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Author: Sven G Meuth (218)


Dec
1969

Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far.
To explore the influence of alemtuzumab on cognitive impairment in active relapsing-remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy.

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Dec
2017

Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability.
Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers.

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Nov
2017

Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

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Feb
2018

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder. The contribution of the immune system to its pathogenesis remains incompletely understood. In this study, we performed comprehensive immune cell profiling in the cerebrospinal fluid (CSF) and peripheral blood of patients with FTD.

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Nov
2017

Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage.

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Dec
1969

Substance P (SP) is a neuropeptide, likely acting as a neurotransmitter in the pharyngeal mucosa enhancing the swallow and cough reflex. Pharyngeal Electrical Stimulation (PES) induces a temporary increase of salivary SP levels in healthy adults. Previous evidence suggests that post-stroke dysphagia is related to reduced SP levels.

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Dec
2017

Recent studies have implicated an important role for coagulation factors in neuroinflammatory disorders like multiple sclerosis (MS). Here, we investigate the role of factor X (FX) in neuroinflammation by using rivaroxaban the selective inhibitor of activated FX (FXa) in experimental autoimmune encephalomyelitis (EAE, an animal model of MS). Rivaroxaban-treated rats were less susceptible to EAE compared to the untreated control group.

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Dec
2017

Cognitive impairment (CI) is common and debilitating in patients with multiple sclerosis. However, little is known about how different disease courses affect CI, impeding prognosis and disease management. Here, we contrasted the magnitude and profile of CI measured with standardized neuropsychological tests in patients with primary progressive multiple sclerosis (PPMS) against relapsing-remitting multiple sclerosis (RRMS) while considering potentially confounding demographic and clinical differences.

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Sep
2017

Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice.

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Dec
2017

Pancreatic cancer is characterized by a massive fibrosis (desmoplasia), which is primarily caused by activated pancreatic stellate cells (PSCs). This leads to a hypoxic tumor microenvironment further reinforcing the activation of PSCs by stimulating their secretion of growth factors and chemokines. Since many of them elicit their effects via G-protein-coupled receptors (GPCRs), we tested whether TRPC6 channels, effector proteins of many G-protein-coupled receptor pathways, are required for the hypoxic activation of PSCs.

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Aug
2017

Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes.
Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States.
Published studies and the verification showed (1) a mean of 10.

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Dec
2017

Immunization of experimental autoimmune encephalomyelitis (EAE)-prone C57BL/6 mice with MOG(a model used to study aspects of human multiple sclerosis) is known to lead to the production of various abzymes. The production of catalytic IgGs that can efficiently hydrolyse myelin basic protein (MBP), MOG and DNA is associated with changes in the profile of differentiation and level of proliferation of mice bone marrow haematopoietic stem cells (HSCs). As MOG simulates the production of abzymes with high DNase activity, we compared the effects of DNA and MOG immunization on EAE-prone mice.

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Jan
2018

A shared decision-making approach is suggested for multiple sclerosis (MS) patients. To properly evaluate benefits and risks of different treatment options accordingly, MS patients require sufficient numeracy - the ability to understand quantitative information. It is unknown whether MS affects numeracy.

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Dec
1969

The investigation of specific white matter areas is a growing field in neurological research and is typically achieved through the use of atlases. However, the definition of anatomically based regions remains challenging for the white matter and thus hinders region-specific analysis in individual subjects. In this article, we focus on creating a whole white matter parcellation method for individual subjects where these areas can be associated to cortex regions.

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Sep
2017

The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained Kcurrents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 Kchannels results in hyperpolarization of interneurons and suppression of their action potential firing.

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Jul
2017

Alzheimer's disease is the most common cause of dementia. Over the last three decades, research has advanced dramatically and provided a detailed understanding of the molecular events underlying the pathogenesis of Alzheimer's disease. In parallel, assays for the detection of biomarkers that reflect the typical Alzheimer's disease-associated pathology have been developed and validated in myriads of clinical studies.

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Jul
2017

Herpes simplex virus-1 has been identified as the trigger factor in certain cases of NMDA-receptor autoimmune encephalitis. We report on a 67-year-old female patient, who was severely affected by post-herpetic NMDA-receptor autoimmune encephalitis. Her symptoms did not improve under methylprednisolone pulse therapy and plasma exchange under acyclovir prophylaxis.

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Nov
2017

The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of T17 cells, and regulatory T cell (T) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Using a CCL17/EGFP reporter mouse model, we could show that CCL17 expression in the CNS can be found in a subset of classical dendritic cells (DCs) that immigrate into the CNS during the effector phase of MOG-induced EAE.

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Jun
2017

Repetitive cortical spreading depression (CSD) can lead to cell death in immature brain tissue. Caspases are involved in neuronal cell death in several CSD-related neurological disorders, such as stroke and epilepsy. Yet, whether repetitive CSD itself can induce caspase activation in adult or juvenile tissue remains unknown.

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Jan
2017

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians.

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May
2017

Natalizumab (NAT) is associated with the risk of progressive multifocal leukoencephalopathy (PML). Risk stratification algorithms have been developed, however, without detectable reduction of PML incidence.
To evaluate to which extent patients and physicians understand and accept risks associated with NAT treatment.

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Dec
1969

Progressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing.
We addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?
699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study.

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Apr
2017

High dietary salt (NaCl) is a known risk factor for cardiovascular pathologies and inflammation. High plasma Naconcentrations (high Na) have been shown to stiffen the endothelial cortex and decrease nitric oxide (NO) release, a hallmark of endothelial dysfunction. Here we report that chronic high Nadamages the endothelial glycocalyx (eGC), induces release of inflammatory cytokines from the endothelium and promotes monocyte adhesion.

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Apr
2017

Recombinant TWIK2 channels produce weak basal background Kcurrents. Current amplitudes depend on the animal species the channels have been isolated from and on the heterologous system used for their re-expression. Here we show that this variability is due to a unique cellular trafficking.

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Jan
2017

Background Cortical spreading depression (CSD) related diseases such as migraine, cerebrovascular diseases, and epilepsy have been associated with reactive astrocytosis, yet the mechanisms of these tissue changes remain unclear. CSD-induced inflammatory response has been proposed to play a role in some neurological disorders and thus may also contribute to reactive astrocytosis. Methods Using ex vivo brain slices and in vitro astrocytic cultures, we aimed to characterize CSD related changes in astrocytes and markers of inflammation by immunocyto- and immunohistochemistry.

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May
2017

Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies.

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Dec
2016

Breakdown of the blood-brain barrier (BBB) is a critical step in the development of autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). This process is characterized by the transmigration of activated T cells across brain endothelial cells (ECs), the main constituents of the BBB. However, the consequences on brain EC function upon interaction with such T cells are largely unknown.

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Dec
1969

Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases.
Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.

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Jan
2017

To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.
Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot.

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Oct
2016

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (T1) and T17 cells cause demyelination and neuronal degeneration. Regulatory T cells (T) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Tfunction is impaired.

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Dec
2016

Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls.

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Dec
2016

To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.
Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined.

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Oct
2016

Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The identification of novel molecular mechanisms linking inflammation and to platelets has highlighted them as new targets for therapeutic interventions. In particular, genetic and pharmacological studies have identified an important role for platelets in neuroinflammation.

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Dec
1969

K5.1 channels (also called TASK-2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K5.

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Dec
1969

Optic neuritis (ON) has detrimental effects on the transmission of neuronal signals generated at the earliest stages of visual information processing. The amount, as well as the speed of transmitted visual signals is impaired. Measurements of visual evoked potentials (VEP) are often implemented in clinical routine.

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Dec
1969

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice).

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Dec
1969

Inherited, autosomal dominant spinocerebellar ataxia type 11 (SCA11) is caused by loss of function mutations of TTBK2 (tau tubulin kinase 2). Mutations observed in patients with SCA11 include truncated TTBK2(450). The present study explored the possibility that TTBK2 influences the function of the glutamate receptor GluK2.

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Jan
2017

Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood.

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Oct
2016

Two-pore domain potassium (K) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca-concentration [Ca]While the physiological importance of Kchannels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown.

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Jun
2017

Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS).
To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts.
Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation.

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Jul
2016

In the past 5 years, the combination of developments in diagnostic strategy and approval of new disease-modifying therapies has provided an opportunity to achieve dramatic improvements in patient outcomes in multiple sclerosis (MS). However, across Europe there are several factors that may prevent patients from receiving the best therapy at the appropriate time, and there is variation among countries in terms of which of these factors are most relevant. Here, we review current MS clinical practices in a number of countries in the European Union to identify differences regarding initiation of treatment in patients with clinically isolated syndrome or relapsing-remitting MS, and differences in the timing of treatment switch or escalation.

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Dec
1969

Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood.

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Dec
1969

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Sci Adv 2016 06 17;2(6):e1501678. Epub 2016 Jun 17.
Till F M Andlauer, Dorothea Buck, Gisela Antony, Antonios Bayas, Lukas Bechmann, Achim Berthele, Andrew Chan, Christiane Gasperi, Ralf Gold, Christiane Graetz, Jürgen Haas, Michael Hecker, Carmen Infante-Duarte, Matthias Knop, Tania Kümpfel, Volker Limmroth, Ralf A Linker, Verena Loleit, Felix Luessi, Sven G Meuth, Mark Mühlau, Sandra Nischwitz, Friedemann Paul, Michael Pütz, Tobias Ruck, Anke Salmen, Martin Stangel, Jan-Patrick Stellmann, Klarissa H Stürner, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Clemens Warnke, Frank Weber, Heinz Wiendl, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Frauke Zipp, Janine Arloth, Peter Weber, Milena Radivojkov-Blagojevic, Markus O Scheinhardt, Theresa Dankowski, Thomas Bettecken, Peter Lichtner, Darina Czamara, Tania Carrillo-Roa, Elisabeth B Binder, Klaus Berger, Lars Bertram, Andre Franke, Christian Gieger, Stefan Herms, Georg Homuth, Marcus Ising, Karl-Heinz Jöckel, Tim Kacprowski, Stefan Kloiber, Matthias Laudes, Wolfgang Lieb, Christina M Lill, Susanne Lucae, Thomas Meitinger, Susanne Moebus, Martina Müller-Nurasyid, Markus M Nöthen, Astrid Petersmann, Rajesh Rawal, Ulf Schminke, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Jürgen Wellmann, Eleonora Porcu, Antonella Mulas, Maristella Pitzalis, Carlo Sidore, Ilenia Zara, Francesco Cucca, Magdalena Zoledziewska, Andreas Ziegler, Bernhard Hemmer, Bertram Müller-Myhsok
We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci.

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Sep
2016

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses.

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Jun
2016

Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS.
Using murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro.

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