Metformin protects retinal pigment epithelium cells against H2O2-induced oxidative stress and inflammation via the Nrf2 signaling cascade.

PURPOSE: Dysfunctions of retinal pigment epithelium (RPE) attributed to oxidative stress and inflammation are implicated with age-related macular degeneration (AMD). A debate on the curative role of metformin in AMD has been raised, though several recent clinical studies support the lower odds by using metformin. This study aimed to determine whether metformin could exert cytoprotection against RPE oxidative damages and the potential mechanisms. METHODS: A cellular AMD model was established by treating ARPE-19 cells with hydrogen peroxide (H2O2) for 24 h. The reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and levels of pro-inflammatory cytokines were monitored under administrations with H2O2 with/without metformin. The expression and DNA-binding activity of transcription factor erythroid-related factor 2 (Nrf2) were determined by western blot, immunofluorescence, and electrophoretic mobility shift assay. Knockout of Nrf2 was conducted by CRISPR/Cas9 gene deletion system. RESULTS: Metformin pretreatment significantly improved the H2O2-induced low viability of ARPE-19 cells, reduced ROS production, and increased contents of antioxidative molecules. Concurrently, metformin also suppressed levels of pro-inflammatory cytokines caused by H2O2. The metformin-augmented nuclear translocation and DNA-binding activity of Nrf2 were further verified by the increased expression of its downstream targets. Genetic deletion of Nrf2 blocked the cytoprotective role of metformin. CONCLUSION: Metformin possesses antioxidative and anti-inflammatory properties in ARPE-19 cells by activating the Nrf2 signaling. It supports the potential use for the control and prevention of AMD.

Calpain-TRPC6 signaling pathway contributes to propofol-induced developmental neurotoxicity in rats.

Growing animal studies suggest a risk of neuronal damage following early childhood exposure to anesthesia and sedation drugs including propofol. Inhibition of transient receptor potential canonical 6 (TRPC6) degradation has been shown to protect neurons from neuronal damage induced by multiple brain injury models. Our aim was to investigate whether calpain-TRPC6 pathway is a target in propofol-induced neurotoxicity. Postnatal day (PND) 7 rats were exposed to five bolus injections of 25 mg/kg propofol or 10 % intralipid at hourly intervals. Neuronal injury was assessed by the expression pattern of TUNEL staining and cleaved-caspase-3. The Morris water maze test was used to evaluate learning and memory functions in later life. Pretreatments consisting of intracerebroventricular injections of a TRPC6 agonist, TRPC6 inhibitor, or calpain inhibitor were used to confirm the potential role of the calpain-TRPC6 pathway in propofol-induced neurotoxicity. Prolonged exposure to propofol induced neuronal injury, downregulation of TRPC6, and enhancement of calpain activity in the cerebral cortex up to 24 h after anesthesia. It also induced long-term behavioral disorders, manifesting as longer escape latency at PND40 and PND41 and as fewer platform-crossing times and less time spent in the target quadrant at PND42. These propofol-induced effects were attenuated by treatment with the TRPC6 agonist and exaggerated by the TRPC6 inhibitor. Pretreatment with the calpain inhibitor alleviated the propofol-induced TRPC6 downregulation and neuronal injury in the cerebral cortex. In conclusion, our data suggest that a calpain-TRPC6 signaling pathway contributes to propofol-induced acute cortical neuron injury and long-term behavioral disorders in rats.

Somatostatin Neurons from Periaqueductal Gray to Medulla Facilitate Neuropathic Pain in Male Mice.

Projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) are known to engage in descending pain modulation, but how the neural substrates of the PAG-RVM projections contribute to neuropathic pain remains largely unknown. In this study, we showed somatostatin-expressing glutamatergic neurons in the lateral/ventrolateral PAG that facilitate mechanical and thermal hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain. We found that these neurons form direct excitatory connections with neurons in the RVM region. Inhibition of this PAG-RVM projection alleviates mechanical and thermal hypersensitivity associated with neuropathy, whereas its activation enhances hypersensitivity in the mice. Thus, our findings revealed that somatostatin neurons within the PAG-RVM axial are crucial for descending pain facilitation and can potentially be exploited as a useful therapeutic target for neuropathic pain. PERSPECTIVE: We report the profound contribution of somatostatin neurons within the PAG-RVM projections to descending pain facilitation underlying neuropathic pain. These results may help to develop central therapeutic strategies for neuropathic pain.

An NTS-CeA projection modulates depression-like behaviors in a mouse model of chronic pain.

Depressive symptoms comorbid with chronic pain are a common health problem, but the underlying neural circuit mechanisms remain elusive. Here, we identify a glutamatergic projection from the nucleus of the solitary tract (NTS) to the central nucleus of the amygdala (CeA) that mediates depression-like behaviors in a chemotherapy-induced neuropathic pain model. Inhibition or ablation of the glutamatergic NTS neurons alleviates depressive but not hypersensitive behaviors in these mice. The projected neurons form excitatory synapses with somatostatin-expressing neurons in the CeA. Silencing the NTS-CeA projection alleviates depressive but not hypersensitive behaviors, whereas activating the proection promotes depressive behaviors. In addition, in naïve mice, activation of the NTS-CeA projection induces obvious depressive behaviors that can be blocked by silencing the CeA somatostatin-expressing neurons. Together, we reveal a modulatory role of the NTS and its glutamatergic projection to the CeA circuit in modulating depression-like behaviors comorbid to chronic pain.

Low-dose dexmedetomidine as a perineural adjuvant for postoperative analgesia: a randomized controlled trial.

PURPOSE: Dexmedetomidine has been proposed as an additive to local anesthetics to prolong peripheral nerve block duration; however, perineural dexmedetomidine has been associated with an increased risk of bradycardia and hypotension This randomized controlled study investigated the effects of low-dose dexmedetomidine as a perineural adjuvant for postoperative analgesia. METHODS: Fifty-five patients who had undergone elective upper extremity surgery were randomized to receive an ultrasound-guided supraclavicular brachial plexus block with 20 mL 0.5% ropivacaine with or without 30 µg dexmedetomidine. The primary outcome was the duration of analgesia. Secondary outcomes included the onset time and duration of the motor and sensory blocks, incidence of hypotension and bradycardia, total postoperative analgesics, and safety assessment during the 24 h after surgery. RESULTS: Dexmedetomidine significantly prolonged the duration of analgesia (887 ± 92 min vs 661 ± 83 min, P < 0.0001). The onset time and the duration of motor and sensory block were significantly different between the groups (all P < 0.001). No episodes of hypotension or bradycardia were detected in the dexmedetomidine group. The total postoperative analgesic use and side effect profiles in the first 24 h postoperative period were similar for both groups. CONCLUSIONS: Low-dose dexmedetomidine (30 µg) as a perineural adjuvant significantly prolonged the analgesic duration of a brachial plexus block without inducing hemodynamic instability. TRIAL REGISTRATION: This trial was registered at ClinicalTrial.gov (NCT02630290).

SIRT3 Regulates Neuronal Excitability of Alzheimer's Disease Models in an Oxidative Stress-Dependent Manner.

Mitochondrial deacetylase Sirtuin-3 (SIRT3) has been shown to regulate metabolic and antioxidant functions. Previous studies have reported that SIRT3 mediates change of neuronal excitability. However, the underlying mechanism is unclear. Here, we show that SIRT3 deficiency results in neural hyperactivity, decreased survival rate, and increased oxidative stress of culture neurons, while a superoxide dismutase 2 mimetic reduces oxidative stress and suppresses the neuronal hyperactivity. In culture neurons treated with Aß, SIRT3 activator reduces level of reactive oxygen species (ROS) and hyperactivity of neurons while increasing level of ROS restores the neuronal hyperactivity. Utilizing two photon in vivo brain imaging, we show that inhibition of SIRT3 results in elevated neuronal excitatory in an animal model of Alzheimer's disease of early stage, whereas suppression of the ROS level reverses it. These findings demonstrate an oxidative stress-dependent role of SIRT3 in regulation of neuronal excitability in Alzheimer's disease.

Preoperative pericapsular nerve group (PENG) block for total hip arthroplasty: a randomized, placebo-controlled trial.

BACKGROUND: We hypothesized that the addition of a preoperative pericapsular nerve group (PENG) block to intra-articular local anesthetic injection would improve analgesia after total hip arthroplasty. METHOD: In this double-blinded trial, 71 patients scheduled for primary total hip arthroplasty were randomized to receive preoperative PENG block with 20 mL 0.5% ropivacaine (PENG group) or 20 mL saline (placebo group). All the patients received an intra-articular injection of 20 mL 0.5% ropivacaine by surgeon after the completion of the procedure. The primary outcome was the highest pain score reported in the recovery room. The secondary outcomes included quadriceps strength, pain scores, opioid use, and opioid-related side effects up to 48 hours after surgery. RESULTS: Seventy patients were included in the final analysis. The highest visual analog scale in the recovery room showed significant intergroup difference (placebo: 5.2±3.1 vs PENG: 3.3±2.7, p<0.01) but the difference did not persist after discharge from the recovery room. The two groups' postoperative pain scores at rest were similar. A lower intraoperative morphine equivalent dose and lower postoperative vomiting were found in the PENG group. There were no differences in the other outcomes. CONCLUSION: The addition of a preoperative PENG block to intra-articular injections of local anesthetic provides a limited benefit to postoperative analgesia in the recovery room with no discernible benefits thereafter. TRIAL REGISTRATION NUMBER: NCT04480320.

Downregulation of metallothionein-2 contributes to oxaliplatin-induced neuropathic pain.

BACKGROUND: We previously reported a correlation between small doses of oxaliplatin penetrating onto the spinal cord and acute pain after chemotherapy. Here, we propose that MT2 within the spinal dorsal horns participates in the development of oxaliplatin-induced neuropathic pain and may be a pharmacological target for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: The rat model of CIPN was established by 5 consecutive injections of oxaliplatin (0.4 mg/100 g/day). Genetic restoration of neuron-specific metallothionein-2 was implemented 21 days before oxaliplatin treatment, and also, genetic inhibition by metallothionein-2 siRNA was performed. Mechanical allodynia and locomotor activity were assayed. Cell-specific expression of metallothionein-2, the mRNA levels of pro-inflammatory cytokines, nuclear translocation of NF-κB, the protein levels of expression of IκB-α, and interaction between IκB-α and P65 were evaluated in the spinal dorsal horns. Also, in vitro interaction of sequentially deleted IκB-α promoter with metallothionein-2 was used to assess the signal transduction mechanism. RESULTS: We found that oxaliplatin induced downregulation of metallothionein-2 in rat spinal cord neurons. By contrast, genetic restoration of metallothionein-2 in the spinal dorsal horn neuron blocked and reversed neuropathic pain in oxaliplatin-treated rats of both sexes, whereas genetic inhibition of metallothionein-2 triggered neuropathic pain in normal rats. Overall locomotor activity was not impaired after the genetic alterations of metallothionein-2. At the molecular level, metallothionein-2 modulated oxaliplatin-induced neuroinflammation, activation of NF-κB, and inactive transcriptional expression of IκB-α promoter, and these processes could be blocked by genetic restoration of metallothionein-2 in the spinal dorsal horn neurons. CONCLUSIONS: Metallothionein-2 is a potential target for the prevention and treatment of CIPN. A reduction of NF-κB activation and inflammatory responses by enhancing the transcription of IκB-α promoter is proposed in the mechanism.

Effectiveness of double-gloving method on prevention of surgical glove perforations and blood contamination: A systematic review and meta-analysis.

AIMS: To determine the effectiveness of the double-gloving method on preventing surgical glove perforation and blood contamination compared with single gloving. DESIGN: Systematic review. DATA SOURCES: Seven electronic databases were searched including: Embase, CINAHL, OVID, Medline, Pubmed, Web of Science, and Foreign Medical Literature Retrieval Service in March 2020. REVIEW METHOD: Our systematic review and meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline. Risk of bias of Cochrane Handbook (Version 5.1.0) was applied to evaluate the study quality. Revman 5.3 was used to calculate the effect size of odds ratio (OR) with 95% confidence interval (CI). Meta-analysis with forest plot and funnel plot was performed to compare the rate of surgical glove perforation and to determine the published bias, respectively. This review has been registered with ID: CRD42020189694 on the web site of PROSPERO. RESULTS: Seven randomized controlled trials regarding the efficacy of double gloving on reducing surgical glove perforation were identified and a total of 7090 gloves were tested. After analyzing the pooled data, we identified that the rate of surgical glove perforation in the double-gloving group was lower than that of single gloving with statistical significance (OR = 0.75, 95% CI: 0.64-0.89, p < .05). It was statistically significant that surgical glove perforation was lower in the double-inner gloves as well as matched outer-inner perforated gloves compared with that of single glove (OR = 0.05, 95% CI: 0.03-0.07, p < .05). CONCLUSION: Findings of this systematic review demonstrate that double gloving could reduce the rate of surgical-glove perforation. Meanwhile, the risk of being contaminated by a blood-borne pathogen during surgery could be reduced by wearing double gloves. We strongly suggest that surgical team members when operating should wear double gloves to protect themselves and reduce the risk of occupational blood exposure. IMPACT: The necessity of double gloving for preventing blood contamination was demonstrated. The rate of surgical glove perforation is statistically significant in double-gloving group compared to single gloving. Double gloving could reduce the risk of being contaminated during surgery by blood-borne pathogen. Evidence is provided for surgical team and decision makers that double gloving could reduce occupational exposure.

Oxaliplatin-induced neuropathic pain involves HOXA6 via a TET1-dependent demethylation of the SOX10 promoter.

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole-genome expression microarray and gene ontology analysis to identify the upregulation of a sequence-specific DNA-binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV-SOX10-EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1-mediated promoter demethylation of SOX10 may contribute to oxaliplatin-induced neuropathic pain.

Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion.

BACKGROUND: Although the action mechanism of antineoplastic agents is different, oxaliplatin, paclitaxel, or bortezomib as first-line antineoplastic drugs can induce painful neuropathy. In rodents, mechanical allodynia is a common phenotype of painful neuropathy for 3 chemotherapeutics. However, whether there is a common molecular involved in the different chemotherapeutics-induced painful peripheral neuropathy remains unclear. METHODS: Mechanical allodynia was tested by von Frey hairs following i.p. injection of vehicle, oxaliplatin, paclitaxel, or bortezomib in Sprague-Dawley rats. Reduced representation bisulfite sequencing and methylated DNA immunoprecipitation were used to detect the change of DNA methylation. Western blot, quantitative polymerase chain reaction, chromatin immunoprecipitation, and immunohistochemistry were employed to explore the molecular mechanisms. RESULTS: In 3 chemotherapeutic models, oxaliplatin, paclitaxel, or bortezomib accordantly upregulated the expression of transient receptor potential cation channel, subfamily C6 (TRPC6) mRNA and protein without affecting the DNA methylation level of TRPC6 gene in DRG. Inhibition of TRPC6 by using TRPC6 siRNA (i.t., 10 consecutive days) relieved mechanical allodynia significantly following application of chemotherapeutics. Furthermore, the downregulated recruitment of DNA methyltransferase 3 beta (DNMT3b) at paired box protein 6 (PAX6) gene led to the hypomethylation of PAX6 gene and increased PAX6 expression. Finally, the increased PAX6 via binding to the TPRC6 promoter contributes to the TRPC6 increase and mechanical allodynia following chemotherapeutics treatment. CONCLUSIONS: The TRPC6 upregulation through DNMT3b-mediated PAX6 gene hypomethylation participated in mechanical allodynia following application of different chemotherapeutic drugs.

HDAC1 and HDAC2 regulate anti-inflammatory effects of anesthetic isoflurane in human monocytes.

Pre-exposure to volatile anesthetics inhibits inflammation induced by various stimuli, including surgical procedures and ischemia. We hypothesize that volatile anesthetics may induce anti-inflammatory effects via a mechanism involving regulation of histone deacetylases (HDACs). Pre-exposure of 1.5% isoflurane for 0.5 h induced anti-inflammatory effects [measured by cytokine production of tumor necrosis factor-ɑ, interleukin-8 (IL-8) and IL-1ß] in both human THP-1 cells and primary human peripheral blood monocytes stimulated by lipopolysaccharide. In human THP-1 cells, coadministration of the HDAC inhibitor trichostatin A (TSA) blocked the isoflurane-induced anti-inflammatory effects. TSA also blocked isoflurane-upregulated HDAC1-3 expression and isoflurane-reduced nuclear translocation of p65 and p50 subunits of nuclear factor-κB (NF-κB). The ability of isoflurane to reduce NF-κB nuclear translocation and proinflammatory responses in the cell line was blocked by gene silencing of HDAC1 and HDAC2, but not by gene silencing of HDAC3. A coimmunoprecipitation assay demonstrated that the decreased interaction between HDAC1 and HDAC2 through lipopolysaccharide was restored by isoflurane pretreatment. These findings were validated in primary human peripheral blood monocytes  wherein gene silencing of HDAC1 and HDAC2 resulted in increased cytokine production and NF-κB nuclear translocation induced by isoflurane pre-exposure and lipopolysaccharide stimulation. These results indicate that anti-inflammatory effects of the volatile anesthetic isoflurane in human monocytes involve regulation of HDAC1 and HDAC2.

TNF-α/STAT3 pathway epigenetically upregulates Nav1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT.

BACKGROUND: Studies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG). However, the molecular mechanisms underlying Nav1.6 upregulation were not reported yet. METHODS: The paw withdrawal threshold was measured in the rodents following lumbar 5 ventral root transection (L5-VRT). Then qPCR, western blotting, immunoprecipitation, immunohistochemistry, and chromatin immunoprecipitation assays were performed to explore the molecular mechanisms in vivo and in vitro. RESULTS: We found that the levels of Nav1.6 and phosphorylated STAT3 were significantly increased in DRG neurons following L5-VRT, and TNF-α incubation also upregulated the Nav1.6 expression in cultured DRG neurons. Furthermore, immunoprecipitation and chromatin immunoprecipitation assays demonstrated that L5-VRT increased the binding of STAT3 to the Scn8a (encoding Nav1.6) promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of Scn8a by increasing histone H4 acetylation in Scn8a promoter in DRG. Importantly, intraperitoneal injection of the TNF-α inhibitor thalidomide reduced the phosphorylation of STAT3 and decreased the recruitment of STAT3 and histone H4 hyperacetylation in the Scn8a promoter, thus subsequently attenuating Nav1.6 upregulation in DRG neurons and mechanical allodynia induced by L5-VRT. CONCLUSION: These results suggested a new mechanism for Nav1.6 upregulation involving TNF-α/STAT3 pathway activation and subsequent STAT3-mediated histone H4 hyperacetylation in the Scn8a promoter region in DRG, which contributed to L5-VRT-induced neuropathic pain.

Up-regulation of P-gp via NF-κB activation confers protection against oxidative damage in the retinal pigment epithelium cells.

Dysfunction of retinal pigment epithelial (RPE) cells has been associated with the pathogenesis of age-related macular degeneration in relation to increased oxidative stress, subsequent mitochondrial dysfunction and cell death. Permeability-glycoprotein (P-gp), encoded by the multidrug resistance 1 gene (MDR1), is an active efflux pump involved in cell homeostasis and nuclear factor κB (NF-κB) shows potential involvement in P-gp regulation due to its binding to the promoter domains of MDR1 gene. This study sought to determine the role of P-gp expression regulated by NF-κB in RPE cells during oxidative stress. The human RPE D407 cells were exposed to increasing concentrations of hydrogen peroxide (H2O2) for 24 h. The small-interfering RNA (siRNA) transfection was used to down-regulate P-gp and NF-κB, and the expressions of P-gp and NF-κB p65 were determined by quantitative real-time PCR, western blot and immunofluorescence. The activity of NF-κB was detected by luciferase reporter assay. Mitochondrial membrane potential and cell death rate were detected by flow cytometry. We found that H2O2 exposure caused increasing rate of cell death and induced an elevated expression of P-gp as well as NF-κB activation and nucleus translocation in D407 cells. Inhibiting or silencing NF-κB led to a decrease in the oxidative-induced expression of P-gp. Down-regulation of P-gp by siRNA transfection further impaired the mitochondrial membrane potential and cell death rate in oxidative cells. Moreover, inhibition/knockdown of NF-κB decreased the high rate of cell death caused by H2O2. In conclusion, P-gp can provide moderate cytoprotection for the human RPE cells by ameliorating the mitochondrial dysfunction and NF-κB activation may be a potential regulator of P-gp expression response to oxidative stress.

Administration of Dexmedetomidine inhibited NLRP3 inflammasome and microglial cell activities in hippocampus of traumatic brain injury rats.

The abnormally high nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity is a typical characteristic of traumatic brain injury (TBI). Dexmedetomidine (Dex) is a highly selective α-2 adrenergic receptor agonist that inhibits the activation of NLRP3. Thus, it was hypothesized that Dex could attenuate TBI by inhibiting NLRP3 inflammasome activity in hippocampus. Rats were subjected to controlled cortical impact method to induce TBI, and treated with Dex. The effect of Dex treatment on the cognitive function, NLRP3 activity, and microglial activation in rat brain tissues was assessed. The administration of Dex improved performance of TBI rats in Morris water maze (MWM) test, which was associated with the increased neurone viability and suppressed microglia activity. Moreover, the administration of Dex inhibited the neuroinflammation in brain tissue as well as the expressions of NLRP3 and caspase-1. Additionally, Dex and NLRP3 inhibitor, BAY-11-7082 had a synergistic effect in inhibiting NLRP3/caspase-1 axis activity and improving TBI. The findings outlined in the current study indicated that the improvement effect of Dex on TBI was related to its effect on NLRP3 activity.

Crutchlike Incision Along the Mastoid Groove and Above the Occipital Artery Protects the Lesser Occipital Nerve and Occipital Artery in Microvascular Decompression Surgery.

BACKGROUND: Patients who have had microvascular decompression (MVD) surgery often report sensory discomfort around the surgical area. In most cases, injury of the lesser occipital nerve (LON) is responsible for this postoperative complication. This study aimed to explore an effective method to protect the LON and reduce postoperative discomfort. METHODS: Doppler was used to determine the course of the occipital artery (OA) and the incision. Direct LON identification and a novel crutchlike incision were performed from January 1, 2016, to February 1, 2017, to reduce postoperative sensory disturbance. Postoperative sensory disturbance was evaluated and retrospectively analyzed compared with previous linear incision cases (from January 1, 2015, to December 31, 2015). Anatomic information at the lateral occiput was measured and recorded. RESULTS: The difference in the amount of postoperative sensory disturbance at 3-month follow-up was significant (P = 0.008). Sensory disturbance was significantly lower in patients who had crutchlike incision (P = 0.002) and patients with direct LON identification (P = 0.035) compared with the previous linear incision cases. The distance from OA to the projection of the transverse sinus was 3.2 ± 0.6 cm at the mastoid groove and 2.5 ± 0.4 cm at a site 0.5-1.0 cm from the mastoid groove. CONCLUSIONS: A crutchlike incision at the mastoid groove superior to the OA reduced the incidence of postoperative sensory disturbance and OA injury. The mastoid groove and OA are simple landmarks for determination of the incision in microvascular decompression.

The role of P2X7R/ERK signaling in dorsal root ganglia satellite glial cells in the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR).

The mechanisms of chronic postsurgical pain remain to be elucidated. We reported here that skin/muscle incision and retraction (SMIR), a rat model of postsurgical pain, phosphorylated the extracellular regulated protein kinases (ERK) signaling components c-Raf, MEK (ERK kinase) and ERK1/2 in lumbar 3 dorsal root ganglion (L3 DRG) in rats. Intrathecal injection of ERK specific inhibitor SCH772984 suppressed the mechanical allodynia induced by SMIR. Furthermore, SMIR upregulated tumor necrosis factor alpha (TNFα) in L3 DRG, which could be inhibited by SCH772984. Intrathecal injection of TNF antagonist Etanercept could also inhibit the mechanical allodynia and the increased ERK phosphorylation in L3 DRG induced by SMIR. In addition, immunofluorescent data showed that P2X7R was located exclusively in GFAP labeled satellite glial cells and was highly colocalized with p-ERK1/2 following SMIR. Pretreatment with P2X7R antagonist Brilliant Blue G (BBG) could also block the mechanical allodynia, inhibited the phosphorylation of c-Raf, MEK, ERK1/2, and decrease the expression of TNF-α. Finally, intrathecal injection of BzATP produced mechanical allodynia and induced ERK phosphorylation in satellite glial cells in L3 DRG. Thus, P2X7R activation in satellite glial cells in L3 DRG, leading to a positive feedback between ERK pathway activation and TNF-α production, is suggested to be involved in the induction of chronic postsurgical pain following SMIR.

High ocular CMV copies and mismatched receipts may predict poor visual prognosis in CMV retinitis patients following allogeneic haematopoietic stem cell transplantation.

BACKGROUND: To summarize the clinical characteristics and potential factors affecting the visual outcomes in patients with cytomegalovirus retinitis following allogeneic haematopoietic stem cell transplantation (HSCT). METHODS: This retrospective study enrolled 12 patients (19 eyes) with cytomegalovirus retinitis after HSCT at Guangzhou First People's Hospital in China between January 2013 and December 2014. Demographic and clinical characteristics, ocular manifestations and visual outcomes were evaluated by reviewing medical records at the Departments of Hematology and Ophthalmology. All patients were followed up at least 6 months after stopping antiviral therapy. The visual outcome was defined as improvement, stabilization and deterioration. RESULTS: The subjects were composed of 7 human leucocyte antigen-matched and 5 mismatched receipts. All patients received combined systemic and intravitreous antiviral therapy. Eleven eyes gained improved or stabilized visual acuity, while 8 eyes suffered deterioration. Eyes with cytomegalovirus load less than 1 × 104 copies/ml in vitreous accounted for higher rate in eyes with good visual prognosis than those with cytomegalovirus copies above 1 × 104 copies/ml (52.63% vs 5.26%, P < 0.001). Human leucocyte antigen-matched receipts gained better visual prognosis than those mismatched ones (47.37% vs10.53%, P < 0.05). The virus types, cytomegalovirus peak in the blood, involved retinal zone and size had no influence on the visual outcomes (all P > 0.05). CONCLUSIONS: High ocular cytomegalovirus copies and mismatched receipts may be potential adverse factors affecting visual outcomes in cytomegalovirus retinitis patients following allogeneic HSCT.

Propofol inhibits the release of interleukin-6, 8 and tumor necrosis factor-α correlating with high-mobility group box 1 expression in lipopolysaccharides-stimulated RAW 264.7 cells.

BACKGROUND: Studies have found that propofol can inhibit endotoxin-induced monocyte-macrophages to produce various inflammatory factors. This study is to disclose whether the propofol affects the expression of high-mobility group box 1 (HMGB1) in lipopolysaccharides (LPS)-stimulated RAW 264.7 cells and the release of interleukin-6 (IL-6), 8 (IL-8) and tumor necrosis factor-α (TNF-α). METHODS: RAW 264.7 cells were divided into four groups for intervention. After culturing for 16 h, the cells and culture supernatants were collected. The expression of HMGB1 in RAW 264.7 cells was detected by Western blot. The levels of IL-6, IL-8 and TNF-α in supernatants of cells were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Stimulation of LPS increased the expression of HMGB1 and promoted the release of IL-6, IL-8 and TNF-α in supernatants of RAW 264.7 cells (p < 0.05); however, propofol down-regulated the expression of LPS-stimulated HMGB1 and reduced the LPS-stimulated releases of IL-6, IL-8 and TNF-α in supernatants of RAW 264.7 cells (p < 0.05). Moreover, the releases of IL-6, IL-8 and TNF-α intimately correlated with the expression of HMGB1 in this process (p < 0.05). CONCLUSION: Propofol inhibited the releases of IL-6, IL-8 and TNF-α in LPS-stimulated RAW 264.7 cells, and the levels of IL-6, IL-8 and TNF-α intimately correlated with the expression of HMGB1, which indicating that propofol may prevent inflammatory responses through reducing the releases of these cytokines and inflammatory mediators.