Exploring the contextual risk factors and characteristics of individuals who died from the acute toxic effects of opioids and other illegal substances: listening to the coroner and medical examiner voice. / Exploration des facteurs de risque contextuels et des caractéristiques des personnes décédées des effets toxiques aigus d'opioïdes et d'autres substances illégales : prise en compte de l'avis des coroners et des médecins légistes.

INTRODUCTION: Substance-related acute toxicity deaths continue to be a serious public health concern in Canada. This study explored coroner and medical examiner (C/ME)perspectives of contextual risk factors and characteristics associated with deaths from acute toxic effects of opioids and other illegal substances in Canada. METHODS: In-depth interviews were conducted with 36 C/MEs in eight provinces and territories between December 2017 and February 2018. Interview audio recordings were transcribed and coded for key themes using thematic analysis. RESULTS: Four themes described the perspectives of C/MEs: (1) Who is experiencing a substance-related acute toxicity death?; (2) Who is present at the time of death?; (3) Why are people experiencing an acute toxicity death?; (4) What are the social contextual factors contributing to deaths? Deaths crossed demographic and socioeconomic groups and included people who used substances on occasion, chronically, or for the first time. Using alone presents risk, while using in the presence of others can also contribute to risk if others are unable or unprepared to respond. People who died from a substance-related acute toxicity often had one or more contextual risk factors: contaminated substances, history of substance use, history of chronic pain and decreased tolerance. Social contextual factors contributing to deaths included diagnosed or undiagnosed mental illness, stigma, lack of support and lack of follow-up from health care. CONCLUSION: Findings revealed contextual factors and characteristics associated with substance-related acute toxicity deaths that contribute to a better understanding of the circumstances surrounding these deaths across Canada and that can inform targeted prevention and intervention efforts.

State regulations governing oral sedation in dental practice.

PURPOSE: The purpose of this study was to survey 50 state dental boards concerning their regulations governing the practice of moderate sedation administered by the oral route. METHODS: An online search was conducted to review each state's dental practice act. When interpretation of the information provided online was difficult, clarification was achieved by contacting that state board directly by telephone interview. To assist in further interpretation, the ADA's Statutory Guidelines for Conscious Sedation Permit were reviewed for comparison with the data collected. RESULTS: Forty-one states required a permit to administer moderate sedation by the oral route. Every state except Kansas required minimum didactic educational requirements for permit issuance. Every state required monitoring of the patient throughout the procedure and during recovery until discharge. In addition, all states expected the practitioner and clinical staff to be adequately trained to manage a sedation-related emergency. CONCLUSIONS: State dental boards have significantly increased regulation of oral sedation over the past 10 years, but vary widely in their permit requirements for issuance. This dis-harmony among the states should foster the national desire to develop a more unified approach in regulating oral sedation.

Differential regulation of primitive myelopoiesis in the zebrafish by Spi-1/Pu.1 and C/ebp1.

The zebrafish has become a powerful tool for analysis of vertebrate hematopoiesis. Zebrafish, unlike mammals, have a robust primitive myeloid pathway that generates both granulocytes and macrophages. It is not clear how this unique primitive myeloid pathway relates to mammalian definitive hematopoiesis. In this study, we show that the two myeloid subsets can be distinguished using RNA in situ hybridization. Using a morpholino-antisense gene knockdown approach, we have characterized the hematopoietic defects resulting from knockdown of the myeloid transcription factor gene pu.1 and the unique zebrafish gene c/ebp1. Severe reduction of pu.1 resulted in complete loss of primitive macrophage development, with effects on granulocyte development only with maximal knockdown. Reduction of c/ebp1 did not ablate initial macrophage or granulocyte development, but resulted in loss of expression of the secondary granule gene lys C. These data reveal strong functional conservation of pu.1 between zebrafish primitive myelopoiesis and mammalian definitive myelopoiesis. Further, these results are consistent with a conserved role between c/ebp1 and mammalian C/EBPE, whose ortholog in zebrafish has not been identified. These studies validate the examination of zebrafish primitive myeloid development as a model for human myelopoiesis, and form a framework for identification and analysis of myeloid mutants.

The role of histidine residues in modulation of the rat P2X(2) purinoceptor by zinc and pH.

P2X(2) receptor currents are potentiated by acidic pH and zinc. To identify residues necessary for proton and zinc modulation, alanines were singly substituted for each of the nine histidines in the extracellular domain of the rat P2X(2) receptor. Wild-type and mutant receptors were expressed in Xenopus oocytes and analysed with two-electrode voltage clamp. All mutations caused less than a 2-fold change in the EC(50) of the ATP concentration-response relation. Decreasing the extracellular pH from 7.5 to 6.5 potentiated the responses to 10 microM ATP of wild-type P2X(2) and eight mutant receptors more than 4-fold, but the response of the mutant receptor H319A was potentiated only 1.4-fold. The H319A mutation greatly attenuated the maximal potentiation that could be produced by a drop in pH, shifted the pK(a) (-log of dissociation constant) of the potentiation to a more basic pH as compared with P2X(2) and revealed a substantial pH-dependent decrease in the maximum response with a pK(a) near 6.0. Substituting a lysine for H319 reduced the EC(50) for ATP 40-fold. Zinc (20 microM) potentiated the responses to 10 microM ATP of wild-type P2X(2) and seven histidine mutants by approximately 8-fold but had virtually no effect on the responses of two mutants, H120A and H213A. Neither H120A nor H213A removed the voltage-independent inhibition caused by high concentrations of zinc. The observation that different mutations selectively eliminated pH or zinc potentiation implies that there are two independent sites of action, even though the mechanisms of pH and zinc potentiation appear similar.