TY - JOUR A1 - Nguemeni, Carine A1 - Homola, György A. A1 - Nakchbandi, Luis A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - A Single Session of Anodal Cerebellar Transcranial Direct Current Stimulation Does Not Induce Facilitation of Locomotor Consolidation in Patients With Multiple Sclerosis JF - Frontiers in Human Neuroscience N2 - Background: Multiple sclerosis (MS) may cause variable functional impairment. The discrepancy between functional impairment and brain imaging findings in patients with MS (PwMS) might be attributed to differential adaptive and consolidation capacities. Modulating those abilities could contribute to a favorable clinical course of the disease. Objectives: We examined the effect of cerebellar transcranial direct current stimulation (c-tDCS) on locomotor adaptation and consolidation in PwMS using a split-belt treadmill (SBT) paradigm. Methods: 40 PwMS and 30 matched healthy controls performed a locomotor adaptation task on a SBT. First, we assessed locomotor adaptation in PwMS. In a second investigation, this training was followed by cerebellar anodal tDCS applied immediately after the task ipsilateral to the fast leg (T0). The SBT paradigm was repeated 24 h (T1) and 78 h (T2) post-stimulation to evaluate consolidation. Results: The gait dynamics and adaptation on the SBT were comparable between PwMS and controls. We found no effects of offline cerebellar anodal tDCS on locomotor adaptation and consolidation. Participants who received the active stimulation showed the same retention index than sham-stimulated subjects at T1 (p = 0.33) and T2 (p = 0.46). Conclusion: Locomotor adaptation is preserved in people with mild-to-moderate MS. However, cerebellar anodal tDCS applied immediately post-training does not further enhance this ability. Future studies should define the neurobiological substrates of maintained plasticity in PwMS and how these substrates can be manipulated to improve compensation. Systematic assessments of methodological variables for cerebellar tDCS are urgently needed to increase the consistency and replicability of the results across experiments in various settings. KW - multiple sclerosis KW - cerebellar tDCS KW - split-belt treadmill KW - locomotor adaptation KW - consolidation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215291 SN - 1662-5161 VL - 14 ER - TY - JOUR A1 - Wirsching, Isabelle A1 - Ort, Nora A1 - Üçeyler, Nurcan T1 - ALS or ALS mimic by neuroborreliosis — A case report JF - Clinical Case Reports N2 - Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work‐up. However, false‐positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results. KW - ALS mimic KW - El Escorial KW - motor neuron disease KW - muscle atrophy KW - neuroborreliosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201308 VL - 8 ER - TY - JOUR A1 - Appeltshauser, Luise A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Körtvélyessy, Peter A1 - Wandinger, Klaus-Peter A1 - Junker, Ralf A1 - Villmann, Carmen A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. Methods We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barre syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. Results We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. Conclusion Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset. KW - Guillain-Barre-Syndrome KW - inflammatory demyelinating polyradiculoneuropathy KW - musk myasthenia gravis KW - periperal nerve KW - neurofascin KW - autoantibodies KW - ontactin 1 KW - biopsies KW - binding KW - switch Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230079 VL - 7 IS - 5 ER - TY - THES A1 - Buchwald, Sina T1 - Autoimmune Enzephalitiden am Universitätsklinikum Würzburg von 2006-2016 T1 - Cases of autoimmune encephalitis at the Universitätsklinikum Würzburg from 2006-2016 N2 - In den Jahren von 2006 bis 2016 sind am Universitätsklinikum Würzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverläufe, Outcome, die gefundenen Antikörper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben Fällen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu können. N2 - In the time from 2006 to 2016, 26 patients with the diagnosis "autoimmune encephalitis” were treated at the Universitätsklinikum in Würzburg. This paper shows their data, antibody findings, treatments and outcomes. In a second step, this data was compared with cases that have already been described in literature to show similarities and differences. KW - Enzephalitis KW - Autoimmun KW - Encephalitis KW - autoimmune Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207202 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Brumberg, Joachim A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Canessa, Andrea A1 - Marotta, Giogio A1 - Volkmann, Jens A1 - Pezzoli, Gianni T1 - Brain metabolic alterations herald falls in patients with Parkinson's disease JF - Annals of Clinical and Translational Neurology N2 - Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism. KW - Parkionson's disease KW - brain metabolic alterations Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235982 VL - 7 IS - 4 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Dinkel, Philine A1 - Frank, Johanna A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Characterization of dermal skin innervation in fibromyalgia syndrome JF - PLoS One N2 - Introduction We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. Methods Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 mu m each) were investigated for dermal nerve fiber length (DNFL). Results In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. Discussion We found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients. KW - nerve-fibers KW - cutaneous innervation KW - substance-P KW - pain KW - classification KW - reinnervation KW - expression KW - diagnosis KW - epidermis KW - criteria Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229299 VL - 15 IS - 1 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Buchholz, Hans-Georg A1 - Kewenig, Susanne A1 - Ament, Stephan-Johann A1 - Birklein, Frank A1 - Schreckenberger, Mathias A1 - Sommer, Claudia T1 - Cortical Binding Potential of Opioid Receptors in Patients With Fibromyalgia Syndrome and Reduced Systemic Interleukin-4 Levels – A Pilot Study JF - Frontiers in Neuroscience N2 - Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients’ systemic interleukin-4 (IL-4) gene expression. Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values. Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005). Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS. KW - fibromyalgia syndrome KW - PET KW - brain KW - opioid KW - IL-4 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204457 SN - 1662-453X VL - 14 ER - TY - THES A1 - Kuzkina, Anastasia T1 - Dermal α-synuclein oligomers and aggregates in Parkinson’s disease T1 - Nachweis von Alpha-Synuclein-Oligomeren und -Aggregaten in Hautbiopsien von Parkinson-Patienten N2 - Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson’s disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson’s disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24% (cohort 1) and 37% (cohort 2), ASyO5 positive lesions in 17,7% (cohort 1) and 33% (cohort 2), syn211 positive lesions after PK digestion in 38,7% (cohort 1) and 48% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59% were also PK resistant, 41% were 5G4 positive and 45% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy. N2 - Die neuropathologischen Kennzeichen des Morbus Parkinson sind Lewy-Körperchen und Lewy-Neuriten. Diese Ablagerungen im Gehirn bestehen hauptsächlich aus aggregiertem α-Synuclein (α-Syn), das am Ser129 phosphoryliert ist. Mehrere Studien konnten zeigen, dass phosphoryliertes α-Syn (p-α-Syn) auch in Nervenfasern der Haut von Parkinsonpatienten nachweisbar ist. Das Ziel dieser Arbeit war, zu untersuchen, ob es sich bei den pathologischen Ablagerungen von p-α-Syn in der Haut wie im Gehirn um Aggregate handelt. Mehrere Methoden, die dem Nachweis von α-Syn-Oligomere und Aggregate dienen, wurden zuerst an Gehirnen von einem Parkinsonpatienten und Normalkontrolle getestet und optimiert, darunter: Proximity Ligation Assay (PLA), PET-Blot, immunhistochemische Färbungen mit α-Syn-Aggregat- (5G4) oder Oligomer-spezifischen Antikörper (ASyO5) und eine Färbung mit einem Antikörper gegen natives α-Syn (syn211) nach Verdau mit Proteinase K (PK). Danach wurden die spezifischsten Methoden (Färbung mit 5G4, ASyO5 und syn211 nach PK-Verdau) an den Hautstanzbiopsien von zwei Patienten- und Normalkontrollkohorten untersucht. Parallel wurde in den Biopsien das p-α-Syn angefärbt. Einzelschnitte von je mind. 2 Biopsiestellen von 44 Patienten und 22 Kontrollen (Kohorte 1) sowie Serienschnitte von je 4 Biopsiestellen von 27 Patienten und 5 Kontrollen (Kohorte 2) wurden systematisch nach Vorliegen von aggregierten und oligomerischen α-Syn untersucht. Zusammenfassend, wurden 5G4-positive Ablagerungen in 24% (Kohorte 1) und 37% (2. Kohorte), ASyO5-positive Läsionen in 17,7% (Kohorte 1) und 33% (Kohorte 2), syn211-positive Läsionen nach PK-Verdau in 38,7% (Kohorte 1) und 48% (Kohorte 2) der Fälle gefunden. Das p-α-Syn wurde entsprechend in 43,6% und 48% der Fälle detektiert. Es zeigte sich die Tendenz, dass Patienten, bei denen p-α-Syn nachweisbar war, auch für mehrere der neuen Marker positiv waren; auch häufig waren für alle 4 Marker positive Nervenfasern in naheliegenden Schnitte zu sehen, was für eine Kolokalisation spricht. Unter den Hautbiopsien, in den p-α-Syn-Ablagerungen zu sehen waren, hatten 59% gleichzeitig PK-resistente, 41% 5G4- und 45% ASyO5-positive Ablagerungen. Bei Kontrollen waren Ablagerungen weder mit den neu eingeführten Methoden noch mit anti-p-α-Syn-Färbung detektierbar. Mit Hilfe von drei unterschiedlichen immunhistochemischen Methoden waren Oligomere und Aggregate vom α-Syn im Großteil der p-α-Syn-positiven Hautbiopsien nachweisbar. Dieser Befund unterstützt die Hypothese, dass die Ablagerung von α-Syn-Aggregaten auch in peripheren (v.a. dermalen) Nerven vorkommt und spezifisch nachgewiesen werden kann. KW - Parkinson-Krankheit KW - Biomarker KW - Haut KW - Biopsie KW - parkinson's disease KW - skin biopsy KW - alpha-synuclein KW - biomarker Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204369 ER - TY - THES A1 - Kreß, Luisa Sophia T1 - Determination of cytokine and axon guidance molecule profiles in patients with small fiber neuropathy T1 - Bestimmung von Zytokin- und Axon Guidance Molekül-Profilen bei Patienten mit Kleinfaserneuropathie N2 - The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation. N2 - Der Pathomechanismus von Schmerz bei Small fiber Neuropathie (SFN) ist unklar. Auf Grundlage tierexperimenteller und klinischer Studien wird die Einwirkung kutaner und systemischer Schmerzmediatoren auf sensibilisierte Nozizeptoren in der Haut als mögliche Ursache diskutiert. In diesem Zusammenhang gab es Hinweise auf die Bedeutung von pro- und anti-inflammatorischen Zytokinen in der Pathophysiologie neuropathischer Schmerzen. Ziel der Studie war es, die systemische und lokale Genexpression pro- und anti-inflammatorischer Zytokine in Leukozyten sowie kutanen Fibroblasten und Keratinozyten von Patienten mit SFN zu messen. Ferner wurde untersucht, inwieweit die Expression repellierender Axon Guidance Moleküle und ihrer Rezeptoren in Hautzellen die intraepidermale Nervenfaserdichte (IENFD) regulieren könnte. Insgesamt konnten 55 SFN PatientInnen und 31 gesunde KontrollprobandInnen prospektiv rekrutiert werden. Nach ausführlicher klinischer Phänotypisierung und Blutentnahme wurden bei allen StudienteilnehmerInnen 6-mm Hautstanzbiopsien am lateralen Unter- und Oberschenkel entnommen. Die Messung der systemisch relativen Genexpression (ΔG) der Zytokine Interleukin (IL)-1β, IL-2, IL-6, IL-8 und des tumor necrose factors (TNF) erfolgte aus Leukozyten. Aus den Hautstanzbiopsien, die u.a. zur Bestimmung der IENFD verwendet wurden, wurden außerdem Primärzellkulturen von Keratinozyten und Fibroblasten angelegt, aus denen die lokale ΔG von Axon Guidance Molekülen Netrin 1 (NTN1) und Ephrin A4 (EPHA4), deren Rezeptoren Unc5b, und Ephrin A4 receptor (EFNA4) sowie der Zytokine IL-1β, IL-4, IL-6, IL-8, IL-10, TNF und des transforming growth factors (TGF) erfolgte. Systemisch zeigte sich eine höhere Genexpression für IL-2, IL-8 und TNF bei SFN Patienten im Vergleich zu gesunden Kontrollen. In Keratinozyten konnten höhere Expressionen von NTN1 und TGF-β1 bei Vergleich der Patientengruppe mit der Kontrollgruppe nachgewiesen werden. In Fibroblasten zeigte sich im Gruppenvergleich eine höhere Genexpression für NTN1, Unc5b sowie für IL-6 und IL-8. Die systemisch und lokal bei SFN Patienten nachgewiesene höhere Expression algetischer, pro-inflammatorischer Zytokine verglichen mit Kontrollen unterstützt eine mögliche pathophysiologische Rolle bei der Entstehung von neuropathischen Schmerzen. Ferner weisen die Daten darauf hin, dass Fibroblasten und Keratinozyten durch die Expression von NTN1 und Unc5b Einfluss auf das subepidermale und intraepidermale Nervenfaserwachstum nehmen und durch lokale Denervierung bei der Entstehung neuropathischer Schmerzen mitwirken könnten. KW - Neuropathischer Schmerz KW - Pathomechanismus KW - Cytokine KW - small fiber neuropathy KW - axon guidance molecules KW - pathophysilogical mechanisms KW - cytokines KW - skin cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209113 ER - TY - THES A1 - Emmerich, Christoph T1 - Die Rolle der clathrin- und dynaminabhängigen Endozytose bei der Internalisation von anti-Amphiphysin-Autoantikörpern im Falle des Stiff-Person-Syndroms, untersucht am Zellkulturmodell hippocampaler Neurone T1 - The role of clathrin- and dynamin dependent endocytosis in internalisation of anti-amphiphysin-autoantibodies in case of Stiff-Person-Syndrom N2 - In dieser Arbeit wurde mit Hilfe von small-molecule Inhibitoren die Rolle von clathrin- und dynaminabhängigen Endozytosemechanismen bei der Aufnahme von anti-Amphiphysin-Autoantikörpern am Zellkulturmodell primärer hippocampaler Neurone untersucht. Hierbei konnte eine Beeinflussung der Autoaantikörperaufnahme durch die Intervention gezeigt werden. Außerdem erfolgte der Versuch der Etablierung eines siRNA knockdowns unter Zuhilfenahme unterschiedlicher Traansfektionsreaaagenzien. N2 - This thesis investigated the role of clathrin and dynamin dependent endocytosis in internalisation of anti-amphiphysin-autoantibodies in primary mouse hippocampal neurons by using small molecule inhibitors. An influence in the uptake due to small molecule treatment can be shown. Furthermore an attempt of siRNA knockdown establishment was performed using different transfection reagents. KW - siRNA KW - small molecule KW - Stiff-Person-Syndrom KW - anti-Amphiphysin Antikörper KW - siRNA KW - small-molecule Inhibitoren KW - Stiff-Person-Syndrom KW - anti-amphiphysin antibodies KW - small-molecule inhibitors Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209360 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Schröter, Nils A1 - Blazhenets, Ganna A1 - Frings, Lars A1 - Volkmann, Jens A1 - Lapa, Constantin A1 - Jost, Wolfgang H. A1 - Isaias, Ioannis U. A1 - Meyer, Philipp T. T1 - Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy JF - NPJ Parkinsons Disease N2 - [\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator #1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater #1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred. KW - clinical diagnosis KW - F-18-FDG PET KW - disease KW - dementia KW - accuracy KW - stimulation KW - guidelines KW - criteria KW - brain KW - risk Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230675 VL - 6 ER - TY - JOUR A1 - Flachenecker, Peter A1 - Bures, Anna Karoline A1 - Gawlik, Angeli A1 - Weiland, Ann-Christin A1 - Kuld, Sarah A1 - Gusowski, Klaus A1 - Streber, René A1 - Pfeifer, Klaus A1 - Tallner, Alexander T1 - Efficacy of an internet-based program to promote physical activity and exercise after inpatient rehabilitation in persons with multiple sclerosis: a randomized, single-blind, controlled study JF - International Journal of Environmental Research and Public Health N2 - Background: Multimodal rehabilitation improves fatigue and mobility in persons with multiple sclerosis (PwMS). Effects are transient and may be conserved by internet-based physical activity promotion programs. Objective: Evaluate the effects of internet-based physical activity and exercise promotion on fatigue, quality of life, and gait in PwMS after inpatient rehabilitation. Methods: PwMS (Expanded Disability Status Scale (EDSS) ≤ 6.0, fatigue: Würzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) ≥ 32) were randomized into an intervention group (IG) or a control group (CG). After rehabilitation, IG received 3 months of internet-based physical activity promotion, while CG received no intervention. Primary outcome: self-reported fatigue (WEIMuS). Secondary outcomes: quality of life (Multiple Sclerosis Impact Scale 29, MSIS-29), gait (2min/10m walking test, Tinetti score). Measurements: beginning (T0) and end (T1) of inpatient rehabilitation, 3 (T2) and 6 (T3) months afterwards. Results: 64 of 84 PwMS were analyzed (IG: 34, CG: 30). After rehabilitation, fatigue decreased in both groups. At T2 and T3, fatigue increased again in CG but was improved in IG (p < 0.001). MSIS-29 improved in both groups at T1 but remained improved at T2 and T3 only in IG. Gait improvements were more pronounced in IG at T2. Conclusions: The study provides Class II evidence that the effects of rehabilitation on fatigue, quality of life, and gait can be maintained for 3–6 months with an internet-based physical activity and exercise promotion program. KW - multiple sclerosis KW - rehabilitation KW - fatigue KW - quality of life KW - walking KW - physical activity KW - exercise KW - online systems KW - internet-based intervention KW - health behavior Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207863 SN - 1660-4601 VL - 17 IS - 12 ER - TY - THES A1 - Wind, Teresa Elisabeth T1 - Einfluss von Alter und Polyneuropathie auf zeitliche Wahrnehmungsschwellen somatosensorischer und kinästhetischer Stimuli und propriozeptive Leistungsfähigkeit T1 - Temporal Discrimination Thresholds and Proprioceptive Performance: Impact of Age and Nerve Conduction N2 - Zeitliche Diskrimination somatosensorischer und kinästhetischer Stimuli wurde als neurophysiologisches Korrelat für propriozeptive Präzision postuliert und bei verschiedenen Bewegungsstörungen als pathologisch beschrieben. Ziel der Untersuchung war es, den Einfluss von Alter und Polyneuropathie auf die kinästhetische (TDMT) und taktile (STDT) zeitliche Wahrnehmungsschwelle sowie die propriozeptive Genauigkeit bei Zeigeversuchen systematisch zu untersuchen. Hierfür wurden 54 gesunde Probanden und 25 Polyneuropathie-Patienten im Alter zwischen 30 und 76 Jahren untersucht. Die STDT-Messung erfolgte mit Oberflächenelektroden, die an der Zeigefingerspitze bzw. am Großzehengrundgelenk angebracht wurden. Die TDMT-Werte wurden mit Hilfe einer sterilen Nadelelektrode erfasst, welche in den Musculus flexor carpi radialis bzw. Musculus tibialis anterior inseriert wurde. Die Daten zur Propriozeption wurden mit Hilfe eines Goniometers erhoben und beinhalteten dabei aktive Zeigeaufgaben (Zeigen auf eine LED, Nachahmung einer Bewegung anhand einer auf einem Computerbildschirm dargebotenen PFEIL-Darstellung unterschiedlicher Länge) und die Einschätzung der Position der jeweiligen Extremität nach passiver Bewegung (PASSIV). Die Messungen erfolgten jeweils ohne visuelle Rückmeldung. Die Zeigefehler (Abweichung von der Zielposition) bzw. Schätzfehler (Abweichung der geschätzten von der tatsächlichen Position nach passiver Auslenkung) wurden als Maß der propriozeptiven Präzision verwendet. Die Ergebnisse der gesunden Probandengruppe zeigten, dass höheres Alter mit höheren STDT- und TDMT-Werten korrelierte. Die Polyneuropathie-Patienten erzielten in allen Bereichen (Diskriminationsschwellen und Propriozeptionsaufgaben) signifikant schlechtere Ergebnisse als die gesunde Kontrollgruppe. Zusätzlich konnte eine statistisch signifikante positive Korrelation zwischen der propriozeptiven Präzision bei den aktiven Zeige-Aufgaben (LED und PFEIL) und den zeitlichen Diskriminationsschwellen (STDT und TDMT) gezeigt werden. In Anbetracht dieser Ergebnisse sollten das Patienten-Alter und mögliche Störungen der peripheren Nervenleitung berücksichtigt werden, wenn STDT-und TDMT-Bestimmungen bei Patienten mit Bewegungsstörungen angewendet werden. Die Korrelation zwischen den Diskriminationsschwellen und der Performance bei aktiven Zeigeversuchen (PFEIL- und LED-Aufgabe) legt nahe, dass STDT und TDMT Indikatoren der propriozeptiven Funktion sein könnten. Es ist weitere Forschungsarbeit notwendig, um diese Beziehung exakt zu beleuchten. Im Falle einer Bestätigung der Befunde auch bei Patienten mit Bewegungsstörungen erscheint denkbar, dass sich STDT und TDMT als vergleichsweise leicht messbare und gut quantifizierbare Parameter der Propriozeption herausstellen mit Potenzial zur differenzialdiagnostischen Anwendung, möglicherweise aber auch als Surrogatparameter einer gezielten rehabilitativen Behandlung. N2 - Objective: To assess the association of somatosensorytemporal discriminationthreshold (STDT) and temporal movement discrimination threshold (TDMT) with age and proprioception. Methods: STDT and TDMT were assessed in 54 healthy subjects aged 30 to 76 yearsand 25 patients with PNP. STDT was tested with surface electrodes placed over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpiradialis and tibialis anterior muscle. Limb proprioception was assessed by active pointing tasks and by limb position estimation with goniometer-based devices.Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results: Higher age was associated with higher STDT and TDMT, while age did not correlate with proprioceptive performance. In PNP patients,STDT, TDMT and active proprioceptive Peformance were worse at all sites as compared to controls. In Addition,proprioceptive performance in the active pointing task correlated with STDT and TDMT of upper extremities. Conclusions: Temporal discrimination thresholds may prove useful as surrogatemarkers of proprioceptive function. PNP-related impairment of afferent conduction shows high impact on STDT and TDMT. Significance: Comparable modulation of STDT and TDMT by age and peripheral neuropathy may support the notion that their differential changes in movement disorders may result from disease-specific modifications of central networks. KW - Propriozeption KW - Alter KW - Polyneuropathie KW - zeitliche Wahrnehmungsschwellen KW - STDT KW - TDMT KW - Temporal Discrimination Threshold KW - Proprioception KW - Polyneuropathy KW - Age Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208047 ER - TY - JOUR A1 - Jovanovic, Ana A1 - Klassen, Philipp A1 - Heuschmann, Peter A1 - Sommer, Claudia A1 - Roberts, Mark A1 - Üçeyler, Nurcan T1 - English version of the self-administered Fabry Pain Questionnaire for adult patients JF - Orphanet Journal of Rare Diseases N2 - Background Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Wurzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ). Methods After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements. Results Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items. Conclusions We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD. KW - Fabry disease KW - Fabry-associated pain KW - Pain questionnaire KW - English version Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230298 VL - 15 ER - TY - THES A1 - Brandt, Gregor A. T1 - Gait Initiation in Parkinson's Disease: The Interplay of Dopamine and Postural Control T1 - Der erste Schritt bei M. Parkinson: Der Zusammenhang zwischen Dopamin und posturaler Kontrolle N2 - Deterioration of gait and alterations of physiological gait initiation contribute significantly to the burden of disease in Parkinson's disease. This paper systematically investigates disease-specific alterations during the postural phases of gait initiation and demonstrates the influence of dopaminergic networks by assessing levodopa mediated improvements in motor performance and correlation of motor behavior with loss of striatal and cortical dopaminergic neurons. Particular attention is given to known confounders such as initial stance and anthropometrics. N2 - Störungen des Gangbildes und Veränderungen der physiologischen Bewegungsabläufe während des ersten Schrittes tragen einen signifikanten Teil zur Krankheitslast der Parkinsonerkrankung bei. Diese Veröffentlichung untersucht systematisch die krankheitsspezifischen Veränderungen der posturalen Phase des ersten Schrittes und demonstriert den Einfluss dopaminerger Netzwerke durch Untersuchungen Levodopa-induzierter Verbesserungen des Bewegungsablaufs und Korrelationen des Bewegungsverhaltens mit dem Verlust striataler und kortikaler dopaminerger Neuronen. Besondere Sorgfalt wurde bekannten modifizierenden Faktoren wie initaler Standbreite und anthropometrischen Größen zu Teil. KW - Parkinson-Krankheit KW - Parkinson's Disease KW - Gait initiation KW - Motor Control KW - Dopamine Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214636 ER - TY - JOUR A1 - Palmisano, Chiara A1 - Brandt, Gregor A1 - Vissani, Matteo A1 - Pozzi, Nicoló G. A1 - Canessa, Andrea A1 - Brumberg, Joachim A1 - Marotta, Giorgio A1 - Volkmann, Jens A1 - Mazzoni, Alberto A1 - Pezzoli, Gianni A1 - Frigo, Carlo A. A1 - Isaias, Ioannis U. T1 - Gait Initiation in Parkinson’s Disease: Impact of Dopamine Depletion and Initial Stance Condition JF - Frontiers in Bioengineering and Biotechnology N2 - Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson’s disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment. KW - gait initiation KW - Parkinson’s disease KW - basal ganglia KW - dopamine KW - base of support KW - anthropometric measurements Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200801 SN - 2296-4185 VL - 8 ER - TY - JOUR A1 - Rauschenberger, Vera A1 - von Wardenburg, Niels A1 - Schaefer, Natascha A1 - Ogino, Kazutoyo A1 - Hirata, Hiromi A1 - Lillesaar, Christina A1 - Kluck, Christoph J. A1 - Meinck, Hans‐Michael A1 - Borrmann, Marc A1 - Weishaupt, Andreas A1 - Doppler, Kathrin A1 - Wickel, Jonathan A1 - Geis, Christian A1 - Sommer, Claudia A1 - Villmann, Carmen T1 - Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction JF - Annals of Neurology N2 - Objective Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff‐person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. Methods A cell‐based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Results Glycine receptor function as assessed by glycine dose–response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N‐terminal residues \(^{29}\)A to \(^{62}\)G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Interpretation Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff‐person syndrome or progressive encephalitis with rigidity and myoclonus patients. KW - glycine receptor autoantibodies KW - behavioral disorders KW - neurology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216005 VL - 88 IS - 3 SP - 544 EP - 561 ER - TY - JOUR A1 - Beyer, Felix A1 - Jadasz, Janusz A1 - Samper Agrelo, Iria A1 - Schira‐Heinen, Jessica A1 - Groh, Janos A1 - Manousi, Anastasia A1 - Bütermann, Christine A1 - Estrada, Veronica A1 - Reiche, Laura A1 - Cantone, Martina A1 - Vera, Julio A1 - Viganò, Francesca A1 - Dimou, Leda A1 - Müller, Hans Werner A1 - Hartung, Hans‐Peter A1 - Küry, Patrick T1 - Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system JF - Glia N2 - Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell‐dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease. KW - glial fate modulation KW - myelin KW - neural stem cell KW - p57kip2 KW - regional heterogeneity KW - spinal cord injury KW - transplantation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218566 VL - 68 IS - 2 SP - 393 EP - 406 ER - TY - JOUR A1 - Essig, Fabian A1 - Kollikowski, Alexander M. A1 - Pham, Mirko A1 - Solymosi, László A1 - Stoll, Guido A1 - Haeusler, Karl Georg A1 - Kraft, Peter A1 - Schuhmann, Michael K. T1 - Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke JF - International Journal of Molecular Sciences N2 - Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity. KW - acute ischemic stroke KW - thrombemboli KW - neutrophils KW - NETs KW - immunohistochemistry Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236192 SN - 1422-0067 VL - 21 IS - 19 ER - TY - JOUR A1 - Stengel, Felix A1 - Vulinovic, Franca A1 - Meier, Britta A1 - Grütz, Karen A1 - Klein, Christine A1 - Capetian, Philipp T1 - Impaired differentiation of human induced neural stem cells by TOR1A overexpression JF - Molecular Biology Reports N2 - DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation. KW - dystonia KW - DYT1 KW - torsinA KW - TOR1A KW - neuronal stem cells KW - neuronal differentiation KW - inducible expression Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241177 UR - https://doi.org/10.1007/s11033-020-05390-x VL - 47 ER -