Effects of hydromorphone-based patient-controlled intravenous analgesia on postoperative hypoxaemia: a randomised controlled non-inferiority clinical trial.

OBJECTIVE: This study aimed to compare the effects of patient-controlled intravenous analgesia (PCIA) with and without low-basal infusion on postoperative hypoxaemia. DESIGN: A randomised parallel-group non-inferiority trial. SETTING: The trial was conducted at a grade-A tertiary hospital from December 2021 to August 2022. PARTICIPANTS: 160 adults undergoing gastrointestinal tumour surgery and receiving postoperative PCIA. INTERVENTIONS: Participants randomly received a low-basal (0.1 mg/hour of hydromorphone) or no-basal infusion PCIA for postoperative 48 hours. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was area under curve (AUC) per hour for hypoxaemia, defined as pulse oxygen saturation (SpO2) <95%. Secondary outcomes included: AUC per hour at SpO2<90% and <85%, hydromorphone consumption, ambulation time and analgesic outcomes up to 48 hours after surgery. RESULTS: Among 160 randomised patients, 159 completed the trial. An intention-to-treat analysis showed that AUC per hour (SpO2<95%) was greater in the low-basal infusion group compared with the no-basal infusion group, with a median difference of 0.097 (95% CI 0.001 to 0.245). Non-inferiority (margin: ratio of means (ROM) of 1.25) was not confirmed since the ROM between the two groups was 2.146 (95% CI 2.138 to 2.155). Hydromorphone consumption was higher in the low-basal group than in the no-basal group (median: 5.2 mg versus 1.6 mg, p<0.001). Meanwhile, there were no differences in the AUC values at the other two hypoxaemia thresholds, in ambulation time, or pain scores between the groups. CONCLUSIONS: Among the patients receiving hydromorphone PCIA after gastrointestinal tumour resection, low-basal infusion was inferior to no-basal infusion PCIA for postoperative hypoxaemia at SpO2<95% up to 48 hours after surgery. TRIAL REGISTRATION NUMBER: ChiCTR2100054317.

Inhaled Nitric Oxide ReDuce postoperatIve pulmoNAry complicaTions in patiEnts with recent COVID-19 infection (INORDINATE): protocol for a randomised controlled trial.

BACKGROUND: A history of SARS-CoV-2 infection has been reported to be associated with an increased risk of postoperative pulmonary complications (PPCs). Even mild PPCs can elevate the rates of early postoperative mortality, intensive care unit (ICU) admission and prolong the length of ICU and/or hospital stays. Consequently, it is crucial to develop perioperative management strategies that can mitigate these increased risks in surgical patients who have recently been infected with SARS-CoV-2. Accumulating evidence suggests that nitric oxide (NO) inhalation might be effective in treating COVID-19. NO functions in COVID-19 by promoting vasodilation, anticoagulation, anti-inflammatory and antiviral effects. Therefore, our study hypothesises that the perioperative use of NO can effectively reduce PPCs in patients with recent SARS-CoV-2 infection. METHOD AND ANALYSIS: A prospective, double-blind, single-centre, randomised controlled trial is proposed. The trial aims to include participants who are planning to undergo surgery with general anaesthesia and have been recently infected with SARS-CoV-2 (within 7 weeks). Stratified allocation of eligible patients will be performed at a 1:1 ratio based on the predicted risk of PPCs using the Assess Respiratory Risk in Surgical Patients in Catalonia risk index and the time interval between infection and surgery.The primary outcome of the study will be the presence of PPCs within the first 7 days following surgery, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm and aspiration pneumonitis. The primary outcome will be reported as counts (percentage) and will be compared using a two-proportion χ2 test. The common effect across all primary components will be estimated using a multiple generalised linear model. ETHICS AND DISSEMINATION: The trial is approved by the Institutional Review Board of Xijing Hospital (KY20232058-F1). The findings, including positive, negative and inconclusive results, will be published in scientific journals with peer-review processes. TRIAL REGISTRATION NUMBER: NCT05721144.

Association of adherence to the enhanced recovery after surgery pathway and outcomes after laparoscopic total gastrectomy.

OBJECTIVE: The current study used a composite outcome to investigate whether applying the ERAS protocol would enhance the recovery of patients undergoing laparoscopic total gastrectomy (LTG). EXPOSURES: Laparoscopic total gastrectomy and perioperative interventions were the exposure. An ERAS clinical pathway consisting of 14 items was implemented and assessed. Patients were divided into either ERAS-compliant or non-ERAS-compliant group according the adherence above 9/14 or not. MAIN OUTCOMES AND MEASURES: The primary study outcome was a composite outcome called 'optimal postoperative recovery' with the definition as below: discharge within 6 days with no sever complications and no unplanned re-operation or readmission within 30 days postoperatively. Univariate logistic regression analysis and multivariate logistic regression analysis were used to model optimal postoperative recovery and compliance, adjusting for patient-related and disease-related characteristics. RESULTS: A total of 252 patients were included in this retrospective study, 129 in the ERAS compliant group and 123 in the non-ERAS-compliant group. Of these, 79.07% of the patients in ERAS compliant group achieved optimal postoperative recovery, whereas 61.79% of patients in non-ERAS-compliant group did (P = 0.0026). The incidence of sever complications was lower in the ERAS-compliant group (1.55% vs. 6.5%, P = 0.0441). No patients in ERAS compliant group had unplanned re-operation, whereas 5.69% (7/123) of patients in non-ERAS-compliant group had (p = 0.006). The median length of the postoperative hospital stay was shorter in the in the ERAS compliant group (5.51 vs. 5.68 days, P = 0.01). Both logistic (OR 2.01, 95% CI 1.21-3.34) and stepwise regression (OR 2.07, 95% CI 1.25-3.41) analysis showed that high overall compliance with the ERAS protocol facilitated optimal recovery in such patients. In bivariate analysis of compliance for patients who had an optimal postoperative recovery, carbohydrate drinks (p = 0.0196), early oral feeding (P = 0.0043), early mobilization (P = 0.0340), and restrictive intravenous fluid administration (P < 0.0001) were significantly associated with optimal postoperative recovery. CONCLUSIONS AND RELEVANCE: Patients with higher ERAS compliance (almost 70% of the accomplishment) suffered less severe postoperative complications and were more likely to achieve optimal postoperative recovery.

Cardiopulmonary Adverse Events of Remimazolam versus Propofol During Cervical Conization: A Randomized Controlled Trial.

Purpose: This study aimed to compare the cardiopulmonary safety of remimazolam and propofol in patients undergoing cervical conization. Methods: This was a single-blind, parallel, randomized controlled study. A total of 204 patients scheduled for day surgery of cold knife cervical conization received either remimazolam-alfentanil anesthesia (remimazolam group) or propofol-alfentanil anesthesia (propofol group). The primary outcome was the incidence of intraoperative cardiopulmonary adverse events (a composite outcome of hypotension, bradycardia and hypoxemia). The occurrence of hypotension, bradycardia, hypoxemia and the degree of body movement were secondary outcomes, as well as the moment at which consciousness was lost, the interval between the end of anesthesia and the operating room's release of the patient, and the overall dosage of alfentanil administered during the procedure. Results: The incidence of intraoperative cardiopulmonary adverse events was 45 (44.1%) in the remimazolam group and 72 (70.6%) in the propofol group (absolute risk difference [95% CI], -26.47% [-39.55% to -13.39%]; odds ratio (OR) [95% CI], 0.43 [0.28 to 0.65]; P < 0.001). The remimazolam group showed lower incidences of hypotension and hypoxemia compared to the propofol group (P = 0.01 for both). No significant differences were observed in the overall alfentanil dosages administered, bradycardia, bodily movement, or time to losing consciousness between the two groups. Conclusion: In patients who underwent cold knife cervical conization, remimazolam-alfentanil anesthesia was associated with a reduced incidence of intraoperative cardiopulmonary adverse events compared with propofol-alfentanil anesthesia.

Temperature measurements of a wearable and wireless axillary sensor iThermonitor but not a bladder probe represents the core temperature during laparoscopic rectal surgery.

OBJECTIVE: To investigate whether the temperature recorded by an iThermonitor has better concordance with the core temperature than the bladder temperature recorded by a Foley catheter sensor in laparoscopic rectal surgery. METHODS: Eighty-two adults undergoing laparoscopic rectal surgery were enrolled. Temperatures were continuously measured by a distal oesophageal probe (the reference core temperature), axillary iThermonitor and Foley catheter sensor (bladder temperature) in each patient during surgery. Pairs of axillary and core temperatures or pairs of bladder temperature and core temperatures were compared and summarized using linear regression and the repeated-measured Bland-Altman method during the whole surgical period and pneumoperitoneum period. RESULTS: There were 3303 pairs of temperature measurements during the whole surgical period. The mean difference between iThermonitor and oesophageal was 0.05 °C ; the limits of agreement were - 0.48 to 0.56 °C. The mean difference between the oesophagus and bladder was 0.28 °C; the limits of agreement were - 0.39 to 0.94 °C (P < 0.001, F-test vs. iThermonitor). Ninety -five% of all iThermonitor values were within 0.5 °C of oesophageal temperature, whereas the proportion for oesophageal and bladder differences within 0.5 °C was only 84% (95% confidence interval 80-88%). Lin's CCC for the iThermonitor and bladder measurements were 0.842 (95%CI: 0.831-0.851) and 0.688 (95%CI: 0.673-0.703) respectively. Similar results were found during the pneumoperitoneum period. CONCLUSIONS: The temperature recorded by iThermonitor has better concordance with the core temperature than the bladder temperature recorded by Foley catheter sensor in laparoscopic rectal surgery.

Effects of hydromorphone-based intravenous patient-controlled analgesia with and without a low basal infusion on postoperative hypoxaemia: study protocol for a randomised controlled clinical trial.

INTRODUCTION: When patients receive patient-controlled intravenous analgesia (PCIA), no basal infusion is always recommended, as the addition of a basal infusion increases the occurrence of postoperative opioid-induced respiratory depression. However, few studies have investigated whether low basal infusions increase the incidence of postoperative hypoxaemia relative to no basal infusion. We intend to conduct a clinical trial to test the hypothesis that PCIA with a low basal infusion does not increase the occurrence of postoperative hypoxaemia relative to PCIA with no basal infusion. METHODS AND ANALYSIS: This single-centre parallel randomised controlled clinical trial will be conducted with 160 patients undergoing gastrointestinal tumour surgery. The assigned nurse will set analgesic pumps (low or no basal infusion PCIA) according to block-based randomisation sequence. Other investigators and all participants will be blinded to intervention allocation. All patients will be monitored continuously with the ep pod, a wireless wearable device, recording of oxygen saturation (SpO2) and daily ambulation duration for 48 hours postoperatively. Three follow-up evaluations will be conducted to assess the analgesic effect (Numeric Rating Scale (NRS) pain score) and opioid-related side effects (Overall Benefit of Analgesic Score (OBAS)). The primary outcome will be the area under the curve for hypoxaemia (defined as SpO2<95%) per hour. The secondary outcomes will be the areas under the curve for hypoxaemia defined as SpO2<90% and <85% per hour, hydromorphone consumption, OBASs at 24 and 48 hours postoperatively, NRS scores at 4, 24 and 48 hours postoperatively, and the ambulation time per hour over 48 hours. ETHICS AND DISSEMINATION: The study has been approved by the Xijing Hospital Ethics Committee (KY20212163-F-1). Written informed consent will be obtained from all patients or their authorised surrogates. All data will be managed with confidentiality. Findings will be disseminated at international conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2100054317.

Sufentanil Combined with Nalbuphine via Patient-Controlled Intravenous Analgesia After Cesarean Section: A Retrospective Evaluation.

Purpose: This retrospective study evaluated the efficacy, opioid consumption, and safety profile of two patient-controlled intravenous analgesia (PCIA) regimens (sufentanil combined with nalbuphine vs sufentanil alone) after cesarean section (CS). Patients and Methods: Parturients (n = 1808) received sufentanil combined with nalbuphine (SN group) or sufentanil alone (S group) as PCIA after CS. The primary outcome was the numeric rating scale (NRS) pain score with movement (NRS-M) at 24 h after CS. Secondary outcomes were NRS scores at rest (NRS-R) at 24 and 48 h after CS, NRS-M at 48 h after CS, cumulative PCIA bolus times, and opioid consumption during the first 24 and 48 h postoperatively, which was measured in morphine-equivalent doses. Results: The population comprised 993 and 815 subjects in the SN and S groups, respectively. At 24 and 48 h after CS, the respective NRS-M scores of the SN group (4.62, 3.37) were each significantly lower than those of the S group (5.18, 4.01; P < 0.01 for both). The corresponding NRS-S scores were similarly lower in the SN group (0.96, 0.19) than in the S group (2.05, 0.92; P < 0.01 for both). After adjusting for covariates, the SN group still had lower NRS-M than the S group at 24 h after CS (estimate adjusted = 0.565, P < 0.001). The PCIA bolus times were significantly lower in the SN group than in the S group. The rates of bradycardia and respiratory depression were lower in the SN group than in the S group. However, the rates of dizziness and postoperative hypotension were slightly higher in the SN group, and those of nausea/vomiting were comparable. Conclusion: Compared with sufentanil alone, sufentanil combined with nalbuphine for PCIA provided superior analgesia in parturient women after CS.

Postoperative short-term use of the nonsteroidal anti-inflammatory drug flurbiprofen did not increase the anastomotic leakage rate in patients undergoing elective gastrointestinal surgery-a retrospective cohort study.

BACKGROUND: Flurbiprofen has been one of the most commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in China and other Asian countries for perioperative multimodal analgesia in recent years, yet its association with anastomotic leakage in gastrointestinal anastomoses is unknown. The current study was designed to investigate whether short-term administration of flurbiprofen would increase the risk of anastomotic leakage in patients undergoing gastrointestinal surgery for cancer resection. METHODS: A total of 3653 patients (2487 (66.1%) men) undergoing elective operation for gastrointestinal cancer between 18 July 2017 and 30 Oct 2020 were included. The median age was 61 years (interquartile range 53-67 years). The exposure was the short-term postoperative use of flurbiprofen (defined as flurbiprofen treatment within the first week after surgery). The primary outcome was the frequency of clinical anastomotic leakage. RESULTS: Of 3653 patients with available data who were included in the final analysis, 2282 received flurbiprofen administration, and 1371 did not. Anastomotic leakage was not significantly increased among the patients receiving flurbiprofen compared with those who did not (1.62% v 1.46%; P=0.70). In-hospital mortality was comparable between the two groups (0.04% v 0.07%; P=0.72). After adjusted analysis, male sex (OR 3.51, 95% CI 1.80-6.85), ASA score of 3-4 (OR 2.69, 95% CI 1.62-4.48), and intraoperative infusion (OR 2.24, 95% CI 1.19-4.21) were identified as risk factors for anastomotic leakage. CONCLUSIONS: Postoperative short-term use of flurbiprofen did not increase the risk of anastomotic leakage in gastrointestinal anastomoses.

Development and External Validation of Safe Discharge Criteria After Radical Gastrectomy.

AIM: Enhanced recovery after surgery (ERAS) gradually shortens the length of stay but increases the rate of unplanned readmission after discharge. Currently, objective discharge criteria for patients after radical gastrectomy is lacking. This study aimed to construct and validate a nomogram for estimation of the possibility of safe discharge on the fifth-day post radical gastrectomy. METHODS: We enrolled 496 consecutive patients undergoing radical gastrectomy as the development cohort. After the fifth day of surgery, patients were assigned to the postoperative complication group and no postoperative complication group. Multivariate logistic regression analyses were performed for both groups. Then, we constructed the risk prediction model of postoperative severe complications (PSCs) and applied it to evaluate whether the patient could be discharged safely. The external validation cohort comprised 245 patients, whom we used to evaluate the capability of our model to predict the risk of PSCs. The primary measure was the negative predictive rate (NPR) and the area under the curve (AUC). RESULTS: Through multivariate analysis, gender, maximum body temperature on the 4th postoperative day (POD4), oral intake and ambulatory duration on POD4, the proportion of neutrophils (≥75% or <75%) and pain score (≥4 or <4) on POD5, and defecation with 5 days after the procedure (yes or no) were identified as independent predictors for PSCs. Upon incorporation of these variables, the nomogram demonstrated a good NPR of 0.957 and 0.916 and AUC of 0.918 and 0.719 in the two cohorts, respectively. With a nomogram score of 110, patients were stratified into low and high risk of PSCs. CONCLUSION: The nomogram demonstrated good predictive potential for low-risk patients. It could serve as an objective safe discharge approach for patients after the fifth day of radical gastrectomy.

Repeated Preoperative Intranasal Administration of Insulin Decreases the Incidence of Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Radical Gastrointestinal Surgery: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study.

STUDY OBJECTIVES: This study aimed to investigate the effects of repeated preoperative intranasal administration of insulin on the incidence of postoperative delirium (POD) and the levels of serum pro-inflammatory markers in elderly patients undergoing laparoscopic radical gastrointestinal surgery. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING: General Hospital of Western Theater Command from August 2019 to December 2019. PATIENTS: Ninety elderly patients underwent laparoscopic radical gastrointestinal tumor resections under general anesthesia. INTERVENTIONS: Patients were randomly divided into a control group (0.5 mL saline administered intranasally) or an insulin group (20 U/0.5 mL insulin administered intranasally) for 2 days prior to surgery, with 45 patients in each group. MEASUREMENTS: The incidence of delirium was measured at postoperative day 1 (T2), day 3 (T3), and day 5 (T4) using the Confusion Assessment Method for the intensive care unit (CAM-ICU). Plasma levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were measured at T0 (before insulin or saline administration), T1 (at the end of surgery), T2, T3, and T4 by enzyme-linked immunosorbent assay. MAIN RESULTS: Compared with the control group, the insulin group demonstrated a decreased POD incidence (12.5% vs. 47.5%, p = 0.001) within 5 days after surgery. The incidence of POD was significantly lower in the Ins group than in the Con group at T2 (12.5% vs. 32.5%, p = 0.032) and at T3 (2.5% vs. 20%, p = 0.034). The incidence of POD decreased in both groups over time and was similar at T4 (0% vs 10%, p = 0.116). Compared with the baseline value at T0, serum TNF-α, IL-6 and IL-1ß concentrations increased significantly at T1-4 (p <0.05). Compared with the control group at the same time point, the expression levels of TNF-α, IL-6 and IL-1ß in group I at T2 and T3 were significantly reduced (p <0.05). The incidence rates of adverse events were similar in the two groups. CONCLUSIONS: Repeated preoperative intranasal administration of insulin prevented the occurrence of delirium after laparoscopic radical gastrointestinal surgery in elderly patients and reduced TNF-α, IL-1ß, and IL-6 levels.

Perioperative use of renin-angiotensin system inhibitors and outcomes in patients undergoing cardiac surgery.

It remains disputable about perioperative use of renin-angiotensin system inhibitors (RASi) and their outcome effects. This multicenter retrospective cohort study examines association between use of perioperative RASi and outcomes in patients undergoing coronary artery bypass graft and/or valve surgery. After the exclusion, the patients are divided into 2 groups with or without preoperative RASi (PreRASi, n = 8581), or 2 groups with or without postoperative RASi (PostRASi, n = 8130). With using of propensity scores matching to reduce treatment selection bias, the study shows that PreRASi is associated with a significant reduction in postoperative 30-day mortality compared with without one (3.41% vs. 5.02%); PostRASi is associated with reduced long-term mortality rate compared with without one (6.62% vs. 7.70% at 2-year; 17.09% vs. 19.95% at 6-year). The results suggest that perioperative use of RASi has a significant benefit for the postoperative and long-term survival among patients undergoing cardiac surgery.

Comparative Evaluation of a New Depth of Anesthesia Index in ConView® System and the Bispectral Index during Total Intravenous Anesthesia: A Multicenter Clinical Trial.

The performance of a new monitor for the depth of anesthesia (DOA), the Depth of Anesthesia Index (Ai) based on sample entropy (SampEn), 95% spectral edge frequency (95%SEF), and burst suppression ratio (BSR) was evaluated compared to Bispectral Index (BIS) during total intravenous anesthesia (TIVA). 144 patients in six medical centers were enrolled. General anesthesia was induced with stepwise-increased target-controlled infusion (TCI) of propofol until loss of consciousness (LOC). During surgery propofol was titrated according to BIS. Both Ai and BIS were recorded. Primary outcomes: the limits of agreement between Ai and BIS were -17.68 and 16.49, which were, respectively, -30.0% and 28.0% of the mean value of BIS. Secondary outcomes: prediction probability (Pk) of BIS and Ai was 0.943 and 0.935 (p=0.102) during LOC and 0.928 and 0.918 (p=0.037) during recovery of consciousness (ROC). And the values of BIS and Ai were 68.19 and 66.44 at 50%LOC, and 76.65 and 78.60 at 50%ROC. A decrease or an increase of Ai was significantly greater than that of BIS when consciousness changes (during LOC: -9.13±10.20 versus -5.83±9.63, p<0.001; during ROC: 10.88±11.51 versus 5.32±7.53, p<0.001). The conclusion is that Ai has similar characteristic of BIS as a DOA monitor and revealed the advantage of SampEn for indicating conscious level. This trial is registered at Chinese Clinical Trial Registry with ChiCTR-IOR-16009471.

[Effect of Long-term Dairy Manure Amendment on N2O and NO Emissions from Summer Maize-Winter Wheat Cropping Systems].

Annual nitrous oxide (N2O) and nitric oxide (NO) emissions were measured within a 27 year fertilization experiment in Guanzhong Plain. Gas samples were collected using static chambers from June 2017 to June 2018. The primary objectives of this study were to quantify the variations in N2O and NO emissions and evaluate the effect of manure amendment on gas losses. Three treatments were set up in the field using a completely random block design. The control treatment (CK) remained unfertilized throughout the year. The synthetic fertilizers (NPK) and NPK plus dairy manure (NPKM) treatments received an annual nitrogen (N) input at a rate of 353 kg·hm-2. In the summer maize season, the NPK and NPKM treatments received urea as a N source at 188 kg·hm-2. In the winter wheat season, the NPK treatments received urea at 165 kg·hm-2. The NPKM treatment received the same amount of N as the NPK treatment but with 30% from urea and 70% from dairy manure. The results showed that N2O and NO emissions from the CK treatment were consistently low during the experimental period. Large emission peaks were captured in the NPK and NPKM treatments, mostly responding to fertilizer application and irrigation. The largest N2O and NO peaks were up to 103.0 g·(hm2·d)-1 and 71.0 g·(hm2·d)-1, respectively, and both occurred in the NPKM treatment during the summer maize season. The NO/N2O ratio was negatively related to soil water-filled pore space (P<0.01) at soil temperatures above 20℃ for the NPK and NPKM treatments, indicating the regulatory effect of soil temperature and water content on gas fluxes. Annual N2O emissions from the CK, NPK, and NPKM treatments were 0.21 kg·hm-2, 2.32 kg·hm-2, and 2.15 kg·hm-2, respectively, with a non-significant difference between the NPK and NPKM treatments (P=0.74). Annual NO emissions from the CK, NPK, and NPKM treatments were 0.23 kg·hm-2, 0.80 kg·hm-2, and 1.46 kg·hm-2, respectively, with a significant difference between the NPK and NPKM treatments (P<0.05). We concluded that long-term dairy manure amendment did not influence N2O emissions but increased NO emissions.

Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C.

We have previously reported that Cystatin C (CysC) is a pivotal mediator in the neuroprotection induced by hyperbaric oxygen (HBO) preconditioning; however, the underlying mechanism and how CysC changes after stroke are not clear. In the present study, we demonstrated that CysC expression was elevated as early as 3 h after reperfusion, and this was further enhanced by HBO preconditioning. Concurrently, LC3-II and Beclin-1, two positive-markers for autophagy induction, exhibited increases similar to CysC, while knockdown of CysC blocked these elevations. As a marker of autophagy inhibition, p62 was downregulated by HBO preconditioning and this was blocked by CysC knockdown. Besides, the beneficial effects of preserving lysosomal membrane integrity and enhancing autolysosome formation induced by HBO preconditioning were abolished in CysC-/- rats. Furthermore, we demonstrated that exogenous CysC reduced the neurological deficits and infarct volume after brain ischemic injury, while 3-methyladenine partially reversed this neuroprotection. In the present study, we showed that CysC is biochemically and morphologically essential for promoting autophagic flux, and highlighted the translational potential of HBO preconditioning and CysC for stroke treatment.

Cystatin C Is a Crucial Endogenous Protective Determinant Against Stroke.

BACKGROUND AND PURPOSE: Endogenous neuroprotection can be induced by ischemic and nonischemic preconditioning. However, not all subjects that undergo preconditioning exhibit similar favorable outcome. This study is to explore the molecules responsible for this phenomenon and find new therapeutic targets for stroke. METHODS: Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion. High-throughput proteomic technique, isobaric tag for relative and absolute quantification, was used to screen differentially expressed proteins in the rats that developed ischemic tolerance from hyperbaric oxygen (HBO) preconditioning. The proteomic results were verified by Western blot and ELISA. Then, short interfering RNA and gene knockout rats were used to further determine the pivotal role of candidate proteins in HBO preconditioning-induced endogenous neuroprotection. Finally, lysosomal permeability was tested to elaborate the mechanism underlying this intrinsic neuroprotective effect. RESULTS: Nine proteins differentially expressed in the serum of rats, which acquired benefits from HBO preconditioning, were screened and identified. Western blot and ELISA revealed that cystatin C (CysC) and mannose-binding lectin protein C were uniquely changed in rats with smaller infarction after HBO preconditioning and cerebral ischemia. Knockdown and knockout of CysC abolished HBO-induced neuroprotection. Moreover, HBO-induced endogenous CysC elevation preserved lysosomal membrane integrity after stroke in wild-type rats but not in CysC siRNA infusion or CysC-/- rats. Most importantly, exogenous CysC also induced neuroprotection against ischemic/reperfusion injury. CONCLUSIONS: CysC is a crucial determinant contributing to endogenous neuroprotection. It is also a novel candidate for stroke treatment through maintaining lysosomal membrane integrity.

Hydrogen-rich saline improves survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation in rats.

BACKGROUND: Sudden cardiac arrest is a leading cause of death worldwide. Three-fourths of cardiac arrest patients die before hospital discharge or experience significant neurological damage. Hydrogen-rich saline, a portable, easily administered, and safe means of delivering hydrogen gas, can exert organ-protective effects through regulating oxidative stress, inflammation, and apoptosis. We designed this study to investigate whether hydrogen-rich saline treatment could improve survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation, and the mechanism responsible for this effect. METHODS: Sprague-Dawley rats were subjected to 8 minutes of cardiac arrest by asphyxia. Different doses of hydrogen-rich saline or normal saline were administered IV at 1 minute before cardiopulmonary resuscitation, followed by injections at 6 and 12 hours after restoration of spontaneous circulation, respectively. We assessed survival, neurological outcome, oxidative stress, inflammation biomarkers, and apoptosis. RESULTS: Hydrogen-rich saline treatment dose dependently improved survival and neurological function after cardiac arrest/resuscitation. Moreover, hydrogen-rich saline treatment dose dependently ameliorated brain injury after cardiac arrest/resuscitation, which was characterized by the increase of survival neurons in hippocampus CA1, reduction of brain edema in cortex and hippocampus, preservation of blood-brain barrier integrity, as well as the decrease of serum S100ß and neuron-specific enolase. Furthermore, we found that the beneficial effects of hydrogen-rich saline treatment were associated with decreased levels of oxidative products (8-iso-prostaglandin F2α and malondialdehyde) and inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and high-mobility group box protein 1), as well as the increased activity of antioxidant enzymes (superoxide dismutase and catalase) in serum and brain tissues. In addition, hydrogen-rich saline treatment reduced caspase-3 activity in cortex and hippocampus after cardiac arrest/resuscitation. CONCLUSIONS: Hydrogen-rich saline treatment improved survival and neurological outcome after cardiac arrest/resuscitation in rats, which was partially mediated by reducing oxidative stress, inflammation, and apoptosis.

Gastrodin ameliorates depression-like behaviors and up-regulates proliferation of hippocampal-derived neural stem cells in rats: involvement of its anti-inflammatory action.

Gastrodin (GAS), an active constituent of the Chinese herbal medicine tianma, has antidepressant-like activity in animals but no specific molecular mechanisms have been identified. In the present study, chronic unpredictable stress (CUS) was used to establish a rat depression model; The sucrose preference test, forced swim test and Morris water maze test were used to assess depression-like behaviors (anhedonia, behavioral despair, motor retardation, and poor spatial memory), and the proliferation of hippocampal stem cells was tested by BrdU immunohistochemistry. The stress and inflammatory responses were assayed by measuring IL-RA, NF-κB, and p-iκB expression by Western blot and IL-1ß production by ELISA. Direct and indirect effects of GAS on NSC viable cell number were examined in vitro by WST-1 and BrdU assays. It was found that GAS (200 mg/kg daily) reversed all tested depression-like behaviors in CUS model rats and up-regulated NSCs proliferation in the hippocampus. Enhanced expression of p-iκB, NF-κB, and IL-1ß by CUS was also reversed by GAS. Moreover, in vitro experiments revealed that GAS alone did not increase the viability of NSCs but protected them from IL-1ß-induced damage. These results support the antidepressant and neuroprotective effects of GAS, and GAS may reduce depression-like behaviors by protecting hippocampal NSCs against the proinflammatory cytokine IL-1ß.

Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system.

Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose preference test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal cannabinoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors.

Rosmarinic acid ameliorates PTSD-like symptoms in a rat model and promotes cell proliferation in the hippocampus.

Rosmarinic acid (RA) is an important component of Chinese herbal medicine treatments and has been demonstrated to exert therapeutic effects in mood disorders. The present study was designed to assess the effects of RA on post-traumatic stress disorder (PTSD)-like symptoms, hippocampal cell proliferation and phosphorylation extracellular regulated protein kinases (pERK1/2) expression. We found that administration of RA (10mg/kg) alleviated PTSD-like symptoms in rats exposed to an enhanced single prolonged stress (ESPS) paradigm and restored hippocampal proliferation and pERK1/2 expression. Interestingly, the effects of RA were inhibited by the blockage of the ERK signaling. These data support the use of RA for treating PTSD and indicate that the ERK1/2 signaling cascade may play a critical role in the therapeutic efficacy of RA in treating such conditions.

The loss of estrogen efficacy against cerebral ischemia in aged postmenopausal female mice.

Estrogen has been shown to have neuroprotective effects in numerous experimental studies involving young and adult animals. However, several clinical trials have found that in aged postmenopausal women who received estrogen replacement therapy, there did not appear to be a reduction in the incidence of stroke. The aim of this study was to investigate the effects of physiological dosages of estrogen on aged female mice subjected to ischemia-reperfusion injury. Adult ovariectomized (OVX) female mice and 22-month-old female mice received daily subcutaneous injections of 100 µg/kg or 300 µg/kg 17ß-estradiol (E2) at the back of the neck for four weeks, and the expression levels of estrogen receptor (ER) α and ß in the cerebral cortex were determined using real-time PCR and Western blotting analyses. To mimic ischemic stroke, the mice received middle cerebral artery occlusion (MCAO) treatment for 1h followed by a 24-h reperfusion period. The mice were then subjected to neurological deficit testing and infarct volume evaluation. The aged mice showed higher neurological deficit scores and larger infarct volumes compared with the adult mice. Both the lower and higher physiological dosages of E2 significantly improved the neurological test scores and decreased the infarct volume in the adult mice; however, E2 showed no neuroprotective effects in the aged mice. Furthermore, the protein expression of ERα and ERß in the cerebral cortex was significantly decreased in the aged mice compared with the adult mice, and this decrease was not rescued by E2 treatment. These results indicate that the down-regulation of ERα and ERß in the cerebral cortex may contribute to the loss of estrogen efficacy against ischemic injury in aged females and may point to new therapies for ischemic stroke in aged postmenopausal women.