Does treatment delay for blunt cerebrovascular injury affect stroke rate?: An EAST multicenter study.

BACKGROUND: The purpose of this study was to analyze injury characteristics and stroke rates between blunt cerebrovascular injury (BCVI) with delayed vs non-delayed medical therapy. We hypothesized there would be increased stroke formation with delayed medical therapy. METHODS: This is a sub-analysis of a 16 center, prospective, observational trial on BCVI. Delayed medial therapy was defined as initiation >24 hours after admission. BCVI which did not receive medical therapy were excluded. Subgroups for injury presence were created using Abbreviated Injury Scale (AIS) score >0 for AIS categories. RESULTS: 636 BCVI were included. Median time to first medical therapy was 62 hours in the delayed group and 11 hours in the non-delayed group (p < 0.001). The injury severity score (ISS) was greater in the delayed group (24.0 vs the non-delayed group 22.0, p <  0.001) as was the median AIS head score (2.0 vs 1.0, p <  0.001). The overall stroke rate was not different between the delayed vs non-delayed groups respectively (9.7% vs 9.5%, p = 1.00). Further evaluation of carotid vs vertebral artery injury showed no difference in stroke rate, 13.6% and 13.2%, p = 1.00 vs 7.3% and 6.5%, p = 0.84. Additionally, within all AIS categories there was no difference in stroke rate between delayed and non-delayed medical therapy (all N.S.), with AIS head >0 13.8% vs 9.2%, p = 0.20 and AIS spine >0 11.0% vs 9.3%, p = 0.63 respectively. CONCLUSIONS: Modern BCVI therapy is administered early. BCVI with delayed therapy were more severely injured. However, a higher stroke rate was not seen with delayed therapy, even for BCVI with head or spine injuries. This data suggests with competing injuries or other clinical concerns there is not an increased stroke rate with necessary delays of medical treatment for BCVI.

Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity.

p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-α) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure.