Hypoxia causes increased monocyte nitric oxide synthesis which is mediated by changes in dimethylarginine dimethylaminohydrolase 2 expression in animal and human models of normobaric hypoxia.

BACKGROUND: Tissue hypoxia is a cardinal feature of inflammatory diseases and modulates monocyte function. Nitric oxide is a crucial component of the immune cell response. This study explored the metabolism of the endogenous inhibitor of nitric oxide production asymmetric dimethylarginine(ADMA) by monocyte dimethylarginine dimethylaminohydrolase 2(DDAH2), and the role of this pathway in the regulation of the cellular response and the local environment during hypoxia. METHODS: Peritoneal macrophages were isolated from a macrophage-specific DDAH2 knockout mouse that we developed and compared with appropriate controls. Cells were exposed to 3% oxygen followed by reoxygenation at 21%. Healthy volunteers underwent an 8 h exposure to normobaric hypoxia with an inspired oxygen percentage of 12%. Peripheral blood mononuclear cells were isolated from blood samples taken before and at the end of this exposure. RESULTS: Intracellular nitrate plus nitrite(NOx) concentration was higher in wild-type murine monocytes after hypoxia and reoxygenation than in normoxia-treated cells (mean(SD) 13·2(2·4) vs 8·1(1·7) pmols/mg protein, p = 0·009). DDAH2 protein was 4·5-fold (SD 1·3) higher than in control cells (p = 0·03). This increase led to a 24% reduction in ADMA concentration, 0·33(0.04) pmols/mg to 0·24(0·03), p = 0·002). DDAH2-deficient murine monocytes demonstrated no increase in nitric oxide production after hypoxic challenge. These findings were recapitulated in a human observational study. Mean plasma NOx concentration was elevated after hypoxic exposure (3·6(1.8)µM vs 6·4(3·2), p = 0·01), which was associated with a reduction in intracellular ADMA in paired samples from 3·6(0.27) pmols/mg protein to 3·15(0·3) (p < 0·01). This finding was associated with a 1·9-fold(0·6) increase in DDAH2 expression over baseline(p = 0·03). DISCUSSION: This study shows that in both human and murine models of acute hypoxia, increased DDAH2 expression mediates a reduction in intracellular ADMA concentration which in turn leads to elevated nitric oxide concentrations both within the cell and in the local environment. Cells deficient in DDAH2 were unable to mount this response.

Observational Skill-based Clinical Assessment tool for Resuscitation (OSCAR): development and validation.

AIM: The aim of the study reported here was to address the need to assess and train teamwork and non-technical skills in the context of Resuscitation. Specifically, we sought to develop a tool that is feasible to use and psychometrically sound to assess team behaviours during cardiac arrest resuscitation attempts. METHODS: To ensure validity, reliability, and feasibility, the Observational Skill based Clinical Assessment tool for Resuscitation (OSCAR) was developed in 3 phases. A review of the literature leading to initial tool development was followed by an assessment of face and content validity, and finally a thorough reliability assessment, using Cronbach's α to assess internal consistency and intraclass correlation to assess inter-rater reliability. RESULTS: OSCAR was developed methodically, and tested for face and content validity. Cronbach's α results ranged from 0.736 to 0.965 demonstrating high internal consistency, and intraclass correlation results ranged from 0.652 to 0.911, all of which are strongly significant and indicate good inter-rater reliability. CONCLUSION: On the basis of our results, we conclude that OSCAR is psychometrically robust, scientifically sound, and clinically relevant. We have developed the Observational Skill-based Clinical Assessment tool for Resuscitation (OSCAR) for the assessment of non-technical skills in Resuscitation teams. We propose the use of this tool in simulation and real Cardiac Arrest Resuscitation attempts to assess, guide and train non-technical skills to team members, to improve patient safety and maximise the chances of successful resuscitation.

Bilateral objective tinnitus secondary to congenital middle-ear myoclonus.

Subjective tinnitus (heard only by the patient) is a common otological complaint. Objective tinnitus (heard by the examiner as well as the patient) is extremely rare. There are only a few cases of objective tinnitus, secondary to middle-ear myoclonus, described in the literature. We present the case of a child with bilateral, congenital, objective tinnitus, secondary to middle-ear myoclonus, with otherwise normal hearing thresholds (250 Hz-8 kHz), and with no evidence of intra-cerebral or systemic disorders. No similar case has been reported in the world literature.