142 research outputs found

    Estimating flow and transport parameters in the unsaturated zone with pore water stable isotopes

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    The first author was funded by the DFG Research Group: From Catchments as Organised Systems to Models based on Functional Units (FOR 1598). The second author was funded by the DFG project Coupled soil-plant water dynamics – Environmental drivers and species effects (contract numbers: GE 1090/10-1 and WE 4598/2-1). The isotope data in the precipitation for Roodt were provided by FNR/CORE/SOWAT, project of the Luxembourg Institute of Science and Technology – LIST. Sampling of the isotope profiles was made possible by the support of the CAOS Team and Begona Lorente Sistiaga, Benjamin Gralher, Andre Böker, Marvin Reich and Andrea Popp. Special thanks to Britta Kattenstroth and Jean Francois Iffly for their technical support in the field and Barbara Herbstritt for her support in the laboratory. For Roodt, soil texture and hydraulic parameter information were provided by Conrad Jackisch and Christoph Messer (KIT, Karlsruhe, Germany) and hydraulic conductivity data were provided by Christophe Hissler and Jérôme Juilleret (LIST). Pore water isotope and soil moisture data for Hartheim were provided by Steffen Holzkämper and Paul Königer. Temperature and precipitation data for Hartheim were provided by the Chair of Meteorology and Climatology, University of Freiburg.Peer reviewedPublisher PD

    Neurometabolic correlates of depression and disability in episodic cluster headache

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    A close association between pain, depression and disability has been shown. However, the neurometabolic correlates of this association have been barely investigated in disease states. Episodic cluster headache is a severe headache syndrome and represents a suitable disease model for the investigation of episodic pain. The aim of this study was to explore the relationship between depression and disability as well as pain scores and brain metabolism in patients with cluster headache during the disease period with repetitive pain attacks, but outside an acute attack. Thirteen patients with cluster headache underwent 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission (FDG-PET) and completed questionnaires on depression and disability as well as a pain visual analogue rating scale (VAS). A positive correlation between the depression scores and glucose metabolism was observed in the insular cortex. A positive correlation between the pain disability scores and brain metabolism was detected in the amygdala. The same applied to the pain visual analogue rating scores. Our data underline the association between severe episodic pain, depression and disability. In addition to this clinical observation, our results stress the importance of the insula and amygdala in pain processing and suffering

    50 Jahre UNDERSTANDING MEDIA

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    Vor 50 Jahren erschien "Understanding Media" von Marshall McLuhan. Das aktuelle "Navigationen"-Heft nimmt in fünf Beiträgen das Jubiläum zum Anlass, dieses Buch systematisch und historisch unter die Lupe zu nehmen. Die Beiträge setzen dazu an, die Situation des Buches zu verstehen, um etwas über seine Medien zu erfahren. Die Dramaturgie der Texte reicht von der handwerklichen Bearbeitung des Buches und seine Weitsicht hinsichtlich der Zukunft der Bücher über das Fernsehen seiner Zeit bis hin zur Rezeption seiner Inhalte in der deutschsprachigen Presse und seinem technikphilosophischen Kontext

    Longitudinal analysis of new multiple sclerosis lesions with magnetization transfer and diffusion tensor imaging

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    Objective The potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed. Methods Nineteen patients with MS obtained conventional MRI, MTI, and DTI examinations bimonthly for 12 months and again after 24 months at 1.5 T MRI. MTI was acquired with balanced steady-state free precession (bSSFP) in 10 min (1.3 mm3^{3} isotropic resolution) yielding both magnetization transfer ratio (MTR) and quantitative magnetization transfer (qMT) parameters (pool size ratio (F), exchange rate (kf), and relaxation times (T1/T2)). DTI provided fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Results At the time of their appearance on MRI, the 21 newly detected MS lesions showed significantly reduced MTR/F/kf and prolonged T1/T2 parameters, as well as significantly reduced FA and increased AD/MD/RD. Significant differences were already observed for MTR 4 months and for qMT parameters 2 months prior to lesions’ detection on MRI. DTI did not show any significant pre-lesional differences. Slightly reversed trends were observed for most lesions up to 8 months after their detection for qMT and less pronounced for MTR and three diffusion parameters, while appearing unchanged on MRI. Conclusions MTI provides more information than DTI in MS lesions and detects tissue changes 2 to 4 months prior to their appearance on MRI. After lesions’ detection, qMT parameter changes promise to be more sensitive than MTR for the lesions’ evolutional assessment. Overall, bSSFP-based MTI adumbrates to be more sensitive than MRI and DTI for the early detection and follow-up assessment of MS lesions. Clinical relevance statement When additionally acquired in routine MRI, fast bSSFP-based MTI can complement the MRI/DTI longitudinal lesion assessment by detecting MS lesions 2–4 months earlier than with MRI, which could implicate earlier clinical decisions and better follow-up/treatment assessment in MS patients. Key Points • Magnetization transfer imaging provides more information than DTI in multiple sclerosis lesions and can detect tissue changes 2 to 4 months prior to their appearance on MRI. • After lesions’ detection, quantitative magnetization transfer changes are more pronounced than magnetization transfer ratio changes and therefore promise to be more sensitive for the lesions’ evolutional assessment. • Balanced steady-state free precession–based magnetization transfer imaging is more sensitive than MRI and DTI for the early detection and follow-up assessment of multiple sclerosis lesions

    Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping

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    Central post-stroke pain of thalamic origin is an extremely distressing and often refractory disorder. There are no well-established predictors for pain development after thalamic stroke, and the role of different thalamic nuclei is unclear. Here, we used structural magnetic resonance imaging to identify the thalamic nuclei, specifically implicated in the generation of central post-stroke pain of thalamic origin. Lesions of 10 patients with central post-stroke pain of thalamic origin and 10 control patients with thalamic strokes without pain were identified as volumes of interest on magnetic resonance imaging data. Non-linear deformations were estimated to match each image with a high-resolution template and were applied to each volume of interest. By using a digital atlas of the thalamus, we elucidated the involvement of different nuclei with respect to each lesion. Patient and control volumes of interest were summed separately to identify unique areas of involvement. Voxelwise odds ratio maps were calculated to localize the anatomical site where lesions put patients at risk of developing central post-stroke pain of thalamic origin. In the patients with pain, mainly lateral and posterior thalamic nuclei were affected, whereas a more anterior-medial lesion pattern was evident in the controls. The lesions of 9 of 10 pain patients overlapped at the border of the ventral posterior nucleus and the pulvinar, coinciding with the ventrocaudalis portae nucleus. The lesions of this area showed an odds ratio of 81 in favour of developing thalamic pain. The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of thalamic origin early after thalamic insults. This provides a basis for pre-emptive treatment studie

    Evaluation of a new approach for semi-automatic segmentation of the cerebellum in patients with multiple sclerosis

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    Cerebellar dysfunction is an important contributor to disability in patients with multiple sclerosis (MS), however, few in vivo studies focused on cerebellar volume loss so far. This relates to technical challenges regarding the segmentation of the cerebellum. In this study, we evaluated the semi-automatic ECCET software for performing cerebellar volumetry using high-resolution 3D T1-MR scans in patients with MS and healthy volunteers. We performed test-retest as well as inter-observer reliability testing of cerebellar segmentation and compared the ECCET results with a fully automatic cerebellar segmentation using the FreeSurfer software pipeline in 15 MS patients. In a pilot matched-pair analysis with another data set from 15 relapsing-remitting MS patients and 15 age- and sex-matched healthy controls (HC), we assessed the feasibility of the ECCET approach to detect MS-related cerebellar volume differences. For total normalized cerebellar volume as well as grey and white matter volumes, intrarater (intraclass correlation coefficient (ICC)=0.99, 95% CI=0.98-0.99) and interobserver agreement (ICC=0.98, 95% CI=0.74-0.99) were strong. Comparison between ECCET and FreeSurfer results likewise yielded a good intraclass correlation (ICC=0.86, 95% CI=0.58-0.95). Compared to HC, MS patients had significantly reduced normalized total brain, total cerebellar, and grey matter volumes (p≤0.05). ECCET is a suitable tool for cerebellar segmentation showing excellent test-retest and inter-observer reliability. Our matched-pair analysis between MS patients and healthy volunteers suggests that the method is sensitive and reliable in detecting cerebellar atrophy in M

    Long-term safety and efficacy of daclizumab beta in relapsing-remitting multiple sclerosis : 6-year results from the SELECTED open-label extension study

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    Objective: SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED. Methods: Eligible participants who completed 1-2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION. Results: Ninety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0-24 was 0.21 (0.16-0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time. Conclusions: The effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED. Trial registration: Clinicaltrials.gov NCT01051349; first registered on January 15, 2010

    Ponesimod Compared with Teriflunomide in Patients with Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study : A Randomized Clinical Trial

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    Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1Pmodulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P <.001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P <.001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P <.001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P =.29) and 16% (8.1% vs 9.9; P =.37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P <.001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P <.001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators

    Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

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    SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks

    Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis

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    Objectives: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity.Methods: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety.Results: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time.Conclusions: MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found.Classification of evidence: This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS
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