Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Genomic gain/methylation modification/hsa-miR-132-3p increases RRS1 overexpression in liver hepatocellular carcinoma.

This study aimed to determine the upstream regulatory factors affecting ribosome biogenesis regulator 1 homolog (RRS1) expression and the development and prognosis of liver hepatocellular carcinoma (LIHC). The expression profiles of RRS1 were evaluated in pan-cancer tissues and liver tumor cell lines. The associations of RRS1 with pan-cancer survival, immune infiltrations, immune checkpoints, and drug sensitivity were identified. We explored the potential upstream regulatory mechanisms of RRS1 expression. Hsa-miR-132-3p knockdown, CCK-8 assays, transwell, and wound healing assays were performed to validate the regulatory effect of hsa-miR-132-3p on RRS1 expression and the development of LIHC. Our findings demonstrated that RRS1 was significantly elevated in 27 types of cancers. RRS1 predicts a poor outcome of LIHC, lung adenocarcinoma, head and neck cancer, and kidney papillary cell carcinoma. RRS1 expression showed a significant association with immune cell infiltrates and the expression of immune checkpoints-related genes in LIHC tissues. Increased RRS1 expression may have a negative effect on these anticancer drugs of LIHC. Low methylation of the RRS1 promoter and its genomic gain may elevate RRS1 expression and predict poor prognosis for LIHC. Increased hsa-miR-132-3p expression may elevate RRS1 expression and result in poor prognosis for LIHC. Hsa-miR-132-3p inhibition can decrease RRS1 expression and the development of liver tumor cell lines. Low methylation of the RRS1 promoter, RRS1 genomic gain, and hsa-miR-132-3p upregulation in LIHC may promote RRS1 upregulation and thus lead to the development and poor prognosis for LIHC. RRS1 is a promising therapeutic target for LIHC.

Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-κB/COX1 inflammatory signaling in ischemic cortex.

Post-stroke anxiety (PSA) is a kind of affective disorder occurring after a stroke, with anxiety as the primary clinical manifestation. PSA's mechanism is unclear, and there are few prevention and treatment measures. Our previous study found that HDAC3 could activate NF-κB signaling through mediated p65 deacetylation, which further influenced microglia activation. That implies HDAC3 may be the key mediator in ischemic stroke mice and modulates anxiety susceptibility to stress. This study established a PSA model in male C57BL/6 mice through photothrombotic stroke combined with chronic restrain stress. We focused on exploring whether esketamine administration can alleviate anxiety-like behavior and neuroinflammation, which may be associated with inhibiting HDAC3 expression and NF-κB pathway activation. The results showed that esketamine administration alleviated anxiety-like behavior in PSA mice. And the results showed that esketamine alleviated cortical microglial activation, altered microglial number, and kept morphology features. Furthermore, the results showed that the expression of HDAC3, phosphor-p65/p65, and COX1 significantly decreased in esketamine-treated PSA mice. Besides, we also found that esketamine reduced PGE2 expression, one of the primary regulators of negative emotions. Interestingly, our results indicate that esketamine reduced the perineuronal net (PNN) number in the pathological process of PSA. In conclusion, this study suggests esketamine could alleviate microglial activation, reduces inflammatory cytokine, and inhibits the expression of HDAC3 and NF-κB in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential therapeutic target for applying esketamine to PSA.

A modified mouse model of perioperative neurocognitive disorders exacerbated by sleep fragmentation.

Aging is one of the greatest risk factors for postoperative cognitive dysfunction (POCD), also known as perioperative neurocognitive disorder (PND). Animal models of PND are usually induced in mice over 18 months of age, which imposes expensive economic and time costs for PND-related studies. Sleep disorders, including sleep fragmentation, are reported to aggravate memory impairment in neurocognitive-related diseases such as Alzheimer's disease (AD). Therefore, the aim of the present study was to explore whether a PND model could be constructed in younger mice with the help of fragmented sleep. We found that fragmented sleep followed by laparotomy under isoflurane anesthesia could stably induce PND in 15-month-old mice. To determine whether the neurocognitive decline in this model could be salvaged by clinical treatments, we administered repetitive transcranial magnetic stimulation (rTMS) to the model mice before anesthesia and surgery. We found that 10 days of high-frequency rTMS (HF-rTMS) could improve spatial learning and memory deficits in this modified PND model. We are the first to successfully construct a PND model in younger mice,which is more economical, that can be used as an alternative model for future PND studies.

The Impact on 30-Day Mortality From a Brief Focused Ultrasound-Guided Management Protocol Immediately Before Emergency Noncardiac Surgery in Critically Ill Patients: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To determine whether brief ultrasound-guided treatment of hemodynamic shock and respiratory failure immediately before emergency noncardiac surgery reduced 30-day mortality. DESIGN: Parallel, nonblinded, randomized trial with 1:1 allocation to control and intervention groups. SETTING: Twenty-eight major hospitals within China. PARTICIPANTS: Six-hundred sixty patients ≥14 years of age, scheduled for emergency noncardiac surgery with evidence of shock (heart rate >120 beat/min, systolic blood pressure< 90 mmHg or requiring inotrope infusion), or respiratory failure (Pulse Oxygen Saturation <92%, respiratory rate >20 beat/min, or requiring mechanical ventilation). INTERVENTIONS: A brief (<15 minutes) focused ultrasound of ventricular filling and function, lung, and peritoneal spaces, with predefined treatment recommendation based on the ultrasound was performed before surgery or standard care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 30-day mortality. Secondary outcomes included changes in medical or surgical diagnosis and management due to ultrasound, intensive care unit, and hospital stay and cost, and Short Form-8 quality-of-life scores. Although there were frequent changes in diagnosis (82%) and management (49%) after the ultrasound, mortality at 30 days was not different between groups (50 [15.7%] v 53 [16.3%]; odds ratio 1.05, 0.69-1.6, p = 0.826). There were no differences in the secondary outcomes of the days spent in the hospital (mean 13.8 days, 95% confidence interval [CI] 12.1-15.6 v 14.4 d, 11.8-17.1, p = 0.718) or intensive care unit (mean 9.3 days, 95% CI 7.7-11.0 v 8.7 d, 7.2-10.2, p = 0.562), hospital cost (USD$14.5K, 12.2-16.7 v 13.7, 11.5-15.9, p = 0.611) or Short Form-8 scores at one year (mean 80.9, 95% CI 78.4-83.3 v 79.7, 76.9-82.5, p = 0.54) between participants allocated to the ultrasound and control groups. CONCLUSIONS: In critically ill patients with hemodynamic shock or respiratory failure, a focused ultrasound-guided management did not reduce 30-day mortality but led to frequent changes in diagnosis and patient management.

Study protocol for a randomised controlled clinical trial comparing desflurane-based versus propofol-based anaesthesia on postanaesthesia respiratory depression in patients with obstructive sleep apnoea after major abdominal surgery.

INTRODUCTION: Patients with obstructive sleep apnoea (OSA) are more sensitive to postanaesthesia respiratory depression. Whether different anaesthetic regimens (intravenous-based or inhalational-based general anaesthesia) affect the postanaesthesia respiratory depression is controversial. Although desflurane has been reported that presents favourable rapid recovery profile in special patients including whom with OSA, the strong clinical evidence of the benefit on postanaesthesia respiratory depression is far from being revealed. This study aims to fill this knowledge gap by investigating the postanaesthesia respiratory depression in postanaesthesia care unit (PACU) in patients with OSA after major abdominal surgery, followed by desflurane-based anaesthesia compared with propofol-based anaesthesia. METHODS AND ANALYSIS: Eight hundred and fifty-four patients with OSA scheduled for elective major abdominal surgery will be randomly 1:1 assigned to desflurane-based (n=427) or propofol-based anaesthesia (n=427) using a computer-generated randomisation scheme with permuted block size maintained by a centralised randomisation centre. Patients will be assessed before and a consecutive 3 days after their surgery according to the standardised tasks. Demographic data as well as surgical and anaesthesia information will be collected for the duration of the procedure. Incidence of postanaesthesia respiratory depression in PACU as well as anaesthesia recovery, emergence delirium, postoperative nausea and vomiting, rescue analgesia, duration of PACU and hospital stay, and any other adverse events will be assessed at the given study time point. Investigators performing postoperative follow-up are not involved in both anaesthesia implementation and postoperative care. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics board at Xiang'an Hospital of Xiamen University (XAHLL2019003). The results of this study will be published in a peer-review journal and presented at national conferences as poster or oral presentations. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: ChiCTR2000031087.

The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain.

Ulinastatin is a broad-spectrum protease inhibitor widely used for the treatment of various inflammation-related diseases owing to its recognized excellent anti-inflammatory and cytoprotective properties. However, whether ulinastatin can relieve postoperative pain remains unclear. In this study, we evaluated the analgesic effects of ulinastatin administered either as a single agent or in combination with sufentanil in a validated preclinical rat model of postoperative pain induced by plantar incision. We found that incisional surgery on the hind paw of these rats induced sustained ipsilateral mechanical pain hypersensitivity that lasted for at least 10 days. A single intraperitoneal (i.p.) injection of ulinastatin prevented the development and reversed the maintenance of incision-induced mechanical pain hypersensitivity in a dose-dependent manner. However, ulinastatin had no effect on the baseline nociceptive threshold. Moreover, repeated i.p. injections of ulinastatin persistently attenuated incision-induced mechanical pain hypersensitivity and promoted recovery from the surgery. The rats did not develop any analgesic tolerance over the course of repeated injections of ulinastatin. A single i.p. injection of ulinastatin was also sufficient to inhibit the initiation and maintenance of incision-induced hyperalgesic priming when the rats were subsequently challenged with an ipsilateral intraplantar prostaglandin E2 injection. Furthermore, the combined administration of ulinastatin and sufentanil significantly enhanced the analgesic effect of sufentanil on postoperative pain, which involved mechanisms other than a direct influence on opioid receptors. These findings demonstrated that ulinastatin had a significant analgesic effect on postoperative pain and might be a novel pharmacotherapeutic agent for managing postoperative pain either alone or as an adjuvant.

Neuroprotective effect of ketamine against TNF-α-induced necroptosis in hippocampal neurons.

Tumour necrosis factor-α (TNF-α), a crucial cytokine, has various homeostatic and pathogenic bioactivities. The aim of this study was to assess the neuroprotective effect of ketamine against TNF-α-induced motor dysfunction and neuronal necroptosis in male C57BL/6J mice in vivo and HT-22 cell lines in vitro. The behavioural testing results of the present study indicate that ketamine ameliorated TNF-α-induced neurological dysfunction. Moreover, immunohistochemical staining results showed that TNF-α-induced brain dysfunction was caused by necroptosis and microglial activation, which could be attenuated by ketamine pre-treatment inhibiting reactive oxygen species production and mixed lineage kinase domain-like phosphorylation in hippocampal neurons. Therefore, we concluded that ketamine may have neuroprotective effects as a potent inhibitor of necroptosis, which provides a new theoretical and experimental basis for the application of ketamine in TNF-α-induced necroptosis-associated diseases.

Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats.

Analgesic strategy of a single drug analgesia in bone cancer pain (BCP) has shifted to combined analgesia with different drugs which have different mechanism. After tumor cell inculation, the activation of signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK) signaling pathway are involved in the development and maintenance of BCP, whereas a decrease in the expression of spinal STAT3 and ERK through using their specific blocker, lead to attenuation of BCP. Hence, in this study, we clarified that intrathecal (i.t.) injection of midazolam (MZL) and ropivacaine (Ropi) induces synergistic analgesia on BCP and is accompanied with different mechanisms of these analgesic effect. Hargreaves heat test was used to detect the analgesic effect of single dose of i.t. MZL, Ropi and their combination on the BCP rats. At consecutive daily administration experiment, thermal hyperalgesia was recorded, and immunohistochemical staining was used to detect the expression of c-Fos, spinal glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1). Then, western blot analysis was used to examine spinal TSPO, GFAP, IBA-1, pERK/ERK and pSTAT3/STAT3 levels on day 14 after tumor cell inoculation. i.t. MZL or Ropi showed a short-term analgesia dose-dependently, and MZL displayed better effect on inhibition of pSTAT3 expression than pERK, but Ropi was just the reverse, then consecutive daily administrations of their combination acted synergistically to attenuate thermal hyperalgesia with downregulated spinal 'neuron-astrocytic activation' in the BCP rats. i.t. co-delivery of MZL and Ropi shows synergistic analgesia on the BCP with the inhibition of spinal 'neuron-astrocytic activation'. Spinal different signaling pathway inhibition for MZL and Ropi may be involved in this process.

Neuromuscular effect of dexmedetomidine on sevoflurane: an open-label, dose-escalation clinical trial.

BACKGROUND: Sevoflurane presents reliable central neuromuscular effects. However, little knowledge is available regarding the interaction between sevoflurane and demedetomidine. We evaluated the neuromuscular effect of dexmedetomidine on sevoflurane in patients with normal neuromuscular transmission and calculated the 50% effective concentration (EC50). METHODS: One-hundred and forty-four ASA grade I~II patients with normal neuromuscular transmission, aged 20~60 years old, undergoing lower limbs surgery were enrolled in this open-label, dose-escalation clinical trial. Patients were randomly assigned into 12 groups. Each patient received intravenous 0, 0.5, or 1.0 µg/kg dexmedetomidine 15 min after inhaling 0.7, 1.0, 1.4, or 2.0 MAC sevoflurane. Neuromuscular monitoring was recorded from the adductor pollicis muscle by using acceleromyography with train-of-four (TOF) stimulation of the ulnar nerve (2 Hz every 20 s). TOF ratio was recorded before inhaling sevoflurane, 15 min after keeping constant at target MAC of sevoflurane, 30 min after receiving target dose of dexmedetomidine, and 15 min after sevoflurane washing out. RESULTS: Sevoflurane produced a concentration-dependent decrease in TOF ratio. Mean TOF ratio in 0.7, 1.0, 1.4, and 2.0 MAC groups was 97.9%, 94.9%, 84.7%, and 77.2%, respectively. Neuromuscular EC50 of sevoflurane was 1.31 MAC (95% CI: 1.236~1.388 MAC). Intravenous 0.5 and 1.0 µg/kg dexmedetomidine decreased 3.1% (EC50: 1.27 MAC [95% CI: 1.206~1.327 MAC]) and 10.7% (EC50: 1.17 MAC [95% CI: 1.122~1.217 MAC]) of neuromuscular EC50, respectively. CONCLUSIONS: Sevoflurane has a concentration-dependent central neuromuscular effect in patients with normal neuromuscular transmission. Intravenous dexmedetomidine dose-dependently decreases the neuromuscular EC50 of sevoflurane.

The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain.

Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal 'neuron-astrocytic' activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti-inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL. The analgesic effects of ROL were evaluated using the Von Frey and Hargreaves tests. Immunofluorescence staining was used to determine the number of c-Fos immunoreactive neurons, and the expression of spinal astrocytes and microglial activation on day 14 after tumor cell inoculation. Enzyme­linked immunosorbent assay (ELISA) was used to detect the expression of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α] and chemokines (CCL2), and western blot analysis was then used to examine the spinal phosphodiesterase 4 (PDE4), ionized calcium binding adapter molecule-1 (IBA-1) and JNK levels on day 14 after tumor cell inoculation. The results revealed that ROL exerted a short-term analgesic effect in a dose-dependent manner, and consecutive daily injections of ROL exerted continuous analgesic effects. In addition, spinal 'neuron­astrocytic' activation was suppressed and was associated with the downregulation of spinal IL-1ß, IL-6 and TNF-α expression, and the inhibition of PDE4B and JNK levels in the spine was also observed. In addition, the level of CCL2 was decreased in the rats with BCP. The JNK inhibitor, SP600125, decreased CCL2 expression and attenuated pain behavior. Following co-treatment with ROL and SP600125, no significant increases in thermal hyperalgesia and CCL2 expression were observed compared with the ROL group. Thus, our findings suggest that the analgesic effects of ROL in BCP are mainly mediated through the inhibition of 'neuron­astrocytic' activation, which occurs via the suppression of spinal JNK/CCL2 signaling.

Effects of Systemic Magnesium on Post-operative Analgesia: Is the Current Evidence Strong Enough?

BACKGROUND: Clinical studies have been previously carried out on the efficacy of systemic magnesium to minimize postoperative pain, however, with controversial results. A quantitative meta-analysis was performed to evaluate the analgesic efficacy and safety of systemic magnesium on post-operative pain. STUDY DESIGN: Comprehensive systematic review of all relevant, publsished randomized controlled trials. METHODS: A search was conducted of published literature in MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to Sep-Oct 2014. Randomized controlled trials (RCTs) that compared magnesium with placebo were identified. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) with suitable effect model. RESULTS: Twenty-seven RCTs involving 1,504 patients were included. In total, peri-operative magnesium significantly reduced the pain score at rest (SMD, -1.43, 95% CI, -2.74 to -0.12, < 0.01). Magnesium significantly reduced analgesic consumption (SMD, -1.72, 95% CI, -3.21 to -0.23) in patients undergoing urogenital, orthopaedic, and cardiovascular surgeries, but was inconclusive for patients receiving gastrointestinal surgeries. The obvious analgesia of systemic magnesium was observed on reducing the pain score during movement at 24 hours after operation (SMD, -0.05, 95% CI, -0.43 to 0.32). Moreover, magnesium administration showed a beneficial effect with regard to intra-operative hemodynamics and reduced extubation time in the cardiovascular surgery patients (WMD, -29.34 min, 95% CI, -35.74 to -22.94, P < 0.01). LIMITATIONS: Focused only on the quality of analgesia on postoperative pain with regards to surgery type. CONCLUSIONS: Our study suggests that systemic magnesium during general anesthesia significantly decreases post-operative pain scores without increasing adverse events. It should be noted that since there are 18 ongoing RCTs without published data, it is still premature to draw conclusions on the long-term analgesic effects of magnesium as well as potential gender or age difference.