Angelman syndrome is a severe neurological disorder characterized by mental retardation, absent speech, ataxia, seizures, and hyperactivity. The gene affected in this disorder is UBE3A, the gene encoding the E6-associated protein (E6AP) ubiquitin-protein ligase. Most patients have chromosomal deletions that remove the entire maternal allele of UBE3A. However, a small subset of patients have E6AP point mutations that result in single amino acid changes or short in-frame deletions that still allow translation of a full-length protein. By studying these point mutations in E6AP, we found a strong correlation between Angelman-associated mutations and a loss of E3 ubiquitin ligase activity. Interestingly the point mutations affect E6AP activity in different ways. Some mutant proteins cannot form thiol ester intermediates with ubiquitin, others retain the thiol ester formation activity but cannot efficiently transfer ubiquitin to a substrate, and still others are unstable in cells. Our results suggest that the loss of E6AP catalytic activity and likely the improper regulation of E6AP substrate(s) are important in the development of Angelman syndrome.

Utilization of CINB significantly improved pulmonary function, pain control, and shortens LOS in patients with rib fractures.

BACKGROUND Patients' trauma burdens are a combination of anatomic damage, physiologic derangement, and the resultant depletion of reserve. Typically, Injury Severity Score (ISS) >15 defines major anatomic injury and Revised Trauma Score (RTS) <7.84 defines major physiologic derangement, but there is no standard definition for reserve. The Need For Trauma Intervention (NFTI) identifies severely depleted reserves (NFTI+) with emergent interventions and/or early mortality. We hypothesized NFTI would have stronger associations with outcomes and better model fit than ISS and RTS. METHODS Thirty-eight adult and pediatric U.S. trauma centers submitted data for 88,488 encounters. Mixed models tested ISS greater than 15, RTS less than 7.84, and NFTI's associations with complications, survivors' discharge to continuing care, and survivors' length of stay (LOS). RESULTS The NFTI had stronger associations with complications and LOS than ISS and RTS (odds ratios [99.5% confidence interval]: NFTI = 9.44 [8.46–10.53]; ISS = 5.94 [5.36–6.60], RTS = 4.79 [4.29–5.34]; LOS incidence rate ratios (99.5% confidence interval): NFTI = 3.15 [3.08–3.22], ISS = 2.87 [2.80–2.94], RTS = 2.37 [2.30–2.45]). NFTI was more strongly associated with continuing care discharge but not significantly more than ISS (relative risk [99.5% confidence interval]: NFTI = 2.59 [2.52–2.66], ISS = 2.51 [2.44–2.59], RTS = 2.37 [2.28–2.46]). Cross-validation revealed that in all cases NFTI's model provided a much better fit than ISS greater than 15 or RTS less than 7.84. CONCLUSION In this multicenter study, NFTI had better model fit and stronger associations with the outcomes than ISS and RTS. By determining depletion of reserve via resource consumption, NFTI+ may be a better definition of major trauma than the standard definitions of ISS greater than 15 and RTS less than 7.84. Using NFTI may improve retrospective triage monitoring and statistical risk adjustments. LEVEL OF EVIDENCE Prognostic, level IV.

Patients with an ISS between 0 and 15 are often triaged to Level II activation. Our data would suggest that patients older than 60 years should be a criterion for the highest level of trauma activation.