Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness

Background Neutrophils play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and pulmonary infection. Impaired neutrophil phagocytosis predicts hospital-acquired infection. Despite this, remarkably few neutrophil-specific treatments exist. 

Objectives We sought to identify novel pathways for the restoration of effective neutrophil phagocytosis and to activate such pathways effectively in neutrophils from patients with impaired neutrophil phagocytosis. 

Methods Blood neutrophils were isolated from healthy volunteers and patients with impaired neutrophil function. In healthy neutrophils phagocytic impairment was induced experimentally by using β₂-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro. 

Results β₂-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by β₂-agonists was associated with significantly reduced RhoA activity. Inhibition of protein kinase A (PKA) restored phagocytosis and RhoA activity, suggesting that cAMP signals through PKA to drive phagocytic impairment. However, cAMP can signal through effectors other than PKA, such as exchange protein directly activated by cyclic AMP (EPAC). An EPAC-activating analog of cAMP (8CPT-2Me-cAMP) reversed neutrophil dysfunction induced by β₂-agonists or corticosteroids but did not increase RhoA activity. 8CPT-2Me-cAMP reversed phagocytic impairment induced by Rho kinase inhibition but was ineffective in the presence of Rap-1 GTPase inhibitors. 8CPT-2Me-cAMP restored function to neutrophils from patients with known acquired impairment of neutrophil phagocytosis. 

Conclusions EPAC activation consistently reverses clinical and experimental impairment of neutrophil phagocytosis. EPAC signals through Rap-1 and bypasses RhoA. EPAC activation represents a novel potential means by which to reverse impaired neutrophil phagocytosis.

Ultrasound in undergraduate medical education: A systematic and critical review

Introduction: Point-of-care ultrasound (POCUS) use in clinical care is growing rapidly, and advocates have recently proposed the integration of ultrasound into undergraduate medical education (UME). The evidentiary basis for this integration has not been evaluated critically or systematically. In this study, we conducted a critical and systematic review framed by the rationales enumerated by advocates of ultrasound in UME in academic publications.

Methods: This research was conducted in two phases. First, the dominant discursive rationales for the integration of ultrasound in UME were identified using techniques from Foucauldian critical discourse analysis (CDA) from an archive of 403 academic publications. We then sought empirical evidence in support of theses rationales, using a critical synthesis methodology also adapted from CDA.

Results: We identified four dominant discursive rationales, with different levels of evidentiary support. Ultrasound was not demonstrated to improve students’ understanding of anatomy. The benefit of ultrasound in teaching physical examination was inconsistent,and rests on minimal evidence. With POCUS, students’ diagnostic accuracy was improved for certain pathologies, but findings were inconsistent for others. Finally, the rationale that ultrasound training in UME will improve quality of patient care was difficult to evaluate.

Discussion: Our analysis has shown that the frequently repeated rationales for the integration of ultrasound in UME are not supported by a sufficient base of empirical research. The repetition of these dominant discursive rationales in academic publications legitimizes them and may preclude further primary research. Since the value of clinical ultrasound use by medical students remains unproven, educators must consider whether the associated financial and temporal costs are justified or whether more research is required.

Addressing conflict and tolerance through the curriculum

Political, religious and national divisions in Northern Ireland go back many hundreds of years so it is not surprising that the lack of a common national narrative has made the teaching of history in schools difficult. The fact that schools have largely been organized on a denominational basis has added to the challenge. When political violence broke out in the late 1960s many looked to schools to contribute to the promotion of reconciliation and the way history had been taught received significant critical attention. This chapter will outline the evolving nature of the history curriculum and review evidence on the impact of this curriculum on the historical understanding of students and young people. In addition, the chapter will briefly consider other ways in which students engage with historical issues through the teaching of citizenship, and wider family and community influences. Whereas the teaching of history in the past either was largely absent or often took on a partisan character, the development of a statutory curriculum in the 1990s helped promote a more dispassionate, skills-based approach which emphasized critical engagement with evidence and a multiperspectivity. While this represented a significant improvement on what had gone before, evaluation of the impact of this approach has highlighted the need for a consideration of the emotional impact of historical understanding and the need better to connect the lessons of history to contemporary society.