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CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson’s disease: a study in LRRK2 mutation carriers

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Translational Neurodegeneration 2020年第2期9卷 168-177页

作者： Nour K.Majbour Jan O.Aasly Eldbjørg Hustad Mercy A.Thomas Nishant N.Vaikath Naser Elkum Wilma D.Jvan de Berg Takahiko Tokuda brit mollenhauer Henk W.Berendse Omar M.A.El-Agnaf Neurological Disorders Research Center Qatar Biomedical Research InstituteHamad Bin Khalifa UniversityQatar FoundationP.O.Box 5825DohaQatar Department of Neuroscience Norwegian University of Science and Technology(NTNU)TrondheimNorway Department of Neurology St.Olav’s HospitalUniversity Hospital of TrondheimTrondheimNorway Clinical Epidemiology Sidra Medical and Research CenterDohaQatar Department of Anatomy and Neurosciences Neuroscience Campus AmsterdamVU University Medical CentreAmsterdamthe Netherlands Department of Neurology Research Institute for GeriatricsKyoto Prefectural University of MedicineKyoto602-0841Japan Paracelsus-Elena-Klinik KlinikstraßeKasseland University Medical Center GöttingenDepartment of NeurologyGöttingenGermany Department of Neurology Amsterdam UMClocation VU University Medical CentreAmsterdamThe Netherlands

Background Asymptomatic carriers of leucine-rich repeat kinase 2(LRRK2)gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease(PD).In this study,we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation *** We measured the levels of CSF total-(t-),oligomeric(o-)and phosphorylated S129(pS129-)α-syn,total-tau(tTau),phosphorylated threonine 181 tau(pTau),amyloid-beta 40(Aβ-40),amyloid-beta-42(Aβ-42)and 40 inflammatory chemokines in symptomatic(n=23)and asymptomatic(n=51)LRRK2 mutation carriers,subjects with a clinical diagnosis of PD(n=60)and age-matched healthy controls(n=34).General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the *** that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal *** Discriminant function analysis revealed low levels of CSF t-α-syn,high levels of CSF o-α-syn and TNF-αbest discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy *** the discriminative power using receiver operating curve analysis,an area under the curve>0.80 was *** The current study suggests that CSF t-,o-α-syn and TNF-αare candidate risk biomarkers for the detection of PD at the prodromal *** findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’panel approach for an accurate and timely diagnosis of PD.

关键词： Parkinson's disease LRRK2 mutation carriers Alpha-synuclein oligomers Biomarkers Inflammatory markers

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No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors

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Translational Neurodegeneration 2019年第1期8卷 127-133页

作者： Franziska Hopfner Stefanie HMüller Dagmar Steppat Joanna Miller Nele Schmidt Klaus-Peter Wandinger Frank Leypoldt Daniela Berg Andre Franke Wolfgang Lieb Lukas Tittmann Monika Balzer-Geldsetzer Simon Baudrexel Richard Dodel Ruediger Hilker-Roggendorf Elke Kalbe Jan Kassubek Thomas Klockgether Inga Liepelt-Scarfone brit mollenhauer Petra Neuser Kathrin Reetz Oliver Riedel Claudia Schulte Jörg BSchulz Annika Spottke Alexander Storch Claudia Trenkwalder Hans-Ulrich Wittchen Karsten Witt Ullrich Wüllner Günther Deuschl Gregor Kuhlenbäumer Department of Neurology University Hospital Schleswig HolsteinArnold-Heller Str.324105 KielGermany Center of Blood Transfusion University Hospital Schleswig HolsteinKiel&LübeckGermany Department of Clinical Chemistry University Hospital Schleswig-HolsteinKielGermany Institute of Clinical Molecular Biology University Hospital Schleswig-HolsteinKielGermany Institute of Epidemiology University Hospital Schleswig-HolsteinKielGermany Chair of Geriatric Medicine University Hospital EssenEssenGermany Department of Neurology Philipps-University MarburgMarburgGermany Department of Neurology Goethe UniversityFrankfurt/MainGermany Brain Imaging Center Goethe UniversityFrankfurt/MainGermany Department of Medical Psychology|Neuropsychology and Gender Studies&Center for Neuropsychological Diagnostics and Intervention(CeNDI) University Hospital CologneCologneGermany Psychological Gerontology Institute of GerontologyUniversity of VechtaVechtaGermany Department of Neurology University of UlmUlmGermany Department of Neurology University of Bonnand German Center for Neurodegenerative Diseases(DZNE)BonnGermany Center for Neurology Hertie Institute for Clinical Brain ResearchDepartment of Neurodegenerative DiseasesUniversity of TübingenTübingenGermany DZNE German Center for Neurodegenerative DiseasesTübingenGermany Paracelsus-Elena-Klinik KasselGermany Institute of Neuropathology and Department of Neurosurgery University Medical Center GöttingenGöttingenGermany Coordinating Centre for Clinical Trials Philipps-UniversityMarburgGermany Department of Neurology RWTH Aachen UniversityAachenGermany JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging Forschungszentrum Jülich GmbH and RWTH Aachen UniversityAachenGermany Leibniz Institute for Prevention Research and Epidemiology-BIPS Achterstrasse 3028359 BremenGermany Department of Neurology Technische Universität Dresden01307 DresdenGermany German Center for Neurodegenerative Diseases(DZNE) Research Site Rostock18147 RostockGerma

Background:IgG-class autoantibodies to N-Methyl-D-Aspartate(NMDA)-type glutamate receptors define a novel entity of autoimmune *** examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting *** 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 *** phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive ***:NMDA antibodies were analysed in the serum of patients and controls using well established validated *** used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic ***: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 *** 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 ***:It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease *** Parkinson disease with dementia,while NMDA IgG antibodies define a separate disease of its own.

关键词： NMDA antibody NMDA IgA/IgM antibodies Parkinson disease Cognitive impairment

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Molecular determinants of the antitumor effects of trichostatin A in pancreatic cancer cells

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World Journal of Gastroenterology 2010年第16期16卷 1970-1978页

作者： Elisabeth Emonds brit Fitzner Robert Jaster Department of Medicine II Division of GastroenterologyMedical FacultyUniversity of Rostock

AIM:To gain molecular insights into the action of the histone deacetylase inhibitor(HDACI) trichostatin-A(TSA) in pancreatic cancer(PC) ***:Three PC cell lines,BxPC-3,AsPC-1 and CAPAN-1,were treated with various concentrations of TSA for def ined periods of *** synthesis was assessed by measuring the incorporation of 5-bromo-2'*** expression at the level of mRNA was quantif ied by real-time polymerase chain *** and phosphorylation of proteins was monitored by immunoblotting,applying an infrared imaging *** study the role of p38 MAP kinase,the specif ic enzyme inhibitor SB202190 and an inactive control substance,SB202474,were ***:TSA most eff iciently inhibited BrdU incorporation in BxPC-3 cells,while CAPAN-1 cells displayed the lowest and AsPC-1 cells an intermediate *** biological response of the cell lines correlated with the increase of histone H3 acetylation after TSA *** BxPC-3 cells(which are wild-type for KRAS),TSA strongly inhibited phosphorylation of ERK 1/2 and *** contrast,activities of ERK and AKT in AsPC-1 and CAPAN-1 cells(both expressing oncogenic KRAS) were not or were only modestly affected by TSA *** all three cell lines,but most pronounced in BxPC-3 cells,TSA exposure induced an activation of the MAP kinase *** of p38 by SB202190 slightly but signif icantly diminished the antiproliferative effect of TSA in BxPC-3 ***,only BxPC-3 cells responded to TSA treatment by a signif icant increase of the mRNA levels of bax,a pro-apoptotic member of the BCL gene ***,in BxPC-3 and AsPC-1 cells,but not in the cell line CAPAN-1,signif icantly higher levels of the cell cycle inhibitor protein p21Waf1 were observed after TSA ***:The biological effect of TSA in PC cells correlates with the increase of acetyl-H3,p21Waf1,phospho-p38 and bax levels,and the decrease of phosphoERK 1/2 and phospho-AKT.

关键词： Pancreatic cancer Histone deacetylase inhibitor Trichostatin-A KRAS MAP kinases p21Waf1 AKT

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Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

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World Journal of Gastroenterology 2009年第33期15卷 4143-4149页

作者： Anika Jonitz brit Fitzner Robert Jaster Department of Medicine Ⅱ Division of GastroenterologyMedical FacultyUniversity of Rostock

AIM： To gain molecular insights into the expression and functions of endothelin-1 （ET-1） in pancreatic stellate cells （PSC）.METHODS： PSCs were isolated from rat pancreas tissue, cultured, and stimulated with ET-1 or other extracellular mediators. Cell proliferation was assessed by measuring the incorporation of 5-bromo-2＇-deoxyuridine into DNA and cell migration was studied in a transwell chamber assay. Gene expression at the level of mRNA was quantified by real-time Polymerase chain reaction. Expression and phosphorylation of proteins were monitored by immunoblotting, applying an infrared imaging technology. ET-1 levels in cell culture supernatants were determined by an enzyme immunometric assay. To study DNA binding of individual transcription factors, electrophoretic mobility shift assays were ***： Among several mediators tested, transforming growth factor-β1 and tumour necrosis factor-α displayed the strongest stimulatory effects on ET-1 secretion. The cytokines induced binding of Smad3 and NF-κB, respectively, to oligonucleotides derived from the ET-1 promoter, implicating both transcription factors in the induction of ET-1 gene expression. In accordance with previous studies, ET-1 was found to stimulate migration but not proliferation of PSC. Stimulation of ET-1 receptors led to the activation of two distinct rnitogen-activated protein kinases, p38 and extracellular signal-regulated kinases （ERK）1/2, as well as the transcription factor activator protein-1. At the mRNA level, enhanced expression of the PSC activation marker, α-smooth muscle actin and two proinflammatory cytokines, interleukin （IL）-1β and IL-6, was observed. CONCLUSION： This study provides novel lines of evidence for profibrogenic and proinflammatory actions of ET-1 in the pancreas, encouraging further studies with ET-1 inhibitors in chronic pancreatitis.

关键词： Chronic pancreatitis Endothelin-1 Fibrosis Pancreatic stellate cells

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Single and multiple stressor effect of road deicers and Cu on Atlantic salmon (Salmo salar) alevins from hatching till swim-up

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Journal of Environmental Sciences 2018年第4期30卷 368-378页

作者： Urma Mahrosh BjФrn Olav Rosseland brit Salbu Hans-Christian Teien Nortuegian Uniuersity of Life Sciences Department of Environmental Sciences N-1432 As Norway National University of Sciences and Technology H-12 Islamabad Pakistan Norwegian University of Life Sciences Department of Ecology and Natural Resource Management N-1432 As Norway

Road salts are frequently used for deicing of roads in the Nordic countries. During snow-melt, the road run-off containing high concentrations of road salt and various metals such as Cu remobilized from sand, silt and dust may negatively influence organisms in downstream receiving water bodies. The present work focuses on the impact of road salt（NaCl） and Cu, separately and in mixtures on Atlantic salmon alevins from hatching till swim-up. The results showed that high road salt concentrations could induce a series of negative effects in alevins such as reduced growth, deformities, delayed swim-up and mortality. For alevins exposed to all tested road salt concentrations（100–1000 mg/L）,mortality was significantly higher compared to control. In exposure to Cu solutions（5–20 μg Cu/L）, no effects on growth, morphology, swim-up or mortality of alevins compared to control were observed. In mixture solutions（road salt and Cu）, ultrafiltration of the exposure water demonstrated that only 20%–40% of Cu was present as positively charged low molecular mass（LMM） Cu species assumed to be bioavailable. When exposed to road salt and Cu mixtures, negative effects in alevins such as reduced growth, deformities,delayed swim-up and mortality were observed. The overall results indicated that the road salt application could seriously affect sensitive life stages of Atlantic salmon, and application of road salt should be avoided during the late winter–early spring period.

关键词： Road deicers Copper Atlantic salmon Alevins Biological effects

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Distinct antifibrogenic effects of erlotinib,sunitinib and sorafenib on rat pancreatic stellate cells

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World Journal of Gastroenterology 2014年第24期20卷 7914-7925页

作者： Anne Elsner Falko Lange brit Fitzner Martin Heuschkel Bernd Joachim Krause Robert Jaster Department of Medicine Ⅱ Division of GastroenterologyUniversity Medicine Rostock18057 RostockGermany Department of Neurology University Medicine Rostock18119 RostockGermany Department of Nuclear Medicine University Medicine Rostock18057 RostockGermany

AIM: To study if three clinically available small molecule kinase inhibitors (SMI), erlotinib, sunitinib and sorafenib, exert antifibrogenic effects on pancreatic stellate cells (PSC) and analyze the basis of their ac... 详细信息

关键词： Pancreatic stellate cell Fibrosis Erlotinib Sunitinib Sorafenib

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Impact of hyperglycemia on autoimmune pancreatitis and regulatory T-cells

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World Journal of Gastroenterology 2018年第28期24卷 3120-3129页

作者： Franz-Tassilo Müller-Graff brit Fitzner Robert Jaster Brigitte Vollmar Dietmar Zechner Institute for Experimental Surgery Rostock University Medical Center Division of Gastroenterology Department of Medicine Ⅱ Rostock University Medical Center

AIM To evaluate the influence of hyperglycemia on the progression of autoimmune *** We induced hyperglycemia by repetitive intraperitoneal(ip) injection of 50 mg/kg streptozotocin in MRL/Mp J mice, which develop autoimmune pancreatitis due to a genetic predisposition. We compared the extent of inflammation(histological score, CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells) in the pancreas of hyperglycemic and normoglycemic mice. We also analyzed the number of leukocytes, lymphocytes, granulocytes and monocytes in the blood. In addition, we determined the percentage of CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells, Foxp3^+ CD25^+ T-helper and Foxp3^+T-helper cells in the spleen by flow *** Treatment with streptozotocin caused a strong induction of hyperglycemia and a reduction in body weight(P < 0.001). Severe hyperglycemia did not, however, lead to an aggravation, but rather to a slight attenuation of autoimmune pancreatitis. In the pancreas, both the histological score of the pancreas as well as the number of CD3+ lymphocytes(P < 0.053) were decreased by hyperglycemia. No major changes in the percentage of CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells were observed between hyperglycemic and normoglycemic mice. Hyperglycemia increased the numbers of leukocytes(P < 0.001), lymphocytes(P = 0.016), granulocytes and monocytes(P = 0.001) in the blood. Hyperglycemia also moderately reduced the percentage of CD3^+ lymphocytes(P = 0.057), significantly increased the percentage of Foxp3^+ T-helper cells(P = 0.018) and Foxp3^+ CD25^+ T-helper cells(P = 0.021) and reduced the percentage of Foxp3^+T-helper cells(P = 0.034) in the spleen. CONCLUSION Hyperglycemia does not aggravate but moderately attenuates autoimmune pancreatitis, possibly by increasing the percentage of regulatory T-cells in the spleen.

关键词： Autoimmune disease Diabetes Treg FoxP3 Autoimmune pancreatitis MRL/MpJ mice

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Clayton凝析气田应用干扰试井进行储层描述

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油气田开发工程译丛 1993年第1期 8-13页

作者： brit.,LK 杨寿山

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Social Work in Light of Jane Addams

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Sociology Study 2017年第4期7卷 223-233页

作者： Tone Eldcen brit Jφrgensen Sofie Normann Laila Granli Aamodt Pedagogic Psychological Service Norway Center for Child and Adolescent Mental Health Norway Bodφ Family Counseling Norway Outpatient Clinic for Child and Adolescent Mental Health Norway

Classics of literature and science may characteristically be read anew outside their time and interest area, giving birth to new insights, lane Addams is one such classic author. Her writings can be read as classic texts that educate readers in the discipline of social work, among other things. Her impact on the beginnings of modern social work is foundational. She contributed to radical changes on basis of thought, understanding, and practice in the field. Many have read her texts and written about her, resulting in multiple perspectives. The authors will highlight some relevant areas ripe to be re-examined in our time.

关键词： Social work history migration democracy tacit knowledge narratives

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Sorption Properties of a Bentonite Based Material for Removal of Uranium from Alum Shale Leachate

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Journal of Chemistry and Chemical Engineering 2016年第4期10卷 170-179页

作者： Emilio Alvarenga Sergey Hayrapetyan Lindis Skipperud Lusine Hayrapetyan Matte Linjordet brit Salbu Norwegian Institute of Bioeconomy Research NIBIO Frederik A. Dahls vei 20 N0-1430 s Norway Yerevan State University A. Manoogyan St. 1 0025 Yerevan Armenia Dept. of Env. Sci. NMBU (Norwegian University of Life Sciences) N0-1432 s Norway Dept. of Chem. Biotech. and Food Sei. NMBU (Norwegian University of Life Sciences) N0-1432 s Norway

A dynamic sorption experiment was performed for removal of uranium （VI or 6＋） from a leachate from an alum shale landfill with a diatomite-bentonite based sorbent in a laboratory scale. Such material was grounded and treated chemically with H3PO4 （phosphoric acid） and thermally for improving its porosity and resistance to water flow. A specific surface area of 209 m2·g-1 was determined by the BET method. A sorption capacity of 30 μg·gl and 0.6 μg·g-1 was obtained at a pH of 7.5 and 4 respectively by means of Langmuir and Freundlich isotherm models. The flow rate was 3 mL·min-1 was effective for controlling the pH inside of the column. The sorption mechanism was investigated along with desorption of the element of interest for further process design considerations for a treatment unit on the landfill site.

关键词： Clay based sorbents sorption of uranium langmuir and freundlich adsorption models adsorption capacity.

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