Subjective Sleep Disruption and Mood Disorders are Associated with the Risk of Chronic Pain in Patients with Obstructive Sleep Apnea.

Objective: This study aimed to determine the prevalence of chronic pain and its risk factors in patients with obstructive sleep apnea (OSA). Methods: A total of 145 patients diagnosed with OSA were consecutively recruited from the Sleep Medicine Center in West China Hospital. All patients were divided into two groups including OSA with and without chronic pain. They were assessed the subjective sleep (Pittsburgh Sleep Quality Index, Insomnia Severity Index), objective sleep (polysomnography), mood symptoms (Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale), and pain characteristics (Short-Form McGill Pain Questionnaire). Demographic, clinical, subjective and objective sleep parameters were compared between OSA patients with and without chronic pain. Binary logistic regression models and linear regression models were used to examine the risk factors of chronic pain in OSA. Results: Fifty-five (37.9%) patients with OSA were diagnosed with chronic pain. There were more severe subjective sleep disruption and symptoms of anxiety and depression in patients with chronic pain compared to those without chronic pain. After controlling for potential confounders, poor subjective sleep quality and severe insomnia and mood disorders (all ps < 0.05), but not objective sleep fragmentation or nocturnal hypoxemia (all ps > 0.05) were associated with the increased risk of pain and pain intensity, respectively. Conclusion: More than one-third of patients with OSA had chronic pain. Subjective sleep disruption and mood disorders are the risk factors of chronic pain in OSA. Our findings suggest that subjective sleep quality should be valued highly in the relationship between OSA and pain.

Microglial Responses and Pain Behaviors Are Exacerbated by Chronic Sleep Deprivation in Rats with Chronic Pain Via Neuroinflammatory Pathways.

The inflammatory response of central nervous system (CNS) and microglial activation is important in the development of pain behaviors induced by sleep deprivation. We found that chronic sleep deprivation (CSD) aggravated pain behaviors in rats with chronic pain by upregulating expression of Toll-like receptor 4 (TLR4), NOD-like receptor pyrin domain containing 3 (NLRP3), and interleukin 1ß (IL-1ß), which promoted microglial activation in the brain. We also found that CSD increased numbers of Iba1+ and TLR4+ cells, as well as neuronal apoptosis. Inhibitors of TLR4 and NLRP3 (TAK-242 and MCC950, respectively) reduced expression levels of inflammatory factor proteins and M1-related factor mRNA, decreased microglial activation, and relieved the hyperalgesia caused by CSD. These results suggest that CSD aggravated pain behavior in rats with chronic pain through the TLR4/NLRP3/IL-1ß signaling pathway, which mediates microglial activation and promotes CNS inflammation and neuronal apoptosis.

Altered Cortical Reorganization and Brain Functional Connectivity in Phantom Limb Pain: A Functional MRI Study.

OBJECTIVES: Functional neuroimaging studies have shown that amputees have altered cortical reorganization and functional connectivity (FC). This study aimed to investigate whether patients with phantom limb pain (PLP) and PLP-free lower limb amputees exhibit changes in corresponding primary cortical motor area/somatosensory cortex (M1/S1) cortical reorganization and supplementary motor area (SMA) network FC. The association between functional magnetic resonance imaging (fMRI) changes and clinical parameters is also explored. METHODS: A total of 10 PLP patients were matched with 10 PLP-free amputees and 10 healthy controls (HCs). Before undergoing fMRI, all participants completed questionnaires evaluating pain, anxiety, depression, and health-related quality of life. Task-related activation and regions of interest (ROI)-wise connectivity analysis were applied to differentiate the brain regions of amputees from those of HCs. Linear correlation analysis was used to evaluate the correlation between altered FC and clinical manifestations. RESULTS: As compared with HCs, PLP patients showed increased cortical activation in M1/S1 when moving the intact foot, imagining phantom big toe movement, or having the corresponding thumb stimulated. The increased FC in the SMA network included the SMA-caudate nucleus, SMA-bilateral insula, and SMA-anterior cingulate cortex. Furthermore, results of the linear correlation analysis demonstrated that this increased FC was positively correlated with VAS scores, negatively correlated with Medical Outcomes Study 36-item Short-Form (SF-36) scores, and not correlated with anxiety or depression scores. CONCLUSIONS: Phantom limb pain in lower limb amputees is associated with M1/S1 cortical reorganization and altered SMA network FC in different areas of the brain, which could help to support our understanding of the central mechanism of PLP.

SIRT4 suppresses the inflammatory response and oxidative stress in osteoarthritis.

Sirtuins have been involved in the osteoarthritis (OA) process. However, the functions of SIRT4 in the degeneration of human chondrocytes and OA are not fully understood. This study aimed to explore the role of SIRT4 during OA and mechanisms implicated. We extracted total protein and mRNA of the cartilage from OA patients and isolated the chondrocytes from the cartilage in different degenerated degrees for cell culture. Collagen II and SIRT4 levels of the tissues were analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot. Chondrocytes were transferred with SIRT4-siRNA, treated with recombinant human SIRT4 protein for 24 h, respectively. Aggrecan, collagen I, collagen II, MMP-13, IL-6, TNF-α, SOD1, SOD2, and CAT expression, and ROS levels were investigated by Western blot, RT-PCR, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), or flow cytometry. Collagen II decreased significantly in severely degenerated cartilage compared to the mild one, paralleling with SIRT4 expression both in protein and mRNA levels. Chondrocytes in severe OA grade were observed with a decrease in aggrecan, collagen II, SOD1, SOD2, CAT expression, nonetheless, an increase in collagen I, reactive oxygen species (ROS), MMP-13, IL-6, and TNF-α levels. However, SRIT4 protein treatment significantly upregulated aggrecan, collagen II, an antioxidant enzyme, and suppressed ROS and inflammatory response. Further analysis revealed that silencing of SIRT4 expression induced healthy chondrocytes, a decrease in aggrecan, collagen II and antioxidant enzyme expression, and an increase in ROS and inflammatory response, importantly, which can be reversed by SIRT4 protein stimuli. Our results elucidated that SIRT4 was tangled with the development of OA, and SIRT4 overexpression contributes to suppresses the inflammatory response and oxidative stress.

Clinical Efficacy of Ultrasound-Mediated Transdermal Lidocaine and Capsaicin Delivery for the Treatment of Allodynia Caused by Herpes Zoster.

OBJECTIVE: To investigate the efficacy of ultrasound-mediated drug delivery for allodynia caused by herpes zoster. DESIGN: Unblinded randomized controlled study with two treatment groups and an additional control group. SUBJECTS: Patients hospitalized with allodynia caused by herpes zoster were enrolled. METHODS: Patients were randomly assigned to three groups: ultrasound-mediated transdermal drug delivery (group U), lidocaine intradermal injection (group I), or control group (group C). The primary outcome was pain intensity associated with allodynia, assessed with the visual analog scale (VAS) while brushing the skin with clothing after treatment stimulated allodynia. The secondary outcomes included an emotional functioning score (ES), average gabapentin consumption, and incidence of adverse events of each group. RESULTS: Sixty patients were enrolled in the study, but two of them failed to complete the treatment process. Therefore, 58 patients were included in the final analysis. All groups had lower VAS and ES scores after treatment compared with baseline. The VAS scores in groups U and I decreased significantly more than in group C (P < 0.05). Mean VAS scores in group U on days 1, 2, and 3 were lower than in group C (P < 0.01). ES was significantly lower in group U compared with groups I and C after treatment (P < 0.001). Average gabapentin consumption and incidence of adverse events in group C were higher than in the other two groups. CONCLUSIONS: In this study of treatment of allodynia caused by herpetic zoster, ultrasound-mediated lidocaine and capsaicin delivery provided better pain relief and improved emotional functioning compared with intradermal blockade with local anesthetics.

Parecoxib exhibits anti-inflammatory and neuroprotective effects in a rat model of transient global cerebral ischemia.

Transient global cerebral ischemia (tGCI) induces inflammation leading to secondary brain injury. Data suggested that cyclooxygenase-2 (COX-2) is involved in the occurrence and development of inflammatory reaction after reperfusion; however, the effectiveness of a highly selective COX-2 inhibitor, parecoxib, to counteract tGCI remains to be determined. Thus, the aim of this study was to investigate the potential protective actions of parecoxib in a rat model of tGCI and the role inflammation plays in this disorder. Adult male Sprague-Dawley rats were administered parecoxib 10 or 20 mg/kg intraperitoneally (ip) at 5 min, 24 or 48 hr after tGCI. Control rats received an equal volume of 0.9% saline. The rat model of tGCI was established using the method of bilateral common carotid artery occlusion combined with arterial hypotension. The following parameters were measured: Neurological Severity Score, morphological changes in the hippocampal CA1 region, Evans blue (EB) extravasation, brain water content, levels of matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), neuronal apoptosis, the protein expression of Bcl-2, Bax, COX-2, prostaglandin E2 (PGE2), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α). Parecoxib treatment significantly improved neurological function and morphological defects in the hippocampal CA1 region, reduced levels of COX-2, PGE2, IL-1ß, and TNF-α. In addition, parecoxib attenuated brain edema and BBB destruction as evidenced by increased ZO-1 expression and decreased MMP-9 expression. Further, parecoxib reduced neuronal apoptosis via diminished protein expression of Bax and enhanced expression of Bcl-2.

Impact of perioperative intravenous lidocaine infusion on postoperative pain and rapid recovery of patients undergoing gastrointestinal tumor surgery: a randomized, double-blind trial.

BACKGROUND: To explore the effect of perioperative intravenous lidocaine infusion on postoperative pain and the rapid recovery of patients undergoing gastrointestinal tumor surgery. METHODS: The patients who underwent gastrointestinal tumor surgery from May to July 2020 were selected. The patients were randomly divided into the lidocaine group (group L) and control group (group C) by the random number table method, with 60 patients in each group. Both groups of patients received an intravenous drug infusion immediately after induction of tracheal intubation under general anesthesia. In group L, 1.5 mg/kg lidocaine was slowly injected intravenously at a rate of 1.5 mg·kg-1·h-1 to the surgical suture, and intravenous inhalation was used to maintain the depth of anesthesia. Group C patients were given the same volume of normal saline. The 2-, 4-, 7-, 14-, 30-, and 90-day numerical rating scale (NRS) and the proportion of chronic post-surgical pain (CPSP) after 3 months for both groups after surgery were recorded. Each patient's postoperative comfort score, requiring analgesia, return of flatus, bowl movement, hospitalization days, hospitalization expenses, and adverse events were also recorded. RESULTS: One hundred and twenty patients were enrolled but 5 of them failed to complete the treatment process. Therefore, 58 and 57 patients in group L and C were included into the final analysis. The NRS of patients in group L was significantly lower than that of group C at all time points after surgery (P<0.05), and the proportion of CPSP in group L was significantly lower than that of group C (P<0.05). The percentage of patients requiring analgesia and postoperative comfort score of group L was significantly higher than that of group C (P<0.01), patient's return of flatus, bowl movement, hospitalization days, and hospitalization expenses in group L were significantly lower than those in group C (P<0.05). There were no difference of adverse events between the 2 groups (P>0.05). CONCLUSIONS: During the perioperative period of radical gastrointestinal tumor surgery, intravenous lidocaine infusion can reduce acute postoperative pain, promote postoperative gastrointestinal function recovery, and improve postoperative comfort.

The pre-amputation pain and the postoperative deafferentation are the risk factors of phantom limb pain: a clinical survey in a sample of Chinese population.

BACKGROUND: To provide an overview of phantom limb pain (PLP) in China. This includes the prevalence of PLP and possible risk factors. METHODS: In a retrospective study, telephone interviews were conducted with 391 amputation patients who underwent extremity amputations at a tertiary hospital in China. RESULTS: PLP was found in 29% of the amputees. Pre-amputation pain (OR = 10.4, P = 0.002) and postoperative analgesia (OR = 4.9, P = 0.008) were identified as high-risk factors for PLP. 82.1% of PLP patients experienced pre-amputation pain. The average pain intensity of PLP was 5.1 ± 2.2, with 31.9% having severe intensity. The effects of PLP on the quality of the PLP patients were as follows: 7.8% of the patients had to limit their daily life and 29.0% of the patients had to limit their social activities. 17.3 and 25.7% of patients experienced depression and sleeping disorder respectively, while 18.9% had loss of interest and even 16.1% of PLP patients had attempted suicide. No effective treatments were found in 78.9% of these patients. CONCLUSIONS: PLP has markedly affected the lives of patients. Pre-amputation pain and postoperative epidural analgesia might be risk factors for the phantom limb pain after amputation. Prevention of pre-amputation pain and sudden post-amputation deafferentation should be recommended to the amputees.

Effect of bisphenol A on SOCS-3 and insulin signaling transduction in 3T3-L1 adipocytes.

The aim of the present study was to investigate whether environmental endocrine disrupting chemical, bisphenol A (BPA), affects secretion of suppressor of cytokine signaling 3 (SOCS-3) and insulin signaling transduction in 3T3-L1 adipocytes. 3T3-L1 adipocytes were treated for 0, 2, 6, 12 and 24 h with BPA at 80 µM in serum­deprived medium. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the mRNA expression levels of SOCS­3 and protein expression levels of SOCS­3, insulin receptor substrate 1 (IRS­1), phosphorylated (p)­IRS­1, Akt and p­Akt. The levels of p­IRS­1, Akt and p­Akt in cultures treated for 6 h with BPA were also analyzed by immunofluorescence. The SOCS­3 mRNA and protein expression levels were decreased in the 6, 12 and 24 h groups. The levels of p­IRS­1 and p­Akt protein were markedly downregulated, while the level of IRS­1 and Akt protein remained unaltered among these groups, which was consistent with the results observed using immunofluorescence. BPA may inhibit insulin signal transduction and result in the occurrence of insulin resistance via promoting the expression of SOCS-3.

Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas.

Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR.

Association between CEBPE Variant and Childhood Acute Leukemia Risk: Evidence from a Meta-Analysis of 22 Studies.

The CCAAT/enhancer binding proteins (CEBPs) have been involved in the etiology of acute leukemia (AL) and investigated in numerous genetic association studies, however, the results were inconclusive. The current meta-analysis was conducted to clarify the effect of CEBPE rs2239633 variant on childhood AL risk. Electronic literature search was performed on August 15, 2014, from databases of Medline, PubMed, Embase, and Web of Science. A total of 22 case-control studies were eligible for the pooled analysis. The results demonstrated that rs2239633 A allele was significantly associated with a decreased risk of childhood AL (A vs G: OR=0.87, 95%CI = 0.80, 0.94, p<0.001), especially in B-cell ALL subgroup (A vs G: OR = 0.79, 95%CI = 0.74, 0.83, p<0.001), but not among T-cell ALL or AML subgroups. In the stratified analysis by ethnicity, the association was observed in Europeans (A vs G: OR = 0.80, 95%CI = 0.76, 0.84, p<0.001) but not in Asian and mixed populations. Moreover, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. Also, Begg's and Egger's tests did not indicate any evidence of obvious asymmetry. In summary, our study provided evidence that CEBPE rs2239633 variant is associated with decreased risk of childhood B-cell ALL in Europeans.

Contribution of polymorphisms in IKZF1 gene to childhood acute leukemia: a meta-analysis of 33 case-control studies.

OBJECTIVE: Two common polymorphisms in the IKZF1 gene (rs4132601 and rs11978267 variants) have been reported to be associated with childhood acute leukemia (AL) risk, however the results were inconsistent. Here, we conducted a meta-analysis to generate large-scale evidence on whether IKZF1 variants are risk factors for childhood AL. METHODS: The PubMed, Embase, EBSCO, and Web of Science were searched up to June 2, 2014 for studies on the association of IKZF1 polymorphisms with childhood AL risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by a fixed-effects or random-effects model. Subgroup analysis by ethnicity and leukemia subtype, sensitivity and cumulative meta-analyses were performed. Moreover, publication bias was assessed by Begg's and Egger's tests. RESULTS: In total, 33 case control studies were finally included in this meta-analysis. For rs4132601 polymorphism, significantly increased AL risk was observed in all genetic models (the association was still significant when the p value was Bonferroni adjusted to 0.025). In the subgroup analysis by tumor type, statistical association was observed in B-cell precursor ALL (BCP-ALL). Additionally, when stratified by ethnicity, significantly increased AL risk was only observed in European subgroup, but not among African or mixed population subgroups. Finally, similar results were found for rs11978267 polymorphism. CONCLUSION: In summary, this meta-analysis provides evidence that rs4132601 and rs11978267 polymorphisms in the IKZF1 gene might contribute to the occurrence of BCP-ALL, especially in European populations. Moreover, further studies with large sample size are required to clarify possible roles of IKZF1 variants in other ethnic groups (e.g., Asians and Africans).

Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method.

Tramadol is a potent analgesic. However, the analgesia efficacy of tramadol, particularly its minimum effective dose (MED), is not clear. The aim of this study is to find MED of tramadol for postoperative analgesia in infants. The continual reassessment method (CRM) was performed to find MED. Infants undergoing surgeries were included in the 3 phases of this series. In each phase, 24 participants were allocated a different tramadol dose. Pain intensity was measured by face, legs, activity, cry, consolability (FLACC) measurement at 3-hour intervals. Tramadol was considered ineffective if the FLACC score was higher than 4 in 10 at anytime. In phase 1, seven dose levels were used within the range 0.1-0.4 mg·kg(-1)·h(-1). Phase 1 was insufficient to identify the MED, and we increased the dose to 0.4-0.8 mg·kg(-1)·h(-1) in phase 2. Phase 2 was insufficient to identify the MED. In phase 3, local anesthetic wound infiltration was introduced, and the tramadol dose levels tested were the same as in phase 1. The successful analgesia probability of tramadol 0.4 mg·kg(-1)·h(-1) was 82.1% (95% CI, 0.742-0.925) in phase 1. In phase 2, it was 84.7% (95% CI, 0.789-0.991) with the dose 0.8 mg·kg(-1)·h(-1). Phase 1 and phase 2 were insufficient to identify the MED. In phase 3, the successful analgesia probability for dose 0.35 mg·kg(-1)·h(-1) was 96.7% (95% CI, 0.853-0.997).We have demonstrated that tramadol provides insufficient analgesia for surgeries considered to cause moderate-to-severe postoperative pain in infants if used as the sole analgesic, and that local anesthetic wound infiltration enhances the efficacy of tramadol.

[Appraisement of stellate ganglion block therapy for uncertainty statements syndrome with infrared thermography].

We treated 20 patients suffering from uncertainty statements syndrome (USS) with stellate ganglion block (SGB) therapy. The medical infrared thermography was examined before and after the SGB therapy. Analysis on the changes of surface temperature as well as the outcome of the patients was carried out. Among the mentioned 20 patients, 15 (75%) got obvious effect, 4 (20%) fairly good effect and 1 (5%) a little improvement after the SGB therapy. The corresponding surface temperatures of these patients were 1.32 +/- 0.27 degrees C, 0.97 +/- 0.31 degrees C, and 0.76 +/- 0.33 degrees C, respectively. The more the surface temperature changed, the better the efficacy of the therapy was. The medical infrared thermography may objectively represent the therapeutic effect of SGB on the USS.