Acute postoperative pain is correlated with the early onset of postpartum depression after cesarean section: a retrospective cohort study.

The primary purpose of this study was to evaluate the correlation between the intensity of acute postoperative pain and development of postpartum depression (PPD) after cesarean section (CS). The secondary purpose was to investigate perioperative risk factors for PPD detected in the postoperative period after CS. We retrospectively reviewed 615 women who had undergone CS between January 2017 and October 2019 in our hospital. The incidence of PPD was 22.7% on postoperative day (POD) 5 in the 247 women whose numerical rating scale (NRS) scores on POD3 were available. The severity of acute postoperative pain evaluated by NRS was higher in women with than in those without PPD on POD3 (P < 0.02). The independent risk factors for the onset of PPD on POD5 were being a primipara [adjusted odds ratio (aOR), 2.08; 95% confidence interval (CI), 1.03-4.20, P < 0.05], preoperative presence of chronic pain (OR, 4.44; 95% CI 1.82-10.81, P < 0.001), and NRS ≥ 2 on POD3 (aOR, 4.90; 95% CI 1.06-22.61, P < 0.05). Our findings suggest that assessing both acute postoperative pain and presence of PPD can inform the introduction of interventions in the early phase to prevent development of PPD after CS.

Contralateral cerebral hemoglobin oxygen saturation changes in patients undergoing thoracotomy with general anesthesia with or without paravertebral block: a randomized controlled trial.

PURPOSE: Perioperative analgesia during thoracotomy is often achieved by combining paravertebral block (PVB) with general anesthesia (GA). Functional near-infrared spectroscopy (NIRS) can detect changes in cerebral oxygenation resulting from nociceptive stimuli in the awake state or under sedation. We used NIRS to measure changes in cerebral blood flow provoked by thoracotomy incision made under GA and determine how these changes were influenced by supplementation of GA with PVB. METHODS: Thirty-four patients undergoing elective thoracotomy were enrolled. Patients were randomly assigned to a group receiving only GA, or GA combined with PVB (GA + PVB). Changes in cerebral oxygenated hemoglobin (ΔO2Hb), deoxygenated-Hb (ΔHHb), and total-Hb (ΔtotalHb) were evaluated by NIRS as surgery began. RESULTS: In the GA group, ΔO2Hb was significantly higher in the hemisphere contralateral to the side of surgery when the incision was made and 2 min after incision compared with the ipsilateral side (start of surgery, P < 0.01; 2 min, P < 0.05). In contrast, there were no significant changes in the ΔO2Hb at any of the time points in the GA + PVB group. Comparable with ΔO2Hb, the concentration of ΔtotalHb was significantly higher in the contralateral hemisphere in the GA group at the start of surgery (P < 0.05). CONCLUSIONS: Changes in the cerebral O2Hb concentration were detected by NIRS immediately after surgical incision under GA, but not in the presence of a PNB. NIRS could be used to monitor surgical pain. PVB inhibited changes in oxygenation induced by incision-provoked pain.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice.

Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC1-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP-induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC1-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose-dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC1-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-α-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC1-R induces long-lasting nociception through the interaction of neurons and astrocytes.

Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-γ-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes.

BACKGROUND: The wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator-activated receptor (PPAR)-γ agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated. METHODS: The PPARγ agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively. RESULTS: Rosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 ± 0.106 vs. 0.068 ± 0.12) and 7 (0.529 ± 0.184 vs. 0.153 ± 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone-induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds. CONCLUSIONS: In diabetes, exogenous administration of RvD1 is essential for PPARγ-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARγ-mediated macrophage polarization to the M2 phenotype.

[A Case of Liver Contusion during Spinal Operation for Idiopathic Scoliosis].

A 20-year-old man diagnosed as idiopathic scoliosis with Cobb angle 146 degrees was scheduled for two-stage operations. Anterior dissection of the thoracic vertebra in the left lateral decubitus position, and the placement of pedicle screws in the prone position were performed as the first-stage operation. During surgery, the patient developed liver contusion with ascites, probably due to hepatic compression placed between vertebrae and operating table in the prone position. In the second operation for posterior spinal fusion, the occurrence of liver contusion was prevented by performing abdominal ultrasonography before and after surgery, and monitoring AST/ALT during anesthesia as the indicators of liver contusion. Intraoperative management for organ protection is required during anesthesia in patients with idiopathic scoliosis associated with thoracic deformity.

Peripheral administration of morphine attenuates postincisional pain by regulating macrophage polarization through COX-2-dependent pathway.

BACKGROUND: Macrophage infiltration to inflammatory sites promotes wound repair and may be involved in pain hypersensitivity after surgical incision. We recently reported that the development of hyperalgesia during chronic inflammation is regulated by macrophage polarity, often referred to as proinflammatory (M1) or anti-inflammatory (M2) macrophages. Although opioids such as morphine are known to alter the inflammatory milieu of incisional wounds through interactions with immunocytes, the macrophage-mediated effects of morphine on the development of postincisional pain have not been well investigated. In this study, we examined how morphine alters pain hypersensitivity through phenotypic shifts in local macrophages during the course of incision-induced inflammation. RESULTS: Local administration of morphine in the early phase, but not in the late phase alleviated mechanical hyperalgesia, and this effect was reversed by clodronate-induced peripheral depletion of local macrophages. At the morphine-injected incisional sites, the number of pro-inflammatory F4/80+iNOS+M1 macrophages was decreased during the course of pain development whereas increased infiltration of wound healing F4/80+CD206+M2 macrophages was observed during the early phase. Morphine increased the gene expression of endogenous opioid, proenkephalin, and decreased the pronociceptive cytokine, interleukin-1ß. Heme oxygenase (HO)-1 promotes the differentiation of macrophages to the M2 phenotype. An inhibitor of HO-1, tin protoporphyrin reversed morphine-induced analgesic effects and the changes in macrophage phenotype. However, local expression levels of HO-1 were not altered by morphine. Conversely, cyclooxygenase (COX)-2, primarily produced from peripheral macrophages in acute inflammation states, was up-regulated in the early phase at morphine-injected sites. In addition, the analgesic effects and a phenotype switching of infiltrated macrophages by morphine was reversed by local administration of a COX inhibitor, indomethacin. CONCLUSIONS: Local administration of morphine alleviated the development of postincisional pain, possibly by altering macrophage polarity at the incisional sites. A morphine-induced shift in macrophage phenotype may be mediated by a COX-2-dependent mechanism. Therefore, µ-opioid receptor signaling in macrophages may be a potential therapeutic target during the early phase of postincisional pain development.

Suspected intraoperative formation of left atrial thrombus in a patient with atrial fibrillation receiving bridging anticoagulation therapy.

We present a patient with atrial fibrillation (AF) in whom a left atrial (LA) thrombus might have formed during laparotomy despite bridging anticoagulation therapy. No evidence of thrombus was detected by transesophageal echocardiography (TEE) at the start of surgery; however, a thrombus measuring 13 × 10 mm was found in the LA appendage by the end of the procedure, suggesting that thrombus might develop intraoperatively in patients with AF even when bridging anticoagulation is properly established. Intraoperative TEE can assist in detecting intracardiac thrombus in patients with AF regardless of their anticoagulation status and provides a tool for intervention to prevent systemic embolization.

Perfusion index as a possible predictor for postanesthetic shivering.

BACKGROUND: Postanesthetic shivering can be triggered by surgical stress and several aspects of anesthetic management and is frequently preceded by a decrease in peripheral blood flow due to thermoregulatory vasoconstriction. As perfusion index correlates with peripheral blood flow, we examined whether perioperative perfusion index, measured using pulse oximetry, might be correlated with postanesthetic shivering. METHODS: Twenty-eight patients presenting for elective abdominal surgery were enrolled. Core (esophagus) and peripheral (finger) temperatures and perfusion index were recorded in the perioperative periods. Correlations between perfusion index and peripheral temperature and core-to-peripheral temperature gradient were then explored. Plasma levels of epinephrine and norepinephrine were also measured. The extent of shivering was graded after emergence from anesthesia. RESULTS: Perfusion index declined before emergence from anesthesia in patients who then developed postanesthetic shivering. This coincided with the time at which the difference between core and peripheral temperature became dissociated and peripheral temperature declined. Perioperative perfusion index was correlated with peripheral temperature and peripheral-core temperature gradient. Perfusion index at closure of the peritoneum predicted postanesthetic shivering and was significantly correlated with the extent of shivering. Plasma levels of both epinephrine and norepinephrine were significantly elevated after shivering events. CONCLUSIONS: Perfusion index was significantly lower in patients with postanesthetic shivering before emergence from anesthesia, indicating that measurement of perfusion index during and before the end of anesthesia might be a useful means of predicting postanesthetic shivering.

[Plasma levels of anti-oxidant markers during general anesthesia--a comparison between remifentanil- and epidural-based anesthesia].

BACKGROUND: Anesthesia may influence oxidative stress responses to surgical stress during surgery. We performed a prospective study to investigate the impact of anesthesia on oxidative stress responses between patients receiving ropivacaine-based epidural anesthesia and patients receiving remifentanil-based general anesthesia METHODS: Plasma levels of oxidative stress-related substances such as superoxide dismutase (SOD) and myeloperoxidase were measured during anesthesia in patients receiving ropivacaine-based epidural anesthesia (E group) and patients receiving remifentanil-based general anesthesia (R group). RESULTS: SOD, which catalyzes the reduction of superoxide anions to hydrogen peroxide and has anti-oxidative effects, was significantly lower in E group at the end of surgery whereas the levels of myeloperoxydase were not different between the groups. Plasma levels of adrenaline and noradrenaline were significantly higher in R group than E groups after surgery. CONCLUSIONS: Although activation of sympathetic nervous system was effectively inhibited by epidural anesthesia. SOD level was low in E group. Remifentanil might directly increase SOD, independent of sympathetic nervous system.

High prevalence of severe pain is associated with low opioid availability in patients with advanced cancer: Combined database study and nationwide questionnaire survey in Japan.

OBJECTIVES: Opioid availability for the palliative care of patients with advanced cancer is increasing globally. However, opioid availability remains extremely low in Japan. We investigated whether pain is appropriately controlled by low-dose opioid prescriptions in patients with advanced cancer in Japan. METHODS: A web-based nationwide survey for caregivers from 2000 community comprehensive support care centers was performed in Japan to assess details about pain in the 30 days before patients died of end-stage cancer. Separately, the data for opioid prescription doses and medical services in the 90 days before the death of patients with cancer were extracted from a health insurance claim database. RESULTS: Responses from 1034 responders were retrieved and 665 patients were included. In total, 254 patients (38.2%) complained of severe-to-intolerable cancer-related pain. The median cumulative prescription dose of opioids in the 90 days before patient death was 311.0 mg by oral morphine equivalent doses. Multiple regression analyses across prefectures revealed that the proportion of patients with severe-to-intolerable cancer-related pain was negatively associated with the cumulative opioid consumption expressed as morphine-equivalent doses within 90 days before death. CONCLUSIONS: The very low availability of opioids for patients with end-stage cancer could result in high rate of severe-to-intolerable cancer-related pain patients. There were several limitations in this study, and the interpretations of the findings should be carefully. However, the increase in the absolute dose of opioids could improve the palliative care framework to the pain control levels of the global standard.

Increased carboxyhemoglobin level during liver resection with inflow occlusion.

Controlling stress responses associated with ischemic changes due to bleeding and ischemia/reperfusion injury is essential for anesthetic management. Endogenous carboxyhemoglobin (COHb) is produced in the oxidative degradation of heme proteins by the stress-response enzyme heme oxygenase. Although the COHb level is elevated in critically ill patients, changes in endogenous COHb during anesthesia have not been well investigated. Therefore, we evaluated changes in endogenous COHb levels in patients undergoing liver resections with inflow occlusion. Levels of COHb were significantly increased after the Pringle maneuver. The inflow occlusion time in patients with increased COHb after the Pringle maneuver (∆COHb > 0.3 %) was significantly longer than in patients without increased COHb (∆COHb < 0.3 %) (P = 0.01). In addition, COHb changes were correlated with inflow occlusion time (P = 0.005, R(2) = 0.21). Neither total blood loss, transfusion volume of packed red blood cells, operation time, nor anesthetic time differed between patients with and without increased COHb. The results indicated that endogenous COHb levels were increased by inflow occlusion in patients undergoing liver resections, which suggests that changes in COHb may correlate with hepatic ischemia/reperfusion injury induced by inflow occlusion.

Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis.

Injury and inflammation are potent regulators of adult neurogenesis. As the complement system forms a key immune pathway that may also exert critical functions in neural development and neurodegeneration, we asked whether complement receptors regulate neurogenesis. We discovered that complement receptor 2 (CR2), classically known as a coreceptor of the B-lymphocyte antigen receptor, is expressed in adult neural progenitor cells (NPCs) of the dentate gyrus. Two of its ligands, C3d and interferon-α (IFN-α), inhibited proliferation of wild-type NPCs but not NPCs derived from mice lacking Cr2 (Cr2(-/-)), indicating functional Cr2 expression. Young and old Cr2(-/-) mice exhibited prominent increases in basal neurogenesis compared with wild-type littermates, whereas intracerebral injection of C3d resulted in fewer proliferating neuroblasts in wild-type than in Cr2(-/-) mice. We conclude that Cr2 regulates hippocampal neurogenesis and propose that increased C3d and IFN-α production associated with brain injury or viral infections may inhibit neurogenesis.

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization.

Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor γ (PPAR)γ signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPARγ agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPARγ signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPARγ signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor κB (NFκB) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80(+)iNOS(+) M1 macrophages was decreased whereas numbers of F4/80(+)CD206(+) M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin αX, IL-1ß, MIP2α and leptin were decreased at rosiglitazone-treated incisional sites. Moreover, transplantation of rosiglitazone-treated peritoneal macrophages into the incisional sites significantly attenuated hyperalgesia. We speculate that local administration of rosiglitazone significantly alleviated the development of postincisional pain, possibly through regulating macrophage polarity at the inflamed site. PPARγ signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.

Serum levels of apolipoprotein A-I and E are associated with postoperative delirium: A post hoc analysis.

Postoperative delirium is a common complication for elderly patients. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage with postoperative delirium. Although it has been implicated that serum apolipoprotein levels might be associated with senile cognitive disorder, its role in the development of delirium has not been fully investigated. This study examined the association of apolipoproteins with delirium after surgery. This was a post hoc analysis of 117 patients who participated in a prospective observational study of delirium in patients undergoing cancer surgery. Patients were clinically assessed for delirium within the first 5 days of surgery. Serum levels of apolipoprotein A-I, B, and E were measured on postoperative day 3. Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Serum levels of apolipoprotein A-I and B were increased in patients with delirium whereas those of apolipoprotein E were decreased. These changes in apolipoprotein A-I and E levels were associated with the presence of phosphorylated neurofilament heavy subunit in the serum, and were significantly associated with delirium (A-I: adjusted odds ratio [aOR], 6.238; 95% confidence interval [CI], 2.766-20.68; P < .0001; E: aOR, 0.253; 95% CI, 0.066-0.810; P = .0193). A combination of apolipoprotein A-I and E offers significant discrimination between delirium and nondelirium with high accuracy (area under the curve, 0.8899). Serum apolipoprotein A-I and E levels were associated with delirium and the presence of phosphorylated neurofilament heavy subunit in serum. Therefore, apolipoproteins might be useful biomarkers of postoperative delirium.

Elevation of serum plasminogen activator inhibitor-1 predicts postoperative delirium independent of neural damage: a sequential analysis.

Older adult surgical patients are susceptible to developing delirium. Early intervention can be initiated if a potential biomarker associated with delirium can be identified during the acute phase of surgery. Therefore, we investigated the changes in the levels of serum inflammatory mediators responsible for delirium. Serum biomarkers were measured preoperatively to postoperative day 3 in 96 patients who underwent esophageal cancer surgery and compared between patients who did and did not develop delirium. Serum concentrations of the brain-derived phosphorylated neurofilament heavy subunit remained at higher levels throughout the entire perioperative period in patients with delirium (n = 15) than in those without delirium (n = 81). The interaction between delirium and non-delirium was significant for plasminogen activator inhibitor-1 (including age as a covariate, F = 13.360, p < 0.0001, η2 p = 0.134, observed power 1.000) during the perioperative periods. Plasminogen activator inhibitor-1 level discriminated between patients with and without clinically diagnosed delirium with significantly high accuracy (area under curve, 0.864; sensitivity, 1.00: negative predictive value, 1.000; p = 0.002). Rapid increases in the levels of serum plasminogen activator inhibitor-1 may enable clinicians to identify patients at risk of developing postoperative delirium and initiate early prevention and intervention.

The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells.

Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell-deficient WBB6F(1)-W/W(v) mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F(1)-W/W(v) mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca(2+) mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell-mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell-mediated inflammatory diseases.

The macrophage-mediated effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuate tactile allodynia in the early phase of neuropathic pain development.

BACKGROUND: Neuroinflammation triggered by macrophage infiltration into sites of peripheral nerve injury may result in neuropathic pain. Peroxisome proliferator-activated receptor (PPAR)γ signaling regulates the properties of macrophages. However, the macrophage-mediated effects of PPARγ signaling on neuropathic pain triggered by peripheral inflammation have not been investigated. METHODS: To evaluate the peripheral effects of PPARγ signaling on tactile allodynia, we administered the blood-brain barrier-impermeant PPARγ agonist, rosiglitazone, after partial sciatic nerve ligation (PSNL) as (1) systemic treatment during different phases of neuropathic pain development, (2) local injection to the PSNL site in the early phase, or (3) peritoneal macrophages pretreated with rosiglitazone transplanted into the PSNL site. In addition, the direct effect of rosiglitazone was evaluated in peritoneal macrophages activated with interferon-γ. RESULTS: Systemic rosiglitazone treatment early in the course of progressive inflammation ameliorated tactile allodynia, macrophage infiltration, and production of proinflammatory mediators including cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease 9 at the PSNL site. Local injection of rosiglitazone and transplantation of rosiglitazone-treated peritoneal macrophages at the ligation site significantly improved tactile allodynia. In peritoneal macrophages, rosiglitazone down-regulated interferon-γ-induced gene expression of cyclooxygenase-2 and inducible nitric oxide synthase and attenuated the chemotactic response to monocyte chemotactic protein-1. DISCUSSION: Rosiglitazone treatment in the early phase of neuropathic pain significantly alleviated the development of tactile allodynia by regulating macrophage infiltration and production of proinflammatory molecules at the inflamed site. Our results indicate that the activation of PPARγ signaling in macrophages during the early phase may suppress neuropathic pain development.

Lidocaine attenuates the development of diabetic-induced tactile allodynia by inhibiting microglial activation.

BACKGROUND: Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated. METHODS: To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ injection. On day 21, microglial accumulation and p38 mitogen-activated protein kinase activation in the dorsal horn were evaluated. In vitro, the effects of lidocaine on cell viability, chemotactic response to monocyte chemotactic protein-1, and induction of proinflammatory mediators were examined in interferon (IFN)-γ-stimulated primary microglial cells. RESULTS: Continuous systemic administration of lidocaine in the early progression of tactile allodynia produced long-lasting analgesic effects in STZ-treated mice. Lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells in the dorsal horn. In vitro, lidocaine down-regulated IFN-γ-induced gene induction of inducible oxide synthase and interleukin-1ß. Pretreatment with lidocaine significantly reduced chemotactic response to monocyte chemotactic protein-1 of IFN-γ-activated microglial cells. CONCLUSION: Lidocaine alleviates STZ-induced tactile allodynia, possibly by modulating the p38 pathway in spinal microglial cells. Inhibiting microglial activation by lidocaine treatment early in the course of diabetes-induced neuropathy represents a potential therapeutic strategy for tactile allodynia.

Elevated neuron-specific enolase level is associated with postoperative delirium and detection of phosphorylated neurofilament heavy subunit: A prospective observational study.

BACKGROUND: Delirium is the most common central nervous system complication after surgery. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage within the central cervous system and is associated with the severity of postoperative delirium. Neuron-specific enolase and S100 calcium-binding protein ß have been identified as possible serum biomarkers of postoperative delirium. This study examined the association of the levels of these markers with incidence of postoperative delirium and detection of phosphorylated neurofilament heavy subunit. METHODS: This study represents a post hoc analysis of 117 patients who participated in a prospective observational study of postoperative delirium in patients undergoing cancer surgery. Patients were clinically assessed for development of postoperative delirium within the first five days of surgery. Serum levels of phosphorylated neurofilament heavy subunit, neuron-specific enolase, and S100 calcium-binding protein ß levels were measured on postoperative day 3. RESULTS: Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Neuron-specific enolase level (P < 0.0001) and the proportion of patients positive for phosphorylated neurofilament heavy subunit (P < 0.0001) were significantly higher in the group of patients with postoperative delirium. Neuron-specific enolase level discriminated between patients with and without clinically diagnosed postoperative delirium with significantly high accuracy (area under the curve [AUC], 0.87; 95% confidence interval [CI], 0.79-0.95; P < 0.0001). Neuron-specific enolase level was associated with incidence of postoperative delirium independently of age (adjusted odds ratio, 8.291; 95% Cl, 3.506-33.286; P < 0.0001). The AUC for the serum neuron-specific enolase level in detecting phosphorylated neurofilament heavy subunit was significant (AUC, 0.78; 95% CI, 0.66-0.90; P < 0.0001). CONCLUSION: Elevated serum neuron-specific enolase was associated with postoperative delirium independent of age as well as detection of phosphorylated neurofilament heavy subunit in serum. Serum neuron-specific enolase and phosphorylated neurofilament heavy subunit might be useful as biomarkers of postoperative delirium. TRIAL REGISTRATION: University Medical Information Network (UMIN) trial ID: UMIN000010329; https://clinicaltrials.gov/.

Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia.

We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line-derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.