We hypothesized that Nox2, the classical phagocytic NADPH oxidase, plays an important role in calcineurin inhibitor (CNI)-induced renal fibrosis. We tested this hypothesis in vitro, in animal and in human studies. Cyclosporine A (CsA) and tacrolimus (TAC) were associated with greater levels of Nox2 mRNA and epithelial to mesenchymal transition (EMT) in NRK52E cells. CsA increased Nox2, α-SMA and phosphorylated-p38MAPK, Smad3, and NFκB proteins. Nox2 upregulation and EMT were inhibited in TGF-β1 knockout cells suggesting that TGF-β1 is required for Nox2 activation. Fisher344 rats treated with high dose CsA showed increased Nox2 in the tubulointerstitium and greater Nox2, α-SMA, phosphorylated Smad3 and nitrotyrosine by immunoblot analyses. Inhibition of Nox2 by coadministration of apocynin or diphenyleneiodonium was associated with reduced fibrogenesis. We validated these findings by treating wild type and Nox2 null (B6.129S-CybbTm1Din/J) mice with high dose CsA. Western blot analyses confirmed the absence of Nox2 and significantly lower levels of α-SMA and 4-hydroxynonenal in CsA-treated knockout mice. These findings were clinically relevant since Nox2 and α-SMA were increased in the tubulointerstitium of kidneys from 15 liver transplant recipients with biopsy-confirmed chronic CsA or TAC nephrotoxicity. In conclusion, specific Nox2 inhibition strategies may improve chronic CNI nephrotoxicity in solid organ transplantation.
Purpose Ineffective leadership during cardiopulmonary resuscitation (“code”) can negatively affect a patient’s likelihood of survival. In most teaching hospitals, internal medicine residents lead codes. In this study, the authors explored internal medicine residents’ experiences leading codes, with a particular focus on how gender influences the code leadership experience. Method The authors conducted individual, semi-structured telephone or in-person interviews with 25 residents (May 2012 to February 2013) from 9 U.S. internal medicine residency programs. They audio recorded and transcribed the interviews then thematically analyzed the transcribed text. Results Participants viewed a successful code as one with effective leadership. They agreed that the ideal code leader was an authoritative presence; spoke with a deep, loud voice; used clear, direct communication; and appeared calm. Although equally able to lead codes as their male colleagues, female participants described feeling stress from having to violate gender behavioral norms in the role of code leader. In response, some female participants adopted rituals to signal the suspension of gender norms while leading a code. Others apologized afterwards for their counter normative behavior. Conclusions Ideal code leadership embodies highly agentic, stereotypical male behaviors. Female residents employed strategies to better integrate the competing identities of code leader and female gender. In the future, residency training should acknowledge how female gender stereotypes may conflict with the behaviors required to enact code leadership and offer some strategies, such as those used by the female residents in this study, to help women integrate these dual identities.
Background Internal medicine (IM) residents participate in cardiopulmonary resuscitation events (or ''codes''), stressful events that involve the death or near death of patients. Experiencing traumatic stress can lead to posttraumatic stress disorder (PTSD).
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