1,721,035 research outputs found
Neurotoxic and neuroprotective mechanisms of cisplatin-induced polyneuropathies
No full textAuch heute noch spielen Platin-haltige Zytostatika eine wichtige Rolle in der Therapie diverser Krebserkrankungen. Neben ihrer Effektivität in der Behandlung des Tumors führen sie jedoch immer wieder zu schweren Nebenwirkungen. Eine der häufigsten Nebenwirkungen, mit starkem Einfluss auf das Wohlbefinden der Betroffenen, sind schmerzhafte periphere Polyneuropathien. Im Gegensatz zu den Mechanismen der Wirkung von Platin-haltigen Zytostatika auf Tumorzellen, sind die Mechanismen für die Entstehung von Polyneuropathien nicht vollständig verstanden. Einen möglichen Ansatz liefert die bereits in der Literatur beschriebene Störung der intrazellulären Calcium-Homöostase in DRG-Neuronen durch Platin-haltige Zytostatika.
Im Rahmen dieser Arbeit sollte der Einfluss von Cisplatin auf die verschiedenen Subtypen von spannungsabhängigen Calciumkanälen (VGCC) mit Hilfe von Patch-Clamp Messungen, immunozytochemischen und immunohistochemischen Färbungen, sowie Verhaltenstestungen untersucht werden. Das Ziel dabei war es, erste Untersuchungen der Calcium-basierten neurotoxischen und neuroprotektiven Mechanismen der Cisplatin-induzierten Polyneuropathien durchzuführen.
Durch elektrophysiologische Messungen konnte hierbei gezeigt werden, dass Cisplatin die Subtypen von spannungsabhängigen Calciumkanälen unterschiedlich moduliert. So wurden die Ströme der Calciumkanäle des L-Typs, P-/Q-Typs und T-Typs reduziert, wohingegen eine Proteinkinase C vermittelte Zunahme von N-Typ VGCC beobachtet werden konnte.
Durch die Exposition der kultivierten DRG-Neuronen mit Cisplatin konnte eine CaMK II-assoziierte erhöhte Stromdichte von N-Typ VGCC nachgewiesen werden. Diese Erhöhung konnte mit einem erhöhten Proteinlevel dieser Kanäle in Zusammenhang gebracht werden. Auch nach in vivo Cisplatin-Applikation zeigte sich eine signifikante Proteinlevel-Erhöhung der N-Typ VGCC.
In Apoptose-Experimenten zeigte sich, dass die durch Cisplatin erhöhte Apoptoserate durch Blockade der N-Typ VGCC mit 1 µM ω-Conotoxin gesenkt werden konnte. Dieses spricht somit für eine Calcium-vermittelte Neurotoxizität von Cisplatin.
In Verhaltenstestungen konnte durch die i.v. Gabe von ω-Conotoxin frühe Anzeichen einer Cisplatin-induzierten Polyneuropathie verhindert werden.
Durch die in dieser Arbeit durchgeführten Experimente konnte der N-Typ VGCC als wichtiger Faktor für die Genese von schmerzhaften Polyneuropathien nach Cisplatin-Applikationen identifiziert werden. Erstmalig konnte der Einfluss von Cisplatin auf die Subtypen von VGCC beschrieben werden. Durch die Blockade der N-Typ VGCC mit ω-Conotoxin konnte die Induktion einer Polyneuropathie durch Cisplatin in vivo verhindert werden. Dies könnte bereits in naher Zukunft auch in der Therapie bzw. Prävention von Cisplatin-induzierten Polyneuropathien untersucht werden.Platinum-based cytostatic drugs still play an important role in the treatment of cancer. In addition to their high efficacy, they lead to a number of serious side effects. One of the most common side effects with severe impact on the quality of patient´s life is a polyneuropathy, which is a consequence of a neurotoxicity that is focused on dorsal root ganglion neurons with a subsequential axonal damaging. As a key mechanism beside the accumulation of DNA-adducts, which is essential for toxicity in other cell types, disturbances of the calcium-homeostasis by ion channel modulation in dorsal root ganglion (DRG) neurons have been suggested.
This study aims on the prevention and clarification of calcium-based mechanisms of neurotoxicity by cisplatin, using a rat model of chemotherapy-induced polyneuropathy with signs of neuropathic pain. Combining in vitro whole-cell patch clamping, immunohisto- and cytochemical staining of DRG and DRG neurons with in vivo behavioural testing the N-type voltage gated calcium channel (VGCC) was identified as the main mediator of calcium influx in DRG neurons after exposure to cisplatin.
N-Type VGCC were modulated after cisplatin exposure in function and expression in the DRG. After in vivo and in vitro exposure to cisplatin N-type VGCC currents were significantly increased in massive manner. In addition, immunohistochemical and immunocytochemical staining suggested a significant increase of N-type channels in DRG neurons. For it is known that cisplatin induced neuronal cell death is closely related to activation of caspase-3, the pre-emptive incubation of DRG neurons with ω-conotoxin, a highly specific N-type channel inhibitor before exposure to cisplatin, significantly reduces caspase-3 activation in DRG neurons. As a proof-of concept study rats were treated with a combination of cisplatin with ω-conotoxin to examine a possible neuroprotective effect of with ω-conotoxin against cisplatin induced neuronal cell death. The administration of ω-conotoxin for 12d during a cisplatin administration was able to fully prevent the generation of neuropathic pain in an in vivo trial using a behavioural assessment for >21d.
This study provides evidence for a crucial and exclusive role of N-type channels in cisplatin induced neuropathy, which could be prevented by a highly selective ion channel modulator suggesting a neuroprotection. The N-type channel blocker ω-conotoxin is already in common use for the treatment of chronic pain, therefore this data provides evidence for the potential beneficial role of ion channel modulators for neuroprotection and should be easily used for a proof of concept study in a clinical trial
Akute Zytokin-vermittelte thermische Hyperalgesie im Rattenmodell: Rolle von TRPV1
No full textDiese Studie untersucht mittels Verhaltenstestungen (Plantartest, Frey-Haare) am Rattenmodell, ob die akute intrathekale Injektion des proinflammatorischen Zytokins Tumornekrosefaktor (TNF) eine taktile Allodynie und/oder eine thermale Hyperalgesie auslöst und ob das zytokin-induzierte schmerzassoziierte Verhalten durch die intrathekale Applikation des TRPV1 (transient-receptor-potential-vanilloid 1)-Agonisten Resinferatoxin (RTX) moduliert werden kann.
Es wurde nachgewiesen, dass die intrathekale TNF-Injektion nach 24 h in den Dosierungen 2 ng und 200 ng im Vergleich zu den Vortesten eine signifikante taktile Allodynie und in den TNF-Dosierungen 20 ng und 200 ng eine signifikant unterschiedliche thermale Hyperalgesie auslöst. Durch anschließende intrathekale RTX- Applikation kann im Vergleich zu alleiniger intrathekaler TNF- Injektion ein signifikanter Anstieg der thermalen Rückzugslatenzen nach 24 Stunden in den TNF-Dosierungen 20 ng und 200 ng festgestellt und somit die Entstehung einer zuvor von TNF-induzierten thermalen Hyperalgesie verhindert und im Vergleich zur Kontrollgruppe auch eine Veränderung der thermalen Sensibilität festgestellt werden. Die Entwicklung einer taktilen Allodynie wird von der intrathekalen RTX-Injektion nicht beeinflusst.
Aus den Ergebnissen kann ein von der TNF-Dosierung abhängiger analgetischer Wirkungseffekt von RTX vermutet und somit gefolgert werden, dass die Pharmakotherapie mit selektiven TRPV1-Agonisten wie RTX in der medikamentösen Behandlung neuropathischer Schmerzen einen entscheidenden Vorteil bietet. Als mögliches zelluläres Korrelat kommt eine durch TNF induzierte erhöhte TRPV1-Rezeptorexpression oder eine durch TNF induzierte verstärkte Hemmung spannungsabhängiger Calciumkanäle in Betracht.
Diese Studie trägt zur weiteren Erforschung TRPV1-selektiver Pharmaka in der medikamentösen Therapie bei neuropathischen Schmerzsyndromen bei und bietet mittelfristig eine Grundlage für weitere klinische Studien
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Fatigue and associated factors in myasthenia gravis: a nationwide registry study
No full textAbstract Fatigue is commonly associated with myasthenia gravis (MG), but factors contributing to fatigue development in MG are incompletely understood. This nationwide cross-sectional registry study included 1464 patients diagnosed with autoimmune MG, recruited between February 2019 and April 2023. Frequency and severity of fatigue was assessed at study inclusion using the patient-reported Chalder Fatigue Questionnaire (CFQ). Frequency of fatigue was 59%. Fatigue severity strongly correlated with both patient-reported and physician-assessed MG outcome measures (MG-ADL, MG-QoL15, QMG and MGFA classes) and was associated with a history of myasthenic exacerbation and/or myasthenic crises and a delay in diagnosis of more than 1 year after symptom onset. Fatigue was more prevalent in women and coincided with symptoms of depression, anxiety, and sleep dissatisfaction. Differences in fatigue severity were observed between antibody (ab) subgroups, with highest fatigue severity in LRP4-ab-positive patients and lowest fatigue severity in AChR-ab-positive patients. Fatigue is a frequent and clinically highly relevant symptom of MG. Early diagnosis and prevention of MG crises may limit the long-term burden of fatigue in patients with MG
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