Predictors of post-discharge seizures in children with traumatic brain injury.

PURPOSE: In traumatic brain injury (TBI), hyperglycemia and hypothermia are thought to be associated with poor outcomes, but have not been systematically studied in children. Thus, our aim was to evaluate whether serum glucose and temperature at admission, among other clinical variables, were associated with need for post hospital-discharge seizure medication in children diagnosed with TBI. METHODS: We performed a retrospective study of 1814 children who were diagnosed with TBI at a tertiary pediatric hospital. Serum glucose levels at admission and temperature at initial presentation, 12, and 24 h were collected. Ongoing seizure activity was defined as discharge prescription of a seizure-modifying medication. RESULTS: We identified 121 patients with need for continued seizure medications, and 80 patients expired. Independent predictors of prolonged seizures included serum glucose levels above 140 mg/dl (p < 0.003) and 199 mg/dl (p < 0.001), hypothermia (<35 °C), subdural hematoma (p < 0.001), midline shift (p < 0.001), and > 1% temperature change in the first 24 h (p < 0.001). Multivariate regression adjusting for GCS revealed that bilateral bleed (p = 0.008), body-temperature instability (p = 0.026), subdural hematoma (p < 0.001), and mechanism of injury (p = 0.007) were predictive of prolonged seizure activity. CONCLUSIONS: In summary, we conclude that body temperature may be playing a more significant role than glycemic control in propensity for ongoing seizure activity in children sustaining TBI.

Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death.

UNLABELLED: Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPP-family phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumor-selective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis. IMPLICATIONS: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845-55. ©2013 AACR.