Retinoic Acid Receptor γ Regulates B and T Lymphopoiesis via Nestin-Expressing Cells in the Bone Marrow and Thymic Microenvironments.

Vitamin A has essential but largely unexplained roles in regulating lymphopoiesis. We have previously shown that retinoic acid receptor (RAR) γ-deficient mice have hematopoietic defects, some phenotypes of which were microenvironment induced. Bone marrow (BM) microenvironment cells identified by either their expression of nestin (Nes) or osterix (Osx) have previously been shown to have roles in regulating lymphopoiesis. We therefore conditionally deleted Rarγ in Nes- or Osx-expressing microenvironment cells. Osx cell-specific deletion of Rarγ had no impact on hematopoiesis. In contrast, deletion of Rarγ in Nes-expressing cells resulted in reductions in peripheral blood B cells and CD4(+) T cells, accompanied by reductions of immature PreB cells in BM. The mice lacking Rarγ in Nes-expressing cells also had smaller thymi, with reductions in double-negative 4 T cell precursors, accompanied by reduced numbers of both TCRß(low) immature single-positive CD8(+) cells and double-positive T cells. In the thymus, Nes expression was restricted to thymic stromal cells that expressed cerebellar degeneration-related Ag 1 and lacked expression of epithelial cell adhesion molecule. These cells expressed platelet-derived growth factor α and high transcript levels of Rars, Cxcl12, and stem cell factor (Scf). Short-term treatment of mice with all-trans retinoic acid resulted in increased PreB lymphopoiesis in BM and an increase in thymic double-negative 4 T cells, inverse to that observed upon Nes cell-specific deletion of Rarγ. Collectively, these studies show that RARγ is a regulator of B and T lymphopoiesis via Nes-expressing cells in the BM and thymic microenvironments, respectively.

The impact of an education program and written guideline on adherence to low tidal volume ventilation.

BACKGROUND: Low tidal volume ventilation reduces mortality in patients with acute lung injury (ALI) and may reduce the risk of ALI in ventilated patients. A previous audit of our ventilation practices showed poor adherence to low tidal volume ventilation, and we subsequently introduced written ventilation guidelines and an education program to change practice. OBJECTIVES: To determine if adherence to low tidal volume ventilation (defined as mandatory tidal volumes of =?6.5 mL/ kg predicted body weight [PBW]) in ventilated patients was improved with a written guideline and staff education. DESIGN AND SETTING: Retrospective analysis of recorded mandatory ventilator settings from the clinical information system of a tertiary referral intensive care unit from 1 January 2012 to 31 December 2015, involving analysis of mandatory ventilator settings in relation to PBW to determine adherence to guidelines, and interrupted time-series analysis to assess the impact of education. MAIN OUTCOME MEASURE: Adherence to low tidal volume ventilation. RESULTS: The mean tidal volume for the cohort was 7.4 mL/ kg (SD, 1.3 mL/kg) PBW, and 760 patients (26.9%) received an average tidal volume during mandatory ventilation of ≤6.5 mL/kg PBW. Interrupted time-series analysis showed improved adherence after education, with an increase in adherence of 29.4% (95% CI, 19.3%-39.5%) from baseline. Multivariate logistic analysis found height, weight and staff education, but not sex, were associated with adherence to low tidal volume ventilation. CONCLUSION: Written protocols and education can influence clinician behaviour, with substantial improvements in adherence to low tidal volume ventilation. Efforts to improve adherence through ward-based education appear warranted and necessary. Adherence was strongly associated with patient height, which suggested that adherence was partly the result of chance rather than design.