Metformin Ameliorates Postoperative Cognitive Dysfunction through Regulation of the AMPK/SIRT1 Pathway.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients. The purpose of this study was to investigate the mechanism through which metformin improves postoperative cognitive function. METHODS: In the in vivo experiment, 18-month-old Sprague-Dawley (SD) rats were randomly divided into four groups (n = 12 in each group): the control, metformin, operation, and operation plus metformin groups. The animals were pretreated with metformin by gavage once daily for two weeks. The Morris water maze (MWM) was used to measure cognitive ability. In the in vitro experiment, BV2 cells were divided into five groups: the control, metformin, lipopolysaccharide (LPS), LPS plus metformin, and LPS plus metformin plus compound C groups. We stimulated microglia with LPS (500 ng/mL). Immunofluorescence and Western blotting were used to assess ROS (reactive oxygen species) levels, autophagy-associated protein levels and adenosine monophosphate-activated protein kinase (AMPK)/regulator factor 2-related enzyme 1 (SIRT1) signaling pathway activity in the rat cortex and microglial cells. RESULTS: In the MWM test, the metformin-pretreated rats spent a higher proportion of time in the target quadrant. Immunofluorescence showed that the fluorescence intensity of LC3 in the cortex was increased in rats pretreated with metformin. Western blotting indicated that metformin upregulated the expression of autophagy-related and AMPK/SIRT1 signaling pathway-related proteins in the cortex after surgery. By activating the AMPK/SIRT1 signaling pathway in vitro, metformin reduced microglial activation and oxidative stress and promoted autophagy. CONCLUSIONS: Through the AMPK/SIRT1 pathway, metformin can boost autophagy and reduce oxidative stress in cortical microglia in older rats, in turn improving postoperative cognitive function.

Effects of low-dose dexamethasone on inflammatory factors in drainage fluid and wound healing after thyroid surgery during perioperative period.

This study explored the effect of perioperative use of low-dose dexamethasone on inflammatory factors in drainage fluid and wound healing after thyroid surgery. In the prospective, double-blinded, randomised controlled study, adults who underwent elective thyroidectomy received 0.1 mg/kg of intravenous dexamethasone or a matching volume of placebo (saline) after induction of general anaesthesia. The primary outcome was IL6 and IL10 concentration in drainage at 24 hours postoperative. The secondary endpoint was the SBSES (modified Stony Brook Scar Evaluation Scale) total score at 1 week postoperative. From 8 July to 17 December 2020, 64 patients (mean [SD] age, 40.42 [9.52]; 13 males [20.31%]) were recruited, received operation, and completed the 1-month follow-up. Inflammatory factors in drainage did not differ between the two groups but only had significant differences at different timepoint. The dexamethasone group patients had a higher SBSES total score at 1 week after the treatment but, without statistical significance (dexamethasone vs placebo: 3.13 ± 1.24 vs 2.97 ± 0.93, P = .571). The dexamethasone group patients had a higher SBSES total score (dexamethasone vs placebo: 3.103 ± 1.148 vs 2.868 ± 0.827, P = .011) and colour score (dexamethasone vs placebo: 0.603 ± 0.493 vs 0.412 ± 0.496, P = .026) at 1-week follow-up than the placebo group patients. Preoperative single small-dose intravenous dexamethasone did not show to improve wound healing quality nor reduce incision inflammation but may release pain, and reduce tissue angiogenesis, and thus the scar redness.

Determination of the ED95 of a single bolus dose of dexmedetomidine for adequate sedation in obese or nonobese children and adolescents.

BACKGROUND: With the increasing prevalence of children who are overweight and with obesity, anaesthesiologists must determine the optimal dosing of medications given the altered pharmacokinetics and pharmacodynamics in this population. We therefore determined the single dose of dexmedetomidine that provided sufficient sedation in 95% (ED95) of children with and without obesity as measured by a minimum Ramsay sedation score (RSS) of 4. METHODS: Forty children with obesity (BMI >95th percentile for age and gender) and 40 children with normal weight (BMI 25th-84th percentile), aged 3-17 yr, ASA physical status 1-2, undergoing elective surgery, were recruited. The biased coin design was used to determine the target dose. Positive responses were defined as achievement of adequate sedation (RSS ≥4). The initial dose for both groups was dexmedetomidine 0.3 µg kg-1 i.v. infusion for 10 min. An increment or decrement of 0.1 µg kg-1 was used depending on the responses. Isotonic regression and bootstrapping methods were used to determine the ED95 and 95% confidence intervals (CIs), respectively. RESULTS: The ED95 of dexmedetomidine for adequate sedation in children with obesity was 0.75 µg kg-1 with 95% CI of 0.638-0.780 µg kg-1, overlapping the CI of the ED95 estimate of 0.74 µg kg-1 (95% CI: 0.598-0.779 µg kg-1) for their normal-weight peers. CONCLUSIONS: The ED95 values of dexmedetomidine administered over 10 min were 0.75 and 0.74 µg kg-1 in paediatric subjects with and without obesity, respectively, based on total body weight. CLINICAL TRIAL REGISTRATION: ChiCTR1800014266.

Gentle facemask ventilation during induction of anesthesia.

BACKGROUND: To determine the level of inspiratory pressure minimizing the risk of gastric insufflation while providing adequate pulmonary ventilation. METHODS: In this prospective, randomized, double-blind study, patients were allocated to one of the two groups (P10, P15) defined by the inspiratory pressure applied during controlled-pressure ventilation: 10 and 15 cm H2O. Anesthesia was induced using propofol and sufentanil; no neuromuscular-blocking agent was administered. Once loss of eyelash reflex occurred, facemask ventilation was started for a 2-min period. The cross-sectional antral area was measured using ultrasonography before and after facemask ventilation. Respiratory parameters were recorded. RESULTS: Forty patients were analyzed. Mean tidal volume was about 7 ml/kg in group P10, and was >11 ml/kg in group P15 in the same period. As indicated by ultrasonography test, the antral area in P15 group was markedly incresed compared with P10 group. CONCLUSION: Inspiratory pressure of 10 cm H2O allowed for reduced occurrence of gastric insufflation with proper lung ventilation during induction of anesthesia with sufentanil and propofol in nonparalyzed and nonobese patients.

A Perioperative Small Dose of Dexamethasone Enhances Postoperative Recovery by Reducing Volume and Inflammatory Contents in Wound Drainage After Thyroid Surgery: A Double-Blinded, Randomized, Prospective Study.

BACKGROUND: The aims of this study were to assess the effect of perioperative dexamethasone on postoperative thyroid surgery recovery using measures of wound drainage volume and C-reactive protein (CRP) levels and leukocyte counts. MATERIALS AND METHODS: From January to September 2014, healthy patients, aged between 18 and 65 years, had elective thyroid surgery in the tertiary hospital. Eligible patients were randomized into either group D (dexamethasone 0.1 mg/kg IV) or group S (saline IV) after anesthesia induction. At the end of surgery, a drainage tube was placed at the thyroid bed with a negative pressure ball connected outside the wound. Drainage fluids were collected after thyroid surgery. The fluid volume and the levels of C-reactive protein and leukocyte counts inside were analyzed. All patients were followed up for 1 month. RESULTS: The median total drainage in group D (n = 103) was 43 ml (IQR: 21-83 ml), and 68 ml (IQR: 35-104 ml) in group S (n = 111), P = 0.002. More patients in group D were discharged on postoperative day 2 (74.8% vs. 54.1%, P = 0.002). The CRP levels and leukocyte counts were much less in group D than in group S (P = 0.002 and P < 0.001, respectively). Two patients (one in each group) had wound infections 1 week after surgery that healed one additional week later. CONCLUSIONS: One perioperative small dose of dexamethasone reduced wound drainage volume and inflammatory content after thyroid surgery, thereby possibly contributing to early recovery. The effects of dexamethasone have never been evaluated before under these conditions. REGISTRATION NUMBER: NCT02304250 ( http://www.clinicaltrials.gov ).

Down-Regulation of Protein Kinase C-ε by Prolonged Incubation with PMA Inhibits the Proliferation of Vascular Smooth Muscle Cells.

BACKGROUND/AIMS: Phorbol myristate acetate (PMA) exerts a pleiotropic effect on the growth and differentiation of various cells. Protein kinase Cs (PKCs) plays a central role in mediating the effects of PMA on cells. The present study investigated whether the down-regulation of protein kinase C-ε (PKC-ε) is involved in the inhibition of vascular smooth muscle cell (VSMC) proliferation caused by prolonged PMA incubation. METHODS: Using cell counting, Cell Counting Kit-8 (CCK-8) and EdU incorporation assay on VSMCs, we evaluated the inhibitory effects of prolonged incubation of PMA, of lentiviruses carrying the short-hairpin RNAs (shRNA) of PKC-ε and of the PKC-ε inhibitor peptide on the proliferation and viability of cells. The effect of PKC-ε down-regulation on growth of rat breast cancer SHZ-88 cells was also measured. RESULTS: The prolonged incubation of VSMCs with PMA for up to 72 hours resulted in attenuated cell growth rates in a time-dependent manner. The expression of PKC-ε, as assessed by Western blotting, was also decreased accordingly. Notably, the number of EdU-positive cells and the cell viability of VSMCs were decreased by shRNA of PKC-ε and the PKC-ε inhibitor peptide, respectively. The proliferation of rat breast cancer SHZ-88 cells was also attenuated by lentivirus-induced shRNA silencing of PKC-ε. CONCLUSIONS: Prolonged incubation of PMA can inhibit the expression of PKC-ε. The effect results in the inhibition of VSMC proliferation. PKC-ε silencing can also attenuate breast cancer cell growth, suggesting that PKC-ε may be a potential target for anti-cancer drugs.

Protein Kinase C Isoforms Distinctly Regulate Propofol-induced Endothelium-dependent and Endothelium-independent Vasodilation.

Protein kinase C (PKC) isoforms improve endothelial nitric oxide synthase activity and contractile Ca sensitivity in blood vessels. These actions may have opposite effects on propofol-induced vasodilation. This study examines the hypothesis that propofol induces relaxation by enhancing the PKC-mediated nitric oxide synthesis in endothelium and/or inhibiting the PKC-regulated Ca sensitivity in vascular smooth muscle (VSM). Propofol (1-100 µM) induced greater relaxation in endothelium-intact rings compared with denuded rings, and this effect was antagonized by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In contrast, treatment with the general PKC inhibitor GF-109203X augmented both the endothelium-dependent and endothelium-independent relaxation induced by propofol, and this enhancement was more profound in the intact rings at lower propofol concentrations. The enhancement was unaffected by L-NAME. Interestingly, calphostin C (an inhibitor of conventional and novel PKCs) and Gö-6976 (an inhibitor of conventional PKCs) had similar effects in augmenting propofol-induced relaxation in endothelium-denuded rings. Downregulation of novel isoforms not only reduced the norepinephrine-elicited contraction but also decreased the magnitude of propofol-induced relaxation. In vascular smooth muscle cells, propofol prevented norepinephrine-elicited phosphorylation of myosin light chain. Propofol can increase the PKC-mediated availability of nitric oxide but inhibit the novel PKC-regulated Ca-sensitization, which provides a novel explanation for the mechanism of propofol-induced vasodilation.

Optimal interval for hot water immersion tail-flick test in rats.

BACKGROUND: The hot water tail-flick test is widely used to measure the degree of nociception experienced by laboratory animals. This study was carried out to optimise interval times for the hot water immersion tail-flick tests in rats. METHOD: Ten different intervals from 10 s to 1 h were tested in 60 Sprague-Dawley male rats. At least eight rats were tested for each interval in three consecutive hot water tail-flick tests. Dixon's up-and-down method was also used to find the optimal intervals. The same rats were then divided into two groups. In Group N, naloxone was injected to reverse the prolonged latency times, whereas saline was used in the control Group S. RESULTS: Intervals of 10 s, 20 s, 30 min and 1 h did not significantly impact latencies, yielding similar results in three consecutive tests (p > 0.05). However, interval times of between 30 s and 20 min, inclusively, caused significantly prolonged latencies in the second and third tests (p < 0.001). Dixon's up-and-down method showed that 95% of the rats had prolonged latencies in hot water tail-flick tests at intervals longer than 32 s. Naloxone reversed prolonged latencies in Group N, whereas the latencies in Group S were further prolonged in 5 min interval tests. CONCLUSION: The optimal intervals for hot water tail-flick tests are either shorter than 20 s or longer than 20 min. The prolonged latencies after repetitive tests were attributable to an endocrine opioid.

Comparing preoperative and postoperative dexamethasone effects on analgesia duration in shoulder surgery.

Dexamethasone is commonly used as an adjuvant to prolong peripheral nerve block analgesia, but the optimal timing is unclear. This randomized equivalence trial tested whether preoperative versus postoperative intravenous dexamethasone have equivalent analgesic effects when combined with interscalene brachial plexus block for shoulder surgery. 168 patients were randomized to receive 5 mg dexamethasone either preoperatively or postoperatively. The primary outcome was duration of analgesia, analyzed for equivalence with a 2-h margin. The mean durations were equivalent between groups (11.5 h preoperative versus 10.7 h postoperative). The confidence intervals fell within the equivalence margin. There were no other clinically significant differences in secondary outcomes like time to first analgesia, motor recovery, opioid consumption, blood glucose, or complications. In conclusion, as an adjuvant for nerve block, preoperative and postoperative intravenous dexamethasone provide equivalent analgesic duration, allowing for flexibility in clinical use. This addresses previous uncertainty about timing while demonstrating equivalent efficacy.

Peripheral nerve adjustment for postherpetic neuralgia: a randomized, controlled clinical study.

OBJECTIVE: To observe the therapeutic effect of peripheral nerve adjustment for the treatment of postherpetic neuralgia (PHN). METHODS: One hundred and two patients with PHN were randomly assigned to three groups; the control group (A), the experimental group (B), which was subjected to peripheral nerve adjustment, and patients who received a sham peripheral nerve adjustment, thus serving as a positive control group (C). The patients' Visual Analogue Scale (VAS) and total oral rescue dosage for pain management were recorded at days 1, 3, 7, 14, and 28 following treatment. Quality of life (QOL), 36-Item Short-Form Health Survey (SF-36), and side effects were recorded following treatment. RESULTS: We observed that the average VAS score was significantly lower in the treatment group (B) than in the control groups A and C following treatment (P < 0.05). In addition, the QOL and SF-36 scores for group B improved substantially following treatment compared to groups A and C, and this effect was maintained up to 180 days after treatment (P < 0.05). The average dosage of pain medication was also lower in group B, compared to groups A and C, following treatment (P < 0.05). CONCLUSIONS: We conclude that peripheral nerve adjustment can relieve PHN pain and improve patients' quality of life. The possible mechanisms involved may include the reduction of both peripheral and central sensitization, the modulation of nerve plasticity, and an increase in endogenous analgesic molecules.

L6 spinal nerve ligation produces prolonged development of mechanical allodynia and gradual increase of GFAP on ipsilateral dorsal horn.

BACKGROUND: L5/6 spinal nerve ligation (SNL), one of the most widely used approaches rat models for neuropathic pain, results in the rapid development of mechanical allodynia within 24-72 h. However, the result of a single L6 SNL remains unclear. METHODS: The first series of experiments were performed to examine the pain behavior of rats with different nerve ligations. Thirty-six rats were randomly assigned to four groups as follows: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 6); group III, single L6 nerve ligation (n = 18); and group IV, the sham operation group (n = 6). The mechanical allodynia of rats was assessed using a 50 % paw withdrawal threshold (PWT), and tail antinociception was determined using the percentage of the maximal possible antinociceptive effect (% MPE). The second series of experiments were performed using Western blots to evaluate dorsal horn GFAP expression in different groups at different time points (D1, D7, D14, and D28). For this series of experiments, fifty-four rats were randomly divided into three groups: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 24); and group III, L6 nerve ligation (n = 24). RESULTS: In this study, a single L6 SNL induced prolonged development (1-14 days) of mechanical allodynia and gradually increased expression of glial fibrillary acidic protein (GFAP) in the ipsilateral dorsal horn. Notably, once mechanical allodynia developed, both the severity of mechanical allodynia and the alteration of GFAP expression were similar regardless of the identity of the ligated nerve (L5/6 or L6 only). CONCLUSIONS: Single L6 SNL might be used as an effective model for researching the development period of neuropathic pain and is thus worth further investigation.

Different effects of a perioperative single dose of dexamethasone on wound healing in mice with or without sepsis.

Introduction: Sepsis delays wound healing owing to uncontrolled inflammation. A single perioperative dose of dexamethasone is widely used because of its anti-inflammatory effects. However, the effects of dexamethasone on wound healing in sepsis remain unclear. Methods: We discuss the methods to obtain dose curves and explore the safe dosage range for wound healing in mice with or without sepsis. A saline or LPS intraperitoneal injection was applied to C57BL/6 mice. After 24 hours, the mice received a saline or DEX intraperitoneal injection and full-thickness, dorsal wounding operation. Wound healing was observed by image record, immunofluorescence and histological staining. Inflammatory cytokines and M1/M2 macrophages in wounds were determined by ELISA and immunofluorescence, respectively. Results: Dose-response curves reflected the safe dosage range of DEX in mice with or without sepsis, from 0.121 to 2.03 mg/kg and from 0 to 0.633 mg/kg, respectively. we found that a single dose of dexamethasone (1 mg/kg, i.p.) promoted wound healing in septic mice, but delayed wound healing in normal mice. In normal mice, dexamethasone delays inflammation, resulting in an insufficient number of macrophages during the healing process. In septic mice, dexamethasone alleviated excessive inflammation and maintained the balance of M1/M2 macrophages in the early and late healing process. Discussion: In summary, the safe dosage range of dexamethasone in septic mice is wider than that in normal mice. A single dose of dexamethasone (1 mg/kg) increased wound healing in septic mice, but delayed it in normal mice. Our findings provide helpful suggestions for the rational use of dexamethasone.

Effectiveness and safety of new umbilical paramedian semilunaris approach for transverse abdominis plane block: a prospective, single-arm, observational, evaluation study.

Background: The transversus abdominis plane (TAP) block is a widely used, safe and effective technique for abdominal surgery analgesia, but its range of blocking is not sufficient for some surgeries requiring a large incision. Here we present the novel concept of an ultrasound-guided linea semilunaris block, a modified approach to TAP block, which can potentially offer a wider blocking range. Methods: Patients undergoing open colorectal surgery at the Shanghai Jiaotong University Affiliated Sixth People's Hospital between May and July 2021 were enrolled to receive ultrasound-guided linea semilunaris block. All blocks were performed in the holding area of the operating theater under routine hemodynamic monitoring while patients were conscious with low-dose opioids. All patients were supine, and a linear probe identified the semilunar line as the connection between the transverse and rectus muscles. Next, 20 mL of 0.25% ropivacaine was injected in the semilunar line using the in-plane technique bilaterally. The main indicator of the blocking range was measured. Postoperatively, the visual analog score (VAS) from 4 to 24 h (every 2 h), the time of the first remedial analgesia, the bowel movement starting time and complications were also recorded. Results: A total of 31 potentially eligible studies were identified for inclusion. The extent of the cutaneous sensory block was: 3.46±0.59 cm below the xiphoid, 1.74±0.37 cm above the symphysis pubis, 2.02±1.24 cm outside the left midclavicular line, and 2.19±1.25 cm outside the right midclavicular line. The highest and lowest median [interquartile range (IQR)] VAS pain scores were 4 [4-5] of 10 h and 2 [1-2] of 4 h postoperatively. The bowel movement starting time was 3.7±1.1 days after gastrointestinal surgery. There were four patients with nausea and vomiting but none had adverse reactions attributable to local anesthetic (LA) poisoning. Conclusions: The ultrasound-guided umbilical paramedian semilunaris approach to TAP block is a safe and effective technique in clinical practice, which may provide more effective analgesia than traditional TAP block for open colorectal surgery with a median abdominal incision. Further randomized controlled trials are needed to confirm our results.

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study.

Background: Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities. Methods: We conducted an open-label, multicenter, randomized controlled trial in which hospitalized adult patients with severe comorbidities were eligible and assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 h for 5 days with standard treatment or only standard treatment. All-cause mortality on day 28, the duration of SARS-CoV-2 RNA clearance, and safety were evaluated. Findings: 264 patients (mean age, 70.35 years; 122 [46.21%] female) who met the criteria were enrolled at 5 sites in Shanghai from April 10 to May 19 in 2022. After randomization, a total of 132 patients were assigned to receive Paxlovid treatment plus standard treatment, and 132 patients were assigned to receive only standard treatment. The overall 28-day mortality was 4.92%, 8 patients died in the standard treatment group and 5 died in the Paxlovid plus standard treatment group. There was no significant difference in mortality from any cause at 28 days between the Paxlovid plus standard treatment group and the standard treatment group (absolute risk difference [ARD], 2.27; 95% CI -2.94 to 7.49, P = 0.39). There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group; ARD, -0.62; 95% CI -2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39; serious adverse events, 4.55% vs. 3.788%, P = 0.76). Interpretation: Paxlovid showed no significant reduction in the risk of all-cause mortality on day 28 and the duration of SARS-CoV-2 RNA clearance in hospitalized adult COVID-19 patients with severe comorbidities. Funding: National Natural Science Foundation of China (grant number: 82172152, 81873944).

The effect of intrathecal administration of glial activation inhibitors on dorsal horn BDNF overexpression and hind paw mechanical allodynia in spinal nerve ligated rats.

Recent studies have suggested that activated glia in the spinal cord may play a vital role at different times during spinal nerve ligation (SNL)-induced neuropathic pain; therefore, glial activation inhibitors have been used as effective painkillers. Brain-derived neurotrophic factor (BDNF) is also known to be a powerful pain modulator, but it remains unclear how it contributes to the glial activation inhibitor-based treatment. This study revealed the following results: (1) intrathecal administration of minocycline (a microglial activation inhibitor) could prevent mechanical allodynia during the initiation of SNL-induced neuropathic pain, and its action was associated with the elimination of BDNF overexpression in the dorsal horn; (2) the spinal injection of fluorocitrate (an astrocytic activation inhibitor) but not minocycline could reverse mechanical allodynia during the maintenance phase of SNL-induced pain, and its action was also related to a decrease in BDNF overexpression in the dorsal horn; and (3) treatment with TrkB/Fc (a BDNF-sequestering protein) had a similar effect during both the early development and maintenance periods. These results led to the following conclusions: (1) elevated BDNF expression in the dorsal horn was required to develop and maintain neuropathic pain; (2) minocycline could only prevent mechanical allodynia in the early stages, possibly by inhibiting BDNF release from microglia; and (3) fluorocitrate could reverse existing mechanical allodynia, and its action was associated with the inhibition of BDNF upregulation induced by astrocytic activation.

Lipid metabolism disturbances and AMPK activation in prolonged propofol-sedated rabbits under mechanical ventilation.

AIM: To explore the mechanisms underlying the propofol infusion syndrome (PRIS), a potentially fatal complication during prolonged propofol infusion. METHODS: Male rabbits under mechanical ventilation through endotracheal intubation were divided into 3 groups (n=6 for each) that were sedated with 1% propofol (Group P), isoflurane (Group I) or isoflurane while receiving 10% intralipid (Group II), respectively. Blood biochemical parameters were collected at 0, 6, 12, 18, 24 and 30-36 h after the initiation of treatments. The hearts were removed out immediately after the experiments, and the level of tumor necrosis factor (TNF)-α in the hearts were studied using immunohistochemistry. AMP-activated protein kinase (AMPK) and phospho-AMPK in the hearts were assessed using Western blotting. RESULTS: The mortality rate was 50% in Group P, and 0% in Groups I and II. The serum lipids and liver function indices in Group P were significantly increased, but moderately increased in Group II. Significant decreases in these indices were found in Groups I. All the groups showed dramatically increased release of creatine kinase (CK). Intense positive staining of TNF-α was found in all the heart samples in Group P, but only weak and neglectful staining was found in the hearts from Group II and Group I, respectively. AMPK phosphorylation was significantly increased in the hearts of Group P. CONCLUSION: Continuous infusion of large dose of propofol in rabbits undergoing prolonged mechanical ventilation causes hyperlipidemia, liver dysfunction, increased CK levels, AMPK activation and myocardial injury. The imbalance between energy demand and utilization may contribute to PRIS.

The Median Effective Analgesic Concentration of Ropivacaine in Sciatic Nerve Block Guided by Ultrasound After Arthroscopic Anterior Cruciate Ligament Reconstruction: A Double-Blind Up-Down Concentration-Finding Study.

Background: The median effective analgesic concentration (MEAC; EC50 = effective concentration in 50% patients) of ropivacaine in sciatic nerve block guided by ultrasound (US) required for effective postoperative analgesia following arthroscopic anterior cruciate ligament (ACL) reconstruction has not yet been found. This study aimed to determine the effectiveness of MEAC of 20 ml ropivacaine of postoperative anesthesia for patients after ACL reconstruction. Methods: In total, 29 patients who underwent elective arthroscopic ACL reconstruction were enrolled in this study. All the subjects were given 20 ml of 0.2% ropivacaine for femoral nerve block. A concentration of 20 ml ropivacaine administered to the sciatic nerve was measured by applying the up-and-down sequential method (UDM). The starting concentration was 0.2% in the first patient, and the next patient received decremented 0.025% ropivacaine if the prior patient's postoperative visual analog pain score was <4 in the initial 8 h. Otherwise, the participant was given an incremental dose of 0.025% ropivacaine. The EC50 of ropivacaine was determined by using centered isotonic, linear-logarithmic, exponential regressions, and linear regression. The "goodness of fit" was compared among various models by calculating the residual standard errors. Results: The concentration of ropivacaine administered ranged from 0.1 to 0.2%. The EC50 [95% confidence interval (CI)] determined by four statistical methods (centered isotonic, exponential regressions, linear-logarithmic, and linear regression) was 0.115, 0.113% (0.108, 0.343%), 0.142% (0.112, 0.347%), and 0.129% (0.103, 0.359%), respectively. Among all models, the residual standard error was the smallest for the exponential regression (0.2243). Conclusion: The EC50 of ropivacaine in US-guided sciatic nerve block was 0.113-0.142%, and exponential regression model best matched the data.

Different effect of glutamine on macrophage tumor necrosis factor-alpha release and heat shock protein 72 expression in vitro and in vivo.

Macrophage plays a vital role in sepsis. However, the modulatory effect of glutamine (Gln) on macrophage/ monocyte-mediate cytokines release is still controversial. Thus, we investigated the effect of Gln on macrophage tumor necrosis factor (TNF)-alpha release and heat shock protein (HSP) 72 expression in vivo and in vitro. Data from our study indicated that the increase of HSP72 expression was significant at 8 mM of Gln 4 h after lipopolysaccharide (LPS) stimulation and became independent of Gln concentrations at 24 h, whereas TNF-alpha release was dose- and time-dependent on Gln. Heat stress (HS) induced more HSP72 and less TNF-alpha production compared with the non-HS group. However, the production of TNF-alpha in cells pretreated with HS was increased with increasing concentrations of Gln. Treatment with various concentrations of Gln for 1 h and then 0.5 mM Gln for 4 h led to an increase in HSP72 expression, but not in TNF-alpha production. In sepsis model mice, Gln treatment led to a significantly lower intracellular TNF-alphalevel and an increase in HSP72 expression in mouse peritoneal macrophages. Our results demonstrate that Gln directly increases TNF-alpha release of LPS-stimulated RAW264.7 macrophages in a dose-dependent manner, and also decreases mouse peritoneal macrophages TNF-a release in the sepsis model. Taken together, our data suggest that there may be more additional pathways by which Gln modulates cytokine production besides HSP72 expression in macrophage during sepsis.

TTX-R Na+ current-reduction by celecoxib correlates with changes in PGE(2) and CGRP within rat DRG neurons during acute incisional pain.

The present study was undertaken to investigate whether celecoxib could regulate the tetrodotoxin-resistant (TTX-R) sodium channel current in rat dorsal root ganglia (DRG) and whether prostaglandin E2 (PGE2) and calcitonin gene-related protein (CGRP) were involved in celecoxib's analgesia during acute incisional pain. Seventy-five rats were randomly allocated into three groups. Group A was the control group receiving a placebo (sugar pill) 1 h before and 12 h after surgery (right hind paw incisional pain). Group B was the test group receiving celecoxib 30 mg/kg orally 1 h before and 12 h after surgery. Group C was the naive group receiving a sham operation. The changes in the mechanical withdrawal thresholds, PGE2 and CGRP concentration in incisional paw tissue and DRG, and total TTX-R sodium channel current density in small DRG neurons were investigated 1 h before the operation and 2 h, 6 h, 12 h, 24 h, 48 h and 96 h after the operation. The results showed both of a decrease in mechanical withdrawal thresholds and an increase of TTX-R sodium channel current density in DRG neurons in group B were significantly lower than those of group A at 24 h and 48 h after the operation (P<0.05). The increase in PGE2 and CGRP concentrations at incisional paw tissue and DRG neurons in group B were lower than those of groups A at 24 h and 48 h after the operation (P<0.05). This study indicates that: 1) celecoxib can inhibit TTX-R sodium channel current density in rat DRG neurons; 2) PGE2 and CGRP participate in celecoxib's analgesic effect on acute incisional pain.