SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia-reperfusion injury.

BACKGROUND: Previous data have reported that Sentrin/SUMO-specific protease 6 (SENP6) is involved in ischaemic brain injury and induces neuronal apoptosis after cerebral ischaemia, but the role of SENP6 in microglia-induced neuroinflammation and its underlying mechanism remain poorly understood. This research systematically explored the function and potential mechanism of SENP6 in microglia-induced neuroinflammation after ischaemic stroke. RESULTS: We first identified an increased protein level of SENP6 in microglia after cerebral ischaemia. Then, we demonstrated that SENP6 promoted detrimental microglial phenotype polarization. Specifically, SENP6-mediated de-SUMOylation of ANXA1 targeted the IκB kinase (IKK) complex and selectively inhibited the autophagic degradation of IKKα in an NBR1-dependent manner, activating the NF-κB pathway and enhancing proinflammatory cytokine expression. In addition, downregulation of SENP6 in microglia effectively reduced cocultured neuronal damage induced by ischaemic stroke. More importantly, we employed an AAV-based technique to specifically knockdown SENP6 in microglia/macrophages, and in vivo experiments showed that SENP6 inhibition in microglia/macrophages notably lessened brain ischaemic infarct size, decreased neurological deficit scores, and ameliorated motor and cognitive function in mice subjected to cerebral ischaemia surgery. CONCLUSION: We demonstrated a previously unidentified mechanism by which SENP6-mediated ANXA1 de-SUMOylation regulates microglial polarization and our results strongly indicated that in microglia, inhibition of SENP6 may be a crucial beneficial therapeutic strategy for ischaemic stroke.

Comparison of temporary abdominal aortic occlusion with internal iliac artery occlusion for patients with placenta accreta - a non-randomised prospective study.

BACKGROUND: To compare the efficacy of temporary abdominal aortic occlusion with internal iliac artery occlusion for the management of placenta accreta. PATIENTS AND METHODS: 105 patients with placenta accreta were selected for treatment with temporary abdominal aortic occlusion (n = 57, group A) or bilateral iliac artery occlusion (n = 48, group B). Temporary abdominal aortic and internal iliac artery balloon occlusions were performed during caesarean sections. Data regarding the clinical success, blood loss, blood transfusion, balloon insertion time, fluoroscopy time, balloon occlusion time, foetal radiation dose, and complications were collected. RESULTS: Temporary abdominal aortic occlusion and bilateral internal iliac artery occlusion were technically successful in all patients. The amount of blood loss (P < 0.001), amount of blood transfusion (P < 0.001), balloon insertion time (P < 0.001), foetal radiation dose (P < 0.001) and fluoroscopy time (P < 0.01) in group A were significantly lower than those of patients in group B. No marked differences were found between these 2 groups with respect to age, mean postoperative hospital stay, balloon occlusion time, and Apgar score (p > 0.05). CONCLUSIONS: Temporary abdominal aortic balloon occlusion resulted in better clinical outcomes with less blood loss, blood transfusion, balloon insertion time, fluoroscopy time and foetal radiation dose than those in bilateral internal iliac balloon occlusion.
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The effect of remifentanil on the minimum alveolar concentration of isoflurane in children.

STUDY OBJECTIVE: To evaluate the effect of remifentanil on the isoflurane end-tidal concentration required to eliminate movement reaction upon surgical incision in children. DESIGN: Prospective, double blinded, serial study. SETTING: Operating room of a university-affiliated hospital. PATIENTS: Patients of ASA status 1 or 2, aged 4 to 7 years, scheduled for either inguinal hernia repair or orchidopexy surgery with general anesthesia. INTERVENTIONS AND MEASUREMENTS: After endotracheal intubation, 108 children serially received 1 of 6 dose (nil, 0.05, 0.10, 0.15, 0.20, or 0.25 µg kg(-1) min(-1)) of remifentanil. End-tidal isoflurane concentration was adjusted according to a Dixon's up-and-down approach. Twenty-five minutes after starting the remifentanil infusion, the surgical incision was performed. The response of patients was classified as either "response" or "no response." Response was defined as a purposeful response in response to skin incision. MAIN RESULTS: The MAC of isoflurane were 1.50 ± 0.16%, 1.33 ± 0.27%, 0.93 ± 0.13%, 0.73 ± 0.27%, 0.63 ± 0.19%, and 0.60 ± 0.15% for remifentanil infusion rates of nil, 0.05, 0.10, 0.15, 0.20, and 0.25 µg kg(-1) min(-1), respectively. CONCLUSION: The MAC of isoflurane decreased with increasing infusion rate of remifentanil, showing an initial step reduction followed by a ceiling effect.

Application of parecoxib in post-uvulopalatopharyngoplasty analgesia.

OBJECTIVE: To investigate the postoperative analgesic effects of parecoxib for uvulopalatopharyngoplasty (UPPP). METHODS: Patients with obstructive sleep apnoea syndrome who underwent UPPP were randomly divided into two groups. In group A, the incision-local block was performed with 5 ml of 0.5% ropivacaine injected subcutaneously before the end of surgery, then 20 ml of physiological saline was injected intravenously every 12 h for 2 days. In group B, in addition to the incision-local block, 40 mg parecoxib was injected intravenously 30 min before the end of UPPP and 40 mg parecoxib was injected intravenously every 12 h for 2 days. Postoperative pain was measured using a visual analogue scale (VAS). Adverse reactions were recorded. RESULTS: A total of 40 patients were randomized (n = 20 per group). Under resting conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 24 h and 48 h after UPPP (24 h 4.0 ± 0.8 versus 2.6 ± 0.6; 48 h 3.8 ± 0.7 versus 2.4 ± 0.5; respectively). Under swallowing conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 8 h, 24 h and 48 h after UPPP. Postoperative adverse reactions were similar in the two groups. CONCLUSION: Intravenous parecoxib combined with incision-local ropivacaine provided effective postoperative analgesia for patients with obstructive sleep apnoea syndrome, undergoing UPPP.

Hydrogen sulfide attenuates surgical trauma-induced inflammatory response and cognitive deficits in mice.

BACKGROUND: It has been increasingly reported that peripheral surgical trauma triggers neuroinflammatory processes associated with postoperative cognitive dysfunction, and that mitigating the neuroinflammatory effects of surgery prevents surgery-induced cognitive dysfunction. Endogenously produced hydrogen sulfide (H2S) has multiple functions in the brain, and an increasing number of studies have demonstrated its anti-inflammatory effects. The present study was designed to investigate the effects of sodium hydrosulfide (NaHS), an H2S donor, on the cognitive impairment of mice as they experience neuroinflammatory changes induced by surgery. METHODS: Each mouse received 5 mg/kg NaHS or volume-matched vehicle administration by intraperitoneal injection once daily, 3 d before surgery, on the day of surgery, and for 3 d afterward. We assessed cognitive function using a Morris water maze and evaluated expression of proinflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in the serum and hippocampus. We performed each test 1, 3, and 7 d after surgery. RESULTS: Hippocampal-dependent memory impairment in mice after surgery was associated with increased serum proinflammatory cytokines, as well as proinflammatory cytokine expression in the hippocampus. Presurgery treatment with NaHS, an H2S donor, significantly attenuated surgery-induced memory impairment and expression of proinflammatory cytokines in the serum and hippocampus. CONCLUSIONS: These findings suggest that intraperitoneal injections of NaHS could significantly mitigate surgery-induced memory impairment in mice, which is strongly associated with reduced levels of serum and hippocampal proinflammatory cytokines.

A comparison of the effects of digoxin, ouabain and milrinone on naloxone-precipitated withdrawal syndrome in mice.

Modulation of Na(+), K(+)-ATPase activity by acute and chronic opiates has been established for many years. However, the effects of digoxin, a putative inhibitor of Na(+), K(+)-ATPase, on naloxone-precipitated morphine withdrawal syndrome are unknown. In the present study, a digoxin dose-response curve was conducted to observe the effects on naloxone-precipitated withdrawal and locomotor activity in mice. Higher doses of digoxin (1.0 and 2.5 mg/kg) inhibited locomotor activity and naloxone-precipitated withdrawal jumping and weight loss, while lower doses of digoxin (0.1 and 0.25 mg/kg) inhibited withdrawal weight loss precipitated by naloxone without affecting locomotor activity and naloxone-precipitated withdrawal jumping. To explore the possible mechanisms underlying this behavior, another Na(+), K(+)-ATPase inhibitor ouabain, which does not cross the blood brain barrier, and another cardiotonic drug milrinone, a non-inhibitor of Na(+), K(+)-ATPase, were also included in the present study. Both milrinone and ouabain inhibited, in a dose-dependent manner, naloxone-precipitated weight loss while neither affected naloxone-precipitated withdrawal jumping nor locomotor activity in mice. These results indicate that both the cardiotonic effects and central inhibition of Na(+), K(+)-ATPase contribute to the inhibitory effects of digoxin on morphine withdrawal syndrome in mice.

CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients.

PURPOSE: To investigate whether the CYP3A4*1G genetic polymorphism contributes to the variability in CYP3A activity and response to fentanyl. METHODS: One hundred and forty-three gynecologic patients who were scheduled to undergo abdominal total hysterectomy or myomectomy with general anesthesia were enrolled in this study. Intravenous fentanyl patient-controlled analgesia was provided postoperatively for satisfactory analgesia. The degrees of pain at rest during PCA treatment were assessed with visual analog scale. The fentanyl consumption and occurrence of any adverse effects were recorded in the first 24 h postoperatively. CYP3A activity was measured by plasma 1'-hydroxymidazolam-to-midazolam ratio 1 h after intravenous administration of 0.1 mg/kg midazolam. CYP3A4*1G variant allele was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequency of the CYP3A4*1G variant allele was 0.269 in 143 Chinese gynecologic patients. The activity of CYP3A4 in patients homozygous for the *1G/*1G variant (0.34 +/- 0.15) was significantly lower than that in patients bearing the wild-type allele (*1/*1) (0.46 +/- 0.14) or in patients heterozygous for the *1/*1G variant (0.46 +/- 0.12) (P < 0.05). The patients with the CYP3A4*1G/*1G genotype needed less fentanyl (227.8 +/- 55.2 microg) to achieve pain control than patients carrying the CYP3A4*1/*1 (381.6 +/- 163.6 microg) and CYP3A4*1/*1G (371.9 +/- 180.1 microg) genotypes (P < 0.05) during the first 24 h postoperatively. There was no significant difference in incidence of adverse events among the different genotype groups (P > 0.05). CONCLUSIONS: CYP3A4*1G genetic polymorphism decreases CYP3A activity and fentanyl consumption for postoperative pain control.