Preoperative frailty predicts postoperative pain after total knee arthroplasty in older patients: a prospective observational study.

PURPOSE: Frailty is reportedly associated with postoperative adverse outcomes and may increase the risk of post-surgical pain. Our study aimed to explore whether frailty was an independent risk factor for pain after total knee arthroplasty (TKA) in older patients. METHODS: Included in this prospective observational study were patients aged 65 or older who underwent primary TKA. Frailty of the patients was assessed before surgery using the comprehensive geriatric assessment-frailty index and pain was evaluated before and after surgery using the Numerical Rating Scale. RESULTS: Of the 164 patients including 125 females with a mean age of 71.4 ± 4.6 years, 51 patients were identified as being frail. Patients with chronic post-surgical pain had a significantly higher frailty index than those without chronic post-surgical pain, which was the same in patients with acute post-surgical pain. After adjusting for other confounding factors, frailty was shown to be an independent risk factor for both acute (OR: 13.23, 95% CI 3.73-46.93, P < 0.001) and chronic post-surgical pain (OR: 4.24, 95% CI 1.29-14.00, P = 0.02). The area under the receiver operating characteristic curve for frailty predicting chronic post-surgical pain was 0.73 (P < 0.001, 95% CI 0.65-0.81). CONCLUSIONS: Our findings demonstrated that preoperative frailty in older patients was a predictor of acute and chronic post-surgical pain after TKA, suggesting that frailty assessment should become a necessary procedure before operations, especially in older patients.

Blocking brown adipocyte ß3-adrenoceptor attenuates blood-spinal cord barrier impairment and chronic postsurgical pain in a rat model of preoperative stress.

Preoperative stress has been recognized as an independent risk factor for chronic postsurgical pain (CPSP). However, the underlying mechanisms of CPSP influenced by preoperative stress remain elusive. Previous studies indicated that excessive stress could induce disruption of the blood-spinal cord barrier (BSCB). We wondered whether and how BSCB involves in CPSP by using a single prolonged stress (SPS) combining plantar incision model in male rats to mimic preoperative stress-related postsurgical pain. Here, we observed that preoperative SPS-exposed rats exhibited relentless incisional pain, which was accompanied by impairment of BSCB and persistent elevation of serum IL-6. Intraperitoneal injections of Tocilizumab (an IL-6 receptor monoclonal antibody) not only mitigated BSCB breakdown but also alleviated pain behaviors. In addition, intervening ß3-adrenoceptor (ADRB3) signaling in brown adipocytes by SR59230a (a specific ADRB3 antagonist) treatment or removal of brown adipose tissues could effectively decrease serum IL-6 levels, ameliorate BSCB disruption, and alleviate incisional pain. Further results displayed that SI-exposed rats also showed markedly spinal microglia activation. And exogenous His-tagged IL-6 could pass through the disrupted BSCB, which might contribute to microglia activation. Injection of SR59230a or ablation of brown adipose tissues could effectively reduce the activation of spinal microglia. Thus, our findings suggest that serum IL-6 induced by brown adipocyte ADRB3 signaling contributed to BSCB disruption and spinal microglia activation, which might be involved in preoperative stress mediated CPSP. This work indicates a promising treatment strategy for preoperative stress induced CPSP by blocking ADRB3.

Psychometric evaluation of the Chinese version of motivation for nursing student scale (MNSS): A quantitative and cross-sectional design.

BACKGROUND: Academic motivation is the psychological factor that promotes learning activities. The persistence of learning activities in nursing education is directly influenced by academic motivation. However, there are currently no specialist instruments for nursing students in China. OBJECTIVE: To translate the Motivation for nursing student scale (MNSS) into Chinese and evaluate its validity and reliability among nursing students in China. DESIGN: A quantitative and cross-sectional design. SETTING: The survey was conducted at a medical university in Jinzhou, China between March and May 2022. PARTICIPANTS: A total of 688 Chinese nursing students were surveyed by questionnaire in this study. METHOD: The Chinese version of MNSS adopted Brislin's transition model and conducted expert consultations to validate the facial validity and testing of the transition version. Reliability and validity were tested using exploratory factor analysis, confirmatory factor analysis, and internal consistency reliability. RESULTS: Nursing experts confirm the high content validity of the Chinese version of the 20-item scale. An exploratory factorial analysis revealed a four-factor solution, with a total variance of 64.1% and confirmatory factor analysis results showed a satisfactory fit (χ2/df=2.738, RMSEA =0.073, SRMR = 0.0719, CFI = 0.914, IFI = 0.915, NFI =0.872, RFI =0.849,). Cronbach's alpha coefficient for the scale was 0.869, and the split-half reliability is 0.727. CONCLUSION: The Chinese version of MNSS has satisfactory reliability and validity and is a reliable instrument to assess the academic motivation of Chinese nursing students.

The work of Chinese chronic conditions: adaptation and validation of the Distribution of Co-Care Activities Scale.

Purpose: The Distribution of Co-Care Activities Scale was adapted into Chinese for the purposes of this study, and then the psychometric characteristics of the Chinese version of the DoCCA scale were confirmed in chronic conditions. Methods: A total of 434 patients with chronic diseases were recruited from three Chinese cities. A cross-cultural adaptation procedure was used to translate the Distribution of Co-Care Activities Scale into Chinese. Cronbach's alpha coefficient, split-half reliability, and test-retest reliability were used to verify the scale's reliability. Content validity indices, exploratory factor analysis, and confirmatory factor analysis were used to confirm the scale's validity. Results: The Chinese DoCCA scale includes five domains: demands, unnecessary tasks, role clarity, needs support, and goal orientation. The S-CVI was 0.964. Exploratory factor analysis yielded a five-factor structure that explained 74.952% of the total variance. According to the confirmatory factor analysis results, the fit indices were within the range of the reference values. Convergent and discriminant validity both met the criteria. Also, the scale's Cronbach's alpha coefficient is 0.936, and the five dimensions' values range from 0.818 to 0.909. The split-half reliability was 0.848, and the test-retest reliability was 0.832. Conclusions: The Chinese version of the Distribution of Co-Care Activities Scale had high levels of validity and reliability for chronic conditions. The scale can assess how patients with chronic diseases feel about their service of care and provide data to optimize their personalized chronic disease self-management strategies.

A Single Preoperative Dose of S-Ketamine Has No Beneficial Effect on Chronic Postsurgical Pain in Patients Undergoing Video-Assisted Thoracoscopic Surgical Lung Lesion Resection: A Prospective Randomized Controlled Study.

OBJECTIVES: To evaluate the efficacy of a single preoperative dose of S-ketamine for chronic postsurgical pain (CPSP) in patients undergoing video-assisted thoracoscopic surgical lung lesion resection (VATS). DESIGN: A prospective randomized, double-blind controlled study. SETTING: Patients were enrolled from March 17, 2021, to November 18, 2021, at a single tertiary academic hospital. PARTICIPANTS: Patients were 18-to-65 years of age and undergoing VATS. INTERVENTIONS: The experiment was divided into an S-ketamine group (0.5 mg/kg intravenous injection before anesthesia induction) or a placebo group (the same volume of normal saline). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the incidence of CPSP and its neuropathic component. The secondary endpoints included acute postoperative pain, the use of postoperative analgesics, anxiety and sleep quality scores, and the occurrence of adverse effects. There were no significant differences between the 2 groups in the incidences of CPSP, neuropathic pain, acute postoperative pain, and postoperative use of analgesics. The sleep quality scores on the first postoperative day differed significantly between the groups (47.45 ± 27.58 v . 52.97 ± 27.57, p = 0.049), but not the anxiety scores. In addition, adverse effects were similar between the 2 groups. CONCLUSIONS: A single preoperative dose of S-ketamine in patients who underwent VATS had no significant effect on acute and chronic postoperative pain or the consumption of analgesics after surgery. A single preoperative dose of S-ketamine could improve sleep on the first day after surgery, whereas it had no significant effect on anxiety levels.

Association between single nucleotide variants and severe chronic pain in older adult patients after lower extremity arthroplasty.

BACKGROUND: Hip or knee osteoarthritis (OA) is one of the main causes of disability worldwide and occurs mostly in the older adults. Total hip or knee arthroplasty is the most effective method to treat OA. However, severe postsurgical pain leading to a poor prognosis. So, investigating the population genetics and genes related to severe chronic pain in older adult patients after lower extremity arthroplasty is helpful to improve the quality of treatment. METHODS: We collected blood samples from elderly patients who underwent lower extremity arthroplasty from September 2020 to February 2021 at the Drum Tower Hospital Affiliated to Nanjing University Medical School. The enrolled patients provided measures of pain intensity using the numerical rating scale on the 90th day after surgery. Patients were divided into the case group (Group A) and the control group (Group B) including 10 patients respectively by the numerical rating scale. DNA was isolated from the blood samples of the two groups for whole-exome sequencing. RESULTS: In total, 661 variants were identified in the 507 gene regions that were significantly different between both groups (P < 0.05), including CASP5, RASGEF1A, CYP4B1, etc. These genes are mainly involved in biological processes, including cell-cell adhesion, ECM-receptor interaction, metabolism, secretion of bioactive substances, ion binding and transport, regulation of DNA methylation, and chromatin assembly. CONCLUSIONS: The current study shows some variants within genes are significantly associated with severe postsurgical chronic pain in older adult patients after lower extremity arthroplasty, indicating a genetic predisposition for chronic postsurgical pain. The study was registered according to ICMJE guidelines. The trial registration number is ChiCTR2000031655 and registration date is April 6th, 2020.

USP48 alleviates bone cancer pain and regulates MrgC stabilization in spinal cord neurons of male mice.

BACKGROUND: Ubiquitin-mediated degradation of the Mas-related G protein-coupled receptor C (MrgC) reduces the number of receptors. However, the specific deubiquitinating enzyme antagonize this process has not been reported. In this study, we investigated the effect of ubiquitin-specific protease-48 (USP48) on bone cancer pain (BCP) and its effect on MrgC. METHODS: A mouse model of BCP was established. BCP behaviours of mice were assessed after intrathecal injection of adeno-associated virus (AAV)-USP48. USP48 and MrgC interactions were studied by immunoprecipitation. Overexpression and knockdown of USP48 were conducted in N2a cells to investigate the effect of USP48 on MrgC receptor number and ubiquitination. RESULTS: Spinal cord level USP48 expression was reduced in mice with BCP. Intrathecal injection of AAV-USP48 increased paw withdrawal mechanical threshold and reduced spontaneous flinching in mice. In N2a cells, there were increased number of MrgC receptors after overexpression of USP48 and decreased number of MrgC receptors after knockdown of USP48. USP48 interacted with MrgC and overexpression of USP48 altered the level of ubiquitination of MrgC. CONCLUSION: USP48 antagonizes ubiquitin-mediated autophagic degradation of MrgC and alleviates BCP in a murine animal model. Our findings may provide a new perspective for the treatment of BCP. SIGNIFICANCE: Our finding may provide an important theoretical basis as well as an intervention target for clinical development of drugs for BCP.

Latent profile analysis of depression among older adults living alone in China.

BACKGROUND: The number of older adults living alone has increased significantly. Depression is one of the significant mental health problems they face; classifying depressive conditions into homogeneous subgroups can help discover hidden information. METHODS: The data comes from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Latent profile analysis (LPA) was used to identify depression subgroups among elderly living alone, Chi-square tests and Kruskal-Wallis tests were used to univariate analysis, multinomial logistic regression was used to analyze the related factors. RESULTS: 1831 older adults living alone were identified and classified as low-level (30.4 %), moderate-level (55.3 %) and high-level (14.4 %). All variables, except age, were significant in the univariate analysis. Multinomial logistic regression showed that not participating in exercise, sometimes interacting with friends, anxiety symptoms, and impaired IADL were associated with the moderate- and high-level of depression in older adults living alone; good or fair self-rated health and life satisfaction were associated with the low-level of depression in older adults living alone. Anxiety symptoms were associated with high-level of depression in older adults living alone compared to moderate-level; good or fair self-rated health and life satisfaction were associated with moderate-level of depression in older adults living alone. LIMITATIONS: The CES-D-10 cannot fully determine the presence of depression in elderly people living alone at high-level. CONCLUSIONS: In future primary health care, it would be more meaningful to provide targeted interventions for different subgroups of depression in older adults living alone.

Incidence and risk factors for chronic postsurgical pain following video-assisted thoracoscopic surgery: a retrospective study.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has been widely used as an alternative for thoracotomy, but the reported incidence of chronic postsurgical pain (CPSP) following VATS varied widely. The purpose of this study was to investigate the incidence and risk factors for CPSP after VATS. METHODS: We retrospectively collected preoperative demographic, anesthesiology, and surgical factors in a cohort of patients undergoing VATS between January 2018 and October 2020. Patients were interviewed via phone survey for pain intensity, and related medical treatment 3 months after VATS. Univariate and multivariate analysis were used to explore independent risk factors associated with CPSP. RESULTS: 2348 patients were included in our study. The incidence of CPSP after VATS were 43.99% (n = 1033 of 2348). Within those suffering CPSP, 14.71% (n = 152 of 1033) patients reported moderate or severe chronic pain. Only 15.23% (n = 23 of 152) patients with moderate to severe chronic pain sought active analgesic therapies. Age < 65 years (OR 1.278, 95% CI 1.057-1.546, P = 0.011), female (OR 1.597, 95% CI 1.344-1.898, P < 0.001), education level less than junior school (OR 1.295, 95% CI 1.090-1.538, P = 0.003), preoperative pain (OR 2.564, 95% CI 1.696-3.877, P < 0.001), consumption of rescue analgesia postoperative (OR 1.248, 95% CI 1.047-1.486, P = 0.013), consumption of sedative hypnotic postoperative (OR 2.035, 95% CI 1.159-3.574, P = 0.013), and history of postoperative wound infection (OR 5.949, 95% CI 3.153-11.223, P < 0.001) were independent risk factors for CPSP development. CONCLUSIONS: CPSP remains a challenge in clinic because half of patients may develop CPSP after VATS. Trial registration Chinese Clinical Trial Registry (ChiCTR2100045765), 2021/04/24.

Advance Care Planning Among Elderly Acquired Immunodeficiency Syndrome Patients: A Qualitative Preference Study.

Complications arising from human immunodeficiency virus may affect the ability of elderly AIDS patients to communicate and make decisions about future medical care. It is important for elderly AIDS patients to be able to express effectively their preferences for future treatments and care. This study explored preferences and influencing factors of advance care planning among elderly AIDS patients. A semistructured interview outline was developed based on the theory of planned behavior. A qualitative preference interview was conducted among 16 eligible elderly AIDS patients. Using thematic analysis, the data were analyzed and categorized into 3 themes and 9 subthemes that were classified under the theory of planned behavior framework. The 3 themes were as follows: a positive attitude toward advance care planning, a strong desire for family and social support, and some obstacles to discussing advance care planning in the current environment. These themes provided valuable insights to advance care planning educators and practitioners from different work environments and units to aid them in constructing future ACP intervention models for elderly AIDS patients.

Risk factors of postoperative nausea and vomiting following ambulatory surgery: A retrospective case-control study.

Objective: To explore potential risk factors of postoperative nausea and vomiting (PONV) following ambulatory surgery. Method: Clinical data of 1670 cases receiving ambulatory surgery in Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from September 2017 to December 2019 were retrospectively analyzed. They were categorized to PONV group and non-PONV group, and perioperative data in both groups were analyzed for assessing risk factors of PONV following ambulatory laparoscopy. Results: There were 156/1,670 (9.3%) PONV cases, and the female and male incidence in recruited cases was 12.0% and 6.0%, respectively. Analyses on perioperative data of them identified that female gender [adjusted odds ratio (aOR) = 2.060, P < 0.001], operation time >1 h (aOR = 1.554, P = 0.011), postoperative pain at rest (aOR = 1.909, P = 0.013) and postoperative pain during activities (aOR = 3.512, P < 0.001) were independent risk factors of PONV following ambulatory surgery. Furthermore, postoperative pain at rest and during activities were linearly, positively correlated to the incidence of PONV. Conclusion: Female gender, operation time >1 h and postoperative pain are closely related with the incidence of PONV following ambulatory surgery. Alleviating postoperative pain properly is one of the methods to reduce risk factors of PONV following ambulatory surgery.

Downregulation of a Dorsal Root Ganglion-Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY-Triggered Ehmt2 Expression.

Nerve injury-induced maladaptive changes of gene expression in dorsal root ganglion (DRG) neurons contribute to neuropathic pain. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Here, a conserved lncRNA is reported, named DRG-specifically enriched lncRNA (DS-lncRNA) for its high expression in DRG neurons. Peripheral nerve injury downregulates DS-lncRNA in injured DRG due, in part, to silencing of POU domain, class 4, transcription factor 3, a transcription factor that interacts with the DS-lncRNA gene promoter. Rescuing DS-lncRNA downregulation blocks nerve injury-induced increases in the transcriptional cofactor RALY-triggered DRG Ehmt2 mRNA and its encoding G9a protein, reverses the G9a-controlled downregulation of opioid receptors and Kcna2 in injured DRG, and attenuates nerve injury-induced pain hypersensitivities in male mice. Conversely, DS-lncRNA downregulation increases RALY-triggered Ehmt2/G9a expression and correspondingly decreases opioid receptor and Kcna2 expression in DRG, leading to neuropathic pain symptoms in male mice in the absence of nerve injury. Mechanistically, downregulated DS-lncRNA promotes more binding of increased RALY to RNA polymerase II and the Ehmt2 gene promoter and enhances Ehmt2 transcription in injured DRG. Thus, downregulation of DS-lncRNA likely contributes to neuropathic pain by negatively regulating the expression of RALY-triggered Ehmt2/G9a, a key neuropathic pain player, in DRG neurons.

Preference and Influencing Factors of Advance Care Planning for Chinese Elderly Patients With Chronic Diseases: A Mixed-Methods Approach.

The incidence of chronic diseases among elderly patients increases annually with the accelerating aging process in China. Complications arising from the progression of these diseases may affect the ability of the aged to communicate and make decisions about future medical and personal care. This study aimed to investigate acceptance and influencing factors of advance care planning for community-dwelling elderly patients with chronic diseases in the Republic of China. Using a convergent parallel mixed-methods design, 471 elderly Chinese nationals older than 60 years with chronic diseases were recruited using convenience sampling. Quantitative data collection used Chinese versions of the Elderly Death Attitude Scale, Modified Barthel Index Rating Scale, and the Advance Care Planning Acceptance Questionnaire, followed by 14 patients drawn from the quantitative phase. Interviews were thematically analyzed. The results showed that attitude to death and quality of life were key predictors of advance care planning implementation preference, whereas family support and past medical experience were significant factors. The study highlighted the importance of conducting regular education about death, paying attention to quality of life, providing family support, and discussing past medical experience in order to implement advance care planning for elderly patients with chronic diseases in China.

Cannabinoid receptor 2­selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord.

Bone cancer pain (BCP) is a severe complication of advanced bone cancer. Although cannabinoid receptor 2 (CB2) agonists may have an analgesic effect, the underlying mechanism remains unclear. CB2 serves a protective role in various pathological states through the activation of autophagy. Therefore, the present study aimed to determine whether the analgesic effects of the selective CB2 agonist JWH015 was mediated by the activation of autophagy in BCP. BCP was induced by the intra­femur implantation of NCTC2472 fibrosarcoma cells in C3H/HeN mice. The pain behaviors were assessed on the following postoperative days. The selective CB2 agonist JWH015 (1 and 2 µg) was intrathecally administered on day 14 following implantation. AM630 (1 µg), a CB2 antagonist, was injected 30 min before JWH015 administration. Lipopolysaccharide (LPS; 100 nM)­stimulated primary neurons were treated with JWH015 (1 µM) and AM630 (1 µM) to further verify the mechanism by which CB2 affects autophagy. The results demonstrated that autophagy flux was impaired in spinal neurons during BCP, as indicated by the increased ratio of microtubule­associated protein 1 light chain 3ß (LC3B)­II/LC3B­I and increased expression of p62. Intrathecal administration of JWH015 attenuated BCP, which was accompanied by the amelioration of impaired autophagy flux (decreased LC3B­II/LC3B­I ratio and decreased p62expression). In addition, the activation of glia cells and upregulation of the glia­derived inflammatory mediators, interleukin (IL)­1ß and IL­6 were suppressed by JWH015. In LPS­stimulated primary neurons, IL­1ß and IL­6 were increased, and autophagy flux was impaired; whereas treatment with JWH015 decreased the expression of IL­1ß and IL­6, LC3B­II/LC3B­I ratio and expression of p62. These effects were by pretreatment with the CB2­selective antagonist AM630. The results of the present study suggested that the impairment of autophagy flux was induced by glia­derived inflammatory mediators in spinal neurons. Intrathecal administration of the selective CB2 agonist JWH015 ameliorated autophagy flux through the downregulation of IL­1ß and IL­6 and attenuated BCP.

The Ubiquitination of Spinal MrgC Alleviates Bone Cancer Pain and Reduces Intracellular Calcium Concentration in Spinal Neurons in Mice.

Mas-related G-protein-coupled receptor subtype C (MrgC) has been shown to play an important role in the development of bone cancer pain. Ubiquitination is reported to participate in pain. However, whether MrgC ubiquitination plays a role in bone cancer pain remains unclear. To answer this question, we designed and performed this study. Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer pain. MrgC agonist bovine adrenal medulla 8-22 (BAM 8-22) or MrgC antagonist anti-MrgC antibody were injected intrathecally on day 14 after bone cancer pain was successfully induced. The pain behaviors, the MrgC ubiquitination levels and intracellular calcium concentration in spinal neurons were measured before and after injection, respectively. With comparison to normal and sham group, mice in tumor group exhibited serious bone cancer pain on day 14, and the level of MrgC ubiquitination and intracellular calcium concentration in spinal neurons was significantly higher. Intrathecal injection of BAM 8-22 significantly alleviated bone cancer pain, increased the MrgC ubiquitination level and decreased intracellular calcium concentration in spinal neurons; however, these effects were reversed by administration of anti-MrgC antibody. Our study reveals that MrgC ubiquitination participates in the production and maintenance of bone cancer pain in mice, possibly through the regulation of intracellular calcium concentration in mice spinal neurons.

Anxiety-induced hyperalgesia in female rats is mediated by cholecystokinin 2 receptor in rostral ventromedial medulla and spinal 5-hydroxytryptamine 2B receptor.

BACKGROUND: Preoperative anxiety is associated with postoperative hyperalgesia; however, few studies have investigated the mechanism underlying this association in female surgical patients. Research has suggested that ON cells in the rostral ventromedial medulla (RVM) receive nerve impulses via cholecystokinin 2 (CCK2) receptors, facilitating hyperalgesia. Additionally, the downstream serotonergic projection system from the RVM to the spinal cord has a dual regulating effect on pain responses, and the 5-hydoxytryptophan 2B (5-HT2B) receptor in spinal dorsal horn neurons is critically involved in mechanical allodynia. METHODS: Ovariectomized rats were treated with estrogen replacement, single prolonged stress (SPS), and plantar incision. Various receptor agonists and antagonists were then administered into the RVM and spinal cord to study the mechanism underlying postoperative hyperalgesia caused by preoperative anxiety in female rats. RESULTS: Behavioral testing revealed that preoperative SPS induced postoperative hyperalgesia, as well as the expression of the CCK2 receptor in the RVM and the expression of the 5-HT2B receptor, protein kinase Cγ (PKCγ), and phosphorylation of the N-methyl-d-aspartate receptor1 (p-NR1) in the spinal cord increased confirmed by Western blot. RVM microinjection of the CCK2 receptor agonist CCK-8 and intrathecal injection of the 5-HT2B receptor agonist BW723C86 both produced hyperalgesia in female rats after plantar incision, whereas the CCK2 receptor antagonist YM022, the 5-HT2B receptor antagonist RS127445, and the PKCγ inhibitor C37H65N9O13 decreased the rats' sensitivity to the same stimulus. Additionally, electrophysiological analysis suggested that activation of the 5-HT2B receptor increased the whole-cell current (IBa) in superficial dorsal horn neurons through the PKCγ pathway. CONCLUSION: Our study demonstrated that preoperative anxiety-induced postoperative hyperalgesia in female rats is associated with descending pain pathways. The CCK2 receptor in the RVM and spinal 5-HT2B receptor may play a role in this hyperalgesic effect.

Perioperative activation of spinal α7 nAChR promotes recovery from preoperative stress-induced prolongation of postsurgical pain.

Preoperative stress could delay the recovery of postoperative pain and has been reported to be a risk factor for chronic postsurgical pain. As stress could facilitate the proinflammatory activation of microglia, we hypothesized that these cells may play a vital role in the development of preoperative stress-induced pain chronification after surgery. Our experiments were conducted in a rat model that consists of a single prolonged stress (SPS) procedure and plantar incision. A previous SPS exposure induced anxiety-like behaviors, prolonged incision-induced mechanical allodynia, and potentiated the activation of spinal microglia. Based on the results from ex vivo experiments, spinal microglia isolated from SPS-exposed rats secreted more proinflammatory cytokines upon challenge with LPS. Our results also demonstrated that microglia played a more important role than astrocytes in the initiation of SPS-induced prolongation of postsurgical pain. We further explored the therapeutic potential of agonism of α7 nAChR, an emerging anti-inflammatory target, for SPS-induced prolongation of postsurgical pain. Multiple intrathecal (i.t.) injections of PHA-543613 (an α7 nAChR agonist) or PNU-120596 (a type II positive allosteric modulator) during the perioperative period shortened the duration of postsurgical pain after SPS and suppressed SPS-potentiated microglia activation, but their effects were abolished by pretreatment with methyllycaconitine (an α7 nAChR antagonist; i.t.). Based on the results from ex vivo experiments, the anti-inflammatory effects of PHA-543613 and PNU-120596 may have been achieved by the direct modulation of microglia. In conclusion, stress-induced priming of spinal microglia played a key role in the initiation of preoperative stress-induced prolongation of postsurgical pain, and PHA-543613 and PNU-120596 may be potential candidates for preventing pain chronification after surgery.

Association between intraoperative hypotension and 30-day mortality, major adverse cardiac events, and acute kidney injury after non-cardiac surgery: A meta-analysis of cohort studies.

BACKGROUND: The association between intraoperative hypotension (IOH) and postoperative outcomes is not fully understood. We performed a meta-analysis to determine whether IOH is associated with increased risk of 30-day mortality, major adverse cardiac events (MACEs) and acute kidney injury (AKI) after non-cardiac surgery. METHODS: We searched PubMed and Embase through May 2016 to identify cohort studies that investigated the association between IOH and risk of 30-day mortality, MACEs, or AKI in adult patients after non-cardiac surgery. Ascertainment of IOH and assessment of outcomes were defined by the individual study. Considering the level of clinical heterogeneity, adjusted odds ratios (ORs) with 95% confidence interval (CIs) were pooled using a random-effects model. This meta-analysis is registered on PROSPERO (CRD42016049405). RESULTS: We included 14 cohort studies that were heterogeneous in terms of definition of IOH. IOH alone was associated with increased risk of 30-day mortality (OR 1.29 [95% CI, 1.19-1.41]), MACEs (OR 1.59 [95% CI, 1.23-2.05]), especially myocardial injury (OR 1.67 [95% CI, 1.31-2.13]), and AKI (OR 1.39 [95% CI, 1.09-1.77]). Triple low (IOH coincident with low bispectral index and low minimum alveolar concentration) also predicts increased risk of 30-day mortality (OR 1.32 [95% CI, 1.03-1.68]). CONCLUSIONS: IOH alone significantly increases the risk of postoperative 30-day mortality, MACEs, especially myocardial injury, and AKI in adult patients after non-cardiac surgery. Triple low also predicts increased risk of 30-day mortality after non-cardiac surgery. These findings provide evidence that IOH should be recognized as an independent risk factor for postoperative adverse outcomes after non-cardiac surgery.

The effects of dexmedetomidine pretreatment on the pro- and anti-inflammation systems after spinal cord injury in rats.

Excessive inflammatory responses play important roles in the aggravation of secondary damage to an injured spinal cord. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist, has recently been implied to be neuroprotective in clinical anesthesia, but the underlying mechanism is elusive. As signaling through Toll-like receptor 4 (TLR4) and nicotinic receptors (nAChRs, notably α7nAChR) play important roles in the pro- and anti-inflammation systems in the central nervous system, respectively, this study investigated whether and how they were modulated by DEX pretreatment in a rat model of spinal cord compression. The model was used to mimic perioperative compressive spinal cord injury (SCI) during spinal correction. DEX preconditioning improved locomotor scores after SCI, which was accompanied by increased α7nAChR and acetylcholine (Ach, an endogenous ligand of α7nAChR) expression as well as PI3K/Akt activation. However, there was a decrease in Ly6h (a negative regulator for α7nAChR trafficking), TLR4, PU.1 (a critical transcriptional regulator of TLR4), HMGB1 (an endogenous ligand of TLR4), and caspase 3-positive cells, which was prevented by intrathecal preconditioning with antagonists of either α2R, α7nAChR or PI3K/Akt. In addition, application of an α7nAChR agonist produced effects similar to those of DEX after SCI, while application of an α7nAChR antagonist reversed these effects. Furthermore, both α7nAChR and TLR4 were mainly co-expressed in NeuN-positive cells of the spinal ventral horn, but not in microglia or astrocytes after SCI. These findings imply that the α2R/PI3K/Akt/Ly6h and α7nAChR/PI3K/Akt/PU.1 cascades are required for upregulated α7nAChR and downregulated TLR4 expression by DEX pretreatment, respectively, which provided a unique insight into understanding DEX-mediated neuroprotection.

Glucocorticoid-Potentiated Spinal Microglia Activation Contributes to Preoperative Anxiety-Induced Postoperative Hyperalgesia.

Clinically, preoperative anxiety adversely affected postoperative hyperalgesia. As stress-induced glucocorticoids (GCs) were reported to sensitize the activation of microglia, the present study investigated whether and how GCs and microglia played in the process of preoperative anxiety-induced postoperative hyperalgesia. The study used an animal model that exposed rats to single prolonged stress (SPS) procedure to induce preoperative anxiety-like behaviors 24 h before the plantar incisional surgery. Behavioral testing revealed that preoperative SPS enhanced the mechanical allodynia induced by plantar incision. SPS was also found to induce elevated circulating corticosterone levels, potentiate the activation of spinal microglia, and increase the expression of spinal proinflammatory cytokines. Inhibition of microglia by pretreatment with minocycline attenuated the SPS-enhanced mechanical allodynia, and this was accompanied by decreased activation of spinal microglia and expression of proinflammatory cytokines. Another experiment was conducted by administering RU486, the GC receptor (GR) antagonist, to rats. The results showed that RU486 suppressed SPS-induced and SPS-potentiated proinflammatory activation of spinal microglia and revealed analgesic effects. Together, these data indicated that inhibition of stress-induced GR activation attenuated the preoperative anxiety-induced exacerbation of postoperative pain, and the suppression of spinal microglia activation may underlie this anti-hyperalgesia effect. Pending further studies, these findings suggested that GR and spinal microglia may play important roles in the development of preoperative anxiety-induced postoperative hyperalgesia and may serve as novel targets to prevent this phenomenon.