@article{ElhfnawyElsalamawyAbdelraoufetal.2020,
  author    = {Elhfnawy, Ahmed Mohamed and Elsalamawy, Doaa and Abdelraouf, Mervat and Schliesser, Mira and Volkmann, Jens and Fluri, Felix},
  title     = {Red flags for a concomitant giant cell arteritis in patients with vertebrobasilar stroke: a cross-sectional study and systematic review},
  series = {Acta Neurologica Belgica},
  volume    = {120},
  journal   = {Acta Neurologica Belgica},
  number    = {6},
  issn      = {0300-9009},
  doi       = {10.1007/s13760-020-01344-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-315610},
  pages     = {1389-1398},
  year      = {2020},
  abstract  = {Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25\% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1\%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100\%), but only five (7.9\%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70\% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke.},
  language  = {en}
}
@article{SamperAgreloSchiraHeinenBeyeretal.2020,
  author    = {Samper Agrelo, Iria and Schira-Heinen, Jessica and Beyer, Felix and Groh, Janos and B{\"u}termann, Christine and Estrada, Veronica and Poschmann, Gereon and Bribian, Ana and Jadasz, Janusz J. and Lopez-Mascaraque, Laura and Kremer, David and Martini, Rudolf and M{\"u}ller, Hans Werner and Hartung, Hans Peter and Adjaye, James and St{\"u}hler, Kai and K{\"u}ry, Patrick},
  title     = {Secretome analysis of mesenchymal stem cell factors fostering oligodendroglial differentiation of neural stem cells in vivo},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {12},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21124350},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285465},
  year      = {2020},
  abstract  = {Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.},
  language  = {en}
}
@article{FlacheneckerBuresGawliketal.2020,
  author    = {Flachenecker, Peter and Bures, Anna Karoline and Gawlik, Angeli and Weiland, Ann-Christin and Kuld, Sarah and Gusowski, Klaus and Streber, Ren{\´e} and Pfeifer, Klaus and Tallner, Alexander},
  title     = {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},
  series = {International Journal of Environmental Research and Public Health},
  volume    = {17},
  journal   = {International Journal of Environmental Research and Public Health},
  number    = {12},
  issn      = {1660-4601},
  doi       = {10.3390/ijerph17124544},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207863},
  year      = {2020},
  abstract  = {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: W{\"u}rzburg 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.},
  language  = {en}
}
@article{GomezFernandezLopezdeLapuentePortillaAstobizaetal.2020,
  author    = {G{\´o}mez-Fern{\´a}ndez, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antig{\"u}edad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Trivi{\~n}o, Tamara and Espino-Pais{\´a}n, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and K{\"u}mpfel, Tania and Luessi, Felix and Zettl, Uwe K. and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M. and Vandenbroeck, Koen},
  title     = {The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis},
  series = {Cells},
  volume    = {9},
  journal   = {Cells},
  number    = {1},
  issn      = {2073-4409},
  doi       = {10.3390/cells9010175},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200769},
  year      = {2020},
  abstract  = {The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50\%-60\% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.},
  language  = {en}
}
@article{FarinelliPalmisanoMarcheseetal.2020,
  author    = {Farinelli, Veronica and Palmisano, Chiara and Marchese, Silvia Maria and Strano, Camilla Mirella Maria and D'Arrigo, Stefano and Pantaleoni, Chiara and Ardissone, Anna and Nardocci, Nardo and Esposti, Roberto and Cavallari, Paolo},
  title     = {Postural control in children with cerebellar ataxia},
  series = {Applied Sciences},
  volume    = {10},
  journal   = {Applied Sciences},
  number    = {5},
  issn      = {2076-3417},
  doi       = {10.3390/app10051606},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200692},
  year      = {2020},
  abstract  = {Controlling posture, i.e., governing the ensemble of involuntary muscular activities that manage body equilibrium, represents a demanding function in which the cerebellum plays a key role. Postural activities are particularly important during gait initiation when passing from quiet standing to locomotion. Indeed, several studies used such motor task for evaluating pathological conditions, including cerebellar disorders. The linkage between cerebellum maturation and the development of postural control has received less attention. Therefore, we evaluated postural control during quiet standing and gait initiation in children affected by a slow progressive generalized cerebellar atrophy (SlowP) or non-progressive vermian hypoplasia (Joubert syndrome, NonP), compared to that of healthy children (H). Despite the similar clinical evaluation of motor impairments in NonP and SlowP, only SlowP showed a less stable quiet standing and a shorter and slower first step than H. Moreover, a descriptive analysis of lower limb and back muscle activities suggested a more severe timing disruption in SlowP. Such differences might stem from the extent of cerebellar damage. However, literature reports that during childhood, neural plasticity of intact brain areas could compensate for cerebellar agenesis. We thus proposed that the difference might stem from disease progression, which contrasts the consolidation of compensatory strategies.},
  language  = {en}
}
@article{BeyerJadaszSamperAgreloetal.2020,
  author    = {Beyer, Felix and Jadasz, Janusz and Samper Agrelo, Iria and Schira-Heinen, Jessica and Groh, Janos and Manousi, Anastasia and B{\"u}termann, Christine and Estrada, Veronica and Reiche, Laura and Cantone, Martina and Vera, Julio and Vigan{\`o}, Francesca and Dimou, Leda and M{\"u}ller, Hans Werner and Hartung, Hans-Peter and K{\"u}ry, Patrick},
  title     = {Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system},
  series = {Glia},
  volume    = {68},
  journal   = {Glia},
  number    = {2},
  doi       = {10.1002/glia.23724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218566},
  pages     = {393 -- 406},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{PetzkeKloseWelschetal.2020,
  author    = {Petzke, Frank and Klose, Petra and Welsch, Patrick and Sommer, Claudia and H{\"a}user, Winfried},
  title     = {Opioids for chronic low back pain: An updated systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks of double-blind duration},
  series = {European Journal of Pain},
  volume    = {24},
  journal   = {European Journal of Pain},
  number    = {3},
  doi       = {10.1002/ejp.1519},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218498},
  pages     = {497 -- 517},
  year      = {2020},
  abstract  = {Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non-malignant chronic low back pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of double-blinded duration were analysed. Primary outcomes were pain relief of 50\% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross-over design: Based on very low to low-quality evidence, opioids provided no clinically relevant pain relief of 50\% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low-quality evidence, opioids provided a clinically relevant pain relief of 50\% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross-over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross-over, but not in studies with EERW design. Conclusions Opioids may provide a safe and clinically relevant pain relief for 4-15 weeks in highly selected patients. Significance Within the context of randomized controlled trials of 4-15 weeks, opioids provided a clinically relevant pain relief of 30\% or greater and a clinically relevant reduction of disability compared to placebo in non-malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95\% confidence interval: 6-33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo.},
  language  = {en}
}
@article{RickertWagenhaeuserNordbecketal.2020,
  author    = {Rickert, V. and Wagenh{\"a}user, L. and Nordbeck, P. and Wanner, C. and Sommer, C. and Rost, S. and {\"U}{\c{c}}eyler, N.},
  title     = {Stratification of Fabry mutations in clinical practice: a closer look at α-galactosidase A-3D structure},
  series = {Journal of Internal Medicine},
  volume    = {288},
  journal   = {Journal of Internal Medicine},
  number    = {5},
  doi       = {10.1111/joim.13125},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218125},
  pages     = {593 -- 604},
  year      = {2020},
  abstract  = {Background Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.},
  language  = {en}
}
@article{GruendahlWackerEinseleetal.2020,
  author    = {Gr{\"u}ndahl, Marie and Wacker, Beate and Einsele, Hermann and Heinz, Werner J.},
  title     = {Invasive fungal diseases in patients with new diagnosed acute lymphoblastic leukaemia},
  series = {Mycoses},
  volume    = {63},
  journal   = {Mycoses},
  number    = {10},
  doi       = {10.1111/myc.13151},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217844},
  pages     = {1101 -- 1106},
  year      = {2020},
  abstract  = {Background Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population. Methods In this retrospective single-centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia. Results In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4\%, 8.6\%, and 17.2\% likelihood, respectively. The incidence might be even higher, as nearly 40\% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection. Conclusion Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated.},
  language  = {en}
}
@article{SommerKloseWelschetal.2020,
  author    = {Sommer, Claudia and Klose, Petra and Welsch, Patrick and Petzke, Frank and H{\"a}user, Winfried},
  title     = {Opioids for chronic non-cancer neuropathic pain. An updated systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration},
  series = {European Journal of Pain},
  volume    = {24},
  journal   = {European Journal of Pain},
  number    = {1},
  doi       = {10.1002/ejp.1494},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218487},
  pages     = {3 -- 18},
  year      = {2020},
  abstract  = {Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non-cancer neuropathic pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double-blinded duration were analysed. Primary outcomes were pain relief of 50\% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross-over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50\% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50\% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo. Conclusions Some opioids provided a short-term substantial pain relief in highly selected patients in some neuropathic pain syndromes. Significance Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4-12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care.},
  language  = {en}
}
@article{RauschenbergervonWardenburgSchaeferetal.2020,
  author    = {Rauschenberger, Vera and von Wardenburg, Niels and Schaefer, Natascha and Ogino, Kazutoyo and Hirata, Hiromi and Lillesaar, Christina and Kluck, Christoph J. and Meinck, Hans-Michael and Borrmann, Marc and Weishaupt, Andreas and Doppler, Kathrin and Wickel, Jonathan and Geis, Christian and Sommer, Claudia and Villmann, Carmen},
  title     = {Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction},
  series = {Annals of Neurology},
  volume    = {88},
  journal   = {Annals of Neurology},
  number    = {3},
  doi       = {10.1002/ana.25832},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216005},
  pages     = {544 -- 561},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{StengelVulinovicMeieretal.2020,
  author    = {Stengel, Felix and Vulinovic, Franca and Meier, Britta and Gr{\"u}tz, Karen and Klein, Christine and Capetian, Philipp},
  title     = {Impaired differentiation of human induced neural stem cells by TOR1A overexpression},
  series = {Molecular Biology Reports},
  volume    = {47},
  journal   = {Molecular Biology Reports},
  doi       = {10.25972/OPUS-24117},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241177},
  pages     = {3993-4001},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{EssigKollikowskiPhametal.2020,
  author    = {Essig, Fabian and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Stoll, Guido and Haeusler, Karl Georg and Kraft, Peter and Schuhmann, Michael K.},
  title     = {Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21197387},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236192},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{CapetianMuellerVolkmannetal.2020,
  author    = {Capetian, Philipp and M{\"u}ller, Lorenz and Volkmann, Jens and Heckmann, Manfred and Erg{\"u}n, S{\"u}leyman and Wagner, Nicole},
  title     = {Visualizing the synaptic and cellular ultrastructure in neurons differentiated from human induced neural stem cells - an optimized protocol},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21051708},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236053},
  year      = {2020},
  abstract  = {The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.},
  language  = {en}
}
@article{IsaiasBrumbergPozzietal.2020,
  author    = {Isaias, Ioannis U. and Brumberg, Joachim and Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Canessa, Andrea and Marotta, Giogio and Volkmann, Jens and Pezzoli, Gianni},
  title     = {Brain metabolic alterations herald falls in patients with Parkinson's disease},
  series = {Annals of Clinical and Translational Neurology},
  volume    = {7},
  journal   = {Annals of Clinical and Translational Neurology},
  number    = {4},
  doi       = {10.1002/acn3.51013},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235982},
  pages     = {579-583},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{BrumbergSchroeterBlazhenetsetal.2020,
  author    = {Brumberg, Joachim and Schr{\"o}ter, Nils and Blazhenets, Ganna and Frings, Lars and Volkmann, Jens and Lapa, Constantin and Jost, Wolfgang H. and Isaias, Ioannis U. and Meyer, Philipp T.},
  title     = {Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy},
  series = {NPJ Parkinsons Disease},
  volume    = {6},
  journal   = {NPJ Parkinsons Disease},
  doi       = {10.1038/s41531-020-00141-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230675},
  year      = {2020},
  abstract  = {[\(^{18}\)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.},
  language  = {en}
}
@article{BrieseSaalBauernschubertLueningschroeretal.2020,
  author    = {Briese, Michael and Saal-Bauernschubert, Lena and L{\"u}ningschr{\"o}r, Patrick and Moradi, Mehri and Dombert, Benjamin and Surrey, Verena and Appenzeller, Silke and Deng, Chunchu and Jablonka, Sibylle and Sendtner, Michael},
  title     = {Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function},
  series = {Acta Neuropathologica Communications},
  volume    = {8},
  journal   = {Acta Neuropathologica Communications},
  doi       = {10.1186/s40478-020-00987-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230322},
  year      = {2020},
  abstract  = {Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.},
  language  = {en}
}
@article{JovanovicKlassenHeuschmannetal.2020,
  author    = {Jovanovic, Ana and Klassen, Philipp and Heuschmann, Peter and Sommer, Claudia and Roberts, Mark and {\"U}{\c{c}}eyler, Nurcan},
  title     = {English version of the self-administered Fabry Pain Questionnaire for adult patients},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {15},
  journal   = {Orphanet Journal of Rare Diseases},
  doi       = {10.1186/s13023-020-01580-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230298},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{BerveWestMartinietal.2020,
  author    = {Berve, Kristina and West, Brian L. and Martini, Rudolf and Groh, Janos},
  title     = {Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice},
  series = {Journal of Neuroinflammation},
  volume    = {17},
  journal   = {Journal of Neuroinflammation},
  doi       = {10.1186/s12974-020-01996-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230234},
  year      = {2020},
  abstract  = {Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1\(^{-/-}\)) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1\(^{-/-}\) mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.},
  language  = {en}
}
@article{PeterkaOdorferSchwabetal.2020,
  author    = {Peterka, Manuel and Odorfer, Thorsten and Schwab, Michael and Volkmann, Jens and Zeller, Daniel},
  title     = {LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration},
  series = {BMC Neurology},
  volume    = {20},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-020-01858-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230084},
  year      = {2020},
  abstract  = {Background There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration. Objective To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception. Methods Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire. Conclusion LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD.},
  language  = {en}
}