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71.
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
72.
Enid F. Gilbert Gabriele M. Zurhein Susan M. Wester Jurgen Herrmann Richard Hong John M. Opitz 《Fetal and pediatric pathology》1985,3(1):59-92
Four cases of familial hemophagocytic lymphohistiocytosis (FHL) from two families with first cousins affected in one family and siblings in another are presented. The pathological findings, including neuropathology, transmission (TEM), and scanning electron microscopy (SEM), are discussed. This is the first study of this condition to include TEM and SEM. One hundred and fifty-nine cases from the literature, including the authors' four cases, are reviewed. The familial occurrence in 116 instances in sibships and consanguinity in 13 of the 73 families support autosomal-recessive inheritance. In five families there were affected first cousins—an observation not readily explained by autosomal-recessive transmission. We suggest that the genetic aspects of PEL be more fully explored and that in future cases parents and other relatives be included in the hematologic, immunologic, and genetic evaluation. 相似文献
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76.
Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice 总被引:4,自引:0,他引:4
Doreulee N Sergeeva OA Yanovsky Y Chepkova AN Selbach O Gödecke A Schrader J Haas HL 《Brain research》2003,964(1):159-163
Nitric oxide (NO) is a retrograde messenger involved in the processes of learning and memory. The role of the endothelial isoform of nitric oxide synthase (eNOS) in striatal synaptic plasticity was investigated in eNOS-deficient (eNOS(-/-)) and wild type (WT) mice. Tetanic stimulation of cortical afferents in WT mice evoked either long-term potentiation (LTP), or long-term depression (LTD) of cortico-striatal transmission. Both these plasticity related phenomena were NMDA-receptor-dependent; LTD was blocked by sulpiride, a dopamine D2-receptor antagonist. LTP occurrence in slices from eNOS(-/-) mice was significantly reduced when compared with WT mice. The NOS inhibitor NL-ARG reduced the occurrence of LTP and increased the occurrence of LTD in WT mice, resembling the balance of LTP/LTD in eNOS(-/-) mice. Impairment of NO-synthesis thus shifts striatal plasticity towards LTD. This indicates a possible involvement of eNOS from endothelia in neuronal modulation. 相似文献
77.
Cabrera-Vera TM Vanhauwe J Thomas TO Medkova M Preininger A Mazzoni MR Hamm HE 《Endocrine reviews》2003,24(6):765-781
In multicellular organisms from Caenorhabditis elegans to Homo sapiens, the maintenance of homeostasis is dependent on the continual flow and processing of information through a complex network of cells. Moreover, in order for the organism to respond to an ever-changing environment, intercellular signals must be transduced, amplified, and ultimately converted to the appropriate physiological response. The resolution of the molecular events underlying signal response and integration forms the basis of the signal transduction field of research. An evolutionarily highly conserved group of molecules known as heterotrimeric guanine nucleotide-binding proteins (G proteins) are key determinants of the specificity and temporal characteristics of many signaling processes and are the topic of this review. Numerous hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells by binding to heptahelical membrane receptors coupled to heterotrimeric G proteins. These highly specialized transducers can modulate the activity of multiple signaling pathways leading to diverse biological responses. In vivo, specific combinations of G alpha- and G beta gamma-subunits are likely required for connecting individual receptors to signaling pathways. The structural determinants of receptor-G protein-effector specificity are not completely understood and, in addition to involving interaction domains of these primary acting proteins, also require the participation of scaffolding and regulatory proteins. 相似文献
78.
BACKGROUND: The recent emergence of BioGlue Surgical Adhesive has widened the field of surgical adhesives for the cardiac surgeon. We believe the present series, in a wider spectrum of cardiac conditions, is the first larger scale evaluation of the use of this new adhesive. METHODS: BioGlue was used in 115 consecutive patients (90 male and 25 female, age range 5 days to 87 years) from September 9, 1998 to March 12, 2001. Preoperative, intraoperative, and postoperative data were examined to establish its use, indications, and outcomes in patients undergoing cardiac surgical procedures. RESULTS: The most common underlying pathologic conditions were aortic dissections (30 patients) and aortic aneurysms (39 patients). The procedures carried out were aortic root replacement (36 patients), aortic wall replacement (39), ascending aorta repair (2), coronary artery bypass grafting (28), valve procedures (11), ventricular aneurysm repair (6), repair of postinfarct ventricular septal defect (2), and correction of congenital conditions (13 patients). The indications for BioGlue use were hemostasis in 79 patients, tissue adherence in 21, and tissue strengthening in 30. The hospital mortality was 10.1% (11 patients). Only 1 patient required a late reoperation for dehiscence of a suture line with formation of a false aneurysm. The mean postoperative blood loss at 12 hours was 702 mL. Ten patients developed a cerebrovascular accident postoperatively, which was considered to be unrelated to the use of BioGlue. CONCLUSIONS: All surgeons in this study believed that BioGlue facilitated the operation. Future follow-up of patients is required to validate our early promising results and to assess the long-term outcome of patients treated with BioGlue. 相似文献
79.
80.
Jurgen Ludwig John P. Fitzgibbons Jr. Fred T. Nobrega 《Virchows Archiv : an international journal of pathology》1969,346(4):287-301
Summary Gross and histologic findings at autopsy in 32 cases of sudden unexpected unexplained death (SUUD) in infants were compared with autopsy findings in (1) 7 cases in which alarming clinical symptoms had been observed but no cause of death was found pathologically (morphologically unexplained death, MUD) and (2) 74 cases in which the cause of death was clearly established [8 cases of sudden unexpected explained death (SUED) and 66 control cases]. Laryngotracheitis was found most often in SUUD cases but did not differ histologically from the upper respiratory infections in the other categories. Other infections in SUUD which may be considered primary were bronchitis, focal pancreatitis, and mild pyelonephritis. Similar lesions were also found in control cases in which death was due to unrelated causes. The history in some SUUD and MUD cases and the morphologic changes in the spleen, thyroid gland, and adrenal gland indicated that unexpected unexplained death may occur at any time during the course of an upper respiratory or other type of infection. Our findings suggest that 2 factors have to combine to initiate the lethal episode: (1) an infection, usually of the upper respiratory tract, and (2) a predisposing condition or a trigger mechanism such as irritating skin lesions, trauma, or pain. The final common pathway appeared to be independent of the underlying disease. The characteristic findings of the terminal episode — hemorrhagic pulmonary edema and petechial hemorrhages — may also be part of a known fatal disease such as encephalitis or sepsis.
This investigation was supported in part by Research Grant GM-14231 from the National Institutes of Health, Public Health Service. 相似文献
Plötzlicher, unerwarteter und ungeklärter Tod im SäuglingsalterEine vergleichende klinisch-pathologische Studie
Zusammenfassung Makroskopische und mikroskopische Autopsiebefunde von 32 plötzlichen, unerwarteten und ungeklärten Todesfällen im Säuglingsalter (SUUD, Krippentod). werden verglichen mit 1. 7 Fällen, bei denen sich morphologisch keine Todesursache fand, obwohl alarmierende klinische Symptome beobachtet worden waren (MUD, morphologisch ungeklärter Tod) und 2. 74 Fällen, bei denen die Todesursache autoptisch gesichert war [8 Kinder dieser Gruppe waren plötzlich und unerwartet gestorben (SUED), und 66 Kinder mit schweren klinischen Symptomen dienten als Kontrollen].Laryngotracheitis war am häufigsten bei Krippentod (SUUD). Histologisch fanden sich keine Unterschiede zu den Infektionen der oberen Atemwege in den anderen Gruppen. Bronchitis, herdförmige Pankreatitis und geringgradige Pyelonephritis kamen ebenfalls als Primärinfektionen in Frage. Ähnliche Befunde wurden jedoch auch in Kontrollfällen mit anderer Todesursache erhoben.Der Krippentod (SUUD) kann wahrscheinlich zu jeder beliebigen Zeit im Ablauf einer Infektion, besonders der oberen Atemwege, auftreten. Dafürd srechen die klinischen Vorgeschichten einiger Krippentodesfälle (SUUD) sowie einiger Fälle von morphologisch ungeklärtem Tod (MUD) und außerdem morphologische Veränderungen in der Milz, der Schilddrüse und der Nebennierenrinde.Nach unseren Befunden müssen 2 Faktoren zusammentreffen, um den Krippentod auszulösen: 1. eine Infektion, gewöhnlich der oberen Atemwege, und 2. eine Disposition, z. B. als Folge einer Frühgeburt, oder Auslösemechanismen wie irritierende Hautschäden, Trauma oder Schmerz. Der Todesmechanismus scheint unabhängig von der auslösenden Krankheit zu sein. Die typischen Befunde des Endstadiums, hämorrhagisches Lungenödem und petechiale Schleimhautblutungen, finden sich auch bei tödlichen Krankheiten bekannter Ursache, wie Encephalitis oder Sepsis.
This investigation was supported in part by Research Grant GM-14231 from the National Institutes of Health, Public Health Service. 相似文献