A cross-tissue transcriptome-wide association study identifies new susceptibility genes for frailty.

Background: Although genome-wide association studies (GWAS) have identified 14 loci associated with frailty index (FI) susceptibility, the underlying causative genes and biological mechanisms remain elusive. Methods: A cross-tissue transcriptome-wide association study (TWAS) was conducted utilizing the Unified Test for Molecular Markers (UTMOST), which integrates GWAS summary statistics from 164,610 individuals of European ancestry and 10,616 Swedish participants, alongside gene expression matrices from the Genotype-Tissue Expression (GTEx) Project. Validation of the significant genes was performed through three distinct methods: FUSION, FOCUS, and Multiple Marker Analysis of Genome-wide Annotation (MAGMA). Exploration of tissue and functional enrichment for FI-associated SNPs was conducted using MAGMA. Conditional and joint analyses, along with fine mapping, were employed to enhance our understanding of FI's genetic architecture. Mendelian randomization was employed to ascertain causal relationships between significant genes and FI, and co-localization analysis was utilized to investigate shared SNPs between significant genes and FI. Results: In this study, two novel susceptibility genes associated with the risk of FI were identified through the application of four TWAS methods. Mendelian randomization demonstrated that HTT may elevate the risk of developing frailty, whereas LRPPRC could offer protection against the onset of frailty. Additionally, co-localization analysis identified a shared SNP between LRPPRC and FI. Tissue enrichment analyses revealed that genomic regions linked to SNPs associated with frailty were predominantly enriched in various brain regions, including the frontal cortex, cerebral cortex, and cerebellar hemispheres. Conditional, combined analyses, and fine mapping collectively identified two genetic regions associated with frailty: 2p21 and 4q16.3. Functional enrichment analyses revealed that the pathways associated with frailty were primarily related to the MHC complex, PD-1 signaling, cognition, inflammatory response to antigenic stimuli, and the production of second messenger molecules. Conclusion: This investigation uncovers two newly identified genes with forecasted expression levels associated with the risk of FI, offering new perspectives on the genetic architecture underlying FI.

A proof-of-concept study of ultrasound-guided continuous parasacral ischial plane block for postoperative pain control in patients undergoing total knee arthroplasty.

BACKGROUND: Continuous peripheral nerve blocks are widely used for anesthesia and postoperative analgesia in lower limb surgeries. The authors aimed to develop a novel continuous sacral plexus block procedure for analgesia during total knee arthroplasty. METHODS: The study comprised two stages. In Stage I, the authors built upon previous theories and technological innovations to develop a novel continuous sacral plexus block method, ultrasound-guided continuous parasacral ischial plane block (UGCPIPB) and subsequently conducted a proof-of-concept study to assess its effectiveness and feasibility. Stage II involved a historical control study to compare clinical outcomes between patients undergoing this new procedure and those receiving the conventional procedure. RESULTS: The study observed a 90% success rate in catheter placement. On postoperative day (POD) 1, POD2, and POD3, the median visual analog scale (VAS) scores were 3 (range, 1.5-3.5), 2.5 (1.6-3.2), and 2.7 (1.3-3.4), respectively. Furthermore, 96.3% of the catheters remained in place until POD3, as confirmed by ultrasound. The study revealed a significant increase in skin temperature and peak systolic velocity of the anterior tibial artery on the blocked side compared with those on the non-blocked side. Complications included catheter clogging in one patient and leakage at the insertion site in two patients. In Stage II, the novel technique was found to be more successful than conventional techniques, with a lower catheter displacement rate than the conventional procedure for continuous sciatic nerve block. CONCLUSION: UGCPIPB proved to be an effective procedure and safe for analgesia in total knee arthroplasty. CHINESE CLINICAL TRIAL REGISTRY NUMBER: ChiCTR2300068902.

Activation of the CD200/CD200R1 axis improves cognitive impairment by enhancing hippocampal neurogenesis via suppression of M1 microglial polarization and neuroinflammation in hypoxic-ischemic neonatal rats.

Following hypoxic-ischemic brain damage (HIBD), there is a decline in cognitive function; however, there are no effective treatment strategies for this condition in neonates. This study aimed to evaluate the role of the cluster of differentiation 200 (CD200)/CD200R1 axis in cognitive function following HIBD using an established model of HIBD in postnatal day 7 rats. Western blotting analysis was conducted to evaluate the protein expression levels of CD200, CD200R1, proteins associated with the PI3K/Akt-NF-κB pathway, and inflammatory factors such as TNF-α, IL-1ß, and IL-6 in the hippocampus. Additionally, double-immunofluorescence labeling was utilized to evaluate M1 microglial polarization and neurogenesis in the hippocampus. To assess the learning and memory function of the experimental rats, the Morris water maze (MWM) test was conducted. HIBDleads to a decrease in the expression of CD200 and CD200R1 proteins in the neonatal rat hippocampus, while simultaneously increasing the expression of TNF-α, IL-6, and IL-1ß proteins, ultimately resulting in cognitive impairment. The administration of CD200Fc, a fusion protein of CD200, was found to enhance the expression of p-PI3K and p-Akt, but reduce the expression of p-NF-κB. Additionally, CD200Fc inhibited M1 polarization of microglia, reduced neuroinflammation, improved hippocampal neurogenesis, and mitigated cognitive impairment caused by HIBD in neonatal rats. In contrast, blocking the interaction between CD200 and CD200R1 with the anti-CD200R1 antibody (CD200R1 Ab) exerted the opposite effect. Furthermore, the PI3K specific activator, 740Y-P, significantly increased the expression of p-PI3K and p-Akt, but reduced p-NF-κB expression. It also inhibited M1 polarization of microglia, reduced neuroinflammation, and improved hippocampal neurogenesis and cognitive function in neonatal rats with HIBD. Our findings illustrate that activation of the CD200/CD200R1 axis inhibits the NF-κB-mediated M1 polarization of microglia to improve HIBD-induced cognitive impairment and hippocampal neurogenesis disorder via the PI3K/Akt signaling pathway.

Activation of the CD200/CD200R1 axis attenuates neuroinflammation and improves postoperative cognitive dysfunction via the PI3K/Akt/NF-κB signaling pathway in aged mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a neurological complication occurring after anesthesia and surgery. Neuroinflammation plays a critical role in the pathogenesis of POCD, and the activation of the cluster of differentiation 200 (CD200)/CD200R1 axis improves neurological recovery in various neurological disorders by modulating inflammation. The aim of this study was to investigate the impact and underlying mechanism of CD200/CD200R1 axis on POCD in aged mice. METHODS: The model of POCD was established in aged mice. To assess the learning and memory abilities of model mice, the Morris water maze test was implemented. CD200Fc (CD200 fusion protein), CD200R1 Ab (anti-CD200R1 antibody), and 740Y-P (a specific PI3K activator) were used to evaluate the effects of the CD200/CD200R1/PI3K/Akt/NF-κB signaling pathway on hippocampal microglial polarization, neuroinflammation, synaptic activity, and cognition in mice. RESULTS: It was observed that anesthesia/surgery induced cognitive decline in aged mice, increased the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1 ß and decreased the levels of postsynaptic density protein 95 (PSD-95), synaptophysin (SYN) in the hippocampus. Moreover, CD200Fc and 740Y-P attenuated neuroinflammation and synaptic deficits and reversed cognitive impairment via the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/nuclear factor-kappa B (NF-κB) signaling pathway, whereas CD200R1 Ab administration exerted the opposite effects. Our results further show that the CD200/CD200R1 axis modulates M1/M2 polarization in hippocampal microglia via the PI3K/Akt/NF-κB signaling pathway. CONCLUSIONS: Our findings indicate that the activation of the CD200/CD200R1 axis reduces neuroinflammation, synaptic deficits, and cognitive impairment in the hippocampus of aged mice by regulating microglial M1/M2 polarization via the PI3K/Akt/NF-κB signaling pathway.

Fluoxetine alleviates postoperative cognitive dysfunction by attenuating TLR4/MyD88/NF-κB signaling pathway activation in aged mice.

OBJECTIVE AND DESIGN: Postoperative cognitive dysfunction (POCD) is a common complication following surgery among elderly patients. Emerging evidence demonstrates that neuroinflammation plays a pivotal role in the pathogenesis of POCD. This study tested the hypothesis that fluoxetine can protect against POCD by suppressing hippocampal neuroinflammation through attenuating TLR4/MyD88/NF-κB signaling pathway activation. SUBJECTS: Aged C57BL/6 J male mice (18 months old) were studied. TREATMENT: Aged mice were intraperitoneally injected with fluoxetine (10 mg/kg) or saline for seven days before splenectomy. In addition, aged mice received an intracerebroventricular injection of a TLR4 agonist or saline seven days before splenectomy in the rescue experiment. METHODS: On postoperative days 1, 3, and 7, we assessed hippocampus-dependent memory, microglial activation status, proinflammatory cytokine levels, protein levels related to the TLR4/MyD88/NF-κB signaling pathway, and hippocampal neural apoptosis in our aged mouse model. RESULTS: Splenectomy induced a decline in spatial cognition, paralleled by parameters indicating exacerbation of hippocampal neuroinflammation. Fluoxetine pretreatment partially restored the deteriorated cognitive function, downregulated proinflammatory cytokine levels, restrained microglial activation, alleviated neural apoptosis, and suppressed the increase in TLR4, MyD88, and p-NF-κB p65 in microglia. Intracerebroventricular injection of LPS (1 µg, 0.5 µg/µL) before surgery weakened the effect of fluoxetine. CONCLUSION: Fluoxetine pretreatment suppressed hippocampal neuroinflammation and mitigated POCD by inhibiting microglial TLR4/MyD88/NF-κB pathway activation in aged mice.

Recognition and management of hemorrhaging in combination with emerging enterogenic sepsis during a hepatectomy: a case report.

BACKGROUND: Patients with hemorrhagic shock may develop emerging enterogenic sepsis due to damage to the intestinal mucosal barrier and translocation of intestinal bacteria and endotoxins caused by ischemic injury. Because of the dual effects of anesthesia state and hemorrhagic shock, perioperative emerging enterogenic sepsis is even more rare and insidious. CASE PRESENTATION: We reported a case of 56-year-old man who underwent right hepatectomy for intrahepatic bile duct stones. Severe hemorrhage occurred during the procedure and the hemodynamics neither improved nor worsened after rehydration therapy and vasoactive drug administration. Based on the patient's history and clinical presentation, a possible enterogenic sepsis was considered. After anti-infective treatment and hormone supplementation, the patient's circulation improved significantly and he had an uneventful recovery. CONCLUSION: The possibility of emerging enterogenic sepsis in hemorrhagic shock must always be taken into consideration. Familiarity with the risk factors and pathophysiological alterations of enterogenic sepsis is a prerequisite for early recognition and sound clinical decision making.

Fluoxetine for reducing postoperative cognitive dysfunction in elderly patients after total knee replacement: study protocol for a single-centre, double-blind, randomised, parallel-group, superiority, placebo-controlled trial.

INTRODUCTION: Postoperative cognitive dysfunction (POCD) is a common complication following major surgical procedures. The underlying pathophysiology is poorly understood, but the role of neuroinflammation is strongly implicated. Given the antineuroinflammatory and neuroprotective effects of fluoxetine, we hypothesise that fluoxetine may reduce the cumulative incidence of POCD in elderly patients undergoing total knee arthroplasty (TKA). METHODS AND ANALYSIS: This is a prospective, randomised, double-blind, parallel-group, placebo-controlled, superiority trial. Five hundred elderly patients undergoing unilateral TKA will be randomly assigned to the fluoxetine and placebo groups. The fluoxetine group will receive fluoxetine 20 mg daily 8 weeks preoperatively, and the placebo group will receive placebo capsules daily 8 weeks preoperatively. The primary outcome is the cumulative incidence of POCD at 1 month postoperatively. The secondary outcomes include the occurrence of delirium, the area under the curve of the Numeric Rating Scale pain scores over time, and sleep disturbance. Data on all the results, risk factors and adverse events will also be collected and analysed. ETHICS AND DISSEMINATION: The Fujian Provincial Hospital Ethics Board has approved the protocol for this trial (identifier number: K2021-01-009). All participants will be required to provide written informed consent before any protocol-specific procedures. TRIAL REGISTRATION NUMBER: ChiCTR2100050424.

Preoperative ultrasound-guided multilevel paravertebral blocks reduce the incidence of postmastectomy chronic pain: a double-blind, placebo-controlled randomized trial.

PURPOSE: Chronic postsurgical pain is a challenging problem after breast cancer surgery. This prospective, randomized, double-blinded, parallel-group, placebo-controlled trial was conducted to evaluate the influence of preoperative ultrasound-guided multilevel paravertebral blocks (PVBs) on chronic pain following mastectomy. PATIENTS AND METHODS: One hundred eighty-four women were randomized to receive ultrasound-guided multilevel (T1-T5) PVBs with 5 mL of ropivacaine 0.5% or normal saline per level. The primary end point was the incidence of chronic pain at 3 months following mastectomy assessed by the brief pain inventory (BPI), while the secondary end points were the acute postoperative pain, the number of patients requiring rescue analgesia, postoperative nausea and vomiting (PONV), side effects, and chronic pain at 6 months after surgery assessed by the BPI. RESULTS: A total of 172 patients completed the study. Ultrasound-guided multilevel PVBs significantly decreased immediate postoperative pain for the first 12 hours (P<0.001). Additionally, fewer patients in the PVB group required rescue analgesia in the first 48 hours post-operatively compared to the control group (5/86 vs 28/86, OR =0.128, 95% CI: 0.047-0.351, P<0.001). No statistically significant difference was tested between the two groups (9.3% vs 17.4%, OR =0.419, 95% CI: 0.162-1.087, P=0.068) in the incidence of PONV. At 3 months, the incidence of chronic pain (BPI average pain score ≥3) was 34.5% and 51.2% (OR =0.511, 95% CI: 0.277-0.944, P=0.031) in the PVB and control groups, respectively, and at 6 months, the incidence was 22.1% and 37.2% (OR =0.479, 95% CI: 0.245-0.936, P=0.03), respectively. No complications occurred during the study. CONCLUSION: This study indicated that perioperative ultrasound-guided multilevel PVBs with ropivacaine improved acute postoperative pain and decreased postmastectomy chronic pain at 3 and 6 months postoperatively.