2,6-Diamino-N-([1-(1-oxotridecyl)-2-piperidinyl] methyl)hexanamide (NPC 15437): a novel inhibitor of protein kinase C interacting at the regulatory domain.

NPC 15437 is a prototype member of a new class of synthetically derived protein kinase C (PKC) inhibitors. PKC activity and binding of phorbol ester to the enzyme were inhibited by NPC 15437, with IC50 values of 19 +/- 2 microM and 23 +/- 4 microM, respectively. No inhibition of cAMP-dependent or calcium/calmodulin-dependent protein kinases was observed at concentrations of NPC 15437 up to 300 microM. To investigate the mechanism by which NPC 15437 exerts its effects, a kinetic analysis of the inhibition with respect to three activators of the enzyme, phosphatidylserine, calcium, and phorbol ester, was performed. NPC 15437 was a competitive inhibitor of the activation of PKC by phorbol ester (Ki = 5 +/- 3 microM). Stimulation of PKC alpha by phosphatidylserine was competitively inhibited by NPC 15437 (Ki = 12 +/- 4 microM). The inhibition was mixed with respect to activation by calcium. These results suggest that NPC 15437 is a selective inhibitor of PKC, interacting at the regulatory region of the enzyme. NPC 15437 inhibited PKC in intact cells, dose-dependently antagonizing the phorbol ester-induced phosphorylation of a 47-kDa protein in human platelets.     

The effect of total arterial grafting on medium-term outcomes following coronary artery bypass grafting

Background  

While it is believed that total arterial grafting (TAG) for coronary artery bypass grafting (CABG) confers improved long-term outcomes when compared to conventional grafting with left internal mammary artery and saphenous vein grafts (LIMA+SVG), to date, this has not become the standard of care. In this study, we assessed the impact of TAG on medium-term outcomes after CABG.     

Don’t Let an Opportunity Go by: Validation of the EIGHT Gambling Screen

The EIGHT Screen is a brief problem gambling screen originally designed for use by family doctors. Its wider use indicated the need for further validation. A triangulated approach used a range of measures in different settings in both the current study and findings from a number of earlier projects, and reviewed current use. The EIGHT Screen had acceptable correlations with the SOGS (r = 74–90%) and with the NODS-12 months Screen (r = 62.4%). Measurements remained relatively constant amongst a range of cultures, settings, age and gender, while few false positives were produced by the screen. The EIGHT Screen appears to be a valid tool for untrained users to identify Level 2 and 3 problem gambling in a wide range of cultures and settings.