Mechanism of the inhibition of lysosomal functions in the retinal pigment epithelium by lipofuscin retinoid component A2-E

BACKGROUND: Excessive accumulation of lipofuscin in the retinal pigment epithelium with age and in various hereditary and degenerative retinal diseases, is of pathogenetic significance. We have shown that the major lipofuscin fluorophor A2-E (N-retinylidene-N-retinylethanolamine) affects the lysosomal degradation of human RPE cells and damages the cellular metabolism by phototoxic properties. Herein we sought to determine mechanisms for the inhibitory effect on lysosomal function apart from pH elevation. METHODS: Potter-Elvejem homogenates of RPE cells were used to measure the activity of 24 lysosomal enzymes before and after incubation with A2-E. RESULTS: This is the first time that RPE cells have been screened for a large spectrum of lysosomal hydrolases including proteases, lipidases, glycosidases, nucleases, sulfatases and phosphatases. The activities of these hydrolases were readily detectable in cultured RPE cells. Incubation of RPE cell homogenates even with high A2-E concentrations (up to 10 microM) did not affect the activity of isolated lysosomal enzymes. CONCLUSIONS: The results suggest that a direct inhibition of lysosomal enzyme activity would not explain the inhibitory effect on lysosomal degradation. A2-E increases the acidic intralysosomal pH thereby probably hindering pH-dependent lysosomal enzymatic activities. The understanding of the inhibitory effects of A2-E on RPE cell metabolism may contribute to new approaches for treatment of retinal diseases with excessive lipofuscin accumulation such as ARMD or M. Stargardt.     

Die Implantation einer unikondyl?ren Schlittenprothese

Zusammenfassung Operationsziel Wiederherstellung einer geraden Beinachse und schmerzfreien Gelenkfunktion. Indikationen Mediale oder laterale, auf eine Gelenkhälfte beschränkte Arthrose mit Fehlstellung der Beinachse unter 20°, bei der eine sog. Umstellungsosteotomie nicht in Frage kommt. Osteonekrose des medialen Femurkondylus (Morbus Ahlbäck). Voraussetzung: Alter über 60 Jahre. Kontraindikationen Panarthrose. Instabilität des Kniegelenks (abgesehen von relativer Aufklappbarkeit wegen Knorpelschwunds). Polyarthritis. Systemische Gelenkerkrankung wie z. B. Hämophilie. Neuropathische Arthropathie. Starke Adipositas. Fehlstellung der Beinachse über 20°, Beugekontraktur über 20°. Operationstechnik Darstellung des Kniegelenks über einen medianen Zugang. Horizontale Resektion des betroffenen Tibiaplateaus unter Erhalt der Kreuz- und Seitenbänder. Zurichtung des Femurkondylus zur Aufnahme des entsprechenden Prothesenteils. Einzementierung der Prothesenkomponenten in achsengerechter Position. Ergebnisse Retrospektive Studie an 149 Patienten (34 Männer und 115 Frauen im Alter zwischen 62 und 86 Jahren), die in den Jahren 1986-1990 operiert wurden. Der Nachuntersuchungszeitraum betrug 8-12 Jahre, durchschnittlich 10,07 Jahre. 44 Patienten sind zwischenzeitlich an knieunabhängigen Erkrankungen gestorben. 23 Prothesen wurden aus unterschiedlichen Gründen gewechselt. Die Ergebnisse wurden bei 35 Patienten telefonisch erfragt, bei 45 nach klinischen und radiologischen Untersuchungen sowie nach dem HSS-Score festgestellt: Bei 80% der Patienten fanden sich sehr gute und gute, bei 7,5% mäßige und bei 12,5% schlechte Resultate. Hauptgründe für die schlechten Ergebnisse waren ungünstige Ausgangssituationen wie z. B. rheumatische Polyarthritis, zu weit fortgeschrittene Gonarthrose, Lockerung oder Einsinken der tibialen Prothesenkomponente. Die Überlebensrate ("survival rate") betrug bei 84 Patienten nach mehr als 10-jähriger Laufzeit und Revisionserfordernis als Endpunkt 83,7%. Abstract Objectives Correction of axial malalignment and restoration of a normal pain-free joint function through insertion of a unicompartmental runner. Indications Medial or lateral unicompartmental osteoarthritis. Osteonecrosis of the medial femoral condyle. Age over 60 years. Contraindications Osteoarthritis of more than one compartment. Ligamentous instability (instability due to cartilage loss is not a contraindication). Rheumatoid arthritis. Chronic synovitis. Systemic affections of joints (i. e., hemophilia). Neuropathic joint diseases. Obesity. Axial malalignment exceeding 20°. Flexion contracture exceeding 20°. Sugical Technique Medial approach. After visual confirmation that only one compartment is affected, resection of the tibial plateau while preserving cruciate and collateral ligaments. Preparation of the femoral condyle and restoration of axial alignment through insertion of the unicompartmental components. Avoid overcorrection. Results Between 1986 and 1990 a unicompartmental arthroplasty was done in 34 men and 115 women (62-86 years). 44 had died for unrelated reasons. 35 answered a questionnaire by phone, 45 could be examined clinically and radiologically. 23 patients had undergone a revision surgery for various reasons. The duration of follow-up varied between 8 and 12 years. The clinical assessment was based on the HSS score. Results were good to excellent in 80%, moderate in 7.5%, and poor in 12.5%. Patients with a poor result were scrutinized paying special attention to the surgical indication. Main reasons for poor results were rheumatoid arthritis, advanced osteoarthritis, loosening and subsidence of the tibial component. The survival rate after more than 10 years of 84 patients at risk, with the need of revision as endpoint, was 83.7%.     

Calcium-independent receptor for alpha-latrotoxin and neurexin 1alpha [corrected] facilitate toxin-induced channel formation: evidence that channel formation results from tethering of toxin to membrane

alpha-Latrotoxin binding to the calcium-independent receptor for alpha-latrotoxin (CIRL-1), a putative G-protein-coupled receptor, stimulates secretion from chromaffin and PC12 cells. Using patch clamp techniques and microspectrofluorimetry, we demonstrate that the interaction of alpha-latrotoxin with CIRL-1 produces a high conductance channel that permits increases in cytosolic Ca(2+). alpha-Latrotoxin interaction with CIRL-1 transiently expressed in bovine chromaffin cells produced a 400-pS channel, which rarely closed under Ca(2+)-free conditions. The major effect of overexpressing CIRL-1 was to greatly increase the sensitivity of chromaffin cells to channel formation by alpha-latrotoxin. alpha-Latrotoxin interaction with CIRL-1 transiently overexpressed in non-neuronal human embryonic kidney 293 (HEK293) cells produced channels that were nearly identical with those observed in chromaffin cells. Channel currents were reduced by millimolar Ca(2+). At alpha-latrotoxin concentrations below 500 pM, channel formation occurred many seconds after binding of toxin to CIRL-1 indicating distinct steps in channel formation. In all cases there was a rapid, sequential addition of channels once the first channel appeared. An analysis of CIRL-1 mutants indicated that channel formation in HEK293 cells is unlikely to be transduced by a G-protein-dependent mechanism. alpha-Latrotoxin interaction with a fusion construct composed of the extracellular domain of CIRL-1 anchored to the membrane by the transmembrane domain of vesicular stomatitis virus glycoprotein, and with neurexin 1alpha, an alpha-latrotoxin receptor structurally unrelated to CIRL-1, produced channels virtually identical with those observed with wild-type CIRL-1. We propose that alpha-latrotoxin receptors recruit toxin to facilitate its insertion across the membrane and that alpha-latrotoxin itself controls the conductance properties of the channels it produces.     

Experimentelle Nachweise adrenergischer Fasern und deren Aufteilung in der Cochlea

Ohne Zusammenfassung     

Subkutaner Tumor bei einem Jugendlichen

A 13-year-old adolescent presented with an enlarging subcutaneous mass beneath the right eyebrow. Clinically suspicious for dermoid cyst or pilomatrixoma, it was decided to remove the tumour completely. Based on histopathological examination the diagnosis of intravascular papillary endothelial hyperplasia (IPEH) was made. Histopathological features are discussed with regard to the possible pathogenesis.     

Noninvasive methods to measure airway inflammation: future considerations.

This last contribution to the series focuses on open questions regarding: 1) methodological issues; and 2) the potential clinical application of the noninvasive methods such as induced sputum and the analysis of exhaled air for the assessment of airway inflammation. In addition their potential future role in occupational health and the early diagnosis of neoplastic lesions are briefly discussed. The future clinical application of noninvasive methods will depend on the progress made to improve their practicability, particularly in rendering them less time consuming and cheaper. To assess their clinical value, prospective studies are needed to establish whether patients actually benefit from the results obtained. This is also important to implement the methods into the healthcare system and to obtain adequate financial compensation. Therefore, it is necessary to know: 1) whether the assessment of airwav inflammation can aid in coming to an earlier and better defined diagnosis; 2) whether by repeated monitoring it is possible to avoid exacerbations through earlier interventions; and 3) whether the long-term outcome of patients is improved through knowledge of the type and degree of airway inflammation that is taken into account in selecting the appropriate treatment. In the meantime a wealth of data has become available, both for induced sputum and the analysis of exhaled air, which give these methods the potential to be incorporated into future clinical practice. This, however, will, amongst the other issues, depend on favourable cost-benefit ratios which should also be the subject of future prospective studies.