observe epigenetic differences between stable and unstable irradiated clones. The fact that the DNA methylation (DNAm) age of clones derived from the same primary culture varied greatly suggests that DNAm age of a single cell (represented by a clone) can be quite different from the DNAm age of a tissue. We propose that DNAm age reflects the emergent property of a large number of individual cells whose respective DNAm ages can be highly variable. KW - copy number variation (CNV) KW - delayed radiation effects KW - DNA methylation (DNAm) age KW - global DNA methylation KW - loss of chromosome Y (LOY); KW - methylation array analysis KW - radiation-induced genome instability (RIGI) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228177 VL - 370 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Arad, Michael A1 - Burlina, Alessandro A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Feldt-Rasmussen, Ulla A1 - Hilz, Max J. A1 - Hughes, Derralynn A. A1 - Ortiz, Alberto A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Spada, Marco T1 - The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease – A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism N2 - Background Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. Methods A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. Results Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. Conclusions This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - adult female patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232963 VL - 126 ER - TY - JOUR A1 - Omeñaca, Felix A1 - Vázquez, Liliana A1 - Garcia-Corbeira, Pilar A1 - Mesaros, Narcisa A1 - Hanssens, Linda A1 - Dolhain, Jan A1 - Puente Gómez, Ivonne A1 - Liese, Johannes A1 - Knuf, Markus T1 - Immunization of preterm infants with GSK’s hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine: A review of safety and immunogenicity JF - Vaccine N2 - Background Infants with history of prematurity (<37 weeks gestation) and low birth weight (LBW, <2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed. Methods Here we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK’s hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials. Results At least 92.5% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13–30% of medically stable infants with history of prematurity developed apnea after vaccination with GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens. Conclusion GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age. KW - DTPa-HBV-IPV/Hib KW - hexavalent vaccine KW - primary vaccination KW - preterm KW - premature Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234450 VL - 36 ER - TY - JOUR A1 - Spada, Marco A1 - Baron, Ralf A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Hilz, Max J. A1 - Monserrat, Lorenzo A1 - Tøndel, Camilla A1 - Tylki-Szymańska, Anna A1 - Wanner, Christoph A1 - Germain, Dominique P. T1 - The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease – A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism N2 - Background Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. Methods A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Results Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Conclusions Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - paediatric patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239287 VL - 126 ER - TY - JOUR A1 - Argyrousi, Elentina K. A1 - de Nijs, Laurence A1 - Lagatta, Davi C. A1 - Schlütter, Anna A1 - Weidner, Magdalena T. A1 - Zöller, Johanna A1 - van Goethem, Nick P. A1 - Joca, Sâmia R. L. A1 - van den Hove, Daniel L. A. A1 - Prickaerts, Jos T1 - Effects of DNA methyltransferase inhibition on pattern separation performance in mice JF - Neurobiology of Learning and Memory N2 - Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents. KW - object pattern separation KW - DNA methyltransferase inhibitors KW - BDNF KW - CpG islands KW - epigenetics KW - hippocampal plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221226 VL - 159 ER - TY - JOUR A1 - Grayston, Rebecca A1 - Czanner, Gabriela A1 - Elhadd, Kareim A1 - Goebel, Andreas A1 - Frank, Bernhard A1 - Üçeyler, Nurcan A1 - Malik, Rayaz A A1 - Alam, Uazman T1 - A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis JF - Seminars in Arthritis and Rheumatism N2 - Objectives Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia. Methods An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI. Results Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2= 70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2= 51%). Conclusion There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy. KW - small nerve fibres KW - pain KW - fibromyalgia KW - skin biopsy KW - corneal confocal microscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227566 VL - 48 ER - TY - JOUR A1 - Wilson, Duncan A1 - Ambler, Gareth A1 - Lee, Keon-Joo A1 - Lim, Jae-Sung A1 - Shiozawa, Masayuki A1 - Koga, Masatoshi A1 - Li, Linxin A1 - Lovelock, Caroline A1 - Chabriat, Hugues A1 - Hennerici, Michael A1 - Wong, Yuen Kwun A1 - Mak, Henry Ka Fung A1 - Prats-Sánchez, Luis A1 - Martínez-Domeño, Alejandro A1 - Inamura, Shigeru A1 - Yoshifuji, Kazuhisa A1 - Arsava, Ethem Murat A1 - Horstmann, Solveig A1 - Purrucker, Jan A1 - Lam, Bonnie Yin Ka A1 - Wong, Adrian A1 - Kim, Young Dae A1 - Song, Tae-Jin A1 - Schrooten, Maarten A1 - Lemmens, Robin A1 - Eppinger, Sebastian A1 - Gattringer, Thomas A1 - Uysal, Ender A1 - Tanriverdi, Zeynep A1 - Bornstein, Natan M A1 - Ben Assayag, Einor A1 - Hallevi, Hen A1 - Tanaka, Jun A1 - Hara, Hideo A1 - Coutts, Shelagh B A1 - Hert, Lisa A1 - Polymeris, Alexandros A1 - Seiffge, David J A1 - Lyrer, Philippe A1 - Algra, Ale A1 - Kappelle, Jaap A1 - Salman, Rustam Al-Shahi A1 - Jäger, Hans R A1 - Lip, Gregory Y H A1 - Mattle, Heinrich P A1 - Panos, Leonidas D A1 - Mas, Jean-Louis A1 - Legrand, Laurence A1 - Karayiannis, Christopher A1 - Phan, Thanh A1 - Gunkel, Sarah A1 - Christ, Nicolas A1 - Abrigo, Jill A1 - Leung, Thomas A1 - Chu, Winnie A1 - Chappell, Francesca A1 - Makin, Stephen A1 - Hayden, Derek A1 - Williams, David J A1 - Kooi, M Eline A1 - van Dam-Nolen, Dianne H K A1 - Barbato, Carmen A1 - Browning, Simone A1 - Wiegertjes, Kim A1 - Tuladhar, Anil M A1 - Maaijwee, Noortje A1 - Guevarra, Christine A1 - Yatawara, Chathuri A1 - Mendyk, Anne-Marie A1 - Delmaire, Christine A1 - Köhler, Sebastian A1 - van Oostenbrugge, Robert A1 - Zhou, Ying A1 - Xu, Chao A1 - Hilal, Saima A1 - Gyanwali, Bibek A1 - Chen, Christopher A1 - Lou, Min A1 - Staals, Julie A1 - Bordet, Régis A1 - Kandiah, Nagaendran A1 - de Leeuw, Frank-Erik A1 - Simister, Robert A1 - van der Lugt, Aad A1 - Kelly, Peter J A1 - Wardlaw, Joanna M A1 - Soo, Yannie A1 - Fluri, Felix A1 - Srikanth, Velandai A1 - Calvet, David A1 - Jung, Simon A1 - Kwa, Vincent I H A1 - Engelter, Stefan T A1 - Peters, Nils A1 - Smith, Eric E A1 - Yakushiji, Yusuke A1 - Necioglu Orken, Dilek A1 - Fazekas, Franz A1 - Thijs, Vincent A1 - Heo, Ji Hoe A1 - Mok, Vincent A1 - Veltkamp, Roland A1 - Ay, Hakan A1 - Imaizumi, Toshio A1 - Gomez-Anson, Beatriz A1 - Lau, Kui Kai A1 - Jouvent, Eric A1 - Rothwell, Peter M A1 - Toyoda, Kazunori A1 - Bae, Hee-Yoon A1 - Marti-Fabregas, Joan A1 - Werring, David J T1 - Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies JF - The Lancet Neurology N2 - Background Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. Methods We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Findings Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years). Interpretation In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233710 VL - 18 ER - TY - JOUR A1 - Waszak, Sebastian M A1 - Northcott, Paul A A1 - Buchhalter, Ivo A1 - Robinson, Giles W A1 - Sutter, Christian A1 - Groebner, Susanne A1 - Grund, Kerstin B A1 - Brugières, Laurence A1 - Jones, David T W A1 - Pajtler, Kristian W A1 - Morrissy, A Sorana A1 - Kool, Marcel A1 - Sturm, Dominik A1 - Chavez, Lukas A1 - Ernst, Aurelie A1 - Brabetz, Sebastian A1 - Hain, Michael A1 - Zichner, Thomas A1 - Segura-Wang, Maia A1 - Weischenfeldt, Joachim A1 - Rausch, Tobias A1 - Mardin, Balca R A1 - Zhou, Xin A1 - Baciu, Cristina A1 - Lawerenz, Christian A1 - Chan, Jennifer A A1 - Varlet, Pascale A1 - Guerrini-Rousseau, Lea A1 - Fults, Daniel W A1 - Grajkowska, Wiesława A1 - Hauser, Peter A1 - Jabado, Nada A1 - Ra, Young-Shin A1 - Zitterbart, Karel A1 - Shringarpure, Suyash S A1 - De La Vega, Francisco M A1 - Bustamante, Carlos D A1 - Ng, Ho-Keung A1 - Perry, Arie A1 - MacDonald, Tobey J A1 - Driever, Pablo Hernáiz A1 - Bendel, Anne E A1 - Bowers, Daniel C A1 - McCowage, Geoffrey A1 - Chintagumpala, Murali M A1 - Cohn, Richard A1 - Hassall, Timothy A1 - Fleischhack, Gudrun A1 - Eggen, Tone A1 - Wesenberg, Finn A1 - Feychting, Maria A1 - Lannering, Birgitta A1 - Schüz, Joachim A1 - Johansen, Christoffer A1 - Andersen, Tina V A1 - Röösli, Martin A1 - Kuehni, Claudia E A1 - Grotzer, Michael A1 - Kjaerheim, Kristina A1 - Monoranu, Camelia M A1 - Archer, Tenley C A1 - Duke, Elizabeth A1 - Pomeroy, Scott L A1 - Shelagh, Redmond A1 - Frank, Stephan A1 - Sumerauer, David A1 - Scheurlen, Wolfram A1 - Ryzhova, Marina V A1 - Milde, Till A1 - Kratz, Christian P A1 - Samuel, David A1 - Zhang, Jinghui A1 - Solomon, David A A1 - Marra, Marco A1 - Eils, Roland A1 - Bartram, Claus R A1 - von Hoff, Katja A1 - Rutkowksi, Stefan A1 - Ramaswamy, Vijay A1 - Gilbertson, Richard J A1 - Korshunov, Andrey A1 - Taylor, Michael D A1 - Lichter, Peter A1 - Malkin, David A1 - Gajjar, Amar A1 - Korbel, Jan O A1 - Pfister, Stefan M T1 - Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort JF - The Lancet Oncology N2 - Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233425 VL - 19 ER - TY - JOUR A1 - Müntze, Jonas A1 - Gensler, Daniel A1 - Maniuc, Octavian A1 - Liu, Dan A1 - Cairns, Tereza A1 - Oder, Daniel A1 - Hu, Kai A1 - Lorenz, Kristina A1 - Frantz, Stefan A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year JF - Clinical Pharmacology & Therapeutics N2 - Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m2; P = 0.037), and serum creatinine (0.94–1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = −0.546; P = 0.044) but not with renal function (r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231626 VL - 105 ER - TY - JOUR A1 - Barkhuizen, Melinda A1 - van Mechelen, Ralph A1 - Vermeer, Marijne A1 - Chedraui, Peter A1 - Paes, Dean A1 - van den Hove, Daniel L. A. A1 - Vaes, Bart A1 - Mays, Robert W. A1 - Steinbusch, Harry W. M. A1 - Robertson, Nicola J. A1 - Kramer, Boris W. A1 - Gavilanes, Antonio W. D. T1 - Systemic multipotent adult progenitor cells improve long-term neurodevelopmental outcomes after preterm hypoxic-ischemic encephalopathy JF - Behavioural Brain Research N2 - There is an urgent need for therapies that could reduce the disease burden of preterm hypoxic-ischemic encephalopathy. Here, we evaluate the long-term effects of multipotent adult progenitor cells (MAPC) on long-term behavioral outcomes in a preterm rat model of perinatal asphyxia. Rats of both sexes were treated with two doses of MAPCs within 24 h after the insult. Locomotor, cognitive and psychiatric impairments were evaluated starting at 1.5 (juvenile) and 6 months (adult). Hypoxia-ischemia affected locomotion, cognition, and anxiety in a sex-dependent manner, with higher vulnerability observed in males. The MAPC therapy partially attenuated deficits in object recognition memory in females of all tested ages, and in the adult males. The hypoxic insult caused delayed hyperactivity in adult males, which was corrected by MAPC therapy. These results suggest that MAPCs may have long-term benefits for neurodevelopmental outcome after preterm birth and global hypoxia-ischemia, which warrants further preclinical exploration. KW - hypoxic-ischemic encephalopathy KW - preterm brain KW - stem cell therapy KW - neurodevelopment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221506 VL - 362 ER - TY - THES A1 - Brohm, Katharina Andrea T1 - (Differential-) Diagnostik bei primärem Hyperaldosteronismus: Ermittlung eines LC-MS/MS-spezifischen Aldosterongrenzwerts für den Kochsalzbelastungstest und Evaluation des Orthostasetests hinsichtlich der Differenzierung von Subgruppen T1 - (Differential) Diagnosis in Primary Aldosteronism: Determination of an LC-MS/MS-Specific Aldosterone Cut-Off Value for the Saline Infusion Test and Evaluation of the Postural Stimulation Test Regarding the Differentiation of Subtypes N2 - Der primäre Hyperaldosteronismus (PA) stellt aktuell den häufigsten Grund für das Vorliegen einer sekundären Hypertonie dar. Der in der Bestätigungsdiagnostik verwendete Kochsalzbelastungstest basiert dabei auf einem fehlenden Absinken der Aldosteronkonzentration im Testverlauf bei Patient:innen mit PA im Vergleich zu Patient:innen mit essentieller Hypertonie (EH). Die Konzentrationsbestimmung erfolgte bisher mittels Immunoassay. Mit der LC-MS/MS steht jedoch mittlerweile eine weitere wichtige analytische Methode in der quantitativen Bestimmung von Steroidhormonen zur Verfügung, welche in dieser Arbeit im Hinblick auf den Kochsalzbelastungstest untersucht wurde. Hohe Bedeutung kommt außerdem der Subtypdifferenzierung des PA zu, da die Ätiologie der Erkrankung wegweisend für die Art der Therapie ist. Das Ziel dieser Studie war einerseits die Ermittlung eines LC-MS/MS-spezifischen Aldosteron-Cut-off-Wertes im Kochsalzbelastungstest und die Evaluation des Nutzens der Bestimmung von Steroidprofilen in der Diagnostik des PA. Zum anderen wurde der diagnostische Nutzen des Orthostasetests zur Unterscheidung von unilateraler und bilateraler Genese bei vorliegendem PA untersucht. Im Rahmen dieser Studien wurden 187 bzw. 158 Patient:innen analysiert, die zwischen 2009 und 2019 bei Verdacht auf oder Vorliegen eines PA im Universitätsklinikum Würzburg vorstellig wurden. Die Diagnose wurde gemäß der aktuellen Leitlinie anhand der Ergebnisse des Kochsalzbelastungstests, NNVKs, Bildgebung und postoperativen Outcomes gestellt. Mithilfe der LC-MS/MS wurden erneut die Aldosteronkonzentrationen der aufbewahrten Serumproben des Kochsalzbelastungstests, sowie ein erweitertes Steroidpanel bestimmt. Unter Verwendung einer ROC-Analyse wurden die jeweils bestehenden Cut-off-Werte optimiert bzw. neu ermittelt. Die mittels Immunoassay bestimmten Aldosteronkonzentrationen lagen um 28 ng/L höher als die mittels LC-MS/MS bestimmten Konzentrationen. Trotzdem lag der neu ermittelte LC-MS/MS-spezifische Aldosteron-Cut-off-Wert für den Kochsalzbelastungstest bei 69 ng/L und damit höher als der für den Immunoassay geltende, optimierte Aldosteron-Cut-off von 54 ng/L. Unter Verwendung des LC-MS/MS- spezifischen Cut-off-Werts erreichte der Kochsalzbelastungstest eine Sensitivität von 78,6% bei einer Spezifität von 89,3%. Die Sensitivität des Immunoassay-spezifischen Cut-off-Werts betrug 95,2% bei einer Spezifität von 86,9%. Das Bestimmen des gesamten Steroidprofils führte zu keiner zusätzlichen diagnostischen Information bei Durchführung des Kochsalzbelastungstests. Bei Betrachtung der gesamten Patient:innenkohorte erreichte der Orthostasetest, basierend auf einem Absinken der Plasmaaldosteronkonzentration nach 4h in Orthostase um ≥ 28% eine Sensitivität von 36,7% bei einer Spezifität von 100%. Wurde das Vorliegen eines gültigen Tests (Cortisolabfall nach 4h ≥ 10%) oder das Vorliegen einer unilateralen Raumforderung in der Bildgebung vorausgesetzt, stieg die Sensitivität des Orthostasetests auf 51,4% bzw. 51,6% bei gleichbleibend hoher Spezifität von 100% an. Abschließend lässt sich sagen, dass der Orthostasetest keine Alternative zum NNVK darstellt, jedoch als einfache, nicht invasive Methode der zusätzlichen Orientierung zur Untersuchung der Ätiologie des PAs dienen kann. Eine prospektive Evaluation der jeweils neu ermittelten Cut-off-Werte wird notwendig sein, um deren Anwendbarkeit im klinischen Alltag zu überprüfen. Außerdem könnte die Bestimmung der Hybridsteroide 18-Oxocortisol und 18-Hydroxycortisol wegweisend für die Genese des PA sein. N2 - Primary aldosteronism (PA) is currently the most common cause of secondary hypertension. The saline infusion test used in confirmatory diagnostics is based on the lack of decrease in aldosterone concentration during the test in patients with PA compared to those with essential hypertension (EH). Until now, concentration determination has been performed using immunoassay. However, LC-MS/MS has now become an important analytical method for the quantitative determination of steroid hormones, which was investigated in this work in relation to the saline infusion test. Subtype differentiation of PA is also of great significance, as the subtype determines the therapy. The aim of this study was to determine an LC-MS/MS-specific aldosterone cut-off value in the saline infusion test and to evaluate the benefit of determining steroid profiles in the diagnosis of PA. Additionally, the diagnostic value of the postural stimulation test to differentiate between unilateral and bilateral disease in the presence of PA was investigated. In these studies, 187 and 158 patients, respectively, who presented with suspected or confirmed PA at the University Hospital Würzburg between 2009 and 2019 were analyzed. The diagnosis was made according to current guidelines based on the results of the saline infusion test, adrenal vein sampling, imaging, and postoperative outcomes. Using LC-MS/MS, aldosterone concentrations of the stored serum samples from the saline infusion test and an extended steroid panel were determined. ROC analysis was used to optimize or newly determine the existing cut-off values. Aldosterone concentrations determined by immunoassay were 28 ng/L higher than those determined by LC-MS/MS. Nevertheless, the newly determined LC-MS/MS-specific aldosterone cut-off value for the saline infusion test was 69 ng/L, which is higher than the optimized aldosterone cut-off of 54 ng/L for the immunoassay. Using the LC-MS/MS-specific cut-off value, the saline infusion test achieved a sensitivity of 78.6% with a specificity of 89.3%. The sensitivity of the immunoassay-specific cut-off value was 95.2% with a specificity of 86.9%. Determining the entire steroid profile did not provide any additional diagnostic information when performing the saline infusion test. Considering the entire patient cohort, the postural stimulation test, based on a decrease in plasma aldosterone concentration after 4 hours in an upright position by ≥ 28%, achieved a sensitivity of 36.7% with a specificity of 100%. When the test was considered valid (cortisol decrease after 4 hours ≥ 10%) or the presence of a unilateral mass on imaging was assumed, the sensitivity of the postural stimulation test increased to 51.4% and 51.6%, respectively, with a consistently high specificity of 100%. In conclusion, the postural stimulation test does not serve as an alternative to adrenal vein sampling but can provide additional information in investigating the subtype of PA as a simple, non-invasive method. A prospective evaluation of the newly determined cut-off values will be necessary to verify their applicability in clinical practice. Additionally, determining the hybrid steroids 18-oxocortisol and 18-hydroxycortisol could be crucial for understanding the subtype of PA. KW - Aldosteronismus KW - Aldosteron KW - primärer Hyperaldosteronismus KW - LC-MS/MS KW - Kochsalzbelastungstest KW - Orthostasetest Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369382 ER - TY - JOUR A1 - Czimmerer, Zsolt A1 - Daniel, Bence A1 - Horvath, Attila A1 - Rückerl, Dominik A1 - Nagy, Gergely A1 - Kiss, Mate A1 - Peloquin, Matthew A1 - Budai, Marietta M. A1 - Cuaranta-Monroy, Ixchelt A1 - Simandi, Zoltan A1 - Steiner, Laszlo A1 - Nagy Jr., Bela A1 - Poliska, Szilard A1 - Banko, Csaba A1 - Bacso, Zsolt A1 - Schulman, Ira G. A1 - Sauer, Sascha A1 - Deleuze, Jean-Francois A1 - Allen, Judith E. A1 - Benko, Szilvia A1 - Nagy, Laszlo T1 - The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages JF - Immunity N2 - The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli. KW - IL-4 KW - STAT6 KW - alternative macrophage polarization KW - transcription KW - repression KW - inflammation KW - inflammasome activation KW - pyroptosis KW - IL-1β KW - macrophage epigenomics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223380 VL - 48 ER - TY - JOUR A1 - Trübe, Patricia A1 - Hertlein, Tobias A1 - Mrochen, Daniel M. A1 - Schulz, Daniel A1 - Jorde, Ilka A1 - Krause, Bettina A1 - Zeun, Julia A1 - Fischer, Stefan A1 - Wolf, Silver A. A1 - Walther, Birgit A1 - Semmler, Torsten A1 - Bröker, Barbara M. A1 - Ulrich, Rainer G. A1 - Ohlsen, Knut A1 - Holtfreter, Silva T1 - Bringing together what belongs together: Optimizing murine infection models by using mouse-adapted Staphylococcus aureus strains JF - International Journal of Medical Microbiology N2 - Staphylococcus (S.) aureus is a leading cause of bacterial infection world-wide, and currently no vaccine is available for humans. Vaccine development relies heavily on clinically relevant infection models. However, the suitability of mice for S. aureus infection models has often been questioned, because experimental infection of mice with human-adapted S. aureus requires very high infection doses. Moreover, mice were not considered to be natural hosts of S. aureus. The latter has been disproven by our recent findings, showing that both laboratory mice, as well as wild small mammals including mice, voles, and shrews, are naturally colonized with S. aureus. Here, we investigated whether mouse-and vole-derived S. aureus strains show an enhanced virulence in mice as compared to the human-adapted strain Newman. Using a step-wise approach based on the bacterial genotype and in vitro assays for host adaptation, we selected the most promising candidates for murine infection models out of a total of 254 S. aureus isolates from laboratory mice as well as wild rodents and shrews. Four strains representing the clonal complexes (CC) 8, 49, and 88 (n = 2) were selected and compared to the human-adapted S. aureus strain Newman (CC8) in murine pneumonia and bacteremia models. Notably, a bank vole-derived CC49 strain, named DIP, was highly virulent in BALB/c mice in pneumonia and bacteremia models, whereas the other murine and vole strains showed virulence similar to or lower than that of Newman. At one tenth of the standard infection dose DIP induced disease severity, bacterial load and host cytokine and chemokine responses in the murine bacteremia model similar to that of Newman. In the pneumonia model, DIP was also more virulent than Newman but the effect was less pronounced. Whole genome sequencing data analysis identified a pore-forming toxin gene, lukF-PV(P83)/lukM, in DIP but not in the other tested S. aureus isolates. To conclude, the mouse-adapted S. aureus strain DIP allows a significant reduction of the inoculation dose in mice and is hence a promising tool to develop clinically more relevant infection models. KW - Staphylococcus aureus KW - host-adapted KW - infection model KW - mouse KW - vole KW - CC49 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229081 VL - 309 ER - TY - JOUR A1 - Tappenbeck, Nils A1 - Schröder, Hannes M. A1 - Niebergall-Roth, Elke A1 - Hassinger, Fathema A1 - Dehio, Ulf A1 - Dieter, Kathrin A1 - Kraft, Korinna A1 - Kerstan, Andreas A1 - Esterlechner, Jasmina A1 - Frank, Natasha Y. A1 - Scharffetter-Kochanek, Karin A1 - Murphy, George F. A1 - Orgill, Dennis P. A1 - Beck, Joachim A1 - Frank, Markus H. A1 - Ganss, Christoph A1 - Kluth, Mark A. T1 - In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials JF - Cytotherapy N2 - Background aims Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5+ MSCs) represent a promising candidate for stem cell–based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5+ MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice–conforming, MSC-based advanced-therapy medicinal product. Methods To support the development of ABCB5+ MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice–compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction. Results (i) Subcutaneous application of 1 × 107 ABCB5+ MSCs/animal and intravenous application of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5+ MSCs at doses ranging from 1 × 105 to 1 × 107 cells/animal and three biweekly intravenous injections of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 106 ABCB5+ MSCs/animal to immunocompromised mice was locally well tolerated. Discussion The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5+ MSCs. KW - stromal cells KW - stem cells KW - MSC KW - biodistribution KW - safety KW - ABCB5 KW - GMP KW - tumorigenicity KW - toxicity KW - persistence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240456 VL - 21 ER - TY - JOUR A1 - Göttlich, Claudia A1 - Kunz, Meik A1 - Zapp, Cornelia A1 - Nietzer, Sarah L. A1 - Walles, Heike A1 - Dandekar, Thomas A1 - Dandekar, Gudrun T1 - A combined tissue-engineered/in silico signature tool patient stratification in lung cancer JF - Molecular Oncology N2 - Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this, we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations, we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: It correctly shows a strong drug response upon gefitinib (Gef) treatment in a cell line harboring an EGFR-activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549). In contrast, 2D testing implies wrongly KRAS as a biomarker for HSP90 inhibitor treatment, although this fails in clinical studies. Signaling analysis by phospho-arrays showed similar effects of EGFR inhibition by Gef in HCC827 cells, under both 2D and 3D conditions. Western blot analysis confirmed that for 3D conditions, HSP90 inhibitor treatment implies different p53 regulation and decreased MET inhibition in HCC827 and H441 cells. Using in vitro data (western, phospho-kinase array, proliferation, and apoptosis), we generated cell line-specific in silico topologies and condition-specific (2D, 3D) simulations of signaling correctly mirroring in vitro treatment responses. Networks predict drug targets considering key interactions and individual cell line mutations using the Human Protein Reference Database and the COSMIC database. A signature of potential biomarkers and matching drugs improve stratification and treatment in KRAS-mutated tumors. In silico screening and dynamic simulation of drug actions resulted in individual therapeutic suggestions, that is, targeting HIF1A in H441 and LKB1 in A549 cells. In conclusion, our in vitro tumor tissue model combined with an in silico tool improves drug effect prediction and patient stratification. Our tool is used in our comprehensive cancer center and is made now publicly available for targeted therapy decisions. KW - 3D lung tumor model KW - Boolean signaling network KW - chemoresistance KW - HSP90 inhibitor KW - insilico drug screening too KW - KRAS mutation signature Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233137 VL - 12 ER - TY - JOUR A1 - Stromecki, Margaret A1 - Tatari, Nazanin A1 - Coudière Morrison, Ludivine A1 - Kaur, Ravinder A1 - Zagozewski, Jamie A1 - Palidwor, Gareth A1 - Ramaswamy, Vijay A1 - Skowron, Patryk A1 - Wölfl, Matthias A1 - Milde, Till A1 - Del Bigio, Marc R. A1 - Taylor, Michael D. A1 - Werbowetski-Ogilvie, Tamra E. T1 - Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma JF - Molecular Oncology N2 - Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo. To determine how OTX2 contributes to these processes, we employed complementary bioinformatic approaches to characterize the OTX2 regulatory network and identified novel relationships between OTX2 and genes associated with neuronal differentiation and axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX2 levels were negatively correlated with semaphorin (SEMA) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX2 knockdown with some being potential direct OTX2 targets. Importantly, this negative correlation was also observed in patient samples, with lower expression of SEMA4D associated with poor outcome specifically in Group 4 tumors. Functional proof-of-principle studies demonstrated that increased levels of select SEMA pathway genes are associated with decreased self-renewal and growth in vitro and in vivo and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX2 KD phenotype. Our study provides mechanistic insight into the networks controlled by OTX2 in MB stem/progenitor cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors in MB. KW - axon guidance genes KW - medulloblastoma KW - orthodenticle homeobox 2 KW - RHO KW - semaphorin KW - stem cells Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240089 VL - 12 ER - TY - JOUR A1 - Hoenigl, Martin A1 - Orasch, Thomas A1 - Faserl, Klaus A1 - Prattes, Juergen A1 - Loeffler, Juergen A1 - Springer, Jan A1 - Gsaller, Fabio A1 - Reischies, Frederike A1 - Duettmann, Wiebke A1 - Raggam, Reinhard B. A1 - Lindner, Herbert A1 - Haas, Hubertus T1 - Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis JF - Journal of Infection N2 - Objectives Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA. Methods We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples. Results TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient. Conclusion For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis. KW - aspergillosis KW - biomarker KW - diagnosis KW - siderophore KW - urine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320939 VL - 78 ER - TY - JOUR A1 - Heimann, Sebastian M. A1 - Penack, Olaf A1 - Heinz, Werner J. A1 - Rachow, Tobias A1 - Egerer, Gerlinde A1 - Kessel, Johanna A1 - Claßen, Annika Y. A1 - Vehreschild, Jörg Janne T1 - Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals JF - International Journal of Infectious Diseases N2 - Objectives Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. Conclusions Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species. KW - invasive fungal infection KW - neutropenia KW - posaconazole serum level KW - clinical effectiveness KW - high-risk patient Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319567 VL - 83 ER - TY - JOUR A1 - Storey, Benjamin C. A1 - Staplin, Natalie A1 - Haynes, Richard A1 - Reith, Christina A1 - Emberson, Jonathan A1 - Herrington, William G. A1 - Wheeler, David C. A1 - Walker, Robert A1 - Fellström, Bengt A1 - Wanner, Christoph A1 - Landray, Martin J. A1 - Baigent, Colin T1 - Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation JF - Kidney International N2 - Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration. KW - C-reactive protein KW - inflammation KW - LDL cholesterol KW - randomized trials KW - vascular disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240067 VL - 93 ER - TY - JOUR A1 - Zhang, Zishuai A1 - Ye, Siyu A1 - Gbureck, Uwe A1 - Barralet, Jake E. A1 - Merle, Géraldine T1 - Cavitation Mediated 3D Microstructured Architectures from Nanocarbon JF - Advanced Functional Materials N2 - Here, the formation of high surface area microscale assemblies of nanocarbon through phosphate and ultrasound cavitation treatment is reported. Despite high conductivity and large surface area, potential health and safety concerns limit the use of nanocarbon and add challenges to handling. Previously, it is shown that phosphate ultrasonic bonding is ineffective for organic materials but in this study, it is found that by a preliminary oxidizing treatment, several carbons can be readily assembled from xerogels. Assembling nanocarbon into microparticles can usually require a binder or surfactants, which can reduce surface area or conductivity and generate a low microsphere yield. Carbon nanotube microspheres are nitrogen-doped and flower-like nanostructured Pt deposited on their surface, and finally showcased as efficient cathode electrocatalysts for the oxygen reduction reaction (half-wave potential 0.78 V vs reversible hydrogen electrode) and methanol oxidation (417 mA mg−1). In particular, no significant degradation of the catalysts is detected after 12 000 cycles (26.6 h). These results indicate the potential of this multimaterial assembly method and open a new way to improve handling of nanoscale materials. KW - carbon nanotube microspheres KW - cavitation KW - oxygen reduction reaction KW - platinum nanostructures Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233926 VL - 28 ER - TY - JOUR A1 - Mueller, Dolores A1 - Jung, Kathrin A1 - Winter, Manuel A1 - Rogoll, Dorothee A1 - Melcher, Ralph A1 - Kulozik, Ulrich A1 - Schwarz, Karin A1 - Richling, Elke T1 - Encapsulation of anthocyanins from bilberries – Effects on bioavailability and intestinal accessibility in humans JF - Food Chemistry N2 - Anthocyanins are flavonoids that have been suggested to provide beneficial health effects. The biological activity of anthocyanins is influenced by their pharmacokinetic properties, but anthocyanins are associated with limited bioavailability in humans. In the presented study, we investigated how the encapsulation of bilberry extract (BE), a source of anthocyanins, with either whey protein or citrus pectin influences the bioavailability and intestinal accessibility of anthocyanins in humans. We performed an intervention study that analyzed anthocyanins and their degradation products in the urine, plasma, and ileal effluent of healthy volunteers and ileostomists (subjects without an intact colon). We were able to show, that whey protein encapsulation modulated short-term bioavailability and that citrus pectin encapsulation increased intestinal accessibility during passage through the small intestine and modulated the formation of the degradation product phloroglucinol aldehyde (PGAL) in human plasma. KW - anthocyanins KW - encapsulation KW - human intervention KW - bioavailability KW - phloroglucinol aldehyde Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224247 VL - 248 ER - TY - JOUR A1 - McMaster, Rebecca A1 - Hoefner, Christiane A1 - Hrynevich, Andrei A1 - Blum, Carina A1 - Wiesner, Miriam A1 - Wittmann, Katharina A1 - Dargaville, Tim R. A1 - Bauer-Kreisel, Petra A1 - Groll, Jürgen A1 - Dalton, Paul D. A1 - Blunk, Torsten T1 - Tailored Melt Electrowritten Scaffolds for the Generation of Sheet-Like Tissue Constructs from Multicellular Spheroids JF - Advanced Healthcare Materials N2 - Melt electrowriting (MEW) is an additive manufacturing technology that is recently used to fabricate voluminous scaffolds for biomedical applications. In this study, MEW is adapted for the seeding of multicellular spheroids, which permits the easy handling as a single sheet-like tissue-scaffold construct. Spheroids are made from adipose-derived stromal cells (ASCs). Poly(ε-caprolactone) is processed via MEW into scaffolds with box-structured pores, readily tailorable to spheroid size, using 13–15 µm diameter fibers. Two 7–8 µm diameter “catching fibers” near the bottom of the scaffold are threaded through each pore (360 and 380 µm) to prevent loss of spheroids during seeding. Cell viability remains high during the two week culture period, while the differentiation of ASCs into the adipogenic lineage is induced. Subsequent sectioning and staining of the spheroid-scaffold construct can be readily performed and accumulated lipid droplets are observed, while upregulation of molecular markers associated with successful differentiation is demonstrated. Tailoring MEW scaffolds with pores allows the simultaneous seeding of high numbers of spheroids at a time into a construct that can be handled in culture and may be readily transferred to other sites for use as implants or tissue models. KW - 3D printing KW - additive manufacturing KW - adipose tissue engineering Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223921 VL - 8 ER - TY - JOUR A1 - Selcuk, Nalan Alan A1 - Toklu, Turkay A1 - Beykan, Seval A1 - Karaaslan, Serife Ipek T1 - Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer JF - Journal of Applied Clinical Medical Physics N2 - In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole-body counts were collected at 2, 24, 72, and 120 h after I-131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I-131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th-hour uptake and time-integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion-based dosimetry. KW - bone marrow dosimetry KW - remnant tissue dosimetry KW - thyroid ablation treatment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235882 VL - 19 ER - TY - THES A1 - Aljasem, Anwar T1 - Der Einfluss des Hepatocyte growth factors auf die PD-L1-Expression in Kopf-Hals-Karzinomen: Die Bedeutung des MAPK-, AKT- und STAT3-Signalwegs T1 - The impact of Hepatocyte growth factor (HGF) on PD-L1 expression in HNSCC: The meaning of MAPK, AKT, and STAT3 signaling pathways N2 - Die zielgerichtete Therapie und die Immuncheckpoint-Inhibitoren haben die Tumortherapie revolutioniert. Während erstere die Tumorzellen gezielt angreift, verhindern letztere die Hemmung des Immunsystems durch Immuncheckpoints, um eine robuste Immunantwort zu erreichen. Zusätzlich ist das Nebenwirkungsprofil bei direktem Vergleich mit der konventionellen Chemotherapie günstiger. Beim HNSCC werden beide Ansätze angewendet. Cetuximab ist ein monoklonaler Antikörper, der sich gegen EGFR, welcher bei HNSCC überexprimiert ist, richtet. Nivolumab und Pembrolizumab richten sich gegen das Immuncheckpoint-Protein PD-1. Nach wie vor sind die Resistenzen, sowohl die initialen als auch die erworbenen, die größte zu überwindende Herausforderung. Aufbauend auf dem Ergebnis vorangegangener Arbeiten, die zeigen konnten, dass HGF über c-MET die Expression des Immuncheckpointliganden PD-L1 steigert, setzt sich diese Arbeit weiter mit den intrazellulären nachgeschalteten Signalwegen nach c-MET Aktivierung auseinander. Dies ist von besonderem Interesse, weil diese Signalwege ebenfalls für die Resistenzentwicklung verantwortlich sein können, zeitgleich können diese im Rahmen der zielgerichteten Therapie gezielt inhibiert werden. Um den HGF-Einfluss auf die intrazellulären Signalwege zu prüfen, wurden vier etablierte HNSCC-Zelllinien herangezogen. Im ersten Teil der Arbeit wurden die 4 HNSCC-abgeleitete Zelllinien mit HGF stimuliert und mittels Western Blot der PD-L1-Anstieg und die Phosphorylierungsänderung der Schlüsselproteine der einzelnen Signalwege nachgewiesen. Daraus ergab sich, dass HGF die MAPK- und PIK3/AKT-Signalwege aktiviert. Während eine kombinierte Blockade des MAPK-Signalwegs den PD-L1-Anstieg vollständig verhindern konnte, hemmte die PIK3/AKT-Blockade den PD-L1-Anstieg nur partiell. Im zweiten Teil wurde mit siRNA der hauptsächlich für den PD-L1-Anstieg zuständige MAPK-Signalweg unterbunden, was mittels quantitativer PCR auf der mRNA-Ebene nachgewiesen werden konnte. Mittels Western Blot konnte entsprechend gezeigt werden, dass der PD-L1-Anstieg trotz HGF-Stimulation bei nicht funktionsfähigem MAPK-Signalweg eingeschränkt war. Weiter wurde der Effekt mit dem Medikament Trametinib, das im Rahmen der zielgerichteten Therapie bei malignem Melanom und NSCLC für die MAPK-Signalweg-Hemmung zugelassen ist, evaluiert. Sowohl im Western Blot als auch in der Durchflusszytometrie konnte bestätigt werden, dass Trametinib den HGF-induzierten Anstieg von PD-L1 signifikant blockiert. Darüber hinaus konnte im Rahmen der Western Blot-Versuche gezeigt werden, dass die Signalwege und die PD-L1-Expression in den Zelllinien unterschiedlich aktiv bzw. hoch waren. Unter den vier Zelllinien zeigte die FaDu-Zelllinie eine erhöhte PI3K/AKT-Aktivität, Detroit562 und SCC9 eine erhöhte MAPK-Aktivität. Die PD-L1- Expression war in der SCC9-Zelllinie am höchsten. Die Arbeit zeigt eine einheitliche Reaktion der HNSCC-Zelllinien auf den Wachstumsfaktor HGF, welcher im Tumormilieu von HNSCC oft in hoher Konzentration vorhanden ist. Neben dem EGFR-Antikörper (Cetuximab) kann eine kombinierte Hemmung entweder von c-MET oder von den nachgeschalteten Signalwegen MAPK und PI3K/AKT bei Resistenzen, Progression oder Unverträglichkeiten eine Möglichkeit für eine wirksamere Therapie von HNSCC darstellen. Ein Screening der Signalwege und deren Aktivierungsmechanismen könnte bei Resistenzen oder bei einem Rezidiv/Progress dazu beitragen, gezielt die alternative Aktivierung zu hemmen und möglicherweise die Wirksamkeit einer Immuncheckpointblockade zu verbessern. N2 - Targeted therapy and immune checkpoint inhibitors have revolutionized tumor therapy. While the former specifically targets tumor cells, the latter prevents inhibitory immune responses via immune checkpoints to achieve a robust immune response. Additionally, the side effect profile is more favorable when directly compared to conventional chemotherapy. Both approaches are approved for the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC). Cetuximab is a monoclonal antibody that targets EGFR, which is overexpressed in HNSCC. Nivolumab and Pembrolizumab target the immune checkpoint protein PD-1. Resistances, both initial and acquired, however, remain significant challenges to overcome. Building on a previous report that HGF upregulates the immune checkpoint ligand PD-L1 expression via the c-MET pathway, this study investigates the intracellular downstream signaling pathways activated by HGF. This is of particular interest because these signaling pathways contribute to resistance development, while at the same time, they can be specifically inhibited in the context of targeted therapy. To examine the influence of HGF on intracellular signaling pathways, four established HNSCC cell lines were utilized. In the first part of the study, the four HNSCC-derived cell lines were stimulated with HGF, and the increase in PD-L1 expression and changes in phosphorylation levels of key proteins in the individual signaling pathways were analyzed using Western Blots. It was found that HGF activates the MAPK and PI3K/AKT pathways. While MAPK inhibition completely blocked the PD-L1 increase, PI3K/AKT inhibition only partially did so after HGF stimulation. In the second part, the MAPK pathway, mainly responsible for the increase in PD-L1, was inhibited using siRNA. Quantitative PCR validated corresponding mRNA levels. Western Blots further showed that the increase in PD-L1 was reduced despite HGF stimulation when the MAPK pathway was non-functional. In line with previous results, inhibiting MAPKs with the drug Trametinib, which is approved as a targeted therapy for malignant melanoma and NSCLC, significantly blocks HGF-induced PD-L1 expression based on Western Blot and flow cytometry analysis. Notably, the activity of the different signaling pathways and the expression levels of PD-L1 vary among the different cell lines, as Western Blot analyses reveal. For instance, while the FaDu cell line manifested high activity in the PI3K/AKT pathway, Detroit562 and SCC9 showed increased MAPK activity. Nonetheless, the SCC9 cell line showed the highest PD-L1 expression level. This study demonstrated that HNSCC cell lines similarly respond to the growth factor HGF, which is frequently present in high concentrations in the tumor microenvironment of HNSCC. Additionally, the inhibition of c-MET and its downstream MAPK or PI3K/AKT pathways in combination with EGFR blockade by Cetuximab may offer a more effective treatment strategy for HNSCC patients in cases of therapeutic resistance, disease progression, or drug intolerance. Screening of the signaling pathways and their activation mechanisms could, in cases of resistance, recurrence, or progression, contribute to the specific inhibition of alternative activation and potentially improve the efficacy of immune checkpoint blockade. KW - Hepatozyten-Wachstumsfaktor KW - MAP-Kinase KW - Plattenepithelcarcinom KW - PD-L1 Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370358 ER - TY - THES A1 - Müller, Nicole T1 - Modellierung klonaler Evolution beim Multiplen Myelom T1 - Modeling Clonal Evolution in Multiple Myeloma N2 - In dieser Arbeit wurde ein modulares Zelllinienmodell zur Visualisierung klonaler Evolutionsmechanismen etabliert. Hierfür wurden unterschiedlich fluoreszierende Proteine (LSSmKate2, EGFP, mTagBFP2) durch Anwendung eines Sleeping Beauty basierten Vektorsystems in unterschiedliche Sublinien der Myelom Zelllinie L363 eingebracht. Diese vier Sublinien beinhalten jeweils eine von drei aus primären Patientenproben gewonnenen Mutationen in IKZF1 (A152T, E170D, R439H) oder den IKZF1 WT. Die Anwendung von immunmodulatorischen Medikamenten (IMiDs) führt zu einer Ubiquitinierung des Transkriptionsfaktors IKZF1 durch die E3-Ubiquitin-Protein-Ligase (CRBN-CUL4). Durch Mutationen in IKZF1 kommt es zu Störungen in diesem Prozess und damit zu einer Überexpression von IKZF1. Dies wirkt sich wachstumsfördert auf die Myelomzellen aus. Die Auswirkungen der einzelnen Mutationen in IKZF1 ist aufgrund dessen ein klinisch relevantes Forschungsthema. In dieser Arbeit wurden jeweils zwei Sublinien mit Zellen des IKZF1 WT und Zellen mit einer IKZF1 Mutation mit jeweils unterschiedlich fluoreszierenden Proteinen markiert. Diese wurden gemeinsam unter Behandlung mit verschiedenen Konzentrationen von Lenalidomid inkubiert. Somit konnte das Selektionsverhalten mittels Durchflusszytometrie-Auswertungen visualisiert werden. Es konnte gezeigt werden, dass die IKZF1 Mutation A152T einen deutlichen Selektionsvorteil für die Myelomzellen darstellt. Bei den IKZF1 Mutationen E170D und R439H konnte kein Selektionsvorteil gegenüber dem IKZF1 WT beobachtet werden. N2 - In this work, a modular cell line model was established to visualize clonal evolutionary mechanisms. Different fluorescent proteins (LSSmKate2, EGFP, mTagBFP2) were introduced into various sublines of the myeloma cell line L363 using a Sleeping Beauty-based vector system. These four sublines each contain one of three mutations in IKZF1 (A152T, E170D, R439H) derived from primary patient samples or the IKZF1 wild type (WT). The application of immunomodulatory drugs (IMiDs) leads to the ubiquitination of the transcription factor IKZF1 by the E3 ubiquitin-protein ligase (CRBN-CUL4). Mutations in IKZF1 disrupt this process, resulting in the overexpression of IKZF1, which promotes the growth of myeloma cells. The effects of individual mutations in IKZF1 are therefore a clinically relevant research topic. In this study, two sublines each with IKZF1 WT cells and cells with an IKZF1 mutation were labeled with different fluorescent proteins. These were incubated together under treatment with various concentrations of lenalidomide. Thus, the selection behavior could be visualized using flow cytometry analyses. It was shown that the IKZF1 mutation A152T provides a clear selective advantage for the myeloma cells. No selective advantage was observed for the IKZF1 E170D and R439H mutations compared to IKZF1 WT. KW - Lenalidomid KW - Plasmozytom KW - IKZF1 KW - klonale Evolution KW - Vektormodell KW - Multiples Myelom Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370818 ER - TY - JOUR A1 - Gorlova, Anna A1 - Pavlov, Dmitrii A1 - Anthony, Daniel C. A1 - Ponomarev, Eugene D. A1 - Sambon, Margaux A1 - Proshin, Andrey A1 - Shafarevich, Igor A1 - Babaevskaya, Diana A1 - Lesch, Klaus-Peter A1 - Bettendorff, Lucien A1 - Strekalova, Tatyana T1 - Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice JF - Neuropharmacology N2 - The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community. This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’. KW - aggression KW - emotional stress KW - brain oxidative stress KW - plasticity KW - thiamine KW - mice Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227439 VL - 156 ER - TY - JOUR A1 - Verheijen, Bert M. A1 - Stevens, Jo A. A. A1 - Gentier, Romina J. G. A1 - van't Hekke, Christian D. A1 - van den Hove, Daniel L. A. A1 - Hermes, Denise J. H. P. A1 - Steinbusch, Harry W. M. A1 - Ruijter, Jan M. A1 - Grimm, Marcus O. W. A1 - Haupenthal, Viola J. A1 - Annaert, Wim A1 - Hartmann, Tobias A1 - van Leeuwen, Fred W. T1 - Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model JF - Neurobiology of Aging N2 - Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals. KW - mutant ubiquitin KW - ubiquitin-proteasome system KW - γ-secretase KW - amyloid-β KW - behavior KW - Alzheimer's disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233185 VL - 72 ER - TY - THES A1 - Adolf, Jonas Michael T1 - Die Zusammenarbeit zwischen der stationären beziehungsweise teilstationären psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen T1 - The Collaboration between inpatient and semi-inpatient psychotherapeutic treatment and outpatient psychotherapists N2 - Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuität in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)stationären und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und – falls möglich – erste Möglichkeiten zur Verbesserung der derzeitigen Versorgungskontinuität aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich für Medizinische Psychologie und Psychotherapie im Zentrum für psychische Gesundheit des Universitätsklinikums Würzburg wurde hierzu ein Fragebogen entwickelt und acht ausgewählten psychotherapeutischen Fachgesellschaften beziehungsweise Psychotherapeutenkammern mit der Bitte um Weiterleitung an deren Mitglieder zugesandt. In der vorliegenden Studie wurden – neben einer Globalbeurteilung – im Speziellen die Teil-aspekte des Austauschs, der entsprechenden Rahmenbedingungen und die Bereitstellung des poststationären ambulanten Psychotherapieplatzes betrachtet. Die Studienergebnisse bilden den derzeitigen Status Quo der psychotherapeutischen Versorgungslage aus Sicht der niedergelassenen Psychotherapeut:innen ab und weisen im Zuge dessen auf einige Defizite in den untersuchten Teilaspekten hin. Die aufgestellten Nebenfragestellungen zeigen gleichsam aber auch Ansatzunkte für Lösungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es – zur Ermöglichung einer adäquaten kontinuierlichen psychotherapeutischen Versorgung – eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. Für ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)stationären Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten Möglichkeiten der vorliegenden Arbeit gilt es große repräsentative und nationale Studien anzustreben. Hierzu wäre die Etablierung zentral verwalteter Register zur Bündelung der bisherigen und zukünftigen Forschungsarbeiten im Bereich der Psychotherapie wünschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und könnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen. N2 - The aim of the study was to identify the current continuity of care regarding psychotherapeutic care and the collaboration of the (semi-)inpatient and outpatient field from point of view of the outpatient psychotherapists. Furthermore, the study wants to integrate the findings in the recent scientific context and wants to reveal improvements regarding the continuity of care in the field of psychotherapy. An explorative survey was created in collaboration with the working group of medical psychology and psychotherapy at the centre for mental health of the university hospital of Würzburg. Eight selected psychotherapeutic organisations (psychotherapy chambers and societies) were invited to conduct the survey to their members. Apart from a general assessment the study took a closer look at the framework conditions, the field of exchange and the care of outpatient psychotherapy to patients after (semi-)inpatient care. The study results describe the current situation of the psychotherapy care in Germany from the point of view of the outpatient psychotherapists and demonstrate on the one hand deficits regarding the analysed aspects and – as part of the side questions – on the other hand possible approaches for improvements. To facilitate a better continuity of psychotherapeutic care, it is important to take a closer look at the demonstrated deficits reported by the study. Moreover further studies are necessary treating the point of view of (semi-)inpatient psychotherapists as well as to conduct large national-wide representative studies, especially against the backdrop of the limited possibilities of the present study. For this purpose, it is helpful to establish a central-managed register to collect all studies in the field of psychotherapy. That could contribute to improve the current situation of research and care in the field of psychotherapy, in particular against the backdrop of the numerous pilot projects. KW - Psychotherapie KW - Medizinische Versorgung KW - Versorgungskontinuität KW - Sektoren KW - Versorgung KW - Psychiatrie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371098 ER - TY - THES A1 - Weiß, Eva Maria T1 - Einfluss von Makrophagen auf autophagische Vorgänge in Schwann´schen Zellen unter den Bedingungen von Nervenläsion und genetisch bedingter Neuropathie T1 - Influence of macrophages on Schwann cell autophagy under the conditions of nerve lesion and genetic neuropathy N2 - Charcot-Marie-Tooth (CMT) Neuropathien stellen als häufigste erblich bedingte neurologische Erkrankungen eine Gruppe genetisch heterogener, chronisch progredienter peripherer Polyneuropathien dar. Die Lebensqualität der Patienten ist bei fehlender kurativer Therapieoption vor allem durch motorische und sensorische Defizite deutlich eingeschränkt. In verschiedenen Studien konnte die pathophysiologische Relevanz einer sekundären Entzündungsreaktion, insbesondere durch Makrophagen und Lymphozyten vermittelt, in Mausmodellen dreier CMT1 Subtypen (CMT1A, CMT1B, CMT1X) aufgezeigt werden. Auch in Folge einer Läsion peripherer Nerven ist eine akute Entzündungsreaktion von entscheidender Bedeutung, wobei sich bereits Gemeinsamkeiten zwischen der postläsionalen Waller´schen Degeneration (WD) und CMT1 Neuropathien identifizieren ließen. Während die aktive Beteiligung der Autophagie Schwann´scher Zellen (hier kurz SZ Autophagie genannt) an der Myelindegradation im Falle einer WD jedoch vielfach beschrieben wurde, ist Ähnliches in CMT1 Neuropathien bisher nur unzureichend untersucht. Da in einer Studie in Cx32def Mausmodellen der CMT1X Erkrankung auch nach Reduktion endoneuraler Makrophagen anhaltende Demyelinisierung beobachtet werden konnte, sollte das Vorkommen von SZ Autophagie sowie deren mögliche Beeinflussung durch Makrophagen in diesen Myelinmutanten untersucht werden. In der vorliegenden Arbeit wurden sowohl Wildtyp (Wt) Mäuse in ex vivo und in vivo Modellen einer WD als auch Cx32def Myelinmutanten zweier Altersstufen (4 und 12 Monate) mit einem niedermolekularen CSF1-Rezeptor-Inhibitor (CSF1RI) zur Reduktion endoneuraler Makrophagen behandelt, wobei sich vergleichende histochemische bzw. immunhistochemische Analysen peripherer Nerven behandelter und unbehandelter Tiere anschlossen. Im Rahmen der Etablierung immunhistochemischer Methodik zeigte sich hierbei unter den kontrollierten Bedingungen einer ex vivo Ischiasnervenkultur eine vermehrte Aktivierung der SZ Autophagie in behandelten Wt Mäusen. Auch 4 Monate alte behandelte Cx32def Tiere wiesen, verglichen mit unbehandelten Myelinmutanten bzw. Wt Mäusen derselben Altersstufe, eine vermehrte autophagische Aktivität in SZ auf. Diese scheint sich jedoch im weiteren Verlauf der Erkrankung zu reduzieren, da im Falle der 12 Monate alten Cx32def Modelltiere weniger autophagisch aktive SZ Profile bzw. kaum Unterschiede zwischen behandelten und unbehandelten Tieren beobachtet werden konnten. Die Ergebnisse lassen somit eine mögliche aktive Beteiligung von SZ Autophagie insbesondere in der Pathophysiologie der frühen Phase einer CMT1X Erkrankung sowie deren Beeinflussung durch endoneurale Makrophagen vermuten. Dies sollte vornehmlich in der Entwicklung von Therapiestrategien der CMT1X bedacht werden, da sich eine frühe Reduktion pathophysiologisch relevanter endoneuraler Makrophagen somit auch nachteilig auf die Myelinintegrität auswirken könnte. N2 - Charcot-Marie-Tooth (CMT) neuropathies are the most common hereditary neurological diseases and represent a group of genetically heterogeneous, chronically progressive peripheral polyneuropathies. In the absence of curative treatment options, patients' quality of life is significantly impaired, primarily due to motor and sensory deficits. Various studies have demonstrated the pathophysiological relevance of a secondary inflammatory reaction, in particular mediated by macrophages and lymphocytes, in mouse models of three CMT1 subtypes (CMT1A, CMT1B, CMT1X). An acute inflammatory reaction is also of crucial importance following a lesion of peripheral nerves, whereby similarities between postlesional Wallerian degeneration (WD) and CMT1 neuropathies have already been identified. However, while the active involvement of Schwann cell autophagy (here referred to as SC autophagy) in myelin degradation in WD has been widely described, a similar involvement in CMT1 neuropathies has been insufficiently studied. Since in a study in Cx32def mouse models of CMT1X disease persistent demyelination could be observed even after reduction of endoneural macrophages, the occurrence of SC autophagy and its possible influence by macrophages in these myelin mutants should be investigated. In the present study, both wild-type (Wt) mice in ex vivo and in vivo models of WD and Cx32def myelin mutants of two ages (4 and 12 months) were treated with a small molecule CSF1 receptor inhibitor (CSF1RI) to reduce endoneural macrophages, followed by comparative histochemical and immunohistochemical analyses of peripheral nerves of treated and untreated animals, respectively. During the establishment of immunohistochemical methods, an increased activation of SC autophagy was shown in treated Wt mice under the controlled conditions of ex vivo sciatic nerve culture. Even 4-month-old treated Cx32def animals showed increased autophagic activity in SC compared to untreated myelin mutants or Wt mice of the same age. However, this appears to be reduced as the disease progresses, since in the case of the 12-month-old Cx32def model animals fewer autophagically active SC profiles or hardly any differences between treated and untreated animals could be observed. The results thus suggest a possible active involvement of SC autophagy, particularly in the pathophysiology of the early phase of CMT1X disease and its influence by endoneural macrophages. This should primarily be considered in the development of therapeutic strategies for CMT1X, as an early reduction of pathophysiologically relevant endoneural macrophages could therefore also have a detrimental effect on myelin integrity. KW - Schwann-Zelle KW - M-CSF KW - Autophagie KW - Charcot-Marie-Syndrom KW - Makrophage KW - Schwann´sche Zelle KW - Autophagie KW - hereditäre sensomotorische Neuropathie KW - Makrophagen KW - CSF-1 KW - Immunsystem Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369674 ER - TY - THES A1 - Ruppert [geb. Rapp], Elisabeth Marlene T1 - Einfluss von sozialem Stress und 5-Htt-Genotyp: Quantitative Untersuchung der Morphologie von Neuronen der lateralen Amygdala und der CA3-Region des Hippocampus von Mäusen der Serotonintransporter-Knockout-Linie T1 - Influence of social stress and 5-Htt genotype: Quantitative investigation of the morphology of neurons of the lateral amygdala and the CA3 region of the hippocampus of mice of the serotonin transporter knockout line N2 - In dieser Arbeit wurde der Einfluss sozialer Stresserfahrung sowie des 5-Htt-Genotyps auf die neuronale Morphologie bestimmter Hirnregionen anhand eines Mausmodells untersucht. Es wurde in mit Golgi-Cox gefärbten Gehirnen der 5-HTT-KO-Linie in der lateralen Amygdala (LA) die Apikal- und Basaldendriten pyramidenzellähnlicher Neurone und die Apikaldendriten der Pyramidenzellen der Cornu ammonis (CA)3-Region des Hippocampus mithilfe des Neurolucidasystems rekonstruiert und die so gewonnenen Daten anschließend statistisch ausgewertet. Die erzielten Ergebnisse belegen, dass vor allem die Erfahrung von sozialem Verteidigungsstress aber auch der 5-Htt-Genotyp (WT, HET, KO) im Mausmodell signifikanten Einfluss auf die Morphologie der Neurone der LA und der CA3-Region besitzen. Um die in dieser Arbeit mit allen drei 5-Htt-Genotypen erzielten Ergebnisse der LA-Neurone besser mit den Ergebnissen von Nietzer und Bonn (nur WT, KO) vergleichen zu können (Nietzer et al., 2011), wurden die von mir erhobenen Daten nicht nur in einem 3er-Vergleich, sondern auch einem 2er-Vergleich (WT vs. KO) statistisch analysiert. Untersuchungen der LA-Neurone aller drei 5-Htt-Genotypen zeigen, dass sozialer Stress zu einer Zunahme der Komplexität der Dendritenbäume durch längere und auch stärker verzweigte Dendriten vor allem in der Gruppe der WT-Mäuse führt. HET- und KO-Mäuse zeigten keinen entsprechenden Stress-Effekt. Darüber hinaus zeigten sich deutliche Genotypeffekte. Unabhängig vom Stresserleben besitzen HET-Mäuse längere Dendriten als WT-Mäuse sowie eine höhere Spinedichte als WT- und KO-Mäuse. Die Hypothese, die in der Arbeit von Nietzer et al. aufgestellt wurde, dass eine vollständige 5-HTT-Defizienz zu mehr Spines führt, ließ sich hier weder durch den 3er- noch durch den 2er-Vergleich replizieren. Die Pyramidenzellen der CA3-Region, die in dieser Studie zum ersten Mal analysiert wurden, zeigen in Bezug auf die durch den Stress ausgelösten Veränderungen ein im Vergleich zu den LA-Neuronen entgegengesetzten Effekt. Der soziale Stress führt hier zu einer Dendritenatrophie in der WT-Gruppe mit kürzeren und weniger komplexen Dendriten. Außerdem führte er zu einer geringeren Spinedichte bei den HET-Mäusen. Es zeigten sich klare Genotypeffekte, unabhängig von der Stresserfahrung, mit einer reduzierten Spinedichte der KO-Mäuse gegenüber den WT-Mäusen und einer nur in den Kontrollen detektierten, reduzierten Spinedichte der KO-Mäuse im Vergleich zu den WT- und HET-Mäusen. Sowohl in der LA als auch in der CA3-Region lassen sich Kompensationsmechanismen des 5-HTT-Defizits der HET-Tiere vermuten, über die die KO-Tiere nicht verfügen. Die in LA und CA3 gezeigten gegensätzlichen Auswirkungen des sozialen Stresses weisen auf die unterschiedlichen Funktionen dieser beiden Regionen im Furchtkreislauf und/oder bei der Verarbeitung von Stress hin. Darüber hinaus deutet diese Arbeit darauf hin, dass Arbeiten mit ähnlichen Untersuchungsmethoden und sogar gleichem Untersuchungsmaterial unterschiedliche Ergebnisse liefern können. N2 - In this study, the influence of social stress experience and the 5-Htt genotype on the neuronal morphology of certain brain regions was investigated using a mouse model. The apical and basal dendrites of pyramidal cell-like neurons and the apical dendrites of the pyramidal cells of the cornu ammonis (CA)3 region of the hippocampus were reconstructed in Golgi-Cox-stained brains of the 5-HTT-KO line in the lateral amygdala (LA) using the neurolucida system and the data obtained was then statistically analyzed. The results obtained show that especially the experience of social defense stress but also the 5-Htt genotype (WT, HET, KO) have a significant influence on the morphology of the neurons of the LA and the CA3 region in the mouse model. In order to better compare the results of the LA neurons obtained in this study with all three 5-Htt genotypes with the results of Nietzer and Bonn (WT, KO only) (Nietzer et al., 2011), the data collected by me were statistically analyzed not only in a 3-way comparison, but also in a 2-way comparison (WT vs. KO). Investigations of the LA neurons of all three 5-Htt genotypes show that social stress leads to an increase in the complexity of the dendrite trees due to longer and also more branched dendrites, especially in the group of WT mice. HET and KO mice showed no corresponding stress effect. In addition, there were clear genotype effects. Regardless of the stress experience, HET mice have longer dendrites than WT mice and a higher spin density than WT and KO mice. The hypothesis put forward in the work of Nietzer et al. that complete 5-HTT deficiency leads to more spines could not be replicated here by either the 3-way or 2-way comparison. The pyramidal cells of the CA3 region, which were analyzed for the first time in this study, show an opposite effect compared to the LA neurons with regard to the changes triggered by stress. Here, social stress leads to dendrite atrophy in the WT group with shorter and less complex dendrites. It also led to a lower spin density in the HET mice. There were clear genotype effects, independent of the stress experience, with a reduced spin density in the KO mice compared to the WT mice and a reduced spin density in the KO mice compared to the WT and HET mice, which was only detected in the controls. Compensatory mechanisms for the 5-HTT deficit in the HET animals, which the KO animals do not have, can be assumed in both the LA and the CA3 region. The contrasting effects of social stress shown in LA and CA3 indicate the different functions of these two regions in the fear circuit and/or in the processing of stress. Furthermore, this work suggests that studies using similar research methods and even the same research material may yield different results. KW - Serotoninstoffwechsel KW - Hippocampus KW - Stress KW - Corpus amygdaloideum KW - Ammonshorn KW - CA3-Region KW - laterale Amygdala KW - sozialer Stress KW - Serotonintransporter-Knockout-Linie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369488 ER - TY - THES A1 - Klüpfel, Marina Anna T1 - Lagedarstellung und -Bewertung durch den Einsatz des Windmühlenmodells - Einführung und Nutzung im Rahmen der SARS-CoV-2 Pandemie T1 - Situational report and assessment using the windmill model – implementation and application during the SARS-CoV-2 pandemic N2 - Bei Großschadensereignissen oder Katastrophen arbeiten die Einsatzkräfte verschiedener Organisationen und Krankenhäuser zusammen, um die Schadenslage zu bewältigen. Für die Koordinierung dieser Einsätze benötigen die Führungskräfte ein möglichst genaues Bild der aktuellen Lage. Auch im Rahmen der SARS-CoV-2- Pandemie war eine Übersicht über die Versorgungslage der Krankenhäuser erforderlich, um mögliche lokale Ressourcenengpässe frühzeitig zu erkennen und durch geeignete Maßnahmen zu beheben. Zu diesem Zweck wurde in Bayern im November 2021 das Windmühlen-Modell eingeführt. Basierend auf einer Online-Plattform meldeten die zuständigen Bezirkskoordinierenden der bayerischen Regierungsbezirke täglich die Versorgungslage ihrer Kliniken anhand der Komponenten Personal, Material und Raum. Außerdem gab es die Möglichkeit zur Dokumentation von Patientenverlegungen. Die über die Windmühlen-Onlineplattform gesammelten Lagemeldungen und dokumentierten Verlegungen des Zeitraums von 21. November 2021 bis 20. Februar 2022 wurden in der vorliegenden Arbeit detailliert aufbereitet. Zusätzlich wurden die erfassten Daten statistisch ausgewertet und mit den örtlichen 7-Tage-Inzidenzwerten des SARS-CoV-2-Virus verglichen. Durch das Windmühlen-Modell konnten Unterschiede in der Versorgungslage zwischen den Regierungsbezirken sehr effektiv sichtbar gemacht werden. Insgesamt waren Intensivstationen deutlich stärker belastet als Normalstationen. Die Versorgungsqualität war in Covid-Bereichen stärker beeinträchtigt als auf Stationen ohne Covid-Patienten. Es konnte nachgewiesen werden, dass die Windmühlen-Lagemeldungen nicht allein die regionalen Inzidenzwerte, sondern die tatsächliche Versorgungssituation vor Ort abbilden. Die dokumentierten Interhospitaltransfers erfolgten von Regionen mit hohen Inzidenzwerten und schlechter Ressourcenverfügbarkeit in Bezirke mit weniger kritischer Versorgungslage. Damit konnten aus den Windmühlen-Lagemeldungen auch konkrete Handlungskonsequenzen, wie strategische Patientenverlegungen, abgeleitet werden. Lagemeldungen sind wichtig für die abgestimmte Zusammenarbeit verschiedener Stellen bei der Bewältigung einer Krise. Die etablierten Systeme zur Lageerfassung sind meist quantitativ ausgelegt und nur wenig skalierbar. Die Anwendung in einem neuen Kontext erfordert oft zeitaufwändige Anpassungen. Im Gegensatz dazu bietet das Windmühlen-Modell eine skalierbare, eher qualitativ ausgerichtete Lagedarstellung und ist aufgrund seines unkomplizierten Aufbaus innerhalb kürzester Zeit für eine Nutzung in verschiedensten Schadenslagen adaptierbar. N2 - During large-scale emergencies and disasters, relief units and hospital staff work together to manage the critical situation. Command and control structures need a detailed situational assessment to coordinate relief efforts. During the SARS-CoV-2 pandemic an overview of hospital supplies and resources was vital to detect local shortages early and find appropriate measures to resolve them. For this purpose, the windmill model was implemented in Bavaria, Germany, in November 2021. Based on an online platform, the seven Bavarian districts gave daily updates on their hospitals’ situation regarding staff, supplies and space. Additionally, there was a tool to record patient transfers to different hospitals. In the dissertation at hand the data collected by the windmill-online platform from 21. November 2021 to 20. February 2022 was evaluated, statistically analyzed and compared to the local 7-day-incidence rates of SARS-CoV-2 virus. The windmill model was able to very effectively showcase differences in strain on the hospital care capacities amongst the districts. Overall, the intensive care units were burdened more heavily than standard care units. The quality of hospital care on Covid-wards was impaired more strongly than on non-Covid-wards. This thesis provides evidence for the windmill situation reports not only depicting the local incidence rates but portraying the actual current hospital care capacities in the districts. The documented patient transfers took place from regions with high incidence rates and poor resource availability to districts with a less critical situation. Thus, specific consequences, like strategic patient transfers, were deduced from situational reports in the windmill model. Situational reports are crucial in collaboration for crisis management. Established systems for situational assessment are often based on quantitative analysis and lack scalability. Using those in a different scenario would require time-consuming adaptations. In contrast the windmill model provides a scalable more qualitatively based situational assessment and is, due to its straightforward format, quickly adaptable to use in any future disaster. KW - Katastrophenmedizin KW - Massenanfall von Verletzten oder Erkrankten KW - Notfallmedizin KW - Einsatzleitung KW - Lagedarstellung Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369595 ER - TY - JOUR A1 - Kampf, Thomas A1 - Bauer, Wolfgang Rudolf A1 - Reiter, Theresa T1 - Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function JF - Zeitschrift für Medizinische Physik N2 - Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. Materials and methods All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. Results Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25% (18–33%; SD 0.03) in the healthy, 30% (22–40%; SD 0.04) in patients with DCM and 45% (30–60%; SD 0.9) in patients with amyloidosis. Conclusion The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases. KW - T1-mapping KW - ECV KW - MOLLI KW - post-processing Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325481 VL - 28 ER - TY - JOUR A1 - Nanadikar, Maithily S. A1 - Vergel Leon, Ana M. A1 - Borowik, Sergej A1 - Hillemann, Annette A1 - Zieseniss, Anke A1 - Belousov, Vsevolod V. A1 - Bogeski, Ivan A1 - Rehling, Peter A1 - Dudek, Jan A1 - Katschinski, Dörthe M. T1 - O2 affects mitochondrial functionality ex vivo JF - Redox Biology N2 - Mitochondria have originated in eukaryotic cells by endosymbiosis of a specialized prokaryote approximately 2 billion years ago. They are essential for normal cell function by providing energy through their role in oxidizing carbon substrates. Glutathione (GSH) is a major thiol-disulfide redox buffer of the cell including the mitochondrial matrix and intermembrane space. We have generated cardiomyocyte-specific Grx1-roGFP2 GSH redox potential (EGSH) biosensor mice in the past, in which the sensor is targeted to the mitochondrial matrix. Using this mouse model a distinct EGSH of the mitochondrial matrix (−278.9 ± 0.4 mV) in isolated cardiomyocytes is observed. When analyzing the EGSH in isolated mitochondria from the transgenic hearts, however, the EGSH in the mitochondrial matrix is significantly oxidized (−247.7 ± 8.7 mV). This is prevented by adding N-Ethylmaleimide during the mitochondria isolation procedure, which precludes disulfide bond formation. A similar reducing effect is observed by isolating mitochondria in hypoxic (0.1–3% O2) conditions that mimics mitochondrial pO2 levels in cellulo. The reduced EGSH is accompanied by lower ROS production, reduced complex III activity but increased ATP levels produced at baseline and after stimulation with succinate/ADP. Altogether, we demonstrate that oxygenation is an essential factor that needs to be considered when analyzing mitochondrial function ex vivo. KW - glutathione redox potential KW - hypoxia KW - mitochondrial matrix KW - Grx1-roGFP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232217 VL - 22 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Urlaub, Daniela A1 - Mayer, Christine A1 - Uehlein, Sabrina A1 - Held, Melissa A1 - Sommer, Claudia T1 - Tumor necrosis factor-α links heat and inflammation with Fabry pain JF - Molecular Genetics and Metabolism N2 - Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain. KW - Fabry disease KW - Fabry pain KW - tumor necrosis factor-α KW - peripheral blood mononuclear cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229190 VL - 127 ER - TY - JOUR A1 - Kampf, Thomas A1 - Reiter, Theresa A1 - Bauer, Wolfgang Rudolf T1 - An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery – Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts JF - Zeitschrift für Medizinische Physik N2 - Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner. T2 - Ein analytisches Modell, das die apparente T1 Zeit für Modfied Look-Locker Inversion Recovery bestimmt-Analyse der longitudinalen Relaxation unter dem Einfluss diskontinuierlicher balanced (klassische MOLLI) und spoiled gradient echo readouts KW - longitudinal relaxation KW - T1 KW - T2 KW - Lock Locker KW - MOLLI KW - balanced steady state free precession KW - spoiled gradient echo Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325498 VL - 28 ER - TY - JOUR A1 - Duell, Johannes A1 - Lammers, Philip E. A1 - Djuretic, Ivana A1 - Chunyk, Allison G. A1 - Alekar, Shilpa A1 - Jacobs, Ira A1 - Gill, Saar T1 - Bispecific Antibodies in the Treatment of Hematologic Malignancies JF - Clinical Pharmacology & Therapeutics N2 - Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226392 VL - 106 ER - TY - JOUR A1 - Angay, Oguzhan A1 - Friedrich, Mike A1 - Pinnecker, Jürgen A1 - Hintzsche, Henning A1 - Stopper, Helga A1 - Hempel, Klaus A1 - Heinze, Katrin G. T1 - Image-based modeling and scoring of Howell–Jolly Bodies in human erythrocytes JF - Cytometry Part A N2 - The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell–Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a “critical distance” dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit—a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. KW - fluorescence imaging KW - splenic function KW - Jolly bodies KW - image analysis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221140 VL - 93 ER - TY - JOUR A1 - Müntze, Jonas A1 - Nordbeck, Peter T1 - Response to “Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data” JF - Clinical Pharmacology & Therapeutics N2 - No abstract available Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231600 VL - 106 ER - TY - JOUR A1 - Frantz, Stefan A1 - Falcao-Pires, Ines A1 - Balligand, Jean-Luc A1 - Bauersachs, Johann A1 - Brutsaert, Dirk A1 - Ciccarelli, Michele A1 - Dawson, Dana A1 - de Windt, Leon J. A1 - Giacca, Mauro A1 - Hamdani, Nazha A1 - Hilfiker-Kleiner, Denise A1 - Hirsch, Emilio A1 - Leite-Moreira, Adelino A1 - Mayr, Manuel A1 - Thum, Thomas A1 - Tocchetti, Carlo G. A1 - van der Velden, Jolanda A1 - Varricchi, Gilda A1 - Heymans, Stephane T1 - The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC JF - European Journal of Heart Failure N2 - Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies. KW - immune system KW - macrophage KW - T-cell KW - ischaemic cardiomyopathy KW - hypertensive cardiomyopathy KW - diabetic cardiomyopathy KW - toxic cardiomyopathy KW - viral cardiomyopathy KW - genetic cardiomyopathy KW - peripartum cardiomyopathy KW - autoimmune cardiomyopathy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229091 VL - 20 ER - TY - JOUR A1 - de Boer, Rudolf A. A1 - De Keulenaer, Gilles A1 - Bauersachs, Johann A1 - Brutsaert, Dirk A1 - Cleland, John G. A1 - Diez, Javier A1 - Du, Xiao-Jun A1 - Ford, Paul A1 - Heinzel, Frank R. A1 - Lipson, Kenneth E. A1 - McDonagh, Theresa A1 - Lopez-Andres, Natalia A1 - Lunde, Ida G. A1 - Lyon, Alexander R. A1 - Pollesello, Piero A1 - Prasad, Sanjay K. A1 - Tocchetti, Carlo G. A1 - Mayr, Manuel A1 - Sluijter, Joost P. G. A1 - Thum, Thomas A1 - Tschöpe, Carsten A1 - Zannad, Faiez A1 - Zimmermann, Wolfram-Hubertus A1 - Ruschitzka, Frank A1 - Filippatos, Gerasimos A1 - Lindsey, Merry L. A1 - Maack, Christoph A1 - Heymans, Stephane T1 - Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology JF - European Journal of Heart Failure N2 - Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research. KW - fibrosis KW - heart failure KW - biomarkers KW - fibroblast KW - matrix KW - prognosis KW - imaging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223613 VL - 21 ER - TY - JOUR A1 - Nolte, Kathleen A1 - Hermann-Lingen, Christoph A1 - Platschek, Lars A1 - Holzendorf, Volker A1 - Pilz, Stefan A1 - Tomaschitz, Andreas A1 - Düngen, Hans-Dirk A1 - Angermann, Christiane E. A1 - Hasenfuß, Gerd A1 - Pieske, Burkert A1 - Wachter, Rolf A1 - Edelmann, Frank T1 - Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction JF - ESC Heart Failure N2 - Aims Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. Methods and results We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. Conclusions Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities. KW - vitamin D KW - diastolic dysfunction KW - heart failure KW - HFpEF KW - NT-proBNP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232303 VL - 6 ER - TY - JOUR A1 - Bavendiek, Udo A1 - Berliner, Dominik A1 - Aguirre Dávila, Lukas A1 - Schwab, Johannes A1 - Maier, Lars A1 - Philipp, Sebastian A. A1 - Rieth, Andreas A1 - Westenfeld, Ralf A1 - Piorkowski, Christopher A1 - Weber, Kristina A1 - Hänselmann, Anja A1 - Oldhafer, Maximiliane A1 - Schallhorn, Sven A1 - von der Leyen, Heiko A1 - Schröder, Christoph A1 - Veltmann, Christian A1 - Störk, Stefan A1 - Böhm, Michael A1 - Koch, Armin A1 - Bauersachs, Johann T1 - Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study JF - European Journal of Heart Failure N2 - Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment. KW - heart failure KW - cardiac glycosides KW - digitalis KW - digitoxin KW - clinical trial Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221548 VL - 21 ER -