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A 57-year-old woman with recurrent, symptomatic, paroxysmal atrial fibrillation, refractory to multiple cardioversions and oral antiarrhythmic therapy, was referred for pulmonary vein isolation. To evaluate pulmonary vein anatomy and assist with 3-dimensional mapping, pre-procedural cardiac computed

Acute administration of ethanol to 7-day-old mice is known to cause robust apoptotic neurodegeneration in the brain. Our previous studies have shown that such ethanol-induced neurodegeneration is accompanied by increases in lipids, including ceramide, triglyceride (TG), cholesterol ester (ChE), and N-acylphosphatidylethanolamine (NAPE) in the brain. In this study, the effects of ethanol on lipid profiles as well as caspase 3 activation were examined in the cortex, hippocampus, cerebellum, and inferior colliculus of the postnatal day 7 mouse brain. We found that the cortex, hippocampus, and inferior colliculus, which showed substantial caspase 3 activation by ethanol, manifested significant elevations in ceramide, TG, and NAPE. In contrast, the cerebellum, with the least caspase 3 activation, failed to show significant changes in ceramide and TG, and exhibits much smaller increases in NAPE than other brain regions. Ethanol-induced increases in ChE were observed in all brain regions tested. Inhibitors of serine palmitoyltransferase effectively blocked ethanol-induced caspase 3 activation as well as elevations in ceramide, ChE, and NAPE. Immunohistochemical studies indicated that the expression of serine palmitoyltransferase was mainly localized in neurons and was enhanced in activated caspase 3-positive neurons generated by ethanol. These results indicate that de novo ceramide synthesis has a vital role in ethanol-induced apoptotic neurodegeneration in the developing brain.

Previous studies indicated that ethanol-induced neurodegeneration in postnatal day 7 (P7) mice, widely used as a model for the fetal alcohol spectrum disorders, was accompanied by glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activation. Presently, we examined whether tau, a microtubule associated protein, is modified by GSK-3beta and caspase-3 in ethanol-treated P7 mouse forebrains. We found that ethanol increased phosphorylated tau recognized by the paired helical filament (PHF)-1 antibody and by the antibody against tau phosphorylated at Ser199. Ethanol also generated tau fragments recognized by an antibody against caspase-cleaved tau (C-tau). C-tau was localized in neurons bearing activated caspase-3 and fragmented nuclei. Over time, cell debris and degenerated projections containing C-tau appeared to be engulfed by activated microglia. A caspase-3 inhibitor partially blocked C-tau formation. Lithium, a GSK-3beta inhibitor, blocked ethanol-induced caspase-3 activation, phosphorylated tau elevation, C-tau formation, and microglial activation. These results indicate that tau is phosphorylated by GSK-3beta and cleaved by caspase-3 during ethanol-induced neurodegeneration in the developing brain.

Acute administration of ethanol to 7-day-old mice is known to cause robust apoptotic neurodegeneration in the brain. Our previous studies have shown that such ethanol-induced neurodegeneration is accompanied by increases in lipids including ceramide, triglyceride, cholesterol ester, and N-acyl phosphatidylethanolamine in the brain. In this study, the effects of ethanol on lipid profiles as well as caspase-3 activation were examined in the cortex, hippocampus, cerebellum, and inferior colliculus of the P7 mouse brain. We found that the cortex, hippocampus, and inferior colliculus, which showed substantial caspase-3 activation by ethanol, manifested significant elevations in ceramide, triglyceride, and N-acylphosphatidylethanolamine. In contrast, the cerebellum, with the least caspase-3 activation, failed to show significant changes in ceramide and triglyceride, and exhibits much smaller increases in N-acyl phosphatidylethanolamine than other brain regions. Ethanol-induced increases in cholesterol ester were observed in all brain regions tested. Inhibitors of serine palmitoyltransferase effectively blocked ethanol-induced caspase-3 activation as well as elevations in ceramide, cholesterol ester, and N-acyl phosphatidylethanolamine. Immunohistochemical studies indicated that the expression of serine palmitoyltransferase was mainly localized in neurons and was enhanced in activated caspase-3-positive neurons generated by ethanol. These results indicate that de novo ceramide synthesis has a vital role in ethanol-induced apoptotic neurodegeneration in the developing brain.