RFA resulted in long-term restoration of sinus rhythm in only 50% of patients. RFA did not improve CMR LVEF compared with a strategy of rate control. RFA did improve radionuclide LVEF but did not improve other secondary outcomes and was associated with a significant rate of serious complications.

Protein kinase B (PKB) isoforms became activated [and glycogen synthase kinase-3 (GSK3) became inhibited] when mouse Swiss 3T3 fibroblasts were exposed to oxidative stress (H2O2) or heat shock, but not when they were exposed to osmotic shock (0.5 M sorbitol or 0. 7 M NaCl), chemical stress (sodium arsenite), the protein-synthesis inhibitor anisomycin, or UV radiation. In contrast, all seven stimuli activated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2). The activation of MAPKAP-K2 was suppressed by the drug SB 203580, but not by inhibitors of phosphoinositide (phosphatidylinositide, PI) 3-kinase. In contrast, the activation of PKB isoforms and the inhibition of GSK3 by oxidative stress or heat shock were prevented by inhibitors of PI 3-kinase, but not by SB 203580. Thus the activation of PKB by oxidative stress or heat shock is mediated by PI 3-kinase and not by MAPKAP-K2. PKBalpha and PKBgamma were also activated by heat shock and oxidative stress in human embryonic kidney 293 cells and PKBgamma was activated by heat shock in NIH 3T3 cells; in each case activation was suppressed by inhibitors of PI 3-kinase. The activation of PKB isoforms by H2O2 may underlie some of the insulin-mimetic effects of this compound.

293 cells were transfected with wild-type GSK3ß (WT-GSK3ß) or a mutant in which the PKB phosphorylation site (Ser-9) was altered to Ala (A9-GSK3ß). Upon stimulation with IGF-1 or insulin, WT-GSK3ß was inhibited 75% or 60%, respectively, whereas the activity of the A9-GSK3ß mutant was unaffected. Incubation of WT-GSK3ß with ΡΡ2Αχ (a Ser/Thrspecific phosphatase) completely reversed the IGF-1-or insulininduced inhibition. IGF-1 stimulation did not induce any tv rosine dephosphorylation of WT-GSK3ß or A9-GSK3ß. Coexpression of WT-GSK3ß in 293 cells with either PKBa (also known as AKT) or PDK1 (the 'upstream' activator of PKB) mimicked the IGF-1-or insulin-induced phosphorylation of Ser-9 and inactivation of GSK3ß.