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Florian Schutt Marion Bergmann Frank G. Holz Stefan Dithmar Hans-Eberhard Volcker Jurgen Kopitz 《Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie》2007,245(3):391-398
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 14C-labelled A2-E in cultured human RPE cells. We specifically loaded lysosomes of cultured human RPE cells with [14C]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.
DFG Grant Ho 1926/2-2, DFG Priority Research Program AMD (1088), Germany. 相似文献
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OBJECTIVE: Syndromes with genetically determined retinal diseases and concurrent multiple neurologic abnormalities are rare. Kjellin described an autosomal recessive entity with spastic paraplegia, mental retardation, amyotrophia, and macular dystrophy. We sought to further characterize the retinal phenotype and to contrast fundus changes and the genotype to Stargardt's disease in a young patient with progressive Kjellin's syndrome. DESIGN: Observational case report and family genetic study. PATIENTS: One affected and 11 unaffected members of a family with Kjellin's syndrome were investigated. METHODS: Complete ophthalmologic and neurologic examinations were performed, including electrophysiologic evaluation, color vision assessment, fundus autofluorescence, and fluorescence angiography. To investigate a possible role of the ABCA4 gene in the etiology of the macular changes, the entire 50 coding exons, including flanking intronic sequences of the patient, were analyzed by direct sequencing. MAIN OUTCOME MEASURES: The patient was evaluated for her symptoms, retinal function, fundus autofluorescence, angiography, and mutations in the ABCA4 gene. RESULTS: A 27-year-old female patient initially was seen with trembling of her right hand. Subsequently, progressive paraspasticity occurred, and a diagnostic workup revealed mild mental retardation. Biomicroscopy disclosed symmetric multiple round yellowish flecks at the level of the retinal pigment epithelium scattered at the posterior pole, which showed increased intrinsic fluorescence in the center, with a halo of reduced autofluorescence. Multifocal electroretinography elicited abnormal responses in the macular area in the presence of normal Ganzfeld electroretinography recordings. In gene mapping, several common variants were identified, although none seem to be associated with the disease features. CONCLUSIONS: Macular changes in Kjellin's syndrome share phenotypic characteristics with Stargardt's disease, although there are differences with regard to appearance, distribution, angiographic, and autofluorescence behavior of the retinal flecks. Ophthalmologic examination is prudent in patients with similar neurologic deficits, because it is essential for the diagnosis and because visual symptoms may be absent even in the presence of obvious and widespread retinal manifestations. The abnormal gene product in Kjellin's syndrome seems to cause progressive dysfunction in various neuronal tissues but seems to be distinct from the major defect underlying the Stargardt's disease phenotype. 相似文献
25.
Isolated ruptures of the subscapularis tendon are rare injuries which are often missed initially. After recent treatment of 3 patients treated in our clinic typical courses and pitfalls are demonstrated. Due to the traumatic genesis of subscapularis tendon ruptures, lesions of the rotator cuff must be excluded generally by an adequate diagnostic concept. Conventional x-rays of the shoulder in 2 views to exclude a bony lesion, clinical and ultrasound examination are seen as a standard because these methods will allow the correct diagnosis in most cases. Typical clinical signs for a subscapularis lesion are the "lift-off-test" and the "napoleon sign." The ultrasound examination should be done statically and dynamically by comparing the injured with the uninjured shoulder. The typical view in case of a subscapularis tendon rupture is a thinned tendon overlying the humeral head. In our opinion nuclear magnetic resonance imaging should not be the first diagnostic procedure. It should be reserved for such cases with unclear clinical and ultrasound results. 相似文献
26.
Thomas A Albini Matthew S Benz Robert E Coffee Andrew C Westfall Rohit R Lakhanpal Alice R McPherson Eric R Holz 《Ophthalmic surgery, lasers & imaging》2006,37(2):120-128
BACKGROUND AND OBJECTIVE: To document optical coherence tomography (OCT) findings in a series of eyes with group 2A idiopathic juxtafoveal telangiectasia. PATIENTS AND METHODS: This study is a retrospective review of patient charts, OCT, fundus photography, and fluorescein angiography involving 23 eyes (12 patients). Mean retinal thickness in 9 macular areas was calculated and compared to previously published measurements from normal eyes. RESULTS: OCT in 8 of 13 stage 3 eyes revealed foveal cysts without evidence of cystoid macular edema on fluorescein angiography or biomicroscopy, and 1 lamellar hole. In stage 3 eyes, mild retinal thickening was found in 7 of 9 macular areas (P < .05). CONCLUSIONS: OCT commonly reveals foveal cysts in stage 3 idiopathic juxtafoveal telangiectasia. Consistent findings of associated mild macular thickening and lack of late petaloid hyperfluorescence on fluorescein angiography suggest that these cysts differ in pathophysiology from cystoid macular 相似文献
27.
Arnold HP Zillig W Ziese U Holz I Crosby M Utterback T Weidmann JF Kristjanson JK Klenk HP Nelson KE Fraser CM 《Virology》2000,267(2):252-266
We describe a novel lipothrixvirus, SIFV, of the crenarchaeotal archaeon Sulfolobus islandicus. SIFV (S. islandicus filamentous virus) has a linear virion with a linear double-stranded DNA genome. These two features coincide in several crenarchaeotal but not in any other viruses. The SIFV core is formed by a zipper-like array of DNA-associated protein subunits and is covered by a lipid envelope containing host lipids. We sequenced approximately 96% of the virus genome excepting the DNA termini, which were modified in an unusual, yet uncharacterized, manner. Both, the 5' and the 3' DNA termini were insensitive to enzymatic degradation and labelling. Two open reading frames (ORFs) of the SIFV genome are likely to encode helicases and resemble uncharacterized ORFs from other archaea in sequence. Three ORFs showed sequence similarity with each other and each contained a glycosyl transferase motif. Another ORF of the SIFV genome showed significant sequence similarity to the ORF a291 from the well characterized, spindle-shaped Sulfolobus virus SSV1. Due to its structure, SIFV is classified as a lipothrixvirus. 相似文献
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Effects of the 5-HT3 antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy man: a double-blind crossover trial
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Stacher G Weber U Stacher-Janotta G Bauer P Huber K Holzäpfel A Krause G Steinborn C 《British journal of clinical pharmacology》2000,49(5):429-436
AIMS: 5-hydroxytryptamine3 receptor antagonists act antiemetically and slow colonic transit. This study evaluated effects of the high-affinity 5-HT3 antagonist, cilansetron, on fasting, meal-and anticholinesterase-stimulated phasic contractile activity of the human sigmoid colon as well as on bowel habits and stool consistency. METHODS: Five female and seven male healthy volunteers received, during three 7 day periods separated by 7 day wash-out periods, 4 mg cilansetron, 8 mg cilansetron or placebo three times daily orally under random, double-blind, crossover conditions. On day 8 of each treatment period, motility 20-40 cm from the anal verge was recorded using five pressure sensors spaced at 5 cm intervals. After a basal 30 min, subjects swallowed a further dose of the scheduled treatment; 60 min later, blood was taken for the determination of plasma cilansetron levels. Thereafter, subjects ingested a 4200 kJ meal and 250 ml sweetened mallow tea (166 kJ); 90 min after meal onset, 1 mg neostigmine was administered intramuscularly and motility recording was continued for 60 min RESULTS: Phasic contractile activity and intraluminal base-line pressure increased postprandially and more so after neostigmine. With cilansetron, the area under the pressure curve as the primary outcome variable and the number of contractions were significantly greater than with placebo (P = 0.005), amplitude and duration of contractions and base-line pressure were not affected. The effects of the two cilansetron dosages did not differ. With cilansetron, stool tended to become firmer. No adverse effects were observed. Plasma levels were highest with 8 mg cilansetron. CONCLUSIONS: Cilansetron slightly augments meal-stimulated and markedly neostigmine-stimulated phasic motility of the sigmoid colon. When administered over 7 days, it tends to increase stool consistency and is well tolerated. 相似文献
30.
Serotonin depolarizes type A and C primary afferents: an intracellular study in bullfrog dorsal root ganglion 总被引:2,自引:0,他引:2
Intracellular recordings were obtained from the somata of type A and C primary afferents in the isolated bullfrog dorsal root ganglion (DRG) preparation. Bath application of serotonin (5-HT) in concentrations of 0.25-1.0 mM led to slow and fast depolarizing responses. Slow, maintained 5-HT depolarizations were observed in 47% of type A and 70% of type C neurons. These slow depolarizations were associated with an underlying increase in input resistance (Rin). In some type A neurons, the Rin increase was masked by a decrease in Rin due to depolarization-induced rectification. The slow 5-HT depolarization of type A, but not type C neurons showed pronounced tachyphylaxis to repeated 5-HT applications. In type C afferents, serotonin's slow action was often accompanied by spontaneous firing. Manganese decreased slow 5-HT depolarizations of both cell types. A slow depolarization and excitation of type C afferents by methysergide and cinanserin was also observed. Fast transient 5-HT depolarizations accompanied by a rapid decrease in Rin were observed in 7% of type A and 24% of type C neurons. In some DRG cells the fast and slow depolarizations combined to form a biphasic response. The actions of 5-HT reported here resemble in some ways 5-HT responses recorded extracellularly from the spinal terminations of primary afferents. 相似文献