Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding.

Lung ischemia-reperfusion (IR) injury is induced by pulmonary artery occlusion and reperfusion. Lung IR injury commonly happens after weaning from extracorporeal circulation, lung transplantation, and pulmonary thromboendarterectomy; it is a lethal perioperative complication. A definite therapeutic intervention remains to be determined. It is known that the enzyme activity of angiotensin-converting enzyme 2 (ACE2) is critical in maintaining pulmonary vascular tone and epithelial integrity. In a noxious environment to the lungs, inactivation of ACE2 is mainly due to a disintegrin and metalloprotease 17 (ADAM17) protein-mediated ACE2 shedding. Thus, we assumed that protection of local ACE2 in the lung against ADAM17-mediated shedding would be a therapeutic target for lung IR injury. In this study, we established both in vivo and in vitro models to demonstrate that the damage degree of lung IR injury depends on the loss of ACE2 and ACE2 enzyme dysfunction in lung tissue. Treatment with ACE2 protectant diminazen aceturate (DIZE) maintained higher ACE2 enzyme activity and reduced angiotensin II, angiotensin type 1 receptor, and ADAM17 levels in the lung tissue. Concurrently, DIZE-inhibited oxidative stress and nitrosative stress via p38MAPK and NF-κB pathways consequently reduced release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß. The underlying molecular mechanism of DIZE contributed to its protective effect against lung IR injury and resulted in the improvement of oxygenation index and ameliorating pulmonary pathological damage. We concluded that DIZE protects the lungs from IR injury via inhibition of ADAM17-mediated ACE2 shedding.

How Do Innate Immune Cells Contribute to Airway Remodeling in COPD Progression?

Recently, the therapeutic potential of immune-modulation during the progression of chronic obstructive pulmonary disease (COPD) has been attracting increasing interest. However, chronic inflammatory response has been over-simplified in descriptions of the mechanism of COPD progression. As a form of first-line airway defense, epithelial cells exhibit phenotypic alteration, and participate in epithelial layer disorganization, mucus hypersecretion, and extracellular matrix deposition. Dendritic cells (DCs) exhibit attenuated antigen-presenting capacity in patients with advanced COPD. Immature DCs migrate into small airways, where they promote a pro-inflammatory microenvironment and bacterial colonization. In response to damage-associated molecular patterns (DAMPs) in lung tissue affected by COPD, neutrophils are excessively recruited and activated, where they promote a proteolytic microenvironment and fibrotic repair in small airways. Macrophages exhibit decreased phagocytosis in the large airways, while they demonstrate high pro-inflammatory potential in the small airways, and mediate alveolar destruction and chronic airway inflammation. Natural killer T (NKT) cells, eosinophils, and mast cells also play supplementary roles in COPD progression; however, their cellular activities are not yet entirely clear. Overall, during COPD progression, "exhausted" innate immune responses can be observed in the large airways. On the other hand, the innate immune response is enhanced in the small airways. Approaches that inhibit the inflammatory cascade, chemotaxis, or the activation of inflammatory cells could possibly delay the progression of airway remodeling in COPD, and may thus have potential clinical significance.

Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats.

The α5 subunit-containing gamma-amino butyric acid type A receptors (α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose (1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young (3-month-old) and aged (24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia. The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China (approval No. NBCDSER-IACUC-2015128) in December 2015.

Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: a randomized controlled preliminary trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a serious complication after surgery, especially in elderly patients. The anesthesia technique is a potentially modifiable risk factor for POCD. This study assessed the effects of dexmedetomidine, propofol or midazolam sedation on POCD in elderly patients who underwent hip or knee replacement under spinal anesthesia. METHODS: The present study was a prospective randomized controlled preliminary trial. From July 2013 and December 2014, a total of 164 patients aged 65 years or older who underwent hip or knee arthroplasty at China-Japan Friendship Hospital and 41 non-surgical controls were included in this study. Patients were randomized in a 1:1:1 ratio to 3 sedative groups. All the patients received combined spinal-epidural anesthesia (CSEA) with midazolam, dexmedetomidine or propofol sedation. The sedative dose was adjusted to achieve light sedation (bispectral index[BIS] score between 70 and 85). All study participants and controls completed a battery of 5 neuropsychological tests before and 7 days after surgery. One year postoperatively, the patients and controls were interviewed over the telephone using the Montreal cognitive assessment 5-minute protocol. RESULTS: In all, 60 of 164 patients (36.6%) were diagnosed with POCD 7 days postoperatively, POCD incidence in propofol group was significantly lower than that in dexmedetomidine and midazolam groups (18.2% vs. 40.0%, 51.9%, χ = 6.342 and 13.603, P = 0.012 and < 0.001). When the patients were re-tested 1 year postoperatively, the incidence of POCD was not significantly different among the 3 groups (14.0%, 10.6% vs. 14.9%, χ = 0.016 and 0.382, P = 0.899 and 0.536). CONCLUSION: Among dexmedetomidine, propofol and midazolam sedation in elderly patients, propofol sedation shows a significant advantage in term of short-term POCD incidence.

[Comparison of the Effectiveness of Different Supraglottic Ventilation Methods during Bronchial Thermoplasty].

OBJECTIVE: To compare the effectiveness of high-frequency jet ventilation via Wei jet nasal airway and controlled ventilation with improved laryngeal mask airway during bronchial thermoplasty. METHODS: Twenty-eight patients undergoing bronchial thermoplasty were equally divided into two groups: group A (high-frequency jet ventilation through Wei jet nasal airway) and group B (controlled ventilation with improved laryngeal mask airway). Pulse oxygenation,heart rate,and mean arterial blood pressure were recorded after entering the operating room (T0), 1 minute after administration/induction (T1), bronchoscope inserting (T2), 15 minutes (T3)/30 minutes (T4)/45 minutes (T5) after ventilation,at the end of the operation (T6), and at the recovery of patients' consciousness (T7). The pH,arterial oxygen partial pressure,and arterial carbon dioxide partial pressure were recorded at T0, T4, and T6. The endoscope indwelling duration,operative time,patients' awakening time,adverse events during anesthesia,satisfactions of patients and operators, anesthesic effectiveness were also recorded. RESULTS: The arterial carbon dioxide partial pressur in group A at T4 and T6 were significantly higher than in group B (P<0.05). The pH in group A at T4 and T6 was significantly lower than in group B (P<0.05). The endoscope indwelling duration and the operative time in group B were significantly shorter than in group A (P<0.05) while the recovery of consciousness in group B was significantly longer than in group A (P<0.05). The satisfaction for operators and the efficacy of anesthesia in group B were better than in group A (P<0.05). The number of adverse events in group B was significantly smaller than in group A (P<0.05). CONCLUSION: The improved laryngeal mask airway with controlled ventilation is more suitable for bronchial thermoplasty.

In vivo field recordings effectively monitor the mouse cortex and hippocampus under isoflurane anesthesia.

Isoflurane is a widely used inhaled anesthetic in the clinical setting. However, the mechanism underlying its effect on consciousness is under discussion. Therefore, we investigated the effect of isoflurane on the hippocampus and cortex using an in vivo field recording approach. Our results showed that 1.3%, 0.8%, and 0.4% isoflurane exerted an inhibitory influence on the mouse hippocampus and cortex. Further, high frequency bands in the cortex and hippocampus showed greater suppression with increasing isoflurane concentration. Our findings suggest that in vivo field recordings can monitor the effect of isoflurane anesthesia on the mouse cortex and hippocampus.

Effect of admission time on mortality in an intensive care unit in Mainland China: a propensity score matching analysis.

INTRODUCTION: The relationship between admission time and intensive care unit (ICU) mortality is inconclusive and influenced by various factors. This study aims to estimate the effect of admission time on ICU outcomes in a tertiary teaching hospital in China by propensity score matching (PSM) and stratified analysis. METHODS: A total of 2,891 consecutive patients were enrolled in this study from 1 January 2009 to 29 December 2011. Multivariate logistic regression and survival analysis were performed in this retrospective study. PSM and stratified analysis were applied for confounding factors, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) score and admission types. RESULTS: Compared with office hour subgroup (n = 2,716), nighttime (NT, n = 175) subgroup had higher APACHE II scores (14 vs. 8, P < 0.001), prolonged length of stay in the ICU (42 vs. 24 h, P = 0.011), and higher percentages of medical (8.6% vs. 3.3%, P < 0.001) and emergency (59.4% vs. 12.2%, P < 0.001) patients. Moreover, NT admissions were related to higher ICU mortality [odds ratio (OR), 1.725 (95% CI 1.118-2.744), P = 0.01] and elevated mortality risk at 28 days [14.3% vs. 3.2%; OR, 1.920 (95% CI 1.171-3.150), P = 0.01]. PSM showed that admission time remained related to ICU outcome (P = 0.045) and mortality risk at 28 days [OR, 2.187 (95% CI 1.119-4.271), P = 0.022]. However, no mortality difference was found between weekend and workday admissions (P = 0.849), even if weekend admissions were more related to higher APACHE II scores compared with workday admissions. CONCLUSIONS: NT admission was associated with poor ICU outcomes. This finding may be related to shortage of onsite intensivists and qualified residents during NT. The current staffing model and training system should be improved in the future.

[Study on clinical efficacy of combination of traditional Chinese medicine and western medicine in treatment of pit viper bites and peripheral blood inflammatory factors].

OBJECTIVE: To observe the clinical efficacy of combination of traditional Chinese medicine and western medicine in the treatment of patient bitten by agkistrodon halys pallas, and the changes in peripheral blood inflammatory factors (hs-PCR, IL-6, TNF-alpha). METHOD: Ninty-eight patients were divided into three groups according to their hospitalization dates: the western medicine group, in which 32 patients were treated with antivenom serum (6 000 U) for five days, once every day; the traditional Chinese medicine group, in which 32 patients were treated with anti pit viper No. 2 concentrated decoction (300 mL), twice to three times every day, for five days; and the combined traditional Chinese medicine and western medicine group, in which 35 patients were treated with the combination of Chinese and Western medicine treatment described above. Then blood samples of all of patients were obtained, and serum factors (hs-PCR, IL-6, TNF-alpha) in peripheral blood were measured by Elisa assay. Another 30 health volunteers were chosen as the normal control group. RESULT: The serum inflammatory factors were significantly higher in all patients of the three groups than that in healthy control before treatment (P < 0.01), and decreased significantly after treatment. In particular, the more remarkable reduction was found in the combined traditional Chinese medicine and western medicine group compared with the western medicine group and the traditional medicine group (P < 0.01). Symptom elimination in the three groups was superior to the western medicine group and the traditional medicine group at the first day and the third day of treatment (P < 0.05, P < 0.01). Total clinical effective rate was 100% in the combined traditional Chinese medicine and western medicine group, 84. 37% in the traditional medicine group and 65.62% in the western medicine group, the clinical effective rate of the combined traditional Chinese medicine and western medicine group was notably superior to that of the western medicine group and the traditional medicine group (P < 0.01). CONCLUSION: The serum inflammatory factors increased significantly in patients bitten by agkistrodon halys pallas. Treatment with the combined traditional Chinese medicine and western medicine can significantly decrease the serum inflammatory factors, and increase clinical effect, with more obvious clinical efficacy compared with the western medicine group and the traditional medicine group.

[Efficacy of intravenous scopolamine for preventing postoperative nausea and vomiting after cesarean section].

OBJECTIVE: To observe the efficacy of intravenous scopolamine in the prevention of postoperative nausea and vomiting (PONV) after cesarean section (CS). METHODS: A total of 260 pregnant women with American Society of Anesthesiologists (ASA) Physical Status Classification class I-II who underwent elective CS under combined spinal-epidural anesthesia (CSEA) were randomly divided into four groups (n = 65): at the end of surgery, 0.3 mg/5 ml scopolamine (scopolamine group), 4 mg/5 ml ondansetron (ondansetron group), 0.3 mg scopolamine plus 4 mg ondansetron per 5 ml (combination group), or 0.9% normal saline 5 ml (control group) were intravenously infused, respectively. The episodes of PONV and adverse effects were observed within 24 hours after operation. RESULTS: The incidences of PONV within 24 hours after surgery were 87.7%, 89.2%, and 92.3%, respectively, in scopolamine group, ondansetron group, and combination group, which were all significantly higher than that in control group (73.8%) (all P < 0.05). However, the incidences of PONV showed no significant difference among these three groups (P > 0.05). No significant difference in the incidence of adverse effects was observed among the four groups (P > 0.05). CONCLUSION: Intravenous scopolamine (0.3 mg), with a comparable efficacy as ondansetron 4 mg, can effectively decrease the incidence of PONV after CS.

[Effects of melatonin on the voltage-gated delayed rectifier potassium channels of cultured hippocampal neurons of new-born rats].

OBJECTIVE: To investigate the effects of melatonin on voltage-gated delayed rectifier potassium channels. METHODS: Hippocampus neurons were obtained from newborn Wistar rat and cultured. Primary cultured for 7 to 12 days of new-born Wistar rat were selected as objectives. Patch clamp whole-cell recording technique was used on the hippocampus neurons cultured for 7 to 12 day. to record the delayed rectifier potassium current to analyze the basic electrophysiological characteristics. The effects of melatonin of the concentrations of 1 nmol/L, 10 nmol/L, 100 nmol/L, 1 mol/L, 10 mol/L, 100 mol/L, and 1 mmol/L on the amplitudes and kinetics of delayed rectifier potassium currents were investigated. RESULTS: With different voltage protocols and specific blockers of potassium channel (4-AP and TEA) a delayed rectifier potassium current that activated and inactivated slowly and had the outward rectifying characteristics (Ik) from the outward potassium currents in cultured new-born hippocampus neurons was separated. The effect of melatonin on the delayed rectifier channel was rapid, reversible and voltage-dependent Melatonin had no effect on the kinetic characteristics of the I -V curve. Melatonin increased the potassium current concentration-dependently. 1 - 100 nmol/L melatonin increased the amplitude of potassium current gradually; the effects of 1 - 100 micromol/L melatonin on the potassium current increased concentration-dependently, while the action of 1 mmol/L melatonin decreased. CONCLUSION: Melatonin reversibly increases the rectifier delayed potassium currents of the cultured hippocampus neurons of new-born rat. This may be involved in some aspects of physiological and pathological significance of potassium currents.

Postoperative neuropsychological change and its underlying mechanism in patients undergoing coronary artery bypass grafting.

BACKGROUND: The high incidence of neuropsychologic deficits after cardiac surgery, including cognitive dysfunction and mood status, has significantly influenced the prognosis, outcome of treatment and long-term quality of life of patients. With a circadian secretion pattern, melatonin and cortisol are capable of modulating the human physiological processes and neuropsychological status, whereas disorder of their secretion pattern may lead to many diseases. However, it is unclear whether neuroendocrine variations are related to the neuropsychologic status in patients undergoing coronary artery bypass grafting (CABG). METHODS: Forty male patients scheduled for CABG with hypothermic cardiopulmonary bypass (CPB) (n = 20) or off-pump coronary artery bypass (OPCAB) (n = 20) were studied. Blood samples were taken intraoperatively at specific time-points and every 3 hours within the first postoperative 24 hours to determine plasma concentrations of melatonin and cortisol. A neuropsychologic test battery including depression and anxiety was administered preoperatively and 7 to 10 days postoperatively. Statistical methods included the nonparametric analysis, multiple linear regression and cosinor analysis. RESULTS: The patients in the CPB group exhibited more severe neuropsychologic deficits and more anxious than those in the OPCAB group after surgery. In both groups, patients were more depressed postoperatively than preoperatively and recovered 3 months after surgery. Depression and anxiety were correlated with some factors of cognitive dysfunctions. In the postoperative 24 hours, 2 patients in the CPB group, and 6 patients in the OPCAB group showed a circadian rhythm of melatonin secretion. As for cortisol secretion, there were 3 patients in the CPB group and 7 in the OPCAB group respectively. Parameters of circadian rhythm of melatonin in the CPB group and those of secretion rhythm of cortisol in both groups were correlated with depression and some neuropsychologic tests. CONCLUSIONS: The incidence of neuropsychological deficits was higher in patients receiving CABG with CPB than in those without CPB. The status of mood may contribute to the perioperative cognitive dysfunctions. The disordered circadian rhythm of melatonin secretion in patients undergoing CABG with CPB and the disordered cortisol secretion may correlate directly or indirectly through mood with neuropsychological deficits.

[Perioperative cortisol circadian secretion and neuropsychological states in patients undergoing coronary artery bypass grafting surgery].

OBJECTIVE: To investigate the relationship between the circadian rhythm of perioperative cortisol secretion and neuropsychological states in patients undergoing coronary artery bypass grafting surgery. METHODS: Forty male patients scheduled for elective coronary artery bypass grafting (CABG) under hypothermic cardio-pulmonary bypass (CPB) or off-pump were enrolled in this study. They were allocated into CPB group or off-pump group with 20 patients in each group. Blood samples were withdrawn during surgery at specific time-points and every 3 h for 24 h in the immediate postoperative period. Plasma cortisol was measured by radioimmunoassay. All subjects were investigated preoperatively as well as 7 to 10 d and 3 months postoperatively with a comprehensive neuropsychologic assessment, while depression and anxiety were assessed by Self-Rating Depression Scale and the State-Trait Anxiety Inventory respectively. RESULTS: During postoperative 24 h, three patients in the CPB group and 7 patients in the off-pump group were demonstrating a circadian secretion pattern, while they were disturbed in the remaining patients in both groups. Postoperative depression scores of patients in both groups were significantly higher than preoperative values. Postoperative anxiety scores of patients in the CPB group were significantly higher than those in the off-pump group. The CABG with CPB patients showed a significant deficit in the Digit Span subtest of the WAIS-R and the Stroop colour word interference test. The disturbed cortisol circadian secretion in the CPB group correlated with depression and the Stroop colour word interference test, whereas in the off-pump group it correlated with depression, Digit Span subtest (forward), symbol digit modalities test and the Stroop colour word interference test. Degree of depression correlated with some items of cognitive dysfunctions. CONCLUSION: Perioperative secretion rhythm of cortisol in patients undergoing CABG surgery with CPB or off-pump was disturbed. The disordered cortisol may correlate directly or indirectly through mood with neuropsychological deficits.

[Perioperative melatonin circadian secretion in patients undergoing coronary artery bypass grafting surgery].

OBJECTIVE: To investigate the circadian rhythm of perioperative melatonin secretion in patients undergoing coronary artery bypass grafting surgery. METHODS: Forty male patients scheduled for elective coronary artery bypass grafting surgery (CABG) under hypothermic cardiopulmonary bypass (CPB) or off-pump were allocated into two groups of 20 patients: CPB group and off-pump group. Blood samples were withdrawn from all patients immediately before the induction of anesthesia (baseline), 10 min after the induction of anesthesia, 10 min after heparinization, 30 min after commencement of CPB (or 2h after skin incision), before reversal of heparin with protamine, at the end of surgery, and. every 3 hours after operation until the twenty-fourth hour. The plasma concentration of melatonin was measured by using enzyme-linked immunosorbent assay. RESULTS: The plasma melatonin concentrations during and after CPB were higher than the baseline value in the CPB group. There were no differences in the melatonin concentrations in the off-pump group. In the CPB group the melatonin concentrations after induction, during CPB, and after CPB were 7.2 +/- 3.4, 10.5 +/- 5.2, and 9.5 +/- 4.0 respectively, all significantly higher than those in the off-pump (5.5 +/- 2.5, 6.3 +/- 2.0, and 5.7 +/- 2.1 respectively, all P < 0.05). During the twenty-four hours after operation, two patients in the CPB group and six patients in the off-pump group showed circadian rhythm of melatonin secretion. CONCLUSION: The perioperative circadian rhythm of melatonin secretion in patients undergoing CABG surgery with CPB or off-pump is disturbed, however relatively more patients under off-pump group regain secretion rhythm of melatonin in the immediate postoperative period. CPB may be one of the reasons for perioperative melatonin circadian secretion disturbance.