Purkinje cell-specific deletion of CREB worsens alcohol-induced cerebellar neuronal losses and motor deficits.

INTRODUCTION: Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to fetal alcohol spectrum disorder (FASD) in the offspring. However, not all fetuses are equally vulnerable to alcohol toxicity. These differences in vulnerability among individuals are likely due, at least in part, to genetic differences. Some genes encode neuroprotective molecules that act through signaling pathways to protect neurons against alcohol's toxic effects. One signaling pathway that can protect cultured neurons against alcohol-induced cell death in vitro is the cAMP pathway. A goal of this study was to determine whether the cAMP pathway can exert a similar neuroprotective effect against alcohol in vivo. A key molecule within the cAMP pathway is cAMP response element binding protein (CREB). In this study, CREB was specifically disrupted in cerebellar Purkinje cells to study its role in protection of cerebellar neurons against alcohol toxicity. METHODS: Mice with Purkinje cell-specific knockout of CREB were generated with the Cre-lox system. A 2 × 2 design was used in which Cre-negative and Cre-positive mice received either 0.0 or 2.2 mg/g ethanol by intraperitoneal (i.p.) injection daily over postnatal day (PD) 4-9. Stereological cell counts of cerebellar Purkinje cells and granule cells were performed on PD 10. Motor function was assessed on PD 40 using the rotarod. RESULTS: Purkinje cell-specific disruption of CREB alone (in the absence of alcohol) induced only a small reduction in Purkinje cell number. However, the loss of CREB function from Purkinje cells greatly increased the vulnerability of Purkinje cells to alcohol-induced cell death. While alcohol killed 20% of Purkinje cells in the Cre-negative (CREB-expressing) mice, alcohol killed 57% of Purkinje cells in the Cre-positive (CREB-nonexpressing) mice. This large loss of Purkinje cells did not lead to similar alcohol-induced losses of granule cells. In the absence of alcohol, lack of CREB function in Purkinje cells had no effect on rotarod performance. However, in the presence of alcohol, disruption of CREB in Purkinje cells substantially worsened rotarod performance. DISCUSSION: Disruption of a single gene (CREB) in a single neuronal population (Purkinje cells) greatly increases the vulnerability of that cell population to alcohol-induced cell death and worsens alcohol-induced brain dysfunction. The results suggest that the cAMP pathway can protect cells in vivo against alcohol toxicity and underline the importance of genetics in determining the neuropathology and behavioral deficits of FASD.

Out-of-hospital cardiac arrest outcomes stratified by rhythm analysis.

BACKGROUND: Survival data for out-of-hospital cardiac arrest (OHCA) victims initially in PEA or asystole who convert to a shockable rhythm during attempted resuscitation, relative to an initial shockable rhythm, have never been previously reported. This study was done to assess OHCA outcomes among a large cohort of adults in the CARES dataset stratified by three rhythm categories: initial shockable (IS), converted shockable (CS), and never shockable (NS). METHODS: The study was IRB approved. All adult index events at participating sites (2005-2010) were study eligible. All patient data elements were provided. Odds ratios of CS and NS status for survival to hospital discharge were calculated via multivariate logistic regression that adjusted for demographics, site, resuscitation initiators, AED use, and other covariates. RESULTS: There were 40,274 OHCA records submitted to the CARES registry during the study period. After exclusions, our final sample size was 30,939 (7404 IS [23.9%], 3225 CS [10.4%], 20,310 NS [65.7%]). Raw survival rates of CS and NS patients were similar (4.7% vs. 4.1%, respectively; p=0.08) but significantly lower than IS patients (26.9%; p<0.001). The adjusted OR of survival to hospital discharge for CS was 0.17 (95% CI: 0.14, 0.20) and for NS it was 0.17 (95% CI: 0.15, 0.18) with IS as the referent. CONCLUSION: After OHCA, the survival rate for CS victims is significantly lower than for IS patients. These findings suggest that CS and IS are different entities and that alternatives to existing resuscitation algorithm tailored to patients with CS should be investigated.