331 research outputs found
Introducing Amyotrophic lateral sclerosis.
No full textIntroducing ALS at present times leads to re-define the concept of motor neuron selectivity which characterizes this
disorder. In fact, multiple systems including skin, liver, and bone marrow are altered in ALS patients. The motor
neuron is still the focus of the disorder and the extended pathology did not modify the concept of ALS as a devastating
disorder based on motor neuron loss. Nonetheless, the involvement of non-motor neurons as well as areas
outside the central nervous system leads to a different perspective to understand the causes, pathophysiology and
therapy of ALS. For this reason a specific issue is dedicated to understand whether intersecting basic, pre-clinical
and clinical knowledge of ALS may lead to a coherent novel scenario allowing to translate basic findings into clinical
practice. Several pre-clinical issues described in this volume appear robust enough to indicate that we should
modify a number of approaches when designing future therapeutic strategies. Similarly, novel investigations based
on altered cell to cell communication are needed to further progress in understanding amyotrophic lateral sclerosis
Future therapeutical strategies dictated by pre-clinical evidence in ALS.
No full textClassic concepts on amyotrophic lateral sclerosis led to define the disease as a selective degeneration of upper
and lower motor neurons. At present such selectivity is questioned by novel findings. For instance, the occurrence
of frontotemporal dementia is now increasingly recognized in the course of ALS. Again, areas outside the central
nervous system are targeted in ALS. In keeping with motor areas other cell types surrounding motor neurons
such as glia and interneurons are key in the pathogenesis of ALS. This multiple cell involvement may be due to a
prion-like diffusion of specific misfolded proteins which are altered in ALS. This is the case of FUS and TDP-43
which harbor a prion domain prone to pathological misfolding. These misfolded proteins are metabolized by the
autophagy, but in ALS there is evidence for a specific deficit of autophagy which impedes the clearance of these
proteins. These concepts lead to re-analyze the potential therapeutics of ALS. In fact, mere cell substitution (stem
cell) therapy appears insufficient to contrast all the alterations in the various pathways affected by ALS. Although
preclinical data speed the application of stem cells in human clinical trials, several hurdles limit their translation
into new therapies. Future treatments are expected to consider the need to target both motor neurons and neighboring
cells which may contribute to the diffusion and persistence of the disease. On this basis the present manuscript
describes which future strategies need to be pursued in order to design optimal therapeutic trial in ALS
Glatiramer Acetate has no impact on disease progression in ALS at 40 mg/day: a double blind, randomized, multicenter, placebo controlled trial
No full textOur objective was to assess the efficacy and safety of 40 mg/day glatiramer acetate (GA) in patients with ALS. We conducted a double-blind, randomized, placebo-controlled, multicentre trial. Three hundred and sixty-six patients with definite, probable or probable laboratory supported ALS and a slow vital capacity ≥ 70% were randomly assigned to treatment with placebo or 40 mg GA daily. The primary intention-to-treat analysis was the comparison between the two treated groups of the rates of deterioration on the ALSFRSR scale. The secondary outcome measure was time to death, tracheostomy or permanent assisted ventilation. Safety and tolerability of GA were evaluated. After 52 weeks of follow-up, the slope of the ALSFRSR score was comparable in the both groups (placebo,-1.00±0.06/month; GA,-1.05±0.06/month; p=0.48). The secondary endpoint was non-significant with 159 patients (87.4%) alive in the placebo group and 162 patients (88.1%) in the GA group (log rank, p=0.75). The most common events were the injection site reactions (76.1% in the GA group, 14.8% in the placebo group), comparable to the known profile of 20 mg GA. In conclusion, GA at a dose of 40 mg/day did not show any beneficial effect in ALS patients, and safety and tolerability of GA were good in this population
Bausteine zu einer Geschichte der Stadt Meiningen
No full textBAUSTEINE ZU EINER GESCHICHTE DER STADT MEININGEN
Bausteine zu einer Geschichte der Stadt Meiningen ( - )
Title page ( - )
Title page ( - )
Preface ( - )
I. Die Entstehung der Jahrmärkte und die Wochenmärkte in Meiningen ( - )
II. Inschriften und Denkmäler der Stadtkirche in Meiningen ( - )
III. Die Beziehungen des letzten Fürstbischofs von Würzburg zur Stadt Meiningen ( - )
IV. Die Gast- und Unterkunftshäuser im alten Meiningen ( - )
V. Ein Leprahaus in Meiningen ( - )
VI. Meininger Gelehrte und andere hervorragende Meininger Stadtkinder aus alter und neuer Zeit ( - )
VII. Übersicht über Herkunft und Bedeutung der Meininger Straßennamen ( - )
VIII. Die Bevölkerungszahlen der Stadt Meiningen sonst und jetzt ( - )
Verzeichnis der benutzten Bücher und Handschriften ( - )
Remarks ( - )
Table of contents ( -
The Peroxisome Proliferator-activated Receptor γ (PPARγ) Controls Natural Protective Mechanisms against Lipid Peroxidation in Amyotrophic Lateral Sclerosis
No full textRecent evidence highlights the peroxisome proliferator-activated receptors (PPARs) as critical neuroprotective factors in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To gain new mechanistic insights into the role of these receptors in the context of ALS, here we investigated how PPAR transcriptional activity varies in hSOD1(G93A) ALS transgenic mice. We demonstrate that PPARγ-driven transcription selectively increases in the spinal cord of symptomatic hSOD1(G93A) mice. This phenomenon correlates with the up-regulation of target genes, such as lipoprotein lipase and glutathione S-transferase α-2, which are implicated in scavenging lipid peroxidation by-products. Such events are associated with enhanced PPARγ immunoreactivity within motor neuronal nuclei. This observation, and the fact that PPARγ displays increased responsiveness in cultured hSOD1(G93A) motor neurons, points to a role for this receptor in neutralizing deleterious lipoperoxidation derivatives within the motor cells. Consistently, in both motor neuron-like cultures and animal models, we report that PPARγ is activated by lipid peroxidation end products, such as 4-hydroxynonenal, whose levels are elevated in the cerebrospinal fluid and spinal cord from ALS patients. We propose that the accumulation of critical concentrations of lipid peroxidation adducts during ALS progression leads to the activation of PPARγ in motor neurons. This in turn triggers self-protective mechanisms that involve the up-regulation of lipid detoxification enzymes, such as lipoprotein lipase and glutathione S-transferase α-2. Our findings indicate that anticipating natural protective reactions by pharmacologically modulating PPARγ transcriptional activity may attenuate neurodegeneration by limiting the damage induced by lipid peroxidation derivatives
Ein Kapitel europäischer Theatergeschichte und eine politische Provokation: Die Meininger Festwoche 1886 mit Henrik Ibsen, Richard Voß und Paul Lindau
No full text Mit der Meininger Festwoche initiierte Georg II. von Sachsen-Meiningen 1886 an seinem Hofthea­ter ein Ereignis, das nicht nur das beschauliche Meiningen verschreckte, sondern einen gesellschaft­lichen Tabubruch bedeutete. Der Herzog brachte das skandalumwitterte Ibsen-Stück Gespenster neben Richard Voß‘ Alexandra und Paul Lindaus Echegaray-Bearbeitung Galeotto zur Aufführung. Damit inszenierte er moderne Gesellschaftsdramen, die in ihrem sozialkritischen Potenzial und ihrem Sittlichkeitsanspruch bereits auf den Naturalismus wiesen und – mit einem norwegischen, spanischen und deutschen Autor – dessen europäische Dimension herausstellten. Diese Festwoche bedeutete im Deutschen Kaiserreich eine politische Provokation, die bei den Gastspielen der Mei­ninger mit Verboten beantwortet wurde.A Chapter of European Theater History and a Political Provocation: The Meiningen Festival Week 1886 with Plays by Henrik Ibsen, Richard Voss and Paul LindauAt the Meiningen Festival Week in 1886, George II of Saxony-Meiningen at his court theater initi­ated an event which not only frightened the contemplative city of Meiningen but signified a social violation of tabus. The Duke had his theater produce the scandalous Ibsen play “Ghosts” in addition to Richard Voss’ “Alexandra” and Paul Lindau’s Echegaray adaptation of “Galeotto”. The socially critical potential of these plays and their new morality pointed to Naturalism. The fact that these plays were written by a Norwegian, a Spanish and a German author demonstrated the European dimension of these ideas. In Imperial Germany, this festival week signified a political provocation that resulted in bans of guest performances by the Meiningen theater troupe. Mit der Meininger Festwoche initiierte Georg II. von Sachsen-Meiningen 1886 an seinem Hofthea­ter ein Ereignis, das nicht nur das beschauliche Meiningen verschreckte, sondern einen gesellschaft­lichen Tabubruch bedeutete. Der Herzog brachte das skandalumwitterte Ibsen-Stück Gespenster neben Richard Voß‘ Alexandra und Paul Lindaus Echegaray-Bearbeitung Galeotto zur Aufführung. Damit inszenierte er moderne Gesellschaftsdramen, die in ihrem sozialkritischen Potenzial und ihrem Sittlichkeitsanspruch bereits auf den Naturalismus wiesen und – mit einem norwegischen, spanischen und deutschen Autor – dessen europäische Dimension herausstellten. Diese Festwoche bedeutete im Deutschen Kaiserreich eine politische Provokation, die bei den Gastspielen der Mei­ninger mit Verboten beantwortet wurde.A Chapter of European Theater History and a Political Provocation: The Meiningen Festival Week 1886 with Plays by Henrik Ibsen, Richard Voss and Paul LindauAt the Meiningen Festival Week in 1886, George II of Saxony-Meiningen at his court theater initi­ated an event which not only frightened the contemplative city of Meiningen but signified a social violation of tabus. The Duke had his theater produce the scandalous Ibsen play “Ghosts” in addition to Richard Voss’ “Alexandra” and Paul Lindau’s Echegaray adaptation of “Galeotto”. The socially critical potential of these plays and their new morality pointed to Naturalism. The fact that these plays were written by a Norwegian, a Spanish and a German author demonstrated the European dimension of these ideas. In Imperial Germany, this festival week signified a political provocation that resulted in bans of guest performances by the Meiningen theater troupe
Shear Stress Induces the Release of an Endothelial Elastase: Role in Integrin alpha(v)beta(3)-Mediated FGF-2 Release
No full textBackground/Aims: Laminar shear stress is an important stimulus in the endothelium-dependent control of vascular tone and of vascular remodeling processes. Based on previous studies demonstrating integrin-mediated release of fibroblast growth factor 2 (FGF-2), we investigated whether shear stress-induced integrin activation requires the involvement of an extracellular protease. Methods: Cultured porcine aortic endothelial cells (PAEC) were exposed to laminar shear stress (16 dyn/cm(2)), whereas static cells served as controls. Results: Exposure of PAEC to shear stress led to an increased activity of a protease in supernatants. This protease could be characterized as elastase but was different from neutrophil and pancreatic elastases. The enhanced activity was accompanied by the activation of integrin alpha(v)beta(3) and p38 MAPK, and followed by an increased FGF-2 concentration in the supernatant. Pretreatment with inhibitors of either elastase or integrin alpha(v)beta(3) resulted in a reduction of FGF-2 release. The observed effects of shear stress on integrin alpha(v)beta(3) and p38 MAPK activation, as well as on FGF-2 release could be mimicked by application of pancreatic elastase to static endothelial cells. Conclusion: By inducing the release of an endothelial elastase, shear stress induces an integrin-dependent release of FGF-2 from endothelial cells. Copyright (C) 2011 S. Karger AG, Base
Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC International Workshop
No full textA transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 - published and unpublished - compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models
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