Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum.

Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR-/- mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR-/- mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1ß (IL-1ß) secretion, and IL-1ß is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1ß secretion is inhibited in the developing cerebellum of N-PKR-/- mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD).

Survival on Venoarterial Extracorporeal Membrane Oxygenation in Cardiogenic Shock: Which Lactate Is Most Useful?

Prognostic significance of elevated serum lactate in patients on venoarterial extracorporeal membrane oxygenation (ECMO) is widely known. Our objective was to study the utility of lactate measured at different points of time and lactate clearance in predicting the two study endpoints: successful ECMO weaning and hospital survival. Among 238 consecutive patients treated with ECMO, lactic acid was collected before initiating ECMO and then on days 1, 3, 5, and 10 while on ECMO. Out of our cohort, 129 (54.2%) were successfully weaned and 98 (41.2%) were discharged alive. Patients successfully weaned from ECMO had a significantly lower lactic acid level pre-ECMO (p = 0.001), at day 1 (p < 0.001), day 3 (p < 0.001), and day 5 (p = 0.001), compared with unsuccessfully weaned patients. Also, patients who survived hospitalization had significantly lower lactic acid pre-ECMO (p = 0.007), at day 1 (p < 0.001), day 3 (p = 0.001), and day 5 (p = 0.001), compared with those who died in-hospital. With regard to hospital survival, day 3 lactic acid was superior to pre-ECMO lactic acid (p = 0.0385), lactic acid on day 1, lactic acid reduction from pre-ECMO to day 1 (p = 0.0177) and from pre-ECMO to day 3 (p = 0.0361), and a day 3 lactic acid ≤ 1.7 meq/L was the optimal value that predicted hospital survival. On multivariable analysis, day 3 lactic acid independently predicted hospital survival after covariate adjustment (odds ratio [OR], 0.505; 95% confidence interval [CI], 0.290-0.880; p = 0.016). In conclusion, the absolute level of lactic acid while on ECMO support is more important for prognosis than a pre-ECMO level or the magnitude of decline from pre-ECMO to on-ECMO.