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  • 1
    Keywords: ANGIOGENESIS ; ENDOTHELIAL GROWTH-FACTOR ; INHIBITION ; mechanisms ; PATHOGENESIS ; OXIDATIVE-STRESS ; LIPOFUSCIN ; MACULAR DEGENERATION ; RETINAL-PIGMENT EPITHELIUM ; RPE
    Abstract: Pathologically increased VEGF-A expression is considered a major pathogenic factor in exudative AMD. Since VEGF-A can exist in isoforms with different individual functions, for a detailed understanding of the role of VEGF-A in normal and disease associated processes, in particular in wet AMD, the expression pattern of VEGF-A isoforms has to be taken into account. Therefore in the present study, adressing the effects of lysosomal dysfunction on VEGF expression and secretion by RPE cells induced by lipid peroxidation products and an inhibitor of lysosomal acidification, we applied quantitative methods discriminating the major VEGF-A isoforms. ARPE-19 cells were treated with the primary lipid peroxidation products 4-hydroxynonenal (HNE), malondialdehyde (MDA) or the lysosomal inhibitor bafilomycin A. VEGF-A isoforms were determined by splice-variant-specific RT-PCR. For detection of protein levels, a protein prefractionation strategy based on the strikingly different isoelectric points of VEGF isoforms was used prior to quantification of VEGF-A 121, -165, -189 and -206 expression by ELISA. On mRNA level, VEGF-A 165 represents the major isoform (60%), VEGF-A 121 accounts for about one-third, and VEGF-A 189 for about 10% of total mRNA detected in untreated cells. No VEGF-A 206 mRNA was detected. Treatment with bafilomycin A increased VEGF-A 121 and VEGF-A 165 mRNA levels. VEGF-A 189 expression remained unaffected, and no induction of VEGF-A 206 mRNA was detectable. Similar effects were observed when cells were stressed with HNE or MDA. On protein level, bafilomycin A as well as the lipid peroxidation products caused an increase of total VEGF-A protein secretion into the culture medium. In analysis of VEGF-A for different splice variants, only VEGF-A 121 and VEGF-A 165 were detected, the latter representing the major secreted isoform, with the ratio of both isoforms being slightly changed in favour of VEGF-A 165 secretion. Lysosomal dysfunction and lipid peroxidation damage might be an inducer of VEGF-A 121 and VEGF-A 165 expression in the retina. Furthermore, the novel technique used to analyze the protein expression pattern of VEGF- A isoforms in biological samples may represent a valuable tool in future analyses of specific VEGF-A isoforms in normal and pathogenic functions.
    Type of Publication: Journal article published
    PubMed ID: 21509530
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  • 2
  • 3
    Keywords: APOPTOSIS ; CELLS ; CELL ; Germany ; human ; PATHWAY ; DISEASE ; DISEASES ; METABOLISM ; MOLECULES ; RELEASE ; CYCLE ; ASSOCIATION ; MOLECULE ; TARGET ; PATHOGENESIS ; MITOCHONDRIA ; ADDUCTS ; TARGETS ; SEGMENTS ; MEMBRANES ; PRODUCTS ; INCREASE ; secretion ; methods ; function ; lysosomes ; FATE ; LEAKAGE
    Abstract: BACKGROUND: Lipofuscin occurs in association with various blinding diseases, including ARMD. Formation of lipofuscin is considered to be initiated by the inability of the RPE lysosome to degrade constituents of phagocytosed material resulting in its intralysosomal accumulation. Thus, the deposition of abnormal retinoid adducts causing the autofluorescent properties of RPE lipofuscin originates from abnormal products of the retinoid cycle contained in phagocytosed photoreceptor outer segments. The major lipofuscin retinoid conjugate A2-E was previously shown to exert toxic effects on RPE cells by directly damaging lysosomal function and structure. However, A2-E was also proposed to severely harm extralysosomal RPE cell structures during the pathogenesis of ARMD. This would require release or leakage of A2-E from the lysosomal compartment with subsequent targeting of other cellular compartments. METHODS: We therefore now investigated intralysosomal accumulation, possible biodegradation, release from the lysosomal compartment and intracellular spreading of (14)C-labelled A2-E in cultured human RPE cells. We specifically loaded lysosomes of cultured human RPE cells with [(14)C]A2-E. RESULTS: A linear increase of intracellular radioactivity was observed during the 4-week loading period. Cell fractionation experiments indicated that more than 90% of loaded A2-E was specifically accumulating in the lysosomes. After loading, the fate of the radioactive label was chased over a period of an additional 4 weeks. No metabolism or secretion of A2-E to the medium was detectable. Subcellular fractionation revealed that during the chase period, about 13% were shifted from the lysosomes to mitochondrial fractions. This effect was strikingly intensified when after loading the cells with the labeled retinoid, its intralysosomal concentration was boosted by an additional load with non-labeled A2-E. Thus about 44% of the label were located in mitochondria at the end of the chase period. No significant spreading to other cell compartments was detectable. CONCLUSIONS: Since A2-E was suggested to act as a proapoptotic molecule via a mitochondrial pathway, we postulate that upon reaching a critical intralysosomal concentration, A2-E is released from the lysosome and then specifically targets the outer mitochondrial membrane thereby initiating apoptosis of the RPE cell. This may also apply correspondingly to other lipofuscin-associated molecules that cause leakage of the lysosomal membrane
    Type of Publication: Journal article published
    PubMed ID: 16896919
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  • 4
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die vorliegende Arbeit schließt an unsere I. Mitteilung an und führt nach statistisch orientierter Auswertung der klinischen Befunde zu folgenden Ergebnissen: 1. Junge Wistar-Ratten (mittleres Körpergewicht 119 g) reagierten auf einmalige intracutane Injektion von 0,08–0,1 ml kompletten Freundschen Adjuvans zu 76,1% mit Arthritis, zu 79,5% mit Augenentzündungen, zu 51,6% mit Ohrknötchen und zu 58,7% mit Schwanzknoten. 2. Nach Latenzzeiten zwischen 1 und 80 Tagen trat bei 67,7% der untersuchten Augen eine Uveitis anterior auf. Bei 21 Tieren blieb sie auf ein Auge beschränkt. In 37 von 49 Fällen beidseitiger Affektion lagen zwischen dem Entzündungsbeginn von rechtem und linkem Auge Intervalle von 1–37 Tagen. 3. Bei 58 von 119 Augen (48,7%) mit einer Uveitis anterior kam es im Verlauf von 101–102 Tagen zu klinisch sicheren Remissionen. 35 Fälle mit einem, 14 mit zwei und 9 Fälle mit drei Rezidiven wurden beobachtet. Beginn. Dauer und Schweregrad der Schübe gleicher Ordnung sowie die Dauer entzündungsfreier Intervalle werden, abgestuft nach der Schubzahl der Verläufe, in Form arithmetischer Mittel angegeben. Remissionslose Entzündungen traten meist später auf und hielten länger an als die ersten Schübe rezidivierender Entzündungen. Die Entzündungsschübe I–III begannen jeweils in Abständen von etwa 2 Wochen, der Schub IV bereits nach einem Intervall von 8–9 Tagen. Eine Tendenz zu rascherem Abklingen in der Reihe aufeinanderfolgender Entzündungsschübe war nicht generell von einer Milderung der Symptome begleitet. 4. Mit der Arthritis als augenfälligstem Symptom der Adjuvans-Krankheit zeigten sich die Augenveränderungen eng, aber nicht zwingend, Ohrknötchen indessen als nahezu obligatorisch assoziiert. Als einziges Zeichen einer Adjuvans-Krankheit wurden Augenentzündungen dreimal häufiger beobachtet als Arthritis.
    Notes: Summary The present publication is a continuation of our first communication. A statistically orientated valuation of clinical findings leads to the following results: 1. Young Wistar rats (average body weight 119 g) responded to a single intracutaneous injection of 0.08–0.1 ml of Freund's complete adjuvant by developing several symptoms of adjuvant disease. 76.1% of the animals developed arthritis, 79.5% inflammations of the eyes and 51.6% and 58.7% respectively showed nodular alterations in external ears and tail. 2. After a latent period from 1 to 80 days 67.7% of the eyes examined developed iridocyclitic changes. In 21 animals inflammation was limited to one eyeball. In 37 out of 49 cases of bilateral affection the interval, between onset of inflammation in the right and the left eyes varied between 1 and 37 days. 3. During a period of 101–102 days clinically assured recidivations were demonstrated in 58 out of 119 eyes (48.7%) showing iridocyclitis. 35 cases showed one, 14 two and 9 cases three recidivations. Onset, duration and severity of batches of the same rank as well as the duration of intervals without inflammatory signs —graduated according to the number of batches per course—are stated as arith-metical means. Non-relapsing inflammations mostly began later and lasted longer than the first batches of relapsing inflammations. The inflammatory batches II and III started after an interval of 2 weeks, and the batch IV already after an interval of 8–9 days. A tendency to quicker improvement in the series of successive batches was not generally accompanied by a moderation of symtoms. 4. Eye lesions showed a close but no obligatory association with the arthritis as the most obvious symptom of adjuvant disease. The development of nodular changes in the external ears, however, seemed bound to the presence of arthritis. As the only sign of an adjuvant disease eye lesions were observed three times more frequently than arthritis.
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  • 5
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Wird das menschliche Auge mit elektrischen Stromimpulsen gereizt, so ist insbesondere unter Dunkeladaptation eine schwache Lichterscheinung wahrzunehmen. Dieser elektrisch evozierte Lichtschein, im folgenden kurz „Elektrophosphen” genannt, besteht in einem formlosen Flimmern der dem gereizten Augezugeordneten Anteile des Gesichtsfeldes. Die vorliegende Arbeit hatte das Ziel, Einflüsse retinaler Schäden auf die Anregbarkeit des Elektrophosphenes zu studieren. Die jeweilige Schwellenspannung, mit der elektrische Reizimpulse das Phosphen gerade auszulösen vermögen, hängt von deren Folgefrequenz ab. In einem Diagramm gegen die Werte dieser Impulsfrequenz aufgetragen definieren die entsprechenden Schwellenspannungen eine Schwellenkurve des Elektrophosphens. An Patienten mit Schädigungen der retinalen Receptorenschicht wurden Schwellenkurven gemessen, die stets den Phosphenschwellen des intakten visuellen Systems ähnelten. Demgegenüber zeigten Patienten in deren Retinen die zentralnervösen Schichten der Bipolar- und Ganglienzellen zerstört waren, eine deutliche Veränderung der Schwellenkurve. Messungen der frequenzabhängigen Anregungsschwelle des Elektrophosphens könnten daher herangezogen werden, wenn es gilt, Schäden der zentralnervösen Netzhautschichten von solchen der Receptorenschicht zu unterscheiden. Die genannte Methode wäre insbesondere anzuwenden, wenn Trübungen der lichtbrechenden Medien des Auges eine ophthalmoskopische und elektroretinographische Untersuchung der Retina erschweren.
    Notes: Summary If the human eye is stimulated with electric current pulses, a light sensation can be observed especially well in darkness. This electrically evoked light phenomenon, called electrophosphene, consists of a formless flicker sensation illuminating the visual field of the excited eye. The influence of retinal damage on the excitability of that electrophosphene was studied. Characteristic diagrams result when threshold values of the stimulating voltage are plotted against the corresponding frequency of impulses. Patients suffering from injury to the retina showed different types of threshold diagram depending on the damage to the retinal receptors or the layers of bipolar and ganglion cells. Therefore measurements of the electric exitability of the phosphen as a function of the stimulation frequency could be used to distinguish damage to different retinal layers. This diagnostic method could be employed even if cataracts prevent ophthalmoscopic explorations of the retina.
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  • 6
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In Untersuchungen an 30 Kaninchen wird der Frage nachgegangen, wie sich die Zahl der Leukocyten im Kammerwasser (LZ) des Kaninchenauges nach experimenteller Verätzung mit Säure bzw. Lauge unterschiedlicher Konzentrationen verhält. Es konnte festgestellt werden, daß die LZ sowohl nach Verätzung mit Säure als auch nach der mit Lauge in einem bestimmten Bereich als Funktion der Konzentration des Ätzmittels dargestellt werden kann. Die Befunde werden im Hinblick auf ihre Bedeutung als ein Maß für den Schweregrad einer verätzungsbedingten Schädigung diskutiert.
    Notes: Summary The change of the number of leucocytes in the aqueous humor (LZ) was investigated in rabbits eyes experimentally burnt with acid or base. It could be pointed out that the LZ is representable in a distinct range by a function of the concentration of the caustic agent. This results were discussed with regard to their importance as a measure for the grade of the injury of an eye burnt with acid or base.
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  • 7
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird über eine schnell und einfach auszuführende Methode zum Einbetten und Schneiden von Augen berichtet. Sie beruht auf einer Kombination der Aceton-Paraffineinbettung nach Matuschka mit der Tesafilm-Methode nach Rydberg und Ziesmer.
    Notes: Summary A simple and quick method for embedding and section cutting of eye globes is reported. It consits of a combination of the acetone-paraffin embedding method of Matuschka and the Tesafilm method of Rydberg and Ziesmer for microtomy difficult material.
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  • 8
    Electronic Resource
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    Springer
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Bestimmung des Blickfeldes auf subjektivem Wege ist genau nur unter Heranziehung eines transfovealen Nachbildes möglich. Dies hat Hering schon getan, ist aber später in Vergessenheit geraten. Man kann die Grenze des Blickfeldes genau festlegen, wenn der Prüfling sich ein transfoveales Nachbild setzt und dann am Goldmann-Perimeter einer kleinen hellen Marke während der Blickexkursionen nachblickt. In dem Augenblick, wo die Reizmarke das Nachbild in extremer Blickstellung verläßt, ist die Grenze des Blickfeldes in dem entsprechenden Meridian gegeben. Die Beleuchtung des Goldmann-Perimeters erfolgt ähnlich wie bei der Euthyskop-Methode nach Cüppers in Hell- und Dunkelphasen. Untersuchungen an 4 normalen Personen ergaben, daß das Blickfeld der temporalen Seite genau mit dem der nasalen Seite übereinstimmt. Im Augenblick, wo das Gegenauge (nach nasal blickend) nicht mehr folgen kann, tritt beim Blick nach temporal die Entspannungstendenz (Kestenbaum) auf. Nach den Blickfeldstudien am Goldmann-Perimeter muß die Annahme Hofmanns und Dittlers bezweifelt werden, daß in peripheren Blickstellungen die Hauptsehrichtung dem Blicke nicht mehr folgt. Offenbar setzten die Autoren nicht in Rechnung, daß auch ein sehr kleiner Lichtreiz sichtbar bleibt, selbst wenn sein Netzhautbild aus der Foveamitte auswandert.
    Notes: Summary Hering already used this method, which unfortunately has been used since. One can easily plot the field of fixation in the Goldmann-Perimeter if the subject induces an after image in his fovea and then fixes a small target. While the gaze follows the target and moves away from the primary position to the periphery the examiner has to find the point at which the target no longer coincides with the after image. The eye is at this moment longer able to follow the stimulus and the retinal image begins to leave the fovea in the direction of the periphery of theretina. We have therefore reached the border of the field of fixation. A phasic illumination of the Perimeter is used in the way Cüppers uses the after image in his Euthycope method. The record of the field of fixation recorded is like that of the field of vision. 4 normal subjects prooved that the field of gaze has a equal extension on the temporal and on the nasal side. As soon as the left eye, looking nasally, is unable to follow binocular fixation, the “tendency of relax” (Kestenbaum) arises in the right eye, looking temporally. According to the results of there fields of fixation on the Goldmann-Perimeter it seems to be doubtful if Hofmann's and Dittler's assumption is correct, that the “principal direction”, “Hauptsehrichtung”, does not follow the gaze in extreme directions. It seems that the authors in their theory were not aware of the fact, that a light stimulus, very small and only imaged in the centre of the fovea, remains visible even whilst the retinal stimulus moves away from the fovea to the periphery; whithin an area of some degrees.
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  • 9
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ten eyes of eight patients with pseudoexfoliation of the lens capsule were first studied by iris fluorescein angiography. Later, iris specimens were obtained at surgery and vessels that were newly formed or showed abnormally rich extravasation of fluorescein were studied electronmicroscopically. The proliferated vessels had an abnormal basement membrane which was thin or absent, and there was abnormal extracellular material around the vessels. The endothelium was thin and in some cases fenestrae were observed. The electron-microscopic changes agreed with the rich extravasation of fluorescein from the capillaries seen in angiography. The results show clearly that there are pronounced vascular changes in the anterior part of the eye in pseudoexfoliation. The way in which these changes affect the collection of pseudoexfoliation material in the eye requires further study.
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  • 10
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung An 17 gesunden Makaken wurde die Innenwand des Schlemmschen Kanals und des anliegenden Trabekelwerks in einem Sechstel seiner ringförmigen Ausdehnung experimentell eingerissen. Danach wurde in verschiedenen Zeitabständen die Reaktion der Kammerwinkelregion des Auges auf den experimentellen Eingriff klinisch, funktionell und morphologisch untersucht. Die Trabekulotomie führt klinisch in keinem Fall zu einer markanten Senkung des intracoularen Druckes. Der Abflußwiderstand vergrößert sich postoperativ in geringem Maß. Nach der Trabekulotomie ist eine weitklaffende Öffnung zwischen dem Schlemmschen Kanal und der Vorderkammer zu sehen. Durch die plötzliche Erschlaffung der normalerweise unter Spannung stehenden Trabekellamellen kommt es zu einer Ablösung der Endothelzellen von der bindegewebigen Zentralzone der Lamellen. Bereits 48 Std nach der Trabekulotomie erscheinen die kollagenen Fasern der Trabekel durch Substanzen, die mit dem Kammerwasser in die Zentralzone eindringen, weitgehend aufgelöst. An den Abbauvorgängen der Gewebstrümmer beteiligen sich neben weißen Blutzellen auch aktivierte Trabekelendothelzellen. 6–8 Wochen nach der Trabekulotomie setzt eine zunächst zellige Regeneration ein. Zwischen den parallel angeordneten Strängen neu entstandener Trabekelendothelzellen treten im weiteren Verlauf der Wundheilung kollagene Fasern in Erscheinung. Es bilden sich also nach der experimentellen Zerstörung der Kammerwinkelregion von Primaten den Trabekeln ähnelnde Strukturen aus. Diese Lamellen blieben allerdings während der ganzen Beobachtungszeit (bis zu 28 Wochen nach der Trabekulotomie) größtenteils untereinander verklebt und bildeten eine verdichtete Narbenzone.
    Notes: Summary In 17 healthy primate monkeys (macaca mulatta and macaca irus) the inner wall of the canal of Schlemm and the trabecular meshwork were destroyed in a sector of about 60° by an experimental trabeculotomy. After various intervals the reaction of the structures in the chamber angle was investigated under clinical, functional and morphological aspects. Trabeculotomy never lowered i.o. pressure. There is a moderate increase of resistance to aqueous outflow postoperatively. After trabeculotomy a gap is visible between anterior chamber and Schlemm's canal. The sudden relaxation of the former distension in the lamellae of the trabecular meshwork causes a detachment of the endothelial cells from their central cores. Only 48 hours after trabeculotomy the collagenous fibers of the trabeculae are desintegrated by matters which enter the central cores from aqueous humour. A process of reduction of the tissue is done by leucocytes and by activated cells of the trabecular endothelium. 6 to 8 weeks after the trabeculotomy a cellular regeneration starts. Between parallel lying strands of new formed cells of the trabecular endothelium collagenous fibers are visible later on. New trabecular lamellae arise after experimental destruction of the inner wall of Schlemm's canal in healthy young monkeys. These lamellae remain stick together during a postoperative follow-up of 28 weeks and form a dense scar.
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