Intraoperative Transesophageal Echocardiography Evaluation of Tricuspid Valve Re-repair for Ebstein's Anomaly.

Postoperative stenosis or regurgitation of the tricuspid valve is common and affects the prognosis after repair surgery of Ebstein's anomaly. However, it is unclear how intraoperative echocardiography influences the postoperative course. We report a longitudinal echocardiography course including intraoperative transesophageal echocardiography in a cone reconstruction procedure for Ebstein's anomaly in a 17-year-old woman. Tight tricuspid valvuloplasty was preferred, but the tricuspid annulus enlarged rather after surgery. The evaluation of the tricuspid valve form and function using intraoperative echocardiography could support the surgeon's impression.

Association between intraoperative pulmonary artery pressure and cardiovascular complications after off-pump coronary artery bypass surgery: a single-center observational study.

BACKGROUND: The impact of intraoperative pulmonary hemodynamics on prognosis after off-pump coronary artery bypass (OPCAB) surgery remains unknown. In this study, we examined the association between intraoperative vital signs and the development of major adverse cardiovascular events (MACE) during hospitalization or within 30 days postoperatively. METHODS: This retrospective study analyzed data from a university hospital. The study cohort comprised consecutive patients who underwent isolated OPCAB surgery between November 2013 and July 2021. We calculated the mean and coefficient of variation of vital signs obtained from the intra-arterial catheter, pulmonary artery catheter, and pulse oximeter. The optimal cut-off was defined as the receiver operating characteristic curve (ROC) with the largest Youden index (Youden index = sensitivity + specificity - 1). Multivariate logistic regression analysis ROC curves were used to adjust all baseline characteristics that yielded P values of < 0.05. RESULTS: In total, 508 patients who underwent OPCAB surgery were analyzed. The mean patient age was 70.0 ± 9.7 years, and 399 (79%) were male. There were no patients with confirmed or suspected preoperative pulmonary hypertension. Postoperative MACE occurred in 32 patients (heart failure in 16, ischemic stroke in 16). The mean pulmonary artery pressure (PAP) was significantly higher in patients with than without MACE (19.3 ± 3.0 vs. 16.7 ± 3.4 mmHg, respectively; absolute difference, 2.6 mmHg; 95% confidence interval, 1.5 to 3.8). The area under the ROC curve of PAP for the prediction of MACE was 0.726 (95% confidence interval, 0.645 to 0.808). The optimal mean PAP cut-off was 18.8 mmHg, with a specificity of 75.8% and sensitivity of 62.5% for predicting MACE. After multivariate adjustments, high PAP remained an independent risk factor for MACE. CONCLUSIONS: Our findings provide the first evidence that intraoperative borderline pulmonary hypertension may affect the prognosis of patients undergoing OPCAB surgery. Future large-scale prospective studies are needed to verify the present findings.

Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance.

Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

Sevoflurane-induced amnesia is associated with inhibition of hippocampal cell ensemble activity after learning.

General anesthesia could induce amnesia, however the mechanism remains unclear. We hypothesized that suppression of neuronal ensemble activity in the hippocampus by anesthesia during the post-learning period causes retrograde amnesia. To test this hypothesis, two experiments were conducted with sevoflurane anesthesia (2.5%, 30 min): a hippocampus-dependent memory task, the context pre-exposure facilitation effect (CPFE) procedure to measure memory function and in vivo calcium imaging to observe neural activity in hippocampal CA1 during context exploration and sevoflurane/home cage session. Sevoflurane treatment just after context pre-exposure session impaired the CPFE memory, suggesting sevoflurane induced retrograde amnesia. Calcium imaging showed sevoflurane treatment prevented neuronal activity in CA1. Further analysis of neuronal activity with non-negative matrix factorization, which extracts neural ensemble activity based on synchronous activity, showed that sevoflurane treatment reduced the reactivation of neuronal ensembles between during context exploration just before and one day after sevoflurane inhalation. These results suggest that sevoflurane treatment immediately after learning induces amnesia, resulting from suppression of reactivation of neuronal ensembles.

Warfarin Reversal With Four-Factor Prothrombin Complex Concentrate for Left Ventricular Assist Device Conversion Surgery Monitored by TEG6s: A Case Report.

Left ventricular assist devices (LVADs) require careful therapeutic anticoagulation with warfarin to prevent pump thrombosis. However, the best method to reverse warfarin for elective LVAD conversion surgery with massive bleeding remains unclear. We report the case of a 39-year-old Japanese man who was administered a four-factor prothrombin complex concentrate (4F-PCC) as warfarin reversal when he underwent conversion surgery from paracorporeal LVAD to implantable LVAD. 4F-PCC with co-administration of vitamin K reduced the international normalized ratio and R time in TEG6s (Haemonetics Corporation, USA) immediately. The effect was prolonged, and good hemostasis was achieved. 4F-PCC with vitamin K provided good hemostasis in our patient; therefore, 4F-PCC could be a useful tool for elective LVAD conversion surgery with expected massive bleeding and requiring immediate warfarin reversal.

Suvorexant and mirtazapine improve chronic pain-related changes in parameters of sleep and voluntary physical performance in mice with sciatic nerve ligation.

Both chronic pain and sleep disorders are associated with a reduction in the quality of life. They can be both a cause and a consequence of each other, and should therefore be simultaneously treated. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related changes in sleep parameters in a preclinical chronic pain mice model, by partial sciatic nerve ligation. We evaluated the quantity, duration, and depth of sleep by analyzing the electroencephalogram and voluntary activity by counting the number of wheel rotations to determine various symptoms of sleep disorders, including reduced total sleep time, fragmentation, low quality, and impaired activity in the daytime. Suvorexant and mirtazapine normalized the reduction in sleep time and fragmented sleep, further regaining the sleep depth at sleep onset in the chronic pain state in nerve-ligated mice. Mirtazapine also increased the percentage of rapid eye movement sleep in mice. Suvorexant decreased voluntary activity, which was prolonged after administration; however, mirtazapine did not decrease it. Although the effects of suvorexant and mirtazapine on sleep and activity are different, both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

The Value of Routine Tests before Pediatric Eye Surgery: A 10-Year Experience at a Tertiary Care Hospital.

Background: Routine tests before ophthalmologic surgery in adult patients are no longer recommended. However, there are limited data on the utility of routine preoperative tests for children. Aims: We aimed to describe the effect of routine preoperative tests on systemic perioperative complications by hospital discharge or by day 30 following eye surgery. Settings and Design: This was a single-center, observational, and descriptive study. Subjects and Methods: We examined all patients ≤ 17 years old for whom ophthalmologists consulted with anesthesiologists before eye surgery under general anesthesia in an academic teaching tertiary care hospital from January 2010 to December 2019. Results: A total of 708 pediatric patients were analyzed. The mean patient age was 8.5 ± 4.6 years. The most frequently performed procedure was strabismus surgery in 433 patients (61.2%). Following anesthetic consultations, 15 patients (2.1%) underwent surgery postponed due to abnormalities at the physical examination. Routine tests identified that the two patients (0.3%) required additional evaluations due to elevated serum creatine kinase and electrocardiographic abnormalities. However, further examinations found that these abnormalities were unremarkable. The remaining 691 patients (97.6%) underwent surgery as scheduled. Substantial intraoperative blood loss was observed only in three patients with malignant tumors or trauma. The incidence of systemic complications was 0 (0%; 95% confidence interval, 0%-0.05%). Conclusions: These data indicated that the development of systemic perioperative complications following pediatric ophthalmic surgery is rare. Preoperative tests should be requested only if they are clinically indicated or before potentially bleeding procedures, such as malignancy or trauma surgery.

Anaesthetic management using remimazolam in a patient with severe aortic stenosis: a case report.

BACKGROUND: The administration of general anaesthesia in patients with aortic stenosis (AS) requires careful attention to haemodynamics. We used remimazolam for the induction and maintenance of anaesthesia in a woman with severe AS undergoing a total mastectomy. CASE PRESENTATION: An 81-year-old woman with severe AS was scheduled to undergo a total mastectomy. We decided to administer total intravenous anaesthesia with remimazolam to minimize haemodynamic changes. Although the patient showed transient hypotension after anaesthesia induction, the cardiac index was preserved with a low dose of continuous noradrenaline. The anaesthesia was then safely maintained without a decrease in the patient's cardiac index. CONCLUSIONS: General anaesthesia using remimazolam preserved cardiac output in this patient; therefore, remimazolam can be safely used to avoid the risk of cardiac suppression in patients with severe AS.

Limited Utility of Routine Tests Prior to Ophthalmologic Surgery: An Observational Study in a Japanese Hospital.

INTRODUCTION: Routine preoperative testing for low-risk surgeries without a clinical indication should be avoided; however, such tests are still frequently performed in Japan. This study was performed to assess the impact of routine preoperative tests in low-risk surgery in a Japanese medical setting. METHODS: We performed a retrospective chart review to examine the utility of routine tests with respect to anesthetic management and postoperative complications in all patients aged ≥ 18 years whom ophthalmologists consulted with anesthesiologists before ophthalmologic surgery under general anesthesia. RESULTS: During the 10-year study period, 1,234 anesthetic consultations and 1,211 routine preoperative tests (laboratory tests, chest X-rays, and electrocardiograms) were performed in Toyama University Hospital. In total, 59 patients (4.8% of the study population) canceled surgery after a battery of preoperative evaluation. Among them, 10 patients had incidental abnormalities that necessitated additional tests, and only three patients (0.2%) canceled surgery. In-hospital postoperative complications developed in nine patients (0.7%) whose routine test results made it difficult to predict development of these adverse events. No severe life-threatening events were noted in this survey. CONCLUSIONS: Routine tests prior to eye surgery for adults were of low value for perioperative management and prediction of development of in-hospital complications in this Japanese medical setting. Anesthesiologists and ophthalmologists should selectively order preoperative tests based on the medical interview and physical examination.

Incompatibility of remimazolam besylate with Ringer's acetate infusion resulting in total occlusion of an intravenous catheter.

Remimazolam besylate is an ultra-short-acting benzodiazepine derivative recently approved in Japan for general anaesthesia. However, less attention has been paid to the compatibility of remimazolam with infusion solutions, and the mechanism underlying the incompatibility remains unknown. The patient was a 65-year-old man who underwent a high tibial osteotomy. After the induction of general anaesthesia using remimazolam solution (5 mg/mL), we noticed precipitate completely blocking the lumen of the intravenous tube connected to a Ringer's acetate Physio140 drip. The mixture of remimazolam solution (5 mg/mL) with Physio140 solution immediately resulted in the formation of substantial precipitate. Nuclear magnetic resonance analysis revealed that the precipitate was remimazolam. Ultraviolet spectrophotometry revealed that the mixture of remimazolam solution with higher ratios of Physio140 resulted in significantly lower solubility, concomitant with an increase in pH. It would be important to consider the remimazolam concentration and infusion solution pH to avoid the production of precipitates.

Configural Cues Associated with Reward Elicit Theta Oscillations of Rat Retrosplenial Cortical Neurons Phase-Locked to LFP Theta Cycles.

Previous behavioral studies implicated the retrosplenial cortex (RSC) in stimulus-stimulus associations, and also in the retrieval of remote associative memory based on EEG theta oscillations. However, neural mechanisms involved in the retrieval of stored information of such associations and memory in the RSC remain unclear. To investigate the neural mechanisms underlying these processes, RSC neurons and local field potentials (LFPs) were simultaneously recorded from well-trained rats performing a cue-reward association task. In the task, simultaneous presentation of two multimodal conditioned stimuli (configural CSs) predicted a reward outcome opposite to that associated with the individual presentation of each elemental CS. Here, we show neurophysiological evidence that the RSC is involved in stimulus-stimulus association where configural CSs are discriminated from each elementary CS that is a constituent of the configural CSs, and that memory retrieval of rewarding CSs is associated with theta oscillation of RSC neurons during CS presentation, which is phase-locked to LFP theta cycles. The results suggest that cue (elementary and configural CSs)-reinforcement associations are stored in the RSC neural circuits, and are retrieved in synchronization with LFP theta rhythm.

Further investigation of the rapid-onset and short-duration action of the G protein-biased µ-ligand oliceridine.

TRV130 (oliceridine), a G protein-biased ligand for µ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 µM) did not produce any µ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3-10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased µ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses.

Analysis of the effects of a tricyclic antidepressant on secondary sleep disturbance induced by chronic pain in a preclinical model.

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Impaired hemodynamic activity in the right dorsolateral prefrontal cortex is associated with impairment of placebo analgesia and clinical symptoms in postherpetic neuralgia.

The dorsolateral prefrontal cortex (dlPFC) is functionally linked to the descending pain modulation system and has been implicated in top down pain inhibition, including placebo analgesia. Therefore, functions of the dlPFC may be impaired in patients with chronic pain. Postherpetic neuralgia (PHN) is one of several syndromes with chronic neuropathic pain. In the present study, we investigated possible dysfunction of the dlPFC in chronic pain using patients with PHN. In a conditioning phase, heathy controls (n = 15) and patients with PHN (n = 7) were exposed to low (LF) and high (HF) frequency tones associated with noxious stimuli: weak (WS) and strong (SS) electrical stimulation, respectively. After the conditioning, cerebral hemodynamic activity was recorded from the bilateral dlPFC while the subjects were subjected to the cue tone-noxious electrical stimulation paradigm, in which incorrectly cued noxious stimuli were sometimes delivered to induce placebo and nocebo effects. The results indicated that hemodynamic responses to the LF tone in the right dlPFC was significantly lower in patients with PHN compared to the healthy controls. Furthermore, the same hemodynamic responses in the right dlPFC were correlated with placebo effects. In addition, clinical symptoms of PHN were negatively correlated to cerebral hemodynamic responses in the right dlPFC and magnitudes of the placebo effects. The results suggest that the right dlPFC, which is closely associated with the descending pain modulation system, is disturbed in PHN.

Chronotherapeutic effect of orexin antagonists on glucose metabolism in diabetic mice.

Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity, and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of pro-inflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep-wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.

Inhibitory actions of general anesthetics on hippocampal CA1 neurons modified by activation of amygdala circuitry are demonstrated on the novel amygdala-hippocampal slice preparation.

In order to examine effects of general anesthetics on hippocampal synaptic transmission in the absence and presence of amygdala circuitry activation, we have developed a unique amygdala-hippocampal slice preparation in which projections between amygdala and hippocampal CA1 are conserved. Stimulating electrodes were placed in radiatum stratum (Rad) to stimulate CA1, and in amygdala-hippocampal area (AH) to simulate amygdala inputs to hippocampus. Two sets of extracellular recording microelectrodes were positioned in cell bodies and dendrites of CA1 to record population spikes (PSs) and excitatory post-synaptic potentials (EPSPs), respectively. Intravenous anesthetics did not elicit consistent effects on PS and EPSP following a test stimulus on Rad. A pre-pulse of AH in addition to a test-pulse on Rad produced significant reduction of PS amplitude without a change in EPSP. Pre-treatment with tetanus-pulse on AH reversed the anesthetic-induced reduction of PS. The results suggest that inhibitory actions of general anesthetics in CA1 can be modified by activation of amygdala, suggesting that preoperative anxiety and fear could modify anesthetic actions. The modification was more prominent in the presence of intravenous anesthetics than with volatile agents.

Relationships Between Intraoperative Hemodynamic Parameters and Delayed Hemodynamic Recovery After Valve Deployment in Transcatheter Aortic Valve Replacement.

OBJECTIVE: To determine the relationships between intraoperative hemodynamic parameters and delayed hemodynamic recovery after valve deployment and identify the predictive factors of delayed hemodynamic recovery by focusing on intraoperative hemodynamics in patients with transcatheter aortic valve replacement (TAVR). DESIGN: A retrospective study. SETTING: A single university hospital. PARTICIPANTS: Sixty-four patients who underwent elective TAVR between 2015 and 2017. INTERVENTIONS: No intervention. MEASUREMENTS AND MAIN RESULTS: The 64 patients were divided into the following 2 groups according to the time for recovery: systolic arterial pressure exceeded 90 mmHg and central venous oxygen saturation (ScvO2) exceeded 65%-delayed recovery (DR) (n = 36) group, and early recovery (ER) (n = 28) group. ScvO2 in the DR group was not lower than that in the ER group after induction of anesthesia. However, ScvO2 in the DR group gradually decreased and was lower than that in the ER group before valve deployment, despite improvement in blood pressure through the administration of vasopressor agents. CONCLUSION: ScvO2 monitoring during TAVR is useful to predict delayed recovery greater than 60 seconds after valve deployment in TAVR.

Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.

Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain).

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1ß-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.