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Monitoring of degeneration of the retinal nerve fiber layer by optical coherence tomography in rats with autoimmune optic neuritis
No full textMonitoring of degeneration of the retinal nerve fiber layer by optical coherence tomography in rats with autoimmune optic neuritis
No full textEffects of interferon-beta-1a on neuronal survival under autoimmune inflammatory conditions
No full textlntcrferon-beta-1a (IFN-beta-1a) is an approved treatment for multiple sclerosis (MS). It improves the disease course by reducing the relapse rate as well as the persistent neurological deficits. Recent MRI and post-mortem studies revealed that neuronal and axonal damage are most relevant for chronic disability in MS patients. We have characterized previously time course and mechanisms of neuronal apoptosis in a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis. In this animal model, application of IFN-beta-1a three times per week slightly decreases the loss of retinal ganglion cells (RGCs), the neurons that form the axons within the optic nerve. In contrast to neurotrophic factors, this cytokine does not directly protect cultured RGCs from apoptosis. We conclude that IFN-beta-1a is a suitable candidate to be combined with a directly neuroprotective agent in order to further decrease axonal and neuronal degeneration in MS patients. (c) 2006 Elsevier Inc. All rights reserved
MRI of optic neuritis in a rat model.
No full textNeuritis of the optic nerve is one of the most frequent early symptoms ofmultiple sclerosis. There are only scarce data correlating magneticresonance imaging (MRI) contrast alterations with the underlyingpathology, that is inflammation, demyelination, and axonal damage.Here we studied optic neuritis in a rat model of experimental autoimmuneencephalomyelitis by comparingin vivoMRI findings from multipletechniques (T1, T2, proton density, magnetization transfer) to histo-pathology. We further assessed a breakdown of the blood–brain barrierby using Gd-DTPA and indirectly estimated the intracellular accumula-tion of calcium as a consequence of axonal damage by using manganese-enhanced MRI. Hyperintensity on T2-weighted images and signalenhancement after Gd-DTPA were highly sensitive to lesions of the opticnerve but did not differentiate between mild, moderate, and severedamage. Signal reduction on T1-weighted images was less sensitive butcorrelated well with the severity of tissue damage. No significant changesin magnetization transfer ratio were observed. Manganese ions tended toaccumulate in the central parts of the inflamed optic nerve. The resultingsignal enhancement at 24 h after administration positively correlated withthe severity of axonal loss. Thus, manganese might be an indicator ofintracellular calcium accumulation that is known to be associated withaxon damage. Although none of the methods alone distinguished betweeninflammation, demyelination, and reduced axon density, their specificcapabilities should prove useful for futurein vivoMRI studies of opticneuritis in both animal models and humans
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
Uloga N-tipa voltazno zavisnih kalcijumskih kanala u degeneraciji aksona tokom eksperimentalnog autoimunog optickog neuritisa
No full textDer entzündliche Befall des Sehnerven stellt eine der häufigsten klinischen Manifestationen der multiplen Sklerose (MS) dar, einer chronisch entzündlichen Erkrankung des zentralen Nervensystems (ZNS). In der Folge einer Optikusneuritis entwickeln etwa 30-50 % der Patienten eine bleibende Sehbehinderung verursacht durch eine Degeneration von Sehnerv-Axonen. In Vorarbeiten konnten wir zeigen, dass die experimentelle autoimmune Enzephalomyelitis (EAE), ausgelöst durch Immunisierung mit Myelin-Oligodendrozyten Glykoprotein (MOG), in braunen Norweger-(BN)-Ratten in 90 % der Fälle zu einer Optikusneuritis führt. Dieser Sehnervenbefall ist gekennzeichnet durch entzündliche Infiltration, Demyelinisierung und axonale Degeneration. Die genauen Mechanismen der entzündlich-bedingten axonalen Degeneration sind unklar. Es wird jedoch als wahrscheinlich angesehen, dass ein pathologischer Einstrom von Kalziumionen (Ca2+) in Axone eine wesentliche pathophysiologische Rolle spielt. Als mögliche Eintrittspforten für Ca2+ kommen dabei verschiedene Typen von spannungsabhängigen Kalziumkanälen (VDCC) in Betracht. Da Mangan (Mn2+) in Neurone ebenfalls über VDCC aufgenommen wird und eine Signalanhebung bei der Magnetresonanztomographie (MRT) bewirkt, haben wir die Technik des Mn2+-gestützten MRTs genutzt, um die Wirkung von Subtyp-spezifischen Kalziumkanalblockern zu untersuchen. Im Rahmen dieser Experimente führte die Applikation von ω Conotoxin GVIA, einem spezifischen Blocker von N-Typ Kalziumkanälen, zu einer signifikanten Hemmung der Mangan-Aufnahme in den entzündeten Sehnerven. Um parallel die Expression dieses Kanaltyps im Sehnerven zu untersuchen, haben wir immunhistochemische Färbungen für α1B durchgeführt. Dabei handelt es sich um die Untereinheit von N-Typ VDCC, die die Membranpore formt. Diese Färbungen ergaben signifikante Unterschiede in Lokalisation und Expression der Kanaluntereinheit in gesunden im Vergleich zu entzündlich befallenen Sehnerven. Während in gesunden, myelinisierten Sehnerven eine mäßige Expression von α1B nachzuweisen war, zeigte sich eine deutliche Hoch-Regulation in den Sehnerven der MOG-immunisierten Tiere. Ferner fand sich eine Korrelation zwischen der Expression von α1B und dem Ausmaß an Demyelinisierung, welches anhand von Myelin-spezifischen Färbungen quantifiziert wurde. Eine hoch-signifikante negative Korrelation ergab sich zwischen der Anzahl α1B-positiver Stellen im Sehnerven und der Anzahl überlebender Axone. In einem weiteren Schritt wurde dann die Wirksamkeit von ω Conotoxin GVIA mittels in vivo-Kalzium Imaging des Sehnerven überprüft. Dabei zeigte sich eine deutliche Reduktion des depolarisations-abhängigen Kalziumeinstroms in den entzündeten Sehnerven nach topischer Applikation des N-Typ Kalziumkanalblockers im Vergleich zu einer Kontrollgruppe Plazebo-behandelter Tiere. Die Applikation von -Conotoxin GVIA in gesunden Tieren hingegen führte lediglich zu einer leichten Verminderung des Kalziumeinstroms, der sich nicht signifikant von gesunden Kontrolltieren nach topischer Applikation von Kochsalzlösung unterschied. Diese Daten ergänzen die oben beschriebenen Expressionsanalysen des N-Typs spannungsabhängiger Kalziumkanäle und belegen ferner, dass die neu gebildeten Kanäle funktionsfähig sind. Zusammengefasst zeigen diese Ergebnisse, dass der pathologische Einstrom von Ca2+ im Rahmen der MOG-induzierten Optikusneuritis wesentlich über den N-Typ spannungsabhängiger Kalziumkanäle erfolgt. Die pathophysiologische Relevanz des gesteigerten Kalziumeinstroms über diesen Kanaltyp wurde ferner im Rahmen einer Therapiestudie mit ω-Conotoxin GVIA gezeigt. Dabei ergab die kontinuierliche zerebroventrikuläre Applikation des N-Typ-Kanalblockers ein signifikant vermindertes Maß an Demyelinisierung und axonalem Schaden. Unsere Daten einer ektopen Expression von N-Typ Kalziumkanälen im Sehnerven von BN- Ratten unter autoimmunen Bedingungen sowie die nachgewiesene Wirksamkeit von ω-Conotoxin GVIA lassen diese Substanz als mögliche neuroprotektive Therapie der autoimmunen Sehnerventzündung erscheinen.Optic neuritis is one of the most common clinical manifestations of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). After an episode of optic neuritis, 30 50 % of patients develop persistent impairment of vision caused by degeneration of optic nerve (ON) axon fibers. Our group has previously shown that in Brown Norway (BN) rats, myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) affects the optic nerve in more than 90% of immunized animals, leading to inflammation, demyelination, and degeneration of axons. The precise pathological mechanisms of axonal degeneration are not fully understood, but are likely to involve excess accumulation of calcium ions (Ca2+) into axons. One of the possible routes of entry of Ca2+ under pathological conditions is via different types of voltage-dependent calcium channels (VDCCs). Since manganese ions (Mn2+) also enter neurons via VDCCs and cause signal enhancement in T1-weighted magnetic resonance images (MRI), we have used Mn2+- enhanced MRI to evaluate the effects of type specific VDCC blockers. We found that application of ω conotoxin GVIA, a specific blocker of N-type VDCCs, caused a significant decrease of Mn2+- induced enhancement in T1-weighted MR images. In order to further investigate N-type VDCC expression in the ON, we have performed immunohistochemistry for α1B, the pore-forming subunit of N-type VDCCs, which revealed a significant difference in both the degree and the pattern of N-type VDCC expression between healthy and inflamed ONs. In healthy, myelinated ONs, a modest degree of α1B immunoreactivity was detected. However, a highly significant up-regulation of expression was seen in MOG-immunized ONs. Furthermore, a highly significant positive correlation between the number of α1B-positive sites per ON and the percentage of demyelination was detected by myelin-specific histopathological staining. A highly significant negative correlation was observed between the number of α1B-positive sites per ON and the percentage of axonal survival. Additionally, we have tested the N-type VDCC blocker, ω conotoxin GVIA, during an in vivo calcium imaging study. After ω-conotoxin GVIA was topically applied to the inflamed ONs, depolarization-induced influx of Ca2+ was significantly inhibited in comparison to the control group of MOG-immunized ONs. Treatment of healthy rats with the N-type VDCC blocker decreased the Ca2+ signal to a smaller extent which was not significantly different to healthy ONs after topical application of normal saline. These results confirm the previously obtained data about up-regulated expression of N-type VDCCs in MOG-immunized ONs and indicate further that the newly expressed N-type VDCCs are functional. Taken together, our data indicate N-type VDCCs to have the most prominent effect on Ca2+ influx in MOG-induced optic neuritis. Further corroboration was acquired by showing therapeutically significant effects of a specific N-type VDCC blocker, ω-conotoxin GVIA, after intracerebroventricular continuous infusion. We detected significantly decreased demyelination and a significant increase of axonal survival in the ONs of ω-conotoxin GVIA-treated animals. Thus, our data show an ectopic expression of N-type VDCCs in MOG-induced optic neuritis in BN rats, which mainly contribute to an increased Ca2+ influx under autoimmune inflammatory conditions. Furthermore, we introduce ω-conotoxin GVIA as a neuroprotective agent in the treatment of autoimmune optic neuritis
Transient hypoxia improves matrix properties in tissue engineered cartilage
No full textAdult articular cartilage is a hypoxic tissue, with oxygen tension ranging from <10% at the cartilage surface to <1% in the deepest layers. In addition to spatial gradients, cartilage development is also associated with temporal changes in oxygen tension. However, a vast majority of cartilage tissue engineering protocols involves cultivation of chondrocytes or their progenitors under ambient oxygen concentration (21% O2), that is, significantly above physiological levels in either developing or adult cartilage. Our study was designed to test the hypothesis that transient hypoxia followed by normoxic conditions results in improved quality of engineered cartilaginous ECM. To this end, we systematically compared the effects of normoxia (21% O2 for 28 days), hypoxia (5% O2 for 28 days) and transient hypoxiareoxygenation (5% O2 for 7 days and 21% O2 for 21 days) on the matrix composition and expression of the chondrogenic genes in cartilage constructs engineered in vitro. We demonstrated that reoxygenation had the most effect on the expression of cartilaginous genes including COL2A1, ACAN, and SOX9 and increased tissue concentrations of amounts of glycosaminoglycans and type II collagen. The equilibrium Young's moduli of tissues grown under transient hypoxia (510.01 +/- 28.15kPa) and under normoxic conditions (417.60 +/- 68.46kPa) were significantly higher than those measured under hypoxic conditions (279.61 +/- 20.52kPa). These data suggest that the cultivation protocols utilizing transient hypoxia with reoxygenation have high potential for efficient cartilage tissue engineering, but need further optimization in order to achieve higher mechanical functionality of engineered constructs. (c) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 544553, 201
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
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