ß1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function.

UNLABELLED: Voltage-gated sodium channel (VGSC) ß subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, ß subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell-cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC ß1 and ß1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of ß1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b(+/W)) with mice heterozygous for the Scn1b-null allele (Scn1b(+/-)) to determine whether the C121W mutation results in loss-of-function in vivo We found that Scn1b(+/W) mice were more susceptible than Scn1b(+/-) and Scn1b(+/+) mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. ß1-C121W subunits are expressed at the neuronal cell surface in vivo However, despite this, ß1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. ß1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1b(W/W) mice. These data, together with our previous results showing that ß1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT: The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to understand the mechanism of a mutation in the sodium channel gene SCN1B linked to genetic epilepsy with febrile seizures plus. We report that sodium channel ß1 subunit proteins encoded by this mutant gene are expressed at the surface of neuronal cell bodies; however, they do not associate with the ion channel complex nor are they transported to areas of the axon that are critical for proper neuronal firing. We conclude that this disease-causing mutation is not simply a loss-of-function, but instead results in a deleterious gain-of-function in the brain.

Patient safety intervention to reduce unnecessary red blood cell utilization.

OBJECTIVES: To measure the impact of a local patient safety intervention and a national guideline to reduce unnecessary red blood cell (RBC) transfusions in the Department of Medicine of an academic medical center. STUDY DESIGN: This was a retrospective, pre-post study. METHODS: In May 2013, a clinical practice guideline, modeled after the 2012 AABB recommendations for RBC use, was implemented with the goal of decreasing unnecessary RBC transfusions. This was done using a previously developed model for change management in the Department of Medicine that included academic safety conferences, e-mail safety alerts, and feedback to providers on global blood product utilization. Data regarding the utilization of RBC products were obtained for the time before the AABB guideline, after the AABB guideline but before the local intervention, and after the local intervention (January 2011 through March 2014). RESULTS: Blood product use started to decline after the AABB guideline, but dropped much further after the focused, local interventions were implemented. The proportion of patients receiving a transfusion decreased from 12.6% prior to the AABB guideline to 8.8% after the intervention (P < .001). The percent of total blood use with a hemoglobin level above 8 g/dL decreased from 20.2% to 12.4%; the total units of RBCs transfused per 100 discharges also decreased from 33.4 to 21.7. The direct RBC costs per discharge dropped from $61.60 to $39.70. CONCLUSIONS: Passive adoption of restrictive transfusion guidelines was shown to reduce blood product use on general medicine floors of an academic medical center, but the effect was greatly improved after a local, targeted intervention to improve patient safety was implemented.