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Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants
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Murni Tio Rujing Wen Yih Lin Lim Zul Haikhel Bin Zukifli Shaoping Xie Patrick Ho Zhidong Zhou Tong‐Wey Koh Yi Zhao Eng‐King Tan 《Human mutation》2017,38(8):978-987
Mutations and polymorphic risk variant of coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) have been associated with late‐onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction that could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress, and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss, and higher hydrogen peroxide production compared with the risk variant. p.Thr61Ile (co‐segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound; Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations. 相似文献
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Mang Thomas Hermosillo Gerardo Wolf Matthias Bogoni Luca Salganicoff Marcos Raykar Vikas Ringl Helmut Weber Michael Mueller-Mang Christina Graser Anno 《European radiology》2012,22(12):2768-2779
European Radiology - To assess the performance of an advanced “first-reader” workflow for computer-aided detection (CAD) of colorectal adenomas ≥ 6 mm at computed tomographic... 相似文献
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Laparoscopic gastric banding (LGB) is the commonest bariatric procedure in Australia. The commonest complication of LGB is access port or tubing (AP/T) problems, requiring revisional surgery. The aim of this study was to document the evolving pattern of AP/T complications. All patients whose LGB procedure (Allergan(TM) Bands) and AP/T revision (Allergan(TM) port revision sets) were performed by one surgeon (1999 to 2008) were included, giving 167 AP/T revisions in 124 patients out of a total 1,928 LGB patients. All patient follow-up details were prospectively recorded and retrospectively analysed. Incidence of LGB AP/T problems was 8.7%. Mean time to first AP/T revision was 2 years. Over the last 4 years of the series, the number of LGB insertions was constant, but the number of AP/T revisions progressively increased. Twenty-seven percent of AP/T revision patients required two or more AP/T revisions. Sixty-two percent of the AP/T complications were leaks. Half the AP complications were flipping of the AP. There was no correlation of AP/T problems with any changes to port design to date. Infection rate for LGB insertion was 0.67%. The incidence of LGB AP/T complications progressively increases with duration after LGB insertion. Occurrence of one AP/T problem appears to select a subgroup more likely to experience further AP/T problems. To date, revisions of port design do not appear to have solved AP/T problems. Recent introduction of a significantly redesigned port may reduce AP/T failures. 相似文献
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Ozone-induced augmentation of eicosanoid metabolism in epithelial cells from bovine trachea 总被引:2,自引:0,他引:2
Epithelial injury and inflammation have been implicated in ozone-induced airway hyperresponsiveness. Because ozone is relatively insoluble and highly reactive, toxicologic effects of this compound may be limited to the plasma membranes of airway epithelium. We hypothesize that oxidant damage to epithelium may result in elaboration of various eicosanoids, which are known to alter airway smooth muscle responsiveness and epithelial cell functions (including ion transport). To examine eicosanoid metabolism after exposure to 0.1 to 10.0 ppm ozone, epithelial cells derived from bovine trachea were isolated and grown to confluency. Bovine tracheal cells in culture expressed differentiated features characteristic of epithelial cells, including a plasma membrane with a specialized polar morphology, an extensive network of filaments that were connected through intercellular junctional complexes, and keratin-containing monofilaments as determined by indirect immunofluorescent localization. Monolayers were alternately exposed to ozone and culture medium for 2 h in a specially designed in vitro chamber using a rotating inclined platform. Eicosanoid products were measured by the release of [3H]-labeled products from cells incubated with [3H]-arachidonic acid for 24 h before exposure and by the release of immunoreactive products into the cell supernatant. Both methods revealed ozone-induced increases in cyclooxygenase and lipoxygenase product formation with significant increases in prostaglandins E2, F2 alpha, 6-keto F1 alpha, and leukotriene B4. Release rates of immunoreactive products were dose-dependent, and ozone concentrations as low as 0.1 ppm produced an increase in prostaglandin F2 alpha. These findings are consistent with the hypothesis that ozone can augment eicosanoid metabolism in airway epithelial cells. 相似文献