Aberrant activation of the Rb/E2F1 pathway in cycling cells, in response to mitogenic or nonmitogenic stress signals, leads to apoptosis through hyperphosphorylation of Rb. To test whether in postmitotic neurons the Rb/E2F1 pathway can be activated by the nonmitogenic stress signaling, we examined the role of the p38 stress-activated protein kinase (SAPK) in regulating Rb phosphorylation in response to Fas (CD95/APO1)-mediated apoptosis of cultured cerebellar granule neurons (CGNs). Anti-Fas antibody induced a dramatic and early activation of p38. Activated p38 was correlated with the induction of hyperphosphorylation of both endogenous and exogenous Rb. The p38-selective inhibitor, SB203580, attenuated such an increase in pRb phosphorylation and significantly protected CGNs from Fas-induced apoptosis. The cyclin-dependent kinase-mediated Rb phosphorylation played a lesser role in this neuronal death paradigm, since cyclin-dependent kinase inhibitors, such as olomoucine, roscovitine, and flavopiridol, did not significantly prevent anti-Fas antibody-evoked neuronal apoptosis. Hyperphosphorylation of Rb by p38 SAPK resulted in the release of Rb-bound E2F1. Increased E2F1 modulated neuronal apoptosis, since E2F1؊/؊ CGNs were significantly less susceptible to Fas-mediated apoptosis in comparison with the wildtype CGNs. Taken together, these studies demonstrate that neuronal Rb/E2F1 is modulated by the nonproliferative p38 SAPK in Fas-mediated neuronal apoptosis.

Nausea and vomiting of pregnancy (NVP) affects up to 80% of all women to some degree during their pregnancies. Diclectin (doxylamine and pyridoxine [vitamin B6]) has been on the Canadian market for many years and is indicated as the drug of choice for the treatment of NVP. However, some women choose not to treat NVP with pharmacologic measures, perhaps due to a persistent fear of teratogenic risk. The objective of this study was to determine the factors that influence a woman's decision not to treat NVP with pharmacologic measures. Fifty-nine women recruited from the Motherisk Nausea and Vomiting Helpline completed a questionnaire. All were informed that Diclectin was considered safe for use during pregnancy. At a follow-up telephone call, 34% were not using any pharmacologic treatment, and of those who were taking the drug, 26% were using less than the recommended dose. Reasons cited for not using the medication were insufficient safety data, preference for non-pharmacologic methods, and being made to feel uncomfortable by the physician. Of the women who did use Diclectin, the most convincing reassuring information that it was safe to use came from friends and family. Many other factors play a large role in a women's decision making.

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