Safety and efficacy of remimazolam for general anesthesia in elderly patients undergoing laparoscopic cholecystectomy: a randomized controlled trial.

Introduction: There is insufficient evidence regarding the efficacy and safety of remimazolam in elderly patients. Therefore, this study evaluated the differences in the anesthesia characteristics and perioperative hemodynamic profiles of elderly patients receiving total intravenous anesthesia with remimazolam or propofol. Methods: Eighty-four patients aged >65 years with an American Society of Anesthesiologists physical status of I-III were randomly assigned to Group R (receiving remimazolam, n = 42) or Group P (receiving propofol, n = 42). In Group R, remimazolam was initiated at a rate of 6 mg/kg/h until loss of consciousness (LOC) was achieved and maintained at 1 mg/kg/h subsequently. In Group P, 1.0-1.5 mg/kg of propofol was injected for 1 min and maintained at 100 µg/kg/min subsequently. The maintenance infusion rate was adjusted to maintain an appropriate depth of anesthesia until the end of the surgery. The primary outcome was the time to LOC. The depth of anesthesia scores and hemodynamic profiles were recorded perioperatively. Results: The time to LOC was significantly longer in Group R (120 s) than in Group P (60 s) (p < 0.001). The time to eye-opening (Group R, 10 min; Group P, 10 min; p = 0.056), the incidence of maintenance of hemodynamic changes within 20% of the peri-anesthetic values, and treatments for hemodynamic instability did not differ significantly between the groups. The depth of anesthesia scores did not differ significantly between the groups; however, the scores were higher in Group R than those in Group P before endotracheal intubation. The hemodynamic parameters did not differ significantly at any time point. The time to extubation was longer in Group R (12 min) than that in Group P (10 min) (p = 0.007). Similarly, the time to discharge from the operating room was significantly longer in Group R (15 min) compared to Group P (12 min) (p = 0.018). Conclusion: Remimazolam does not exhibit a comparable effect to propofol in terms of anesthesia induction and recovery. However, it demonstrates a similar effect to propofol regarding intraoperative anesthesia depth and hemodynamic profile in elderly patients undergoing remifentanil-based total intravenous anesthesia.

Arsenite-induced cytotoxicity is regulated by poly-ADP ribose polymerase 1 activation and parthanatos in p53-deficient H1299 cells: The roles of autophagy and p53.

Arsenic is a double-edged sword metalloid since it is both an environmental carcinogen and a chemopreventive agent. Arsenic cytotoxicity can be dependent or independent of the tumor suppressor p53. However, the effects and the underlying molecular mechanisms of arsenic cytotoxicity in p53-deficient cells are still unclear. Here, we report a distinctive cell death mode via PARP-1 activation by arsenic in p53-deficient H1299 cells. H1299 (p53-/-) cells showed higher sensitivity to sodium arsenite (NaAR) than H460 (p53+/+) cells. H460 cells induced canonical apoptosis through caspase-dependent poly-ADP ribose polymerase 1 (PARP-1) cleavage and induced the expression of phospho-p53 and p21. However, H1299 cells induced poly-ADP-ribose (PAR) polymer accumulation and caspase-independent parthanatos, which was inhibited by 3-aminobenzamide (AB) and nicotinamide (NAM). Fractionation studies revealed the mitochondrial translocation of PAR polymers and nuclear translocation of the apoptosis-inducing factor (AIF). Although the exposure of NaAR to p53-overexpressing H1299 cells increased the PAR polymer levels, it inhibited parthanatos by inducing p21 and phospho-p53 expression. LC3-II and p62 accumulated in a NaAR dose- and exposure time-dependent manner, and this accumulation was further enhanced by autophagy inhibition, indicating that arsenic inhibits autophagic flux. p53 overexpression led to a decrease in the p62 levels, an increase in the LC3-II levels, and reduced parthanatos, indicating that arsenic induces p53-dependent functional autophagy. These results show that the NaAR-induced cytotoxicity in p53-deficient H1299 cells is regulated by PARP-1 activation-mediated parthanatos, which is promoted by autophagy inhibition. This suggests that PARP-1 activation could be used as an effective therapeutic approach for arsenic toxicity in p53-deficient cells.

Analgesic Effects of Continuous Wound Infusion Combined with Intravenous Patient-Controlled Analgesia for Thoracic Surgery: A Retrospective Study.

Continuous wound infusion analgesia (CWA) with local anesthetics is a loco-regional anesthetic approach for multimodal analgesia management in surgical procedures. This study analyzed whether the combination of intravenous patient-controlled analgesia (PCA) and CWA would be more effective than PCA alone for postoperative analgesia and in preventing chronic postsurgical pain syndrome (PSPS) after thoracic surgeries. We enrolled 166 patients after propensity score matching, the PCA alone (PCA group, n = 83) and the combination of PCA and CWA (PCA-CWA group, n = 83), through a review of electronic medical records. The primary endpoint was the numeric rating scale (NRS) at postoperative days 1, 2, 3, 4, and 5. The secondary endpoint was the presence of PSPS at 3 and 6 months postoperatively. The NRS were lower in the PCA-CWA group than in the PCA group throughout the postoperative period (p < 0.001). The sedation incidence was lower in the PCA-CWA group (1.2%) than in the PCA group (9.6%) (p = 0.034), and there was no significant difference in other postoperative complications or in the incidence of PSPS (p = 1.000). The combination of intravenous PCA and CWA is an effective postoperative analgesic modality for thoracic surgery.

Cutoff Values for Providing the Ideal Intravenous Patient-Controlled Analgesia According to the Intensity of Postoperative Pain-A Retrospective Observational Study.

Background and Objectives: The cutoff values were analyzed for providing the ideal intravenous patient-controlled analgesia (PCA) that could reduce rescue analgesics or antiemetics requirements, based on the grades of postoperative pain intensity (PPI). Materials and Methods: PCA regimens of 4106 patients were retrospectively analyzed, and they were allocated into three groups with low, moderate, and high PPI grades (groups L, M, and H, respectively) based on numeric rating scores obtained 6 h postoperatively. Opioid and non-opioid analgesic doses were converted into fentanyl-equivalent doses (DOSE-FEN-OP and DOSE-FEN-NONOP, respectively). The primary endpoint was the cutoff values of these parameters. Results: With respect to the PCA settings to reduce rescue analgesic and antiemetic requirements, group L required a background infusion rate (BIR) of 1.75-3 mL/h, bolus volume of 0.5-1.25 mL, and lockout interval of ≤12.5 min. Group M required a BIR of 1.75 mL/h, bolus volume of 0.5-1.75 mL, and lockout interval of ≤5 min. Group H required a BIR of 1.75 mL/h, bolus volume of 0.5 mL, and lockout interval of ≤5 min. In assessments of the analgesic doses to reduce rescue analgesic requirement, the DOSE-FEN-OP was at least 950 µg of fentanyl regardless of group, while the DOSE-FEN-NONOP was ≥250 µg, ≥550 µg, and ≥700 µg for the L, M, and H groups, respectively. In assessments of the analgesic doses to reduce rescue antiemetic requirement, DOSE-FEN-OP was ≤950 µg for groups L and M and ≤850 µg for Group H, while DOSE-FEN-NONOP was ≤50 µg, ≤450 µg, and ≤700 µg for groups L, M, and H, respectively. Conclusion: The ideal PCA for reduction in rescue analgesics or antiemetics can be achieved by adjustment of PCA settings and drug dosages carefully with these cutoff values depending on the expected grades of PPI. Especially, the ideal PCA can be provided by adjusting the lockout interval and bolus volume rather than BIR and by applying smaller bolus doses and shorter lockout intervals with an increasing PPI grade.

Effect of Nefopam-Based Patient-Controlled Analgesia with and without Fentanyl on Postoperative Pain Intensity in Patients Following Laparoscopic Cholecystectomy: A Prospective, Randomized, Controlled, Double-Blind Non-Inferiority Trial.

Background and Objectives: We investigated the non-inferiority of patient-controlled analgesia (PCA), using either nefopam alone or combined nefopam-fentanyl for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Materials and Methods: In this prospective, randomized, controlled study, 78 patients were allocated to receive nefopam 240 mg (Group N240) or nefopam 120 mg with fentanyl 600 µg (Group NF), equivalent to fentanyl 1200 µg, with a total PCA volume of 120 mL. Patients were given a loading dose (0.1 mL/kg) from the PCA device along with ramosetron (0.3 mg) and connected to a PCA device with a background infusion rate of 2 mL/h, bolus dose amount set at 2 mL, and lockout interval set at 15 min. Pain scores were obtained using the numeric rating scale (NRS) at 30 min after recovery room (RR) admission, as well as 8 and 24 h postoperatively. The primary outcome was analgesic efficacy evaluated using NRS-rated 8 h postoperatively. Other evaluated outcomes included the incidence rate of bolus demand, rescue analgesic and antiemetic requirements, and postoperative adverse effects. Results: NRS scores were not significantly different between the groups throughout the postoperative period (p = 0.539). NRS scores of group N240 were not inferior to those of group NF at 30 min after RR admission, or at 8 and 24 h postoperatively (mean difference [95% CI], -0.05 [-0.73 to 0.63], 0.10 [-0.29 to 0.50], and 0.28 [-0.06 to 0.62], respectively). Postoperative adverse effects were not significantly different between the two groups (p = 1.000) and other outcomes were also not significantly different between the two groups (p ≥ 0.225). Conclusions: PCA using nefopam alone has a non-inferior and effective analgesic efficacy and produces a lower incidence of postoperative adverse effects compared to a combination of fentanyl and nefopam after laparoscopic cholecystectomy.

The Optimizing Background Infusion Mode Decreases Intravenous Patient-Controlled Analgesic Volume and Opioid Consumption Compared to Fixed-Rate Background Infusion in Patients Undergoing Laparoscopic Cholecystectomy: A Prospective, Randomized, Controlled, Double-Blind Study.

Background and objectives: The fixed-rate continuous background infusion mode with bolus dosing is a common modality for intravenous patient-controlled analgesia (PCA). However, some patients suffer from inadequate analgesia or opioid-related adverse effects due to the biphasic pattern of postoperative pain. Therefore, we investigated the postoperative analgesic efficacy of PCA using an optimizing background infusion mode (OBIM) where the background injection rate varies depending on the patient's bolus demand. Materials and Methods: We prospectively enrolled 204 patients who underwent laparoscopic cholecystectomy in a randomized, controlled, double-blind study. Patients were allocated to either the optimizing (group OBIM) or the traditional background infusion group (group TBIM). The numeric rating scale (NRS) score for pain was evaluated at admission to and discharge from the recovery room, as well as at the 6th, 24th, and 48th postoperative hours. Data on bolus demand count, total infused volume, and background infusion rate were downloaded from the PCA device at 30-min intervals until the 48th postoperative hour. Results: The NRS score was not significantly different between groups throughout the postoperative period (p = 0.621), decreasing with time in both groups (p < 0.001). The bolus demand count was not significantly different between groups throughout (p = 0.756). The mean total cumulative infused PCA volume was lower in group OBIM (84.0 (95% confidence interval: 78.9-89.1) mL) than in group TBIM (102 (97.8-106.0) mL; p < 0.001). The total cumulative opioid dose in fentanyl equivalents, after converting sufentanil to fentanyl using an equipotential dose ratio, was lower in group OBIM (714.1 (647.4-780.9) µg) than in group TBIM (963.7 (870.5-1056.9) µg); p < 0.001). The background infusion rate was significantly different between groups throughout the study period (p < 0.001); it was higher in group OBIM than in group TBIM before the 12th postoperative hour and lower from the 18th to the 48th postoperative hour. Conclusions: The OBIM combined with bolus dosing reduces the cumulative PCA volume and opioid consumption compared to the TBIM combined with bolus dosing, while yielding comparable postoperative analgesia and bolus demand in patients undergoing laparoscopic cholecystectomy.

Effective dose of intravenous oxycodone depending on sex and age for attenuation of intubation-related hemodynamic responses

Background/aim: Preoperative intravenous oxycodone may help to prevent or attenuate intubation-related hemodynamic responses (IRHRs), but its pharmacokinetics differs according to age and sex. Therefore, we investigated the 95% effective dose (ED95) of intravenous oxycodone for attenuating all IRHRs, depending on the age and sex of the study population. Materials and methods: All patients were allocated to one of 6 groups: 1) 20­40 year old males, 2) 41­65yearold males, 3) 66­80 year old males, 4) 20­40 year old females, 5) 41­65yearold females, and 6) 66­80 year old females (groups YM, OM, EM, YF, OF, and EF, respectively). Using Dixon's up-and-down method, the first patient in each group was slowly injected with intravenous oxycodone (0.1 mg kg­1) 20 min before intubation. The subsequent patient received the next oxycodone dose, which was decreased or increased by 0.01 mg kg­1, depending on the "success" or "failure" of attenuation of all IRHRs to within 20% of the baseline values at 1 min after intubation in the previous patient. After obtaining 8 crossover points, predictive ED95 was estimated with probit regression analysis. Results: ED95 varied greatly according to age and sex. ED95was 0.133 mg kg­1, 0.181 mg kg­1, 0.332 mg kg­1, 0.183 mg kg­1, 0.108 mg kg­1, and 0.147 mg kg­1in groups YM, OM, EM, YF, OF, and EF, respectively. Conclusion: ED95 is higher in males with increasing age but is ambiguous for females. ED95 is higher in males than in females over 40 years of age but is higher in females than in males under 41 years of age. However, after considering the age and sex of the study population, these results can be used as reference doses for further studies to verify the clinical effects of oxycodone for attenuating all IRHRs.

Cytoplasmic sirtuin 6 translocation mediated by p62 polyubiquitination plays a critical role in cadmium-induced kidney toxicity.

Sirtuin 6 (Sirt6) is important for maintaining kidney homeostasis and function. Cd exposure increases the risk of developing kidney diseases. However, the role of Sirt6 in kidney disease mechanisms is unclear. Here, we evaluated the role of Sirt6 in Cd-induced kidney toxicity. After Cd exposure, p62/sequestosome-1 (SQSTM1), an autophagy substrate, accumulated in mouse kidney mesangial cells in monomeric and polyubiquitinated (polyUb) forms. Sirt6 accumulated in response to Cd treatment at concentrations below the half-maximal inhibitory concentration and decreased after 12 h of treatment. Sirt6 and p62 co-localized in the nucleus and redistributed to the cytosol after Cd treatment. Sirt6 was mainly present in nuclei-rich membrane fractions. Sirt6 interacted with p62. Ub, and microtubule-associated protein light chain 3 (LC3). Knockdown of p62 promoted Sirt6 nuclear accumulation and inhibited apoptosis. Sirt6 overexpression altered levels of polyUb-p62 and apoptosis. At earlier times during Cd treatment, polyubiquitination of p62 and apoptosis were reduced. Cytoplasmic translocation of Sirt6 occurred later, with increased polyubiquitination of p62 and apoptosis. Bafilomycin 1 (BaF1) treatment promoted cytosolic Sirt6 accumulation, increasing cell death. Silencing autophagy related 5 (Atg5) increased nuclear Sirt6 levels, reduced polyUb-p62, and inhibited cell death, indicating that autophagy was necessary for Sirt6 redistribution. Cd resistance was associated with reduced polyUb-p62 and persistent Sirt6 expression. Cd treatment in mice for 4 weeks promoted p62, Sirt6, and LC3-II accumulation, inducing apoptosis in kidney tissues. Overall, our findings show that polyUb-p62 targeted Sirt6 to autophagosomes, playing a crucial role in Cd-induced cell death and kidney damage.

Correction to: Cytoplasmic sirtuin 6 translocation mediated by p62 polyubiquitination plays a critical role in cadmium-induced kidney toxicity.

In the original publication the grant number is incorrectly published.

Conus Medullaris Syndrome Due to Missed Thoracolumbar Spinal Fracture in a Patient with Ankylosing Spondylitis who Underwent Hip Surgery.

Ankylosing spondylitis (AS) is vulnerable to fracture, and the missed diagnosis can lead to neurological deterioration. Herein, we present the conus medullaris syndrome due to aggravation of the missed spinal fracture in an 85-year-old woman with AS who underwent hip surgery. She underwent osteosynthesis in a supine position with supports under her shoulders and head due to spine deformity with AS, but was fully supine without supports after surgery. She showed complete paraplegia at postoperative 12 h. The re-reading radiological imaging showed the missed spinal fracture, of which the deteriorated dislocation was revealed on the re-examined radiological evaluation. This deterioration was not recovered ultimately despite an emergent surgery. A thorough preoperative assessment is essential to prevent the missed diagnosis of spinal fracture and minimise deterioration due to its dislocation, with specific spine precaution during transport, transfer and positioning.

Effect of different doses of intravenous oxycodone and fentanyl on intubation-related hemodynamic responses: A prospective double-blind randomized controlled trial (CONSORT).

BACKGROUND: Intubation using direct laryngoscopy is a risky and painful procedure that is associated with undesirable hemodynamic changes such as tachycardia, hypertension, and arrhythmia. Recently, intravenous oxycodone was introduced and used for the control of acute postoperative pain and to attenuate intubation-related hemodynamic responses (IRHRs), but there is insufficient information regarding its proper dosage. We investigated the attenuating effects of different doses of oxycodone and fentanyl on IRHRs. METHODS: For calculating oxycodone effective dose (ED95), which attenuated all IRHR changes to less than 20% over baseline values in 95% of male patients at 1 minute after intubation, oxycodone 0.1 mg/kg was injected for the first patient 1 hour before intubation, and the next dose for each subsequent patient was determined by the response of the previous patient using Dixon up-and-down method with an interval of 0.01 mg/kg. After obtaining the predictive oxycodone ED95, 148 patients were randomly allocated to groups receiving normal saline (group C), oxycodone ED95 (group O1), oxycodone 2 × ED95 (group O2), or fentanyl 2 µg/kg (group F). We recorded the incidence of "success" as a less than 20% change from baseline values in all IRHRs 1 minute after intubation. RESULTS: The predictive oxycodone ED95 was 0.091 (0.081-0.149) mg/kg. The incidence of "success" was highest in group O2 (75.7%), followed by group O1 (62.2%) and group F (45.9%) with significant differences between the groups (P < .001). The systolic, diastolic, mean arterial pressure, and heart rate were not significantly different among groups after administration of either oxycodone or fentanyl. The percentage hemodynamic changes of the group O2 were significantly lower than those of groups F and O1, but the absolute percentage hemodynamic changes were not significantly different among groups F, O1, and O2. The recalculated oxycodone ED95 with probit analysis (0.269 mg/kg) was needed to prevent any arterial pressure and heart rate changes. CONCLUSIONS: Oxycodone 0.182 mg/kg is more effective in attenuating all IRHRs than fentanyl 2 µg/kg with safe hemodynamic changes. Further research is required to determine if the recalculated oxycodone ED95 (0.269 mg/kg) is also effective and hemodynamically safe for preventing all IRHRs.

Effect of intraoperative infusion of sufentanil versus remifentanil on postoperative shivering in Korea: a prospective, double-blinded, randomized control study

Background/aim: The number of published papers that compare the incidence of sufentanil- and remifentanil-related postoperative shivering is insufficient. We investigated the incidence of postoperative shivering after total intravenous anesthesia with either sufentanil or remifentanil in patients who underwent elective surgery. Materials and methods: Eighty-three patients, with a physical status classified as American Society of Anesthesiologists I or II, were randomly allocated to either the remifentanil­propofol (RP group, n = 40) or sufentanil­propofol (SP group, n = 43) group. The primary endpoint was the incidence of postoperative shivering 1 h after entering the recovery room. The secondary endpoints were intraoperative core temperatures of the esophagus and tympanic membrane at 30 min after the induction of anesthesia and at the end of surgery. Results: The overall postoperative shivering incidence was not significantly different between the RP (15%) and SP (11.6%) groups (P = 0.651). The intraoperative temperatures and their changes (the temperature 30 min after induction minus that after surgery) as measured at the distal esophagus and tympanic membrane were not significantly different between the RP and SP groups. Conclusion: The incidence of postoperative shivering related to sufentanil was less than that related to remifentanil, with no significant differences in the intraoperative core temperatures.

The critical role of autophagy in cadmium-induced immunosuppression regulated by endoplasmic reticulum stress-mediated calpain activation in RAW264.7 mouse monocytes.

Cadmium (Cd) has toxic and suppressive effects on the immune system, but the underlying mechanisms remain poorly understood. Here, we show that autophagy plays a critical role in regulation of Cd-induced immunosuppression in RAW264.7 cells. Cd decreased cell viability in a dose-dependent manner; cleaved caspase-8, caspase-3, and poly (ADP-ribose) polymerase (PARP)-1; increased DNA laddering; induced CCAAT-enhancer-binding protein homologous protein (CHOP); and reduced tumor necrosis factor (TNF)-α expression; indicating that caspase-dependent and endoplasmic reticulum (ER)-mediated apoptosis are involved in Cd-induced immunotoxicity. Furthermore, Cd induced autophagy, as demonstrated by microtubule-associated protein 1 light chain 3B (LC3B) plasmid DNA transfection and its conversion from LC3-I to the LC3-II form by autophagy inhibitors, via AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. Pharmacological and genetic inhibition of autophagy suppressed Cd-induced apoptosis, as evidenced by inhibition of caspase-8, caspase-3, and PARP-1 cleavage, indicating that autophagy promotes apoptosis. The pan-caspase inhibitor zVAD inhibited Cd-induced apoptosis, but increased autophagy and decreased cell viability, indicating that autophagy can compensate for reduced apoptotic cell death. Calpain inhibitors blocked Cd-induced apoptosis and autophagy, indicating that calpain plays a critical role in Cd cytotoxicity. Treatment with Ca2+ chelators completely recovered Cd-induced cell viability and inhibited Cd-induced apoptosis and autophagy. Treatment with N-acetyl-l-cysteine (NAC) suppressed Cd-induced antioxidant enzyme levels, apoptosis, and autophagy. Collectively, Cd-induced oxidative stress triggers ER stress, leading to Ca2+-dependent calpain activation and subsequent activation of autophagy and apoptosis, resulting in immune suppression.

Mega Acer Kit® is more effective for warming the intravenous fluid than Ranger™ and ThermoSens® at 440 ml/h of infusion rate: an experimental performance study.

BACKGROUND: Few studies have investigated the effectiveness of intravenous fluid warmers at low and moderate flow rates below 1,000 ml/h. In this study, we compared the effectiveness of three different fluid warmers at a low flow rate (440 ml/h). METHODS: We experimentally investigated the fluid warming performances of Mega Acer Kit® (Group M, n = 10), Ranger™ (Group R, n = 10), and ThermoSens® (Group T, n = 10) at 440 ml/h for 60 min. All devices were set at a warming temperature of 41℃ with preheating for 10 min. Intravenous fluids were then delivered through them. The fluid temperature (primary endpoint) was measured at 76 cm from the device after infusion for 60 min. The expected decrease in mean body temperature (secondary endpoint) after 5 h infusion for a 70 kg patient (ΔMBT5) was also calculated. RESULTS: The fluid temperature (mean [95% CI]) at 76 cm from the device, 60 minutes after the infusion was higher in group M (36.01 [35.73-36.29]℃), compared to groups T (29.81 [29.38-30.24]℃) and R (29.12 [28.52-29.72]℃) (P < 0.001). The ΔMBT5 (mean [95% CI]) was significantly smaller in group M (-0.04 [-0.04 to -0.03]℃) than that in groups T (-0.27 [-0.28 to -0.29]℃; P < 0.001) and R (-0.30 [-0.32 to -0.27]℃; P < 0.001). However, none of the fluid warmers provided a constant normothermic temperature above 36.5℃. CONCLUSIONS: Mega Acer Kit® was more effective in warming the intravenous fluid with the smallest expected change in the mean body temperature, compared to Ranger™ and ThermoSens®, at a flow rate of 440 ml/h.

MAPK/JNK1 activation protects cells against cadmium-induced autophagic cell death via differential regulation of catalase and heme oxygenase-1 in oral cancer cells.

Antioxidant enzymes are related to oral diseases. We investigated the roles of heme oxygenase-1 (HO-1) and catalase in cadmium (Cd)-induced oxidative stress and the underlying molecular mechanism in oral cancer cells. Exposing YD8 cells to Cd reduced the expression levels of catalase and superoxide dismutase 1/2 and induced the expression of HO-1 as well as autophagy and apoptosis, which were reversed by N-acetyl-l-cysteine (NAC). Cd-exposed YD10B cells exhibited milder effects than YD8 cells, indicating that Cd sensitivity is associated with antioxidant enzymes and autophagy. Autophagy inhibition via pharmacologic and genetic modulations enhanced Cd-induced HO-1 expression, caspase-3 cleavage, and the production of reactive oxygen species (ROS). Ho-1 knockdown increased autophagy and apoptosis. Hemin treatment partially suppressed Cd-induced ROS production and apoptosis, but enhanced autophagy and CHOP expression, indicating that autophagy induction is associated with cellular stress. Catalase inhibition by pharmacological and genetic modulations increased Cd-induced ROS production, autophagy, and apoptosis, but suppressed HO-1, indicating that catalase is required for HO-1 induction. p38 inhibition upregulated Cd-induced phospho-JNK and catalase, but suppressed HO-1, autophagy, apoptosis. JNK suppression exhibited contrary results, enhancing the expression of phospho-p38. Co-suppression of p38 and JNK1 failed to upregulate catalase and procaspase-3, which were upregulated by JNK1 overexpression. Overall, the balance between the responses of p38 and JNK activation to Cd appears to have an important role in maintaining cellular homeostasis via the regulation of antioxidant enzymes and autophagy induction. In addition, the upregulation of catalase by JNK1 activation can play a critical role in cell protection against Cd-induced oxidative stress.

Effect of dexamethasone on the onset time and recovery profiles of cisatracurium.

BACKGROUND: The effect of dexamethasone injection on cisatracurium-induced neuromuscular block was compared according to different injection time points. METHODS: One hundred seventeen patients were randomly assigned to three groups: 8 mg of dexamethasone injected intravenously 2-3 h before anesthesia (group A), just before anesthesia induction (group B), and at the end of surgery (control group). Three minutes after anesthesia induction, intubation was performed without neuromuscular blockers, and acceleromyography was initiated. All patients received 0.05 mg/kg cisatracurium; the onset time and recovery profiles were recorded. RESULTS: Eighty patients were finally enrolled. The onset time (median [interquartile range], seconds) was significantly hastened in group A (520.0 [500.0-560.0], n = 30) compared to that in group B (562.5 [514.0-589.0], n = 22) (P = 0.008) and control group (586.5 [575.0-642.5], n = 28) (P < 0.001). The onset time in group B was faster than the control group (P = 0.015). The recovery time [mean (95% CI) minutes] was significantly hastened in group A [28.5 (27.3-29.6)] compared to that in group B [32.3 (31.0-33.6)] (P < 0.001) and control group [30.9 (29.9-31.8)] (P = 0.015). The total recovery time was significantly hastened more in group A [47.1 (45.5-48.6)] than group B [52.8 (51.6-54.0) minutes] (P < 0.001) and control group [50.5 (48.7-52.3) minutes] (P = 0.008). CONCLUSIONS: A single dose of 8 mg of dexamethasone hastened the onset and total recovery times of cisatracurium-induced block by approximately 15 and 9%, respectively if administered 2-3 h prior to surgery.

Cadmium-induced heme-oxygenase-1 expression plays dual roles in autophagy and apoptosis and is regulated by both PKC-δ and PKB/Akt activation in NRK52E kidney cells.

Heme oxygenase-1 (HO-1) protects cells against cadmium (Cd)-induced oxidative stress. However, the mechanism underlying this protection is not well understood. In this study, we elucidated the role of HO-1 in Cd-induced cytotoxicity. Exposure of NRK52E cells to Cd induced protein kinase B (PKB)/Akt, protein kinase C (PKC)-δ, and glycogen synthase kinase (GSK) 3αb phosphorylation, and eukaryotic initiation factor (eIF) 2α dephosphorylation. Pharmacological inhibition of Akt resulted in HO-1 suppression and eIF2α activation, which partially suppressed CHOP and PARP-1 cleavage, but promoted autophagy and decreased cell viability. Pharmacological inactivation of PKC-δ markedly suppressed Cd-induced phospho-serine (p-Ser) GSK3αß, and HO-1, and partially inhibited PARP-1 cleavage, but massively induced autophagy and decreased cell viability. Pharmacological upregulation of p-Ser GSK3αß enhanced Cd-induced HO-1, CHOP, and PARP-1 cleavage, but decreased autophagy. Genetic deficiency of GSK3ß suppressed HO-1 and PARP-1 cleavage and increased autophagy. Genetic suppression of HO-1 reduced Cd-induced PARP-1 cleavage, but increased LC3-II. Cd exposure led to accumulation of p-PKC-δ, p-Ser GSK3αß, and HO-1 in the nucleus and particulate fractions, suggesting that they have dual functions in response to Cd. N-acetylcysteine treatment suppressed Cd-induced activation of PKC-δ and Akt. These results indicate that HO-1 induced by Cd exposure is regulated by PKC-δ, p-Ser GSK3αß, and PKB/Akt, which restrain autophagic cell death, but mildly induce apoptosis in NRK52E cells. Together, the results suggest that HO-1 expression in response to Cd maintains cellular homeostasis during oxidative stress.

Heme oxygenase-1-mediated apoptosis under cadmium-induced oxidative stress is regulated by autophagy, which is sensitized by tumor suppressor p53.

Heme oxygenase-1 (HO-1) is a stress-inducible cytoprotective enzyme. It is often overexpressed in different types of cancers and promotes cell survival. However, the role of HO-1 and the underlying molecular mechanism of cadmium (Cd)-induced oxidative stress in cancer cells remain undefined. Here we show that the role of HO-1 under Cd-induced oxidative stress is dependent upon autophagy, which is sensitized by the tumor suppressor p53. The sensitivity to Cd was 3.5- and 14-fold higher in p53-expressing YD8 and H460 cells than in p53-null YD10B and H1299 cells, respectively. The levels of p53 in YD8 and H460 cells decreased in a Cd concentration-dependent manner, which was inhibited by pretreatment with N-acetylcysteine. In both cell lines, Cd exposure resulted in caspase-3-mediated PARP-1 cleavage and the induction of CHOP, LC3-II, and HO-1, which were limited in YD10B and H1299 cells exposed to high concentrations of Cd. Cd exposure to p53-overexpressing YD10B cells enhanced Cd-induced HO-1 and LC3-II levels, whereas genetic knockdown of p53 in YD8 cells resulted in the suppression of Cd-induced levels of HO-1 and LC3-II, indicating that p53 is required in the sensing of HO-1 and induction of autophagy. The inhibition of autophagy using small interfering RNA (siRNA) for the autophagy-related gene atg5 enhanced HO-1, CHOP, and PARP-1 cleavage induced by Cd. However, transfection with HO-1 siRNA increased Cd-induced LC3-II, and suppressed the expression of CHOP and cleavage of PARP-1. Collectively, the role of HO-1 in apoptosis could be modulated by autophagy, which is sensitized by p53 expression in human cancer cell lines.

Clinical evaluation of a newly designed fluid warming kit on fluid warming and hypothermia during spinal surgery.

BACKGROUND: The Mega Acer Kit® (MAK) is a newly designed heated and humidified breathing circuit that warms fluid passing through the circuit lumen. In this study, we investigated the system's efficacy for the perioperative prevention of hypothermia and fluid warming. METHODS: Ninety patients undergoing spinal surgery were enrolled in this study and randomly assigned to 3 groups based on the fluid warming device used: no fluid warming system (Group C, n = 30), via a Standard Ranger (Group R, n = 30), or via the MAK (Group M, n = 30). Distal esophageal temperatures (Teso) and infusion fluid temperature (TF) were recorded at 15 min intervals for duration of 180 min during surgery. If Teso was < 35.0℃, a forced-air convective warming device was used. RESULTS: Final Teso values were 34.8 ± 0.3℃, 35.1 ± 0.1℃, and 35.8 ± 0.3℃ in groups C, R, and M, respectively (P < 0.01). Teso was significantly higher in group M when compared with that in groups C and R throughout the study period (P < 0.05). The number of patients requiring a forced-air convective warming device was significantly lower in group M (n = 0) when compared with that in groups R (n = 17) and C (n = 30) (P < 0.05). The final infusion fluid temperature was higher in group M when compared with that in groups C and R throughout the study period (35.4 ± 1.0 vs. 23.0 ± 0.3 and 32.8 ± 0.6℃; P < 0.01). CONCLUSIONS: The MAK is more effective for preventing hypothermia and for warming fluid than the Standard Ranger.

Effects of dexmedetomidine on smooth emergence from anaesthesia in elderly patients undergoing orthopaedic surgery.

BACKGROUND: Intraoperative dexmedetomidine may decrease postoperative emergence agitation in elderly patients due to its sedative effect. In this study, we evaluated the effect of adjuvant dexmedetomidine on smooth emergence from anaesthesia after orthopaedic surgery in elderly patients. METHODS: A total 115 patients (ASA I-II, aged over 65 years) were randomly allocated into four groups. Anaesthesia was maintained with either sevoflurane or total intravenous anaesthesia (TIVA) comprising propofol and remifentanil. Patients were also administered either dexmedetomidine (0.4 µg kg(-1) hr(-1); SD and TD) intraoperatively or normal saline (SN or TN) as a control. The bispectral index (BIS) score was maintained from 40-60 intraoperatively. All anaesthetics and dexmedetomidine were discontinued at surgical conclusion, and the recovery times (durations to a BIS = 60, 70, and 80; eye opening; and extubation) were measured. The mean arterial pressure, heart rate, Ricker's agitation-sedation scale (RSAS), visual analogue scale (VAS) for pain, and incidences of emergence agitation and postoperative nausea and vomiting (PONV) were measured in the recovery room. RESULTS: Dexmedetomidine significantly decreased the RSAS score in the SD and TD groups, and a calm state postoperatively occurred more frequently in these groups than in the control groups. The heart rate and incidence of emergence agitation were lower in the dexmedetomidine groups. Recovery time was higher in the SD group than in the SN group, and no significant differences occurred between the TN and TD groups. The VAS score was lower in the SD group than in the SN group, and the PONV did not differ regardless of the use of dexmedetomidine. CONCLUSIONS: Dexmedetomidine may be an effective intraoperative adjuvant for a reducing emergence agitation and smooth emergence from anaesthesia after orthopaedic surgery in elderly patients. TRIAL REGISTRATION: Current Controlled Trials NCT01851005 .