Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhibitory and excitatory input onto PV interneurons enwrapped by PNN, and decreased gamma oscillations in hippocampal CA1. Notably, MMP-9 inhibitor SB-3CT treatment rescued most of these abnormalities. Taken together, our study demonstrates that active MMP-9 mediated PNN remodeling, leading to reduced inhibitory and excitatory input onto PV interneurons and abnormal gamma oscillations in hippocampal CA1, which consequently contributed to cognitive impairments after LPS injection.

Effects of dezocine for the prevention of postoperative catheter-related bladder discomfort: a prospective randomized trial.

Purpose: To evaluate the effects of dezocine on the prevention of postoperative catheter-related bladder discomfort (CRBD). Patients and methods: Ninety-six adult patients undergoing abdominal surgery with urinary catheterization under general anesthesia were randomized into dezocine and control (flurbiprofen) groups. The postoperative CRBD, pain score, sedation score and adverse effects were evaluated at 0, 1, 2 and 6 hrs after tracheal extubation. Results: The primary outcome showed a lower incidence of CRBD at 1 hr post-extubation in the dezocine group (29.17%) than the control group (58.33%, P<0.01). The incidences at 0 and 2 hrs post-extubation and the overall incidence were also lower in the dezocine group than the control group (all P<0.05). The severity of CRBD at 0, 1, 2 and 6 hrs and the pain, sedation score and other adverse effects were comparable between the two groups (P>0.05); however, the overall severity of CRBD was decreased in the dezocine group compared with the control group (P<0.05). Conclusion: Intraoperative dezocine reduces the incidence and severity of postoperative CRBD without clinically relevant adverse effects.

Short- and Long-Term Protective Effects of Melatonin in a Mouse Model of Sepsis-Associated Encephalopathy.

Brain dysfunction is a common complication after sepsis and is an independent risk factor for a poor prognosis, which is partly attributed to the dysregulated inflammatory response and oxidative damage. Melatonin regulates the sleep-wake cycle and also has potent anti-inflammatory and antioxidant properties, yet the protective effects of melatonin on sepsis-induced neurobehavioral dysfunction remain to be elucidated. In the present study, melatonin was administered intraperitoneally daily at a dose of 10 mg/kg for three consecutive days immediately (early treatment) or 7 days (delayed treatment) after sham operation or cecal ligation and puncture (CLP), followed by an additional treatment in drinking water until the end of behavioral tests. The concentrations of pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-10), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were determined at the indicated time points. Compared with the CLP + vehicle group, we found that early melatonin treatment resulted in increased survival rate but not improvement in measures of neurobehavioral outcomes, which was accompanied by significantly lower plasma level of IL-1ß. Intriguingly, delayed melatonin treatment improved neurobehavioral dysfunction by normalization of hippocampal BDNF and GDNF expressions. In conclusion, our study suggests the beneficial effects of both early and delayed melatonin treatment after sepsis development, which implicates melatonin has a potential therapeutic value in sepsis-associated organ damage including brain dysfunction.

The Combination of Long-term Ketamine and Extinction Training Contributes to Fear Erasure by Bdnf Methylation.

A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.

The tracheal detecting-bulb: a new device to distinguish tracheal from esophageal intubation.

BACKGROUND: The tracheal detecting-bulb (TDB) is a diagnostic tool for confirmation of tracheal intubation. Capnography is also accepted as a standard way for such confirmation. The purpose of this investigation was to determine whether the results by TDB agreed with those by capnography. METHODS: Four hundred patients were allocated to three separate studies. In 200 consecutive patients of study 1, tracheal intubation was first confirmed with the TDB followed by capnography. In study 2, 100 patients had the esophagus intentionally intubated, and confirmation was performed likewise as in study 1. The tube was then removed, the trachea was intubated, and confirmation tests followed. Study 3 involved 100 patients and was carried out in a double-blind, randomized manner. The tube was intentionally inserted into either the esophagus (n = 42) or trachea (n = 58), and confirmation tests immediately followed. RESULTS: In study 1, the rhythmic expansion-contraction of TDB was evident in 173 patients, and always agreed with capnographic reading; In 27 instances, the latex bulb of TDB remained collapsed or was scantily filled without the turning-up of capnographic reading as counterchecked, indicating esophageal intubation. In study 2, regardless of esophageal or tracheal intubation, agreement between TDB and capnogram was 100%. In study 3, the agreement between the two detecting instruments was 100% too. In the 400 patients studied, the results from the TDB were in complete accord with those of capnogram. The sensitivity, specificity, and predictive value of the TDB in all of these studies were 100%. CONCLUSIONS: The TDB is a valuable diagnostic technique for confirming tracheal intubation as it could correctly detect esophageal or tracheal intubation of the tracheal tube in all our 400 patients. The results of using TDB agree with the results of using capnography.