Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation.

Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increased the nuclear translocation of transcription factor EB (TFEB). PERK activation by CO increased intracellular Ca2+ concentration and the phosphatase activity of calcineurin against TFEB. Moreover, we found that in the deficiency of TFEB, CO not only failed to recruit Parkin to the mitochondria but also failed to increase expression of lysosomal genes such as Lamp1, CathB, and TPP1. Therefore, we suggest that CO increases mitophagy through TFEB nuclear translocation by PERK-calcinuerin activation. In addition, the inhibition of TFEB with siRNA against TFEB abrogated the increase of mtDNA with CO, markers of mitochondrial biogenesis such as PGC1α, NRF1, and TFAM, and the mitochondrial proteins COX II, COX IV, and cytochrome c. To investigate the effects of CO on mitochondrial homeostasis in vivo, mice were treated with lipopolysaccharide (LPS)/d-galactosamine (D-GalN). CO inhalation reduced liver injury after challenge with LPS/GalN. Furthermore, CO inhalation increased TFEB activation, mitophagy and mitochondrial biogenesis in mice treated with LPS/GalN. Our findings describe novel mechanisms underlying CO-dependent cytoprotection in hepatocytes and liver tissue via activation of TFEB-dependent mitophagy and associated induction of both lysosomal and mitochondrial biogenesis.

IMPORTANCE Emergence agitation is common after nasal surgery under general anesthesia and may lead to serious consequences for the patient, including an increased risk of injury, pain, hemorrhage, and self-extubation. Despite decades of research, studies on the incidence, risk factors, and prevention of emergence agitation in adult patients are ongoing, and opinions differ on the different effects of inhalation and intravenous anesthesia. OBJECTIVE To investigate the effect of anesthetic method on the occurrence of emergence agitation after nasal surgery. DESIGN, SETTING, AND PARTICIPANTS This prospective, randomized, single-blind, clinical trial included 80 patients undergoing open rhinoplasty, septoplasty, turbinoplasty, endoscopic sinus surgery, and functional endoscopic sinus surgery under general anesthesia who were randomized to receive total intravenous anesthesia (TIVA) with remifentanil hydrochloride and propofol (n = 40) or volatile induction and maintenance of anesthesia (VIMA) with sevoflurane and nitrous oxide (n = 40) in Asan Medical Center, a tertiary referral center in

Mannitol, an osmotic diuretic, has been used to prevent acute kidney injury (AKI). However, studies have found divergent effects of intraoperative mannitol administration on postoperative AKI. We therefore evaluated the effects of intraoperative mannitol administration on AKI after robot-assisted laparoscopic radical prostatectomy (RALP) in prostate cancer patients.A total of 864 patients who underwent RALP were divided into mannitol (administered at 0.5 g/kg) and no-mannitol groups. Demographics, cancer-related data, preoperative laboratory values, intraoperative data, and postoperative outcomes such as AKI, chronic kidney disease at 12 months postoperation, duration of hospital stay, and intensive care unit admission rate and duration of stay were compared between the 2 groups using propensity score matching analysis. To determine the risk factors for AKI after RALP, univariate and multivariate logistic regression analyses were performed. Postoperative AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria.After performing 1:1 propensity score matching, the mannitol and no-mannitol groups included 234 patients each. The overall incidence of AKI after RALP was 5.1% and was not significantly different between the no-mannitol and mannitol groups in the propensity score-matched patients (13 [5.6%] vs. 11 [4.7%], P = .832). Univariate logistic regression analysis revealed that body mass index and operative time were associated with AKI in 864 patients who underwent RALP. However, intraoperative mannitol administration was not associated with AKI after RALP (P = .284). Multivariate logistic regression analysis revealed that operative time was significantly associated with AKI after RALP (odds ratio = 1.013, P = .001). The incidence of chronic kidney disease (13 [5.6%] vs. 12 [5.1%], P = 1.000) and other postoperative outcomes were not also significantly different between the no-mannitol and mannitol groups in the propensity score-matched patients.Intraoperative mannitol administration has no beneficial effect on the prevention of AKI after RALP in prostate cancer patients. This result provides useful information for clinical practice guidelines regarding intraoperative mannitol use.

ICD implantation without significant ECG changes or adverse outcomes is feasible under propofol sedation in patients with Brugada syndrome. However, because of significant hemodynamic changes and respiratory compromise, close monitoring and meticulous propofol dose titration is warranted.

Endotoxin tolerance develops in the late phase of sepsis to protect cells from an early hyperinflammatory response. Nonetheless, because it induces an immunosuppressive environment, patients with sepsis in its late phase are affected by secondary infections, particularly bacterial pneumonia. Here, we showed that induction of endoplasmic reticulum (ER) stress leads to activation of glycogen synthase kinase 3β (GSK-3β) and X-box-binding protein 1 (XBP-1) in an inositol-requiring enzyme 1α (IRE1α)-mediated manner, which in turn restores the inflammatory response in endotoxin-tolerant macrophages. Animal and in vitro models of endotoxin tolerance were studied along with a model of LPS-induced endotoxin tolerance and a model of cecal ligation and puncture (CLP)-induced endotoxin tolerance. To detect the suppressed inflammatory response during endotoxin tolerance, inflammatory-cytokine expression levels were measured by quantitative real-time PCR and an ELISA. Our research revealed that induction of ER stress alleviated lung injury in a septic host infected with Pseudomonas aeruginosa via the activation of GSK-3β and XBP-1 in an IRE1α-mediated manner. Consequently, in the lungs of the septic host infected with P. aeruginosa, symptoms of pneumonia improved and the infecting bacteria were cleared. Thus, for septic patients, determination of immune status may guide the selection of appropriate immunomodulation, and ER stress can be a novel therapeutic strategy restoring the immune response in patients with endotoxin tolerance.

Mannitol decreases the ONSD in patients undergoing RALP with CO pneumoperitoneum and the steep Trendelenburg position. This result provides useful information on the beneficial effects of mannitol administration on prostate cancer patients who may develop increased ICP during RALP.

Conventional, intravenous, patient-controlled analgesia, which is only administered by demand bolus without basal continuous infusion, is closely associated with inappropriate analgesia. Pharmacokinetic model-based dosing schemes can quantitatively describe the time course of drug effects and achieve optimal drug therapy. We compared the efficacy and safety of a conventional dosing regimen for intravenous patient-controlled analgesia that was administered by demand bolus without basal continuous infusion (group A) versus a pharmacokinetic model-based dosing scheme performed by decreasing the dosage of basal continuous infusion according to the model-based simulation used to achieve a targeted concentration (group B) following robot-assisted laparoscopic prostatectomy.In total, 70 patients were analyzed: 34 patients in group A and 36 patients in group B. The postoperative opioid requirements, pain scores assessed by the visual analog scale, and adverse events (eg, nausea, vomiting, pruritis, respiratory depression, desaturation, sedation, confusion, and urinary retention) were compared on admission to the postanesthesia care unit and at 0.5, 1, 4, 24, and 48 h after surgery between the 2 groups. All patients were kept for close observation in the postanesthesia care unit for 1 h, and then transferred to the general ward.The fentanyl requirements in the postanesthesia care unit for groups A and B were 110.0 ± 46.4 μg and 77.5 ± 35.3 μg, respectively. The pain scores assessed by visual analog scale at 0.5, 1, 4, and 24 h after surgery in group B were significantly lower than in group A (all P < 0.05). There were no differences in the adverse events between the 2 groups.We found that the pharmacokinetic model-based dosing scheme resulted in lower opioid requirements, lower pain scores, and no significant adverse events in the postanesthesia care unit following robot-assisted laparoscopic prostatectomy in comparison with conventional dosing regimen.