The expression profiling and clinical significance of a chronic pain-related gene IL1R1.

Chronic pain is a disease that existed during cancer treatment for a long time. It has been reported that interleukin (IL)-1 is involved in the inflammatory response during tumor development. IL1R1 and IL1R2 are members of the IL-1 receptor family of cytokine receptors. However, few studies have reported the role of chronic pain-related genes, IL1R1, in pan-cancer. In this study, 8 lumbar disc prolapse (LDP) patients and 8 controls with differentially expressed genes were investigated to find chronic pain-related genes. Then, IL1R1 was analyzed using the TCGA database. The clinical survival data from TCGA were used to analyze the prognostic value of IL1R1. This study further evaluated the relationship between IL1R1 and immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. IL1R1 was expressed in varying degrees in most TCGA tumor types, indicating a better survival status. The expression of IL1R1 is closely related to T cell infiltration, immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. The results show that IL1R1 is a kind of potential cancer biomarker. Coordination with other immune checkpoints IL1R1k may adjust the immune microenvironment, immunotherapy can be applied to the development of new targeted drugs.

Epidural analgesia during labor and its optimal initiation time-points: A real-world study on 400 Chinese nulliparas.

ABSTRACT: Recent research has suggested that 6 cm of cervical dilation should be the threshold for the active labor phase, and it has confirmed that epidural analgesia (EA) is a safe method of pain relief during labor. However, the evidence provided for these findings comes mainly from randomized controlled clinical trials (RCTs), which suffer from the limitation of real-world generalizability.To test the generalizability of the conclusions from these previous RCTs, we conducted a prospective cohort, real-world study (RWS) on 400 Chinese term nulliparas. A total of 200 of the participants (the EA group) received EA upon request. The participants in the EA group were further subdivided as follows according to their cervical dilation when the EA administration was initiated (CDE): [EA1 group (CDE < 3 cm), EA2 group (3 cm ≤ CDE < 6 cm), and EA3 group (CDE ≥ 6 cm)]. We compared the labor duration of the EA group versus the non-EA (NEA) group, and the NEA group versus the 3 EA subgroups. We also compared delivery outcomes between the EA and NEA groups.The median total labor duration for the EA group [676 (511-923) minutes] was significantly longer than that of the NEA group [514 (373-721) minutes] (P < 0.001). The median durations of both the first- and second-stages of labor for the EA group [600 (405-855) minutes, 68 (49-97) minutes] were longer than those of the NEA group [420 (300-630) minutes, 50 (32-85) minutes] (P < .001, P < .001)]. In addition, the median total labor durations in both the EA1 [720 (548-958) minutes] and EA2 groups [688 (534-926) minutes] were longer than in the NEA group (P < .001 and P < .001, respectively), and the first- and second-stage labor durations of these subgroups were similar to their total labor durations. A Cox regression analysis showed that EA was associated with longer first-stage labor [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.42-0.71, P < .001] and longer second-stage labor (HR 0.66, 95% CI 0.51-0.85, P = .001). The delivery modes and neonatal outcomes between the EA and NEA groups were not statistically different, however.Our findings suggest that EA administered before a cervical dilation of 6 cm may be associated with longer total, first-, and second-stage labor durations compared with no EA, while later EA administration is not. In addition, though EA prolongs labor duration, it does not impact delivery outcomes. These results confirm the significance of a 6 cm cervical dilation threshold in real-world labor settings.

Melanocortin-4 receptor in subthalamic nucleus is involved in the modulation of nociception.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) stimulation produces significant improvement of overall pain related to Parkinson disease; however, the mechanisms underlying analgesic effects of STN-DBS are still unknown. This report describes direct neuroanatomical evidence for the central melanocortinergic-opioidergic circuits in the STN. We investigated melanocortin-4 receptor (MC4R) and mu-opioid receptor (MOR)-positive expression of the STN in MC4R-GFP transgenic mice using fluorescence immunohistochemical detection. Immunohistochemistry showed a large number of MC4R-GFP- and MOR-positive neurons within the STN region, and approximately 50% of MC4R-GFP-positive neurons coexpressed MOR. The results of this study showed direct neuroanatomical evidence for the central melanocortinergic-opioidergic signaling in the STN region. These findings contribute to the view of melanocortinergic-opioidergic circuits in the subthalamic nucleus as a reliable source of modulating of nociception with therapeutic potential for alleviating pain.

One case with dexmedetomidine-induced stuporous state in epileptic patient undergoing abdominal surgery.

A 56-year-old epileptic patient underwent right hemicolectomy and cholecystectomy surgery under general endotracheal anesthesia. Anesthesia was maintained with sevoflurane, and sufentanil, rocuronium, and dexmedetomidine infusions. After the operation and confirmation of neuromuscular recovery, the patient woke from anesthesia within 15 min and successfully extubated. After the vital signs of patient were stable, the patient was transported to post anesthesia care unit (PACU). 6 h after the surgery, he fell into a stuporous state for lasting 14 h and EEG showed no epileptiform discharges. Stupor did re-occur in 2 days after operation. 36 hours after operation, all signs of the stuporous state resolved spontaneously. Apparent dexmedetomidine-induced stuporous state has not been reported in the human literature.

Effect of Propofol on the Expression of MMP-9 and Its Relevant Inflammatory Factors in Brain of Rat with Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is bleeding in brain caused by the rupture of brain blood vessel, which may lead to patient unconsciousness or death. In this study, we measured the expression of matrix metalloproteinase-9 (MMP-9) and its relevant inflammatory factors in the brain of rat with ICH. The effect of propofol on the expression of MMP-9 and inflammatory factors was investigated. We found the water content in the brain of ICH rats was significantly higher when compared with normal brain. Expression of MMP-9 and inflammatory factors IL-1ß and TNF-α were up-regulated in ICH rats. Medium or high concentration of propofol can alleviate ICH in rats by inhibition of the inflammatory factor release and up-regulation of MMP-9 in brain. Our study suggests the inflammatory response after reduction of ICH through promotion of MMP-9 expression and neurite regeneration.

Anti-inflammatory Mechanism of Bone Marrow Mesenchymal Stem Cell Transplantation in Rat Model of Spinal Cord Injury.

To explore the effect of bone marrow mesenchymal stem cell (BMSC) transplantation on the levels of toll-like receptor 4 (TLR4), interleukin-1ß (IL-1ß), and tumor necrosis factor (TNF-α) in spinal cord tissue of rat model of spinal cord injury (SCI). BMSCs from 4-week-old male SD rats were isolated, cultured, and characterized after three generations using specific surface markers CD34 and CD44. Fifty four SD male rats were divided into sham group, model group, and cell transplantation group (18 rats each group). SCI model was generated using an improved Allen's method. Rats in cell transplantation group were treated with BMSCs in caudal vein. Rats were sacrificed at 24 h, 72 h, and 7 d post-injury, and spinal cord tissues were taken out for detection of IL-1ß and TNF-α tissue content by enzyme-linked immunosorbent assay. IL-1ß and TNF-α mRNA expression was evaluated by qPCR and TLR4 protein expression was analyzed by Western blotting. IL-1ß and TNF-α protein levels, as well as IL-1ß, TNF-α mRNA, and TLR4 expression were significantly increased in rats with established SCI, and reached its peak in spinal cord tissues at 72 h after the initial injury (p < 0.01 comparing to sham group). BMSC transplantation resulted in significant decrease in IL-1ß and TNF-α tissue content, as well as IL-1ß, TNF-α mRNA, and TLR4 expression as compared with model group (p < 0.01). BMSCs may alleviate the damaging effect of spinal cord inflammation by weakening TLR4-mediated signaling pathways and reducing tissue content of IL-1ß and TNF-α.

Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils.

High-dose i.v. Ig (IVIG) is used to treat various autoimmune and inflammatory diseases; however, the mechanism of action remains unclear. Based on the K/BxN serum transfer arthritis model in mice, IVIG suppression of inflammation has been attributed to a mechanism involving basophils and the binding of highly sialylated IgG Fc to DC-SIGN-expressing myeloid cells. The requirement for sialylation was examined in the collagen Ab-induced arthritis (CAbIA) and K/BxN serum transfer arthritis models in mice. High-dose IVIG (1-2 g/kg body weight) suppressed inflammatory arthritis when given prophylactically. The same doses were also effective in the CAbIA model when given subsequent to disease induction. In this therapeutic CAbIA model, the anti-inflammatory effect of IVIG was dependent on IgG Fc but not F(ab')2 fragments. Removal of sialic acid residues by neuraminidase had no impact on the anti-inflammatory activity of IVIG or Fc fragments. Treatment of mice with basophil-depleting mAbs did not abrogate the suppression of either CAbIA or K/BxN arthritis by IVIG. Our data confirm the therapeutic benefit of IVIG and IgG Fc in Ab-induced arthritis but fail to support the significance of sialylation and basophil involvement in the mechanism of action of IVIG therapy.

Amelioration of murine passive immune thrombocytopenia by IVIg and a therapeutic monoclonal CD44 antibody does not require the Myd88 signaling pathway.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin α(IIb)ß3 (GPIIbIIIa) which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg) which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs) are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of murine ITP.