@article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Ringelstein, Marius and Trebst, Corinna and Winkelmann, Alexander and Schwarz, Alexander and Buttmann, Mathias and Zimmermann, Hanna and Kuchling, Joseph and Franciotta, Diego and Capobianco, Marco and Siebert, Eberhard and Lukas, Carsten and Korporal-Kuhnke, Mirjam and Haas, J{\"u}rgen and Fechner, Kai and Brandt, Alexander U. and Schanda, Kathrin and Aktas, Orhan and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {280}, doi = {10.1186/s12974-016-0718-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165570}, year = {2016}, abstract = {Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80\% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40\% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36\%) and markedly impaired ambulation due to paresis or ataxia (25\%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70\%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70\%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44\%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50\%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70\%, oligoclonal bands in only 13\%, and blood-CSF-barrier dysfunction in 32\%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9\%). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28\%, 32\%, 15\%, 33\%, respectively; MS had been suspected in 36\%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Trebst, Corinna and Ringelstein, Marius and Aktas, Orhan and Winkelmann, Alexander and Buttmann, Mathias and Schwarz, Alexander and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Capobianco, Marco and Kuchling, Joseph and Haas, J{\"u}rgen and Korporal-Kuhnke, Mirjam and Lillevang, Soeren Thue and Fechner, Kai and Schanda, Kathrin and Paul, Friedemann and Wildemann, Brigitte and Reindl, Markus}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {279}, doi = {10.1186/s12974-016-0717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165659}, pages = {1-16}, year = {2016}, abstract = {Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7\%) patients with a history of both ON and myelitis, 22/103 (21.4\%) with a history of ON but no myelitis and 6/45 (13.3\%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67\%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89\%) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.}, language = {en} } @article{JariusKleiterRuprechtetal.2016, author = {Jarius, Sven and Kleiter, Ingo and Ruprecht, Klemens and Asgari, Nasrin and Pitarokoili, Kalliopi and Borisow, Nadja and H{\"u}mmert, Martin W. and Trebst, Corinna and Pache, Florence and Winkelmann, Alexander and Beume, Lena-Alexandra and Ringelstein, Marius and Stich, Oliver and Aktas, Orhan and Korporal-Kuhnke, Mirjam and Schwarz, Alexander and Lukas, Carsten and Haas, J{\"u}rgen and Fechner, Kai and Buttmann, Mathias and Bellmann-Strobl, Judith and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Schanda, Kathrin and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {281}, doi = {10.1186/s12974-016-0719-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165543}, pages = {1-23}, year = {2016}, abstract = {Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 \%) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 \%) patients. 16/21 (76.2 \%) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 \% of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 \%). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 \%); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{KoetschanFoersterKelleretal.2010, author = {Koetschan, Christian and Foerster, Frank and Keller, Alexander and Schleicher, Tina and Ruderisch, Benjamin and Schwarz, Roland and Mueller, Tobias and Wolf, Matthias and Schultz, Joerg}, title = {The ITS2 Database III-sequences and structures for phylogeny}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68390}, year = {2010}, abstract = {The internal transcribed spacer 2 (ITS2) is a widely used phylogenetic marker. In the past, it has mainly been used for species level classifications. Nowadays, a wider applicability becomes apparent. Here, the conserved structure of the RNA molecule plays a vital role. We have developed the ITS2 Database (http://its2.bioapps .biozentrum.uni-wuerzburg.de) which holds information about sequence, structure and taxonomic classification of all ITS2 in GenBank. In the new version, we use Hidden Markov models (HMMs) for the identification and delineation of the ITS2 resulting in a major redesign of the annotation pipeline. This allowed the identification of more than 160 000 correct full ength and more than 50 000 partial structures. In the web interface, these can now be searched with a modified BLAST considering both sequence and structure, enabling rapid taxon sampling. Novel sequences can be annotated using the HMM based approach and modelled according to multiple template structures. Sequences can be searched for known and newly identified motifs. Together, the database and the web server build an exhaustive resource for ITS2 based phylogenetic analyses.}, subject = {Biologie}, language = {en} } @article{KleinschnitzGrundWingleretal.2010, author = {Kleinschnitz, Christoph and Grund, Henrike and Wingler, Kirstin and Armitage, Melanie E. and Jones, Emma and Mittal, Manish and Barit, David and Schwarz, Tobias and Geis, Christian and Kraft, Peter and Barthel, Konstanze and Schuhmann, Michael K. and Herrmann, Alexander M. and Meuth, Sven G. and Stoll, Guido and Meurer, Sabine and Schrewe, Anja and Becker, Lore and Gailus-Durner, Valerie and Fuchs, Helmut and Klopstock, Thomas and de Angelis, Martin Hrabe and Jandeleit-Dahm, Karin and Shah, Ajay M. and Weissmann, Norbert and Schmidt, Harald H. H. W.}, title = {Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68416}, year = {2010}, abstract = {Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90\% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.}, subject = {Schlaganfall}, language = {en} } @article{BijuSchwarzLinkeetal.2011, author = {Biju, Joseph and Schwarz, Roland and Linke, Burkhard and Blom, Jochen and Becker, Anke and Claus, Heike and Goesmann, Alexander and Frosch, Matthias and M{\"u}ller, Tobias and Vogel, Ulrich and Schoen, Christoph}, title = {Virulence Evolution of the Human Pathogen Neisseria meningitidis by Recombination in the Core and Accessory Genome}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0018441}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137960}, pages = {e18441}, year = {2011}, abstract = {Background Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. Principal Findings We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin- and two-partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40\% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. Conclusions Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence.}, language = {en} }