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No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Hopfner, Franziska ; Müller, Stefanie H. ; Steppat, Dagmar ; Miller, Joanna ; Schmidt, Nele ; Wandinger, Klaus-Peter ; Leypoldt, Frank ; Berg, Daniela ; Franke, Andre ; Lieb, Wolfgang ; Tittmann, Lukas ; Balzer-Geldsetzer, Monika ; Baudrexel, Simon ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Kalbe, Elke ; Kassubek, Jan ; Klockgether, Thomas ; Liepelt-Scarfone, Inga ; Mollenhauer, Brit ; Neuser, Petra ; Reetz, Kathrin ; Riedel, Oliver ; Schulte, Claudia ; Schulz, Jörg B. ; Spottke, Annika ; Storch, Alexander ; Trenkwalder, Claudia ; Wittchen, Hans-Ulrich ; Witt, Karsten ; Wüllner, Ullrich ; Deuschl, Günther ; Kuhlenbäumer, Gregor
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Wilde, Anne-Christin ; Lieb, Charlotte ; Leicht, Elise ; Greverath, Lena Maria ; Steinhagen, Lara Marleen ; Wald de Chamorro, Nina ; Petersen, Jörg ; Hofmann, Wolf-Peter ; Hinrichsen, Holger ; Heyne, Renate ; Berg, Thomas ; Naumann, Uwe ; Schwenzer, Jeannette ; Vermehren, Johannes ; Geier, Andreas ; Tacke, Frank ; Müller, Tobias
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
Medema, Marnix H. ; Kottmann, Renzo ; Yilmaz, Pelin ; Cummings, Matthew ; Biggins, John B. ; Kai, Blin ; de Bruijn, Irene ; Chooi, Yit Heng ; Claesen, Jan ; Coates, R. Cameron ; Cruz-Morales, Pablo ; Duddela, Srikanth ; Düsterhus, Stephanie ; Edwards, Daniel J. ; Fewer, David P. ; Garg, Neha ; Geiger, Christoph ; Gomez-Escribano, Juan Pablo ; Greule, Anja ; Hadjithomas, Michalis ; Haines, Anthony S. ; Helfrich, Eric J. N. ; Hillwig, Matthew L. ; Ishida, Keishi ; Jones, Adam C. ; Jones, Carla S. ; Jungmann, Katrin ; Kegler, Carsten ; Kim, Hyun Uk ; Kötter, Peter ; Krug, Daniel ; Masschelein, Joleen ; Melnik, Alexey V. ; Mantovan, Simone M. ; Monroe, Emily A. ; Moore, Marcus ; Moss, Nathan ; Nützmann, Hans-Wilhelm ; Pan, Guohui ; Pati, Amrita ; Petras, Daniel ; Reen, F. Jerry ; Rosconi, Federico ; Rui, Zhe ; Tian, Zhenhua ; Tobias, Nicholas J. ; Tsunematsu, Yuta ; Wiemann, Philipp ; Wyckoff, Elizabeth ; Yan, Xiaohui ; Yim, Grace ; Yu, Fengan ; Xie, Yunchang ; Aigle, Bertrand ; Apel, Alexander K. ; Balibar, Carl J. ; Balskus, Emily P. ; Barona-Gómez, Francisco ; Bechthold, Andreas ; Bode, Helge Björn ; Borriss, Rainer ; Brady, Sean F. ; Brakhage, Axel A. ; Caffrey, Patrick ; Cheng, Yi-Qiang ; Clardy, Jon ; Cox, Russell J. ; De Mot, René ; Donadio, Stefano ; Donia, Mohamed S. ; van der Donk, Wilfred A. ; Dorrestein, Pieter C. ; Doyle, Sean ; Driessen, Arnold J. M. ; Ehling-Schulz, Monika ; Entian, Karl-Dieter ; Fischbach, Michael A. ; Gerwick, Lena ; Gerwick, William H. ; Gross, Harald ; Gust, Bertolt ; Hertweck, Christian ; Höfte, Monica ; Jensen, Susan E. ; Ju, Jianhua ; Katz, Leonard ; Kaysser, Leonard ; Klassen, Jonathan L. ; Keller, Nancy P. ; Kormanec, Jan ; Kuipers, Oscar P. ; Kuzuyama, Tomohisa ; Kyrpides, Nikos C. ; Kwon, Hyung-Jin ; Lautru, Sylvie ; Lavigne, Rob ; Lee, Chia Y. ; Linquan, Bai ; Liu, Xinyu ; Liu, Wen ; Luzhetskyy, Andriy ; Mahmud, Taifo ; Mast, Yvonne ; Méndez, Carmen ; Metsä-Ketelä, Mikko ; Micklefield, Jason ; Mitchell, Douglas A. ; Moore, Bradley S. ; Moreira, Leonilde M. ; Müller, Rolf ; Neilan, Brett A. ; Nett, Markus ; Nielsen, Jens ; O’Gara, Fergal ; Oikawa, Hideaki ; Osbourn, Anne ; Osburne, Marcia S. ; Ostash, Bohdan ; Payne, Shelley M. ; Pernodet, Jean-Luc ; Petricek, Miroslav ; Piel, Jörn ; Ploux, Olivier ; Raaijmakers, Jos M. ; Salas, José A. ; Schmitt, Esther K. ; Scott, Barry ; Seipke, Ryan F. ; Shen, Ben ; Sherman, David H. ; Sivonen, Kaarina ; Smanski, Michael J. ; Sosio, Margherita ; Stegmann, Evi ; Süssmuth, Roderich D. ; Tahlan, Kapil ; Thomas, Christopher M. ; Tang, Yi ; Truman, Andrew W. ; Viaud, Muriel ; Walton, Jonathan D. ; Walsh, Christopher T. ; Weber, Tilmann ; van Wezel, Gilles P. ; Wilkinson, Barrie ; Willey, Joanne M. ; Wohlleben, Wolfgang ; Wright, Gerard D. ; Ziemert, Nadine ; Zhang, Changsheng ; Zotchev, Sergey B. ; Breitling, Rainer ; Takano, Eriko ; Glöckner, Frank Oliver
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Grammatikos, Georgios ; Lange, Christian ; Susser, Simone ; Schwendy, Susanne ; Dikopoulos, Nektarios ; Buggisch, Peter ; Encke, Jens ; Teuber, Gerlinde ; Goeser, Tobias ; Thimme, Robert ; Klinker, Hartwig ; Boecher, Wulf O. ; Schulte-Frohlinde, Ewert ; Penna Martinez, Marissa ; Badenhoop, Klaus ; Zeuzem, Stefan ; Berg, Thomas ; Sarrazin, Christoph
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Bernatz, Simon ; Zhdanovich, Yauheniya ; Ackermann, Jörg ; Koch, Ina ; Wild, Peter Johannes ; Pinto dos Santos, Daniel ; Vogl, Thomas J. ; Kaltenbach, Benjamin ; Rosbach, Nicolas
Our purpose was to analyze the robustness and reproducibility of magnetic resonance imaging (MRI) radiomic features. We constructed a multi-object fruit phantom to perform MRI acquisition as scan-rescan using a 3 Tesla MRI scanner. We applied T2-weighted (T2w) half-Fourier acquisition single-shot turbo spin-echo (HASTE), T2w turbo spin-echo (TSE), T2w fluid-attenuated inversion recovery (FLAIR), T2 map and T1-weighted (T1w) TSE. Images were resampled to isotropic voxels. Fruits were segmented. The workflow was repeated by a second reader and the first reader after a pause of one month. We applied PyRadiomics to extract 107 radiomic features per fruit and sequence from seven feature classes. We calculated concordance correlation coefficients (CCC) and dynamic range (DR) to obtain measurements of feature robustness. Intraclass correlation coefficient (ICC) was calculated to assess intra- and inter-observer reproducibility. We calculated Gini scores to test the pairwise discriminative power specific for the features and MRI sequences. We depict Bland Altmann plots of features with top discriminative power (Mann–Whitney U test). Shape features were the most robust feature class. T2 map was the most robust imaging technique (robust features (rf), n = 84). HASTE sequence led to the least amount of rf (n = 20). Intra-observer ICC was excellent (≥ 0.75) for nearly all features (max–min; 99.1–97.2%). Deterioration of ICC values was seen in the inter-observer analyses (max–min; 88.7–81.1%). Complete robustness across all sequences was found for 8 features. Shape features and T2 map yielded the highest pairwise discriminative performance. Radiomics validity depends on the MRI sequence and feature class. T2 map seems to be the most promising imaging technique with the highest feature robustness, high intra-/inter-observer reproducibility and most promising discriminative power.
The seasonality of transport and mixing of air into the lowermost stratosphere (LMS) is studied using distributions of mean age of air and a~mass balance approach, based on in-situ observations of SF6 and CO2 during the SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) aircraft campaigns. Combining the information of the mean age of air and the water vapour distributions we demonstrate that the tropospheric air transported into the LMS above the extratropical tropopause layer (ExTL) originates predominantly from the tropical tropopause layer (TTL). The concept of our mass balance is based on simultaneous measurements of the two passive tracers and the assumption that transport into the LMS can be described by age spectra which are superposition of two different modes. Based on this concept we conclude that the stratospheric influence on LMS composition is strongest in April with tropospheric fractions (α1) below 20% and that the strongest tropospheric signatures are found in October with (α1 greater than 80%. Beyond the fractions, our mass balance concept allows to calculate the associated transit times for transport of tropospheric air from the tropics into the LMS. The shortest transit times (<0.3 years) are derived for the summer, continuously increasing up to 0.8 years by the end of spring. These findings suggest that strong quasi-horizontal mixing across the weak subtropical jet from summer to mid of autumn and the considerably shorter residual transport time-scales within the lower branch of the Brewer-Dobson circulation in summer than in winter dominates the tropospheric influence in the LMS until the beginning of next year's summer.
The seasonality of transport and mixing of air into the lowermost stratosphere (LMS) is studied using distributions of mean age of air and a mass balance approach, based on in-situ observations of SF6 and CO2 during the SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) aircraft campaigns. Combining the information of the mean age of air and the water vapour distributions we demonstrate that the tropospheric air transported into the LMS above the extratropical tropopause layer (ExTL) originates predominantly from the tropical tropopause layer (TTL). The concept of our mass balance is based on simultaneous measurements of the two passive tracers and the assumption that transport into the LMS can be described by age spectra which are superposition of two different modes. Based on this concept we conclude that the stratospheric influence on LMS composition is strongest in April with extreme values of the tropospheric fractions (alpha1) below 20% and that the strongest tropospheric signatures are found in October with alpha1 greater than 80%. Beyond the fractions, our mass balance concept allows us to calculate the associated transit times for transport of tropospheric air from the tropics into the LMS. The shortest transit times (<0.3 years) are derived for the summer, continuously increasing up to 0.8 years by the end of spring. These findings suggest that strong quasi-horizontal mixing across the weak subtropical jet from summer to mid of autumn and the considerably shorter residual transport time-scales within the lower branch of the Brewer-Dobson circulation in summer than in winter dominates the tropospheric influence in the LMS until the beginning of next year's summer.
Broggini, Thomas ; Stange, Lena ; Lucia, Kristin Elizabeth ; Vajkoczy, Peter ; Czabanka, Marcus Alexander
Vascular guidance is critical in developmental vasculogenesis and pathological angiogenesis. Brain tumors are strongly vascularized, and antiangiogenic therapy was anticipated to exhibit a strong anti-tumor effect in this tumor type. However, vascular endothelial growth factor A (VEGFA) specific inhibition had no significant impact in clinical practice of gliomas. More research is needed to understand the failure of this therapeutic approach. EphrinB2 has been found to directly interact with vascular endothelial growth factor receptor 2 (VEGFR2) and regulate its activity. Here we analyzed the expression of ephrinB2 and EphB4 in human glioma, we observed vascular localization of ephrinB2 in physiology and pathology and found a significant survival reduction in patients with elevated ephrinB2 tumor expression. Induced endothelial specific depletion of ephrinB2 in the adult mouse (efnb2i∆EC) had no effect on the quiescent vascular system of the brain. However, we found glioma growth and perfusion altered in efnb2i∆EC animals similar to the effects observed with antiangiogenic therapy. No additional anti-tumor effect was observed in efnb2i∆EC animals treated with antiangiogenic therapy. Our data indicate that ephrinB2 and VEGFR2 converge on the same pathway and intervention with either molecule results in a reduction in angiogenesis.
Wigand, Rainer ; Gottschalk, René ; Pospiech, Thomas ; Falkenbach, Albrecht ; Kaltwasser, Joachim Peter ; Hoelzer, Dieter
Hofmann, Wolf-Peter ; Mauß, Stefan ; Lutz, Thomas ; Schober, Andreas ; Böker, Klaus ; Moog, Gero ; Baumgarten, Axel ; Pfeiffer-Vornkahl, Heike ; Alshuth, Ulrich ; Hüppe, Dietrich ; Wedemeyer, Heiner ; Manns, Michael P. ; Schott, Eckart
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.