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SummaryThis study aims to assess the prevalence and outcomes of inhalational anaesthetic abuse among anaesthesia training programmes. Online surveys were completed by chairpersons of academic anaesthesia training programmes in the United States. The response rate was 84% (106 ⁄ 126 programmes). Twenty-two percent of the departments had had at least one incident of inhalational anaesthetic abuse. Forty-eight percent (15 ⁄ 31) of the persons abusing inhalational anaesthetics were sent for rehabilitation. Only 22% (7 ⁄ 31) of those found to be abusing inhalational anaesthetics were ultimately able to return successfully to anaesthesia practice with sustained recovery. The mortality rate among individuals found abusing inhalational anaesthetics was 26% (8 ⁄ 31). The majority of the anaesthesia departments (97 ⁄ 104, 93%) did not have any pharmacy accounting of inhalational anaesthetics. This is the first published survey of inhalational anaesthesia abuse. Inhalational anaesthetic abuse should be considered in at-risk individuals or those with a history of substance abuse. The concern about substance abuse is not unique to American anaesthetists. Countries around the world deal with similar substance abuse issues.

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Standard of care subcutaneous dosing of unfractionated heparin for VTE prophylaxis in surgical ICU patients leads to subtherapeutic levels of factor Xa inhibition.

SummaryPax5 is a critical regulator of transcription and lineage commitment in B lymphocytes. In B cells, mb-1 (Ig-α) promoter transcription is activated by Pax5 through its recruitment of Ets family proteins to a composite site, the P5-EBS (Pax5-Ets binding site). Previously, X-ray crystallographic analysis revealed a network of contacts between the DNA binding domains of Pax5 and Ets-1 while bound to the P5-EBS. Here, we report that Pax5 assembles these ternary complexes via highly cooperative interactions that overcome the autoinhibition of Ets-1. Using recombinant proteins, we calculated K D(app) values for the binding of Pax5, Ets-1 and GABP proteins, separately or together, to the P5-EBS. By itself, Pax5 binds the P5-EBS with high affinity (K D ≅ 2 nM). Ets-1(331-440) bound the P5-EBS by itself with low affinity (K D = 136 nM). However, autoinhibited Ets-1(280-440) alone does not bind detectably to the suboptimal sequences of the P5-EBS. Recruitment of Ets-1(331-440) or (280-440) resulted in highly efficient ternary complex assembly with Pax5. Pax5 counteracts autoinhibition and increases binding of Ets-1 of the mb-1 promoter by >1000-fold. Mutation of Pax5 Gln22 to alanine (Q22A) enhances promoter binding by Pax5; however, Q22A greatly reduces recruitment of Ets-1(331-440) and (280-440) by Pax5 (8.9-or >300-fold, respectively). Thus, Gln22 of Pax5 is essential for overcoming Ets-1 autoinhibition. Pax5 wild type and Q22A each recruited GABPα/β1 to the mb-1 promoter with similar affinities, but recruitment was less efficient than that of Ets-1 (reduced by ~8-fold). Our results suggest a mechanism that allows Pax5 to overcome autoinhibition of Ets-1 DNA binding. In summary, these data illustrate requirements for partnerships between Ets proteins and Pax5.

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