Late Ventilator-Induced Diaphragmatic Dysfunction After Extubation.

OBJECTIVES: Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model. DESIGN: Experimental randomized study. SETTING: Research laboratory. SUBJECTS: C57/BL6 mice. INTERVENTIONS: Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls. MEASUREMENTS AND MAIN RESULTS: For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas. CONCLUSIONS: We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.

Mitochondrial oxidative stress induces leaky ryanodine receptor during mechanical ventilation.

RATIONALE: Ventilator-induced diaphragm dysfunction (VIDD) increases morbidity and mortality in critical care patients. Although VIDD has been associated with mitochondrial oxidative stress and calcium homeostasis impairment, the underling mechanisms are still unknown. We hypothesized that diaphragmatic mitochondrial oxidative stress causes remodeling of the ryanodine receptor (RyR1)/calcium release channel, contributing to sarcoplasmic reticulum (SR) Ca2+ leak, proteolysis and VIDD. METHOD: In mice diaphragms mechanically ventilated for short (6 h) and long (12 h) period, we assessed mitochondrial ROS production, mitochondrial aconitase activity as a marker of mitochondrial oxidative stress, RyR1 remodeling and function, Ca2+ dependent proteolysis, TGFß1 and STAT3 pathway, muscle fibers cross-sectional area, and diaphragm specific force production, with or without the mitochondrial targeted anti-oxidant peptide d-Arg-2', 6'-dimethyltyrosine-Lys-Phe-NH2 (SS31). MEASUREMENTS AND MAIN RESULTS: 6 h of mechanical ventilation (MV) resulted in increased mitochondrial ROS production, reduction of mitochondrial aconitase activity, increased oxidation, S-nitrosylation, S-glutathionylation and Ser-2844 phosphorylation of RyR1, depletion of stabilizing subunit calstabin1 from RyR1, increased SR Ca2+ leak. Preventing mROS production by SS31 treatment does not affect the TGFß1 and STAT3 activation, which suggests that mitochondrial oxidative stress is a downstream pathway to TGFß1 and STAT3, early involved in VIDD. This is further supported by the fact that SS-31 rescue all the other described cellular events and diaphragm contractile dysfunction induced by MV, while SS20, an analog of SS31 lacking antioxidant properties, failed to prevent these cellular events and the contractile dysfunction. Similar results were found in ventilated for 12 h. Moreover, SS31 treatment prevented calpain1 activity and diaphragm atrophy observed after 12 h of MV. This study emphasizes that mitochondrial oxidative stress during 6 h-MV contributes to SR Ca2+ leak via RyR1 remodeling, and diaphragm weakness, while longer periods of MV (12 h) were also associated with increased Ca2+-dependent proteolysis and diaphragm atrophy.

Sexual dimorphism of mandibular angle in a Lebanese sample.

Sexual dimorphism represents a group of morphologic characteristics that differentiate males from females. Craniofacial morphology and more specifically the mandibular angle have been evaluated for their interest in orthodontic, anthropologic and forensic applications. Currently, limited data are available relative to the significance of the mandibular angle in sex determination in various populations. The objective of this preliminary study is to evaluate the significance of the mandibular angle in sex determination in a sample of Lebanese young individuals. Lateral cephalometric radiographs were obtained from 83 young individuals (40 males and 43 females) aged between 17 and 26 years. No statistically significant differences were detected between both genders relative to the mean values of A1, A2 and A3 measured for each individual using the ramus plane intersected with the mandibular planes of Downs, Sassouni and Steiner, respectively. This study demonstrated no significant difference of the mandibular angle in sex determination in the young Lebanese population. Further investigations with a larger sample size and a strongly established Lebanese background should be conducted to test the applicability of the mandibular angle sexual dimorphism.