Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

Transition in eye gaze as a predictor of emergence from general anesthesia in children and adults: a prospective observational study.

BACKGROUND: It is useful to monitor eye movements during general anesthesia, but few studies have examined neurological finding of the eyes during emergence from general anesthesia maintained with short-acting opioids and volatile anesthetics. METHODS: Thirty children aged 1-6 years and 30 adults aged 20-79 years were enrolled. Patients received general anesthesia maintained with sevoflurane and remifentanil. The timing of three physical-behavioral responses-eye-gaze transition (the cycle from conjugate to disconjugate and back to conjugate), resumption of somatic movement (limbs or body), and resumption of respiration-were recorded until spontaneous awakening. The primary outcome measure was the timing of the physical-behavioral responses. Secondary outcome measures were the incidence of eye-gaze transition, and the bispectral index, concentration of end-tidal sevoflurane, and heart rate at the timing of eye-gaze transition. RESULTS: Eye-gaze transition was evident in 29 children (96.7%; 95% confidence interval, 82.8-99.9). After the end of surgery, eye-gaze transition was observed significantly earlier than resumption of somatic movement or respiration (472 [standard deviation 219] s, 723 [235] s, and 754 [232] s, respectively; p < 0.001). In adults, 3 cases (10%; 95% CI, 0.2-26.5) showed eye-gaze transition during emergence from anesthesia. The incidence of eye-gaze transition was significantly lower in adults than in children (p < 0.001). CONCLUSION: In children, eye-gaze transition was observed significantly earlier than other physical-behavioral responses during emergence from general anesthesia and seemed to reflect emergence from anesthesia. In contrast, observation of eye gaze was not a useful indicator of emergence from anesthesia in adults.

Anesthetic management of a patient undergoing cardioverter defibrillator implantation: usefulness of transesophageal echocardiography and near infrared spectroscopy.

A case of a patient with sustained ventricular tachycardia (VT) undergoing implantable cardiovertor defibrillator (ICD) implantation, using transesophageal echocardiography (TEE) and near infrared spectroscopy (NIR) is described. A 67-year-old man with sustained VT associated with old myocardial infarction underwent ICD implantation. Anesthesia was induced with fentanyl and propofol and maintained with nitrous oxide, oxygen, sevoflurane, and fentanyl. Global hypokinesis of the left ventricle was observed in the short-axis view provided by TEE. Intraoperative systolic blood pressure was maintained between 100 and 120 mmHg, and cerebral oxygenated hemoglobin (HbO2) was between 63% and 65%. During periods of induced ventricular fibrillation, systolic blood pressure decreased to 60 mmHg, HbO2 decreased to 59%, and TEE revealed cardiac arrest. These changes were transient; HbO2 returned to baseline values immediately after the restoration of normal rhythm. TEE confirmed no remarkable change in cardiac function after defibrillation testing. TEE and NIR were found to be beneficial for the anesthetic management of a patient with sustained VT who was underdoing ICD implantation.

[Concentrations of sevoflurane with and without nitrous oxide to block vasomotor reflexes to incision (MACBVR)].

The minimum alveolar concentration of an anesthetic that blocks the skin vasomotor reflex to surgical incision (MACBVR) for sevoflurane was determined in 37 patients aged 30-60 years scheduled for laparotomies with or without nitrous oxide. Thirty seven patients were randomly allocated to one of the two groups: a sevoflurane group and a sevoflurane/N2O (50 vol%) group. The skin blood flow of the finger tip was measured using a laser Doppler flowmeter. Anesthesia was induced with sevoflurane and N2O and tracheal intubation was facilitated with vecuronium 0.1 mg.kg-1. Predetermined end tidal concentrations of sevoflurane and N2O were maintained for at least 15 min before incision. The MACBVR values of sevoflurane in O2 and in the presence of 50% N2O were 3.07% and 1.63%, respectively. The MACBVR level in the total anesthetic MAC multiple was 1.75 MAC for sevoflurane alone and the value decreased to 1.43 MAC when 50% N2O was used. There were no relations between the amplitude of the reduction in skin blood flow and the changes of hemodynamic variables in each group. However, the changes in SBP and HR at incision were significantly suppressed by addition of N2O (changes in SBP and HR: 41.6 +/- 20.4 mmHg and 35.4 +/- 12.5 bpm in the sevoflurane group vs. 24.6 +/- 10.2 mmHg and 18.1 +/- 9.5 bpm in the sevoflurane/N2O group, P < 0.01). The results suggest that N2O is useful to suppress adrenergic responses to a surgical stimulus during sevoflurane anesthesia.