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Background and Purpose: Neurosteroids are allosteric modulators of GABA A currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABA A receptor., Experimental Approach: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABA A R, a chimeric receptor containing transmembrane domains of the α 1 -GABA A receptor. Tryptophan mutagenesis was used to identify specific interactions., Key Results: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3β-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites., Conclusions and Implications: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABA A R were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Glutaric aciduria type I (GA-1) is a rare metabolic disorder caused by an autosomal, recessive, inherited deficiency of glutaryl-CoA dehydrogenase. Reports on the anesthetic management of patients with GA-1 are limited. It has been suggested that inhalation anesthesia is safer than propofol due to the mitochondrial dysfunction inherent in GA-1. However, inhalation anesthesia poses a risk, albeit rare, of malignant hyperthermia, which can result in severe neurological damage in GA-1 patients. Therefore, we considered that management using remimazolam might be effective and, provided a successful general anesthesia using it for a pediatric patient with GA-1. We report a case of a four-year-old girl with GA-1 who underwent a laparoscopic gastrostomy under general anesthesia. Remimazolam was used for both induction and maintenance of anesthesia. Our perioperative management also included measures to prevent a hypercatabolic condition such as adequate hydration and blood glucose control. The patient had an uneventful perioperative course and was discharged on postoperative day 7. Thus, remimazolam is proposed as a new option for anesthetic management in patients with GA-1. Additionally, tailored perioperative management that addresses the unique characteristics of GA-1 is crucial for favorable outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tsuruno et al.)

Background: There is insufficient information regarding the bleeding sites and surgical strategies of cardiac tamponade during catheter ablation for atrial fibrillation (AF)., Case Presentation: Of the five patients with cardiac tamponade, three required surgical intervention and two required pericardiocentesis. In the first case of three cardiac tamponades requiring surgical intervention, considering that the peripheral route was used, the catecholamines did not reach the heart, and due to unstable vital signs, venoarterial extracorporeal membrane oxygenation (VA-ECMO) was inserted. No bleeding point was identified, but a thrombus had spread around the left atrium (LA) with diverticulum. Hemostasis was achieved with adhesives placed around the LA under on-pump beating. In the second case, pericardiocentesis was performed, but the patient showed heavy bleeding and unstable vital signs. Thus, VA-ECMO was inserted. Heavy bleeding was expected, and safety was enhanced by attaching a reservoir to the VA-ECMO. The bleeding point was found between the left upper pulmonary artery and LA under cardiac arrest to obtain a good surgical view for suturing repair. In the third case, the LA diverticulum was damaged. Pericardiocentesis resulted in stable vitals, but sustained bleeding was present. A bleeding point was found at the LA diverticulum, and suture repair under on-pump beating was performed., Conclusions: When cardiac tamponade occured in any patient with LA diverticulum, treatment could not be completed with pericardiocentesis alone, and thoracotomy was likely to be necessary. If the bleeding point could be confirmed, suturing technique is a more reliable surgical strategy than adhesive alone that leads to pseudoaneurysm. If the bleeding point is unclear, it is important to confirm the occurrence of LA diverticulum using a preoperative CT, and if confirmed, cover it with adhesive due to a high possibility of diverticulum bleeding. The necessity of CPB should be determined based on whether these operations can be completed while maintaining vital stability., (© 2024. The Author(s).)

Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABA A ) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed., (© 2024. The Author(s).)

The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA A receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this difference in enantioselectivity. The oocyte electrophysiology studies showed that ent -ALLO potentiates GABA-elicited currents in α 1 β 3 GABA A receptors with lower potency and efficacy than ALLO, PREG or ent -PREG. The small PAM effect of ent -ALLO was prevented by the α 1 (Q242L) mutation in the intersubunit neurosteroid binding site between the β 3 and α 1 subunits. Consistent with this result, neurosteroid analogue photolabeling with mass spectrometric readout, showed that ent -ALLO binds weakly to the β 3 -α 1 intersubunit binding site in comparison to ALLO, PREG and ent -PREG. Rigid body docking predicted that ent -ALLO binds in the intersubunit site with a preferred orientation 180° different than ALLO, PREG or ent -PREG, potentially explaining its weak binding and effect. Photolabeling studies did not identify differences between ALLO and ent -ALLO binding to the α 1 or β 3 intrasubunit binding sites that also mediate neurosteroid modulation of GABA A receptors. The results demonstrate that differential binding of ent -ALLO and ent -PREG to the β 3 -α 1 intersubunit site accounts for the difference in enantioselectivity between ALLO and PREG.

Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABA A receptor. The sites are located in the membrane-spanning domains of the receptor at the β - α subunit interface (site I) and within the α (site II) and β subunits (site III). Here, we have investigated the effects of mutations to these sites on potentiation of the rat α 1 β 2 γ 2L GABA A receptor by the endogenous neurosteroid allopregnanolone (3 α 5 α P). The mutations were introduced alone or in combination to probe the additivity of effects. We show that the effects of amino acid substitutions in sites I and II are energetically additive, indicating independence of the actions of the two steroid binding sites. In site III, none of the mutations tested reduced potentiation by 3 α 5 α P, nor did a mutation in site III modify the effects of mutations in sites I or II. We infer that the binding sites for 3 α 5 α P act independently. The independence of steroid action at each site is supported by photolabeling data showing that mutations in either site I or site II selectively change steroid orientation in the mutated site without affecting labeling at the unmutated site. The findings are discussed in the context of linking energetic additivity to empirical changes in receptor function and ligand binding. SIGNIFICANCE STATEMENT: Prior work has identified three distinct binding sites for potentiating steroids in the heteromeric γ -aminobutyric acid type A receptor. This study shows that the sites act independently and additively in the presence of the steroid allopregnanolone and provide estimates of energetic contributions made by steroid binding to each site., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Long-term opioid treatment for chronic non-cancer pain has become controversial, given the increasing prevalence of opioid dependence. However, there is little information on therapeutic strategies for this condition in Japanese patients. Here, we present a case of successful management of iatrogenic opioid dependence with tramadol in a patient with chronic low back pain., Case Presentation: A 68-year-old male suffering from intractable low back pain was referred to our pain clinic. He was previously treated in another hospital with transdermal fentanyl patches 6 mg/day and fentanyl sublingual tablets (100 μg as required) for this condition. On the basis of medical examination, including a review of the patient's medical history, physical examination, X-ray, and his family statement, we diagnosed him with iatrogenic opioid dependence due to inadequate fentanyl use. Then, we developed a treatment plan consisting in fentanyl detoxification with a weak opioid, tramadol. At first, the use of fentanyl sublingual tablets was interrupted after obtaining informed consent. Then, we reduced the dose of transdermal fentanyl 1 mg per 4-5 days replacing with oral sustained-release tramadol. The patient developed mild to moderate withdrawal symptoms during this period, which could be effectively managed by supportive treatments. The hospital psychiatry liaison team continuously provided the patient and his wife with information, counseling, and education regarding the treatment of opioid dependence. Throughout the detoxification process, his reported pain did not exacerbate, even slightly improved over time. The final prescription was sustained-release tramadol 300 mg/day without fentanyl, and his activities of daily living drastically improved. However, unfortunately, he died due to an aortic dissection of stent-graft edge 65 days after surgery., Conclusions: Our case highlighted that sustained-release tramadol could be effectively applied as a detoxification agent for iatrogenic opioid dependence in patients with chronic non-cancer pain.

The acute neuroinflammatory response to surgery may play a key pathogenic role in postoperative delirium (POD). Here, we investigated the contribution of acute postoperative pain to neuroinflammation and related delirium-like behaviors after surgery in adult and aged rats. Animals were assigned into four groups: control, abdominal surgery, surgery with analgesia using local ropivacaine, and surgery with analgesia using systemic morphine. Pain was assessed by the Rat Grimace Scale (RGS). Trace and context memory retention was evaluated following trace fear conditioning during the first 2 days after surgery. Pro-inflammatory cytokines in medial prefrontal cortex and hippocampus were measured by enzyme-linked immunosorbent assay. In both age groups, the RGS increased significantly from baseline until 6 h after surgery. The postoperative analgesia with either local or systemic regimens comparably alleviated the RGS increase in adult and aged animals. The two analgesic regimens attenuated the surgery-induced trace and context memory deficits, as well as cytokines overproduction in both medial prefrontal cortex and hippocampus. No age-related differences were found in the neuro-cognitive effectiveness of postoperative analgesia. Our experimental findings provide proof-of-concept for adequate postoperative pain management as one of the main preventive strategies of POD.

Purpose: Neuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined., Methods: Aged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5 mg/kg bolus, then 0.5 mg/kg/day infusion), or high-dose (2.0 mg/kg bolus, then 2.0 mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48 h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured., Results: In the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits., Conclusion: Our findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.

The beneficial effects of physical activity for pain are denominated exercise-induced hypoalgesia (EIH). Here, we examined the age-related change and potential role of the neurosteroid allopregnanolone (ALLO) on EIH in rats. Adult and aged rats were randomly divided into one of three groups; non-exercise control, Low-exercise, and High-exercise. The animals in the Low- and High-exercise groups were subjected to a 10-minute treadmill workout at 40% and 80% maximum oxygen intake intensity, respectively. In the Low-exercise groups, a significant EIH response was observed in aged but not in adult rats. The pre-treatment with ALLO synthesis inhibitor finasteride, but not opioid-receptor antagonist naloxone, inhibited the Low-exercise induced EIH response in aged rats. Furthermore, the Low-exercise increased brain ALLO levels in aged animals compared with controls, which was correlated with the mechanical pain sensitivity. On the other hand, High-exercise could induce EIH response in both adult and aged animals, but it was more effective in adult rats. The pre-treatment with naloxone, but not finasteride, reduced the EIH observed after High-exercise in both adult and aged rats. Our findings demonstrated that effective EIH can be achieved even by mild-intensity exercise in aged animals via an increase of the brain ALLO levels., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to investigate the age-, time-, and brain region-dependent postoperative neuroinflammatory trajectory, and its association with neurocognitive outcomes in rats., Methods: Adult and aged rats were randomly assigned to one of three groups: control, isoflurane anesthesia alone, and isoflurane anesthesia with abdominal surgery. On either postoperative day 2 (early phase) or 7 (late phase), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Freezing behavior was used as an index of fear memory. Following the cognitive testing, the levels of pro-inflammatory cytokines in several brain regions were measured using enzyme-linked immunosorbent assay (n = 8 in each group)., Results: In the early postoperative period, surgery under isoflurane anesthesia induced acute neuroinflammation along with related trace and context memory dysfunction. Such acute neuroinflammatory responses were comparably observed in both adult and aged animals, whereas the aged rats were more likely to exhibit behavioral changes. On the other hand, in the late postoperative period, neither neuroinflammation in all tested brain regions nor concomitant memory decline were found in adult animals. Significant neuroinflammation was detected only in the hippocampus of aged rats, which was associated with context, but not trace memory dysfunction., Conclusion: Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.

Aims: This study was aimed to explore the contribution of central brain-derived neurotrophic factor (BDNF) in the neuropathic pain pathogenesis using an aged rodent model., Main Methods: Adult and aged rats were randomly assigned to either a sciatic nerve ligation (SNL) group or a control skin sham surgery group. Sensory behavioral testing were performed on the day before surgery and on the 3rd, 7th, 14th, and 21st days after surgery, followed by measurement of BDNF protein levels in different brain regions. In another experiment, the hippocampal BDNF gene expression after SNL surgery was assessed at different time-points. Furthermore, the analgesic effects of intranasal BDNF administration were tested in SNL animals., Key Findings: Our behavioral results demonstrated that the hyperalgesia-like behavior after painful nerve injury has a higher incidence in aged rats compared with in adult animals. In particular, the hippocampal BDNF levels were inversely correlated with the probability of hyperalgesia-type behavior, in both brain-region specific and age-dependent manner. Time-course analysis showed that the hippocampal levels of BDNF mRNA in aged and adult rats started to decrease 7 and 14 days after surgery, respectively. However, the decrease was more pronounced in aged animals. Moreover, the repeated intranasal BDNF treatment could restore the central BDNF signaling, counteracting the age-related exacerbation of hyperalgesic behavior., Significance: Our findings imply that hippocampal BDNF may be related with the pathogenesis of elderly neuropathic pain. Pharmacological data further suggest that brain BDNF may be modifiable in aged neuropathic animals, and therefore, represent a promising target for intervention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Low-grade endotoxin (lipopolysaccharide; LPS) exposure may contribute to the development of exaggerated acute postoperative pain. In the present study, we investigated the possible impact of intraoperative administration of dexmedetomidine (DEX) on LPS-induced postoperative hyperalgesia in a rat incisional pain model., Methods: The surgical and sham-surgical animals were randomly divided into saline-treated control, 5.0 mg/kg LPS-treated, 10 µg/kg DEX-treated, and 5.0 mg/kg LPS + 10 µg/kg DEX-treated groups. In the surgical animals, a 1-cm-long plantar incision was made through the skin and fascia under isoflurane anesthesia. The sham-surgical rats were only anesthetized. All treatments were administered by a single intraperitoneal (i.p.) injection 60 min before surgery. Acute postoperative pain was assessed using the Rat Grimace Scale (RGS) one day before surgery (baseline) and at 2 h post incision. In another experiment, the involvement of the α 2 -adrenergic receptor was tested using atipamezole, an α 2 -adrenergic receptor antagonist., Results: In the sham-surgical animals, the RGS did not increase at 2 h after sham surgery compared with the corresponding baseline values in all groups. In the surgical rats, however, the postoperative RGS value of the LPS group was significantly higher than the control group, indicating LPS-induced postoperative hyperalgesia. Administration of intraoperative DEX could prevent the development of such LPS-induced exacerbated post-incisional pain. In addition, the preventive effects of intraoperative DEX were inhibited by pretreatment with atipamezole., Conclusion: Our findings indicate that intraoperative DEX treatment can prevent LPS-induced exacerbated post-incisional pain via the α 2 -adrenergic receptor signaling pathway.

Purpose: In this study, we examined the effects of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on sepsis-induced neurocognitive abnormity in aged rats., Methods: Aged rats received an intraperitoneal (i.p.) injection of 5.0 mg/kg lipopolysaccharide (LPS) or saline. Animals were further divided into three groups: control, low-dose EGCG (4.0 mg/kg), and high-dose EGCG (20 mg/kg). EGCG was i.p. injected at the same time, 24 and 48 h after LPS administration. Survival rate was recorded for 1 week. All surviving animals were assessed for cognitive function using the novel object recognition test, followed by measurement of hippocampal cytokine levels. In an additional set of experiments, the liver function test was performed. Furthermore, the effects of EGCG on cytokine release from microglia isolated from young and aged rats were assessed., Results: The survival rate in LPS-treated control rats was 77.8%, which was decreased to 72.2 and 33.3% in the low and high EGCG groups, respectively. In the surviving animals, the LPS-treated control rats exhibited impaired cognitive performance and increased pro-inflammatory cytokine levels compared with untreated animals. None of these neurocognitive alterations were affected by low or high EGCG treatment. Blood chemical analysis showed co-administration of EGCG with LPS resulted in a marked increase in both aspartate aminotransferase and alanine aminotransferase levels. In addition, EGCG inhibited LPS-induced cytokine release, whereas the suppressive ability of EGCG was lower in aged microglia compared with in young microglia., Conclusions: Our findings demonstrated that EGCG cannot prevent hippocampal neuroinflammation and related memory deficits in aged rats surviving sepsis.

Purpose: In the present study, we examined whether and by what mechanisms dexmedetomidine (DMED) prevents the development of systemic inflammation (SI)-induced cognitive dysfunction in aged rats., Methods: Animals received a single intraperitoneal (i.p.) injection of either 5.0 mg/kg lipopolysaccharide (LPS) or vehicle. LPS-treated rats were further divided into three groups: early DMED, late DMED, or midazolam (MDZ) treatment (n = 12 each). Seven days after LPS injection, cognitive function was evaluated using a novel object recognition task, followed by measurement of hippocampal levels of proinflammatory cytokines and Toll-like receptor 4 (TLR-4) expression. For ex vivo experiments, microglia were isolated from the hippocampus for assessment of cytokine response to LPS., Results: LPS-treated rats showed memory deficits, hippocampal neuroinflammation, and TLR-4 upregulation as compared to saline-treated animals. However, early DMED treatment was able to attenuate these SI-induced neurocognitive changes, whereas no benefits were observed in the MDZ and late DMED treatment groups. In ex vivo experiments, early DMED treatment prevented the development of SI-induced excessive microglial hyperactivation, which was blocked by the nonspecific α 2 -adrenergic receptor (AR) antagonist atipamezole or the specific α 2A -AR antagonist BRL-44408, but not by the specific α 2B/C -AR antagonist ARC-239. On the other hand, neither DMED nor MDZ had a direct effect on LPS-induced release of pro-inflammatory cytokines from hippocampal microglia at clinically relevant concentrations., Conclusion: Our findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α 2A -AR signaling pathway.

Background: The major perioperative concern in patients with second-degree atrioventricular (AV) block is the progression to complete AV block. Therefore, the prophylactic implantation of a temporary pacemaker prior to surgery is recommended, especially in symptomatic patients. However, as no quantitative preoperative risk assessment from progression to complete AV block is available, there is currently no established indication for preoperative prophylactic pacemaker implantation. Here, we present a case of progression from asymptomatic second-degree two-to-one (2:1) AV block to complete AV block following the induction of general anesthesia., Case Presentation: A 69-year-old female with degenerative spinal stenosis was scheduled for transforaminal lumbar interbody fusion surgery under general anesthesia. She had no cardiac symptoms, but routine preoperative resting 12-lead electrocardiogram revealed second-degree 2:1 AV block. After discussion with the surgeon and referring cardiologist, we scheduled the surgery without implantation of a temporary pacemaker before surgery for the following reasons: (1) asymptomatic, (2) no evidence of underlying cardiac disease, and (3) a narrow QRS complex. On the day of surgery, general anesthesia was induced with 150 mg of intravenous thiamylal and 25 μg of fentanyl, followed by intravenous administration of 50 mg of rocuronium to facilitate endotracheal intubation. Sevoflurane (1.0-2.0%) was used to maintain anesthesia. A few minutes after induction, the 2:1 AV block progressively converted to complete AV block, and the surgery was postponed. During emergence from anesthesia, the third-degree AV block recovered to 2:1 AV block, similar with the preoperative pattern. The patient was monitored in the intensive care unit for 2 days and then transferred to the normal orthopedic ward uneventfully. One month later, the surgery was rescheduled with preoperative implantation of a temporary pacemaker. A slow mask induction using sevoflurane with oxygen was started. Upon loss of consciousness during the inhalation of initial sevoflurane, complete AV block developed and temporary pacing was immediately initiated. Subsequent anesthesia and surgery were uneventful. The patient made an uncomplicated recovery from surgery with stable hemodynamics. The temporary pacemaker was not required after surgery, and the pacemaker catheter was removed 1 day after surgery., Conclusions: The present case indicates that a prophylactic pacemaker should be implanted preoperatively in patients who have 2:1 AV block even without symptoms.

Background: Patient satisfaction with postoperative pain management is an important quality indicator in patient health care, but its determinants are poorly understood. Here, we examined the contribution of the discrepancy between an individual's estimated acceptable and actual postoperative pain scores to the overall satisfaction with pain treatment., Findings: A total of 93 surgical patients were included in this study. Preoperatively, the subjects were asked to rate their estimated acceptable postoperative pain using a numerical rating scale (NRS). One day after the surgery, the patients were again asked to give NRS ratings of the overall actual pain intensity they had experienced, as well as their satisfaction with the provided pain treatment. The median estimated acceptable and actual NRS values for postoperative pain were 4.0 (3.0-5.0) and 4.0 (2.0-5.0), respectively. Although there was no correlation between the degree of patient satisfaction and preoperative estimated acceptable pain intensity, there was a significant negative correlation between the degree of patient satisfaction and postoperative actual pain intensity. When the preoperative estimated acceptable NRS value was compared with the postoperative actual value for each individual, postoperative NRS was greater in 34 cases (36.6%), less in 43 cases (46.2%), and equal in 16 cases (17.2%). The degree of patient satisfaction was not significantly correlated with the magnitude of difference between preoperative estimated acceptable NRS and postoperative actual NRS., Conclusions: Our findings suggest that inquiring about the estimated acceptable pain before surgery may not help anesthesiologists to understand the patient's goal of pain management for improving patient satisfaction.

Aims: This study aimed to investigate the role of central insulin signaling, including glycogen synthase kinase 3β (GSK-3β), and its therapeutic potential for the prevention of postoperative neurocognitive deficits., Main Methods: In non-insulin experiment, aged rats were divided into a sham group and abdominal surgery group. In insulin experiment, sham and surgically treated rats were distributed into two groups: an intranasal denatured insulin-treated group and intranasal insulin-treated group. Insulin administration started the day of surgery and continued for 3days. Fourteen-days after surgery, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of pro-inflammatory cytokines, GSK-3β, and phosphorylated GSK-3β (pGSK-3β(ser9)). Under identical conditions, lipopolysaccharide (LPS)-induced cytokine release from isolated hippocampal microglia was also tested., Key Findings: In non-insulin experiment, compared with non-surgical animals, the rats that underwent abdominal surgery showed memory deficits and increased hippocampal cytokine levels. The hippocampal ratio of pGSK-3β(ser9)/GSK-3β decreased after surgery, a ratio that was positively correlated with novel object recognition performance in the testing phase. Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery-induced hippocampal neuroinflammation and hyperactivation of GSK-3β, and prevent impairment in novel object recognition. Furthermore, ex vivo experiments indicated that intranasal insulin administration, as well as pretreatment with SB216763, a GSK-3β inhibitor, resulted in reduction of the surgery-related microglial hyper-reactivity to LPS., Significance: Our findings in aged rats suggest that surgical procedures could impair central insulin signaling including GSK-3β, which makes the individual more susceptible to hippocampal neuroinflammation and related cognitive disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is a recently identified but increasingly recognized autoimmune paraneoplastic disease. Because these patients present complex neuropsychiatric symptoms due to NMDA-R dysfunction, the optimal methods of sedation/anesthesia remain controversial. Here, we present animal experiment data, along with a related case report, implying the safe and effective use of dexmedetomidine in patients with anti-NMDA-R encephalitis., Findings: (1) Animal experiment: in order to investigate whether dexmedetomidine may interfere with NMDA-R activity, an NMDA antagonist (MK-801) model in rats was used to simulate anti-NMDA-R encephalitis. Administration of MK-801 produced well-characterized schizophrenia-like behaviors, i.e. hyperlocomotion and stereotyped sniffing. Ketamine, an NMDA receptor-dependent anesthetic, exaggerated both behaviors, even at sub-anesthetic doses. On the other hand, dexmedetomidine did not show any exacerbation, suggesting that dexmedetomidine has no clinically relevant interaction with the NMDA-R in vivo. (2) CASE REPORT: our patient, a 27-year-old female, was diagnosed with anti-NMDA-R encephalitis secondary to ovarian teratoma. She underwent laparoscopic ovariectomy under general anesthesia using thiopental, sevoflurane, and remifentanil, which were well tolerated. After transfer to the intensive care unit, she became increasingly agitated despite repeated boluses of intravenous fentanyl. Infusion of dexmedetomidine (0.5-1.0 μg/kg/h) was started, and an adequate level of sedation was achieved uneventfully. After discontinuation of dexmedetomidine, recovery from sedation was smooth and quick without any deterioration of neurological or psychological symptoms., Conclusions: Our experimental findings and the presented case suggest that dexmedetomidine may be safely used in patients with anti-NMDA-R encephalitis. Further clinical evaluation is warranted to validate this finding.

Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam-induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted.

Aims: The present study aimed to explore the preventive or therapeutic effect of peri-operative pregabalin treatment on the memory deficits and related hippocampal inflammation following surgery in aged rats., Main Methods: Aged rats underwent abdominal or sham surgery, and were then divided into 2 groups, either early or late pregabalin treatment. Fourteen days after surgery, the cognitive function was assessed using novel object recognition test, followed by measurement of hippocampal cytokines and voltage-dependent calcium channel α2δ subunit (CACNA2D1). The parabiotic experiments determined whether the humoral or neuronal pathway was involved in the neuroinflammation development following the abdominal surgery. The effects of pregabalin on LPS-induced cytokine release from hippocampal microglia were also evaluated., Key Findings: Early pregabalin treatment, which was administered pre-operatively and continued for 3 or 7days after surgery, prevented memory deficits and decreased hippocampal pro-inflammatory cytokine levels. In contrast, no beneficial effects were observed when pregabalin was administered late in the post-operative period. The hippocampal levels of CACNA2D1 did not change under any experimental condition. The data from the cross-circulation (parabiosis) experiments indicated that abdominal surgery may induce neuroinflammation via a neural transmission pathway from the periphery to the brain. The ex vivo experiments further demonstrated that pregabalin had no effect on LPS-induced cytokines release from hippocampal microglia., Significance: Our findings highlight reveal that peri-operative pregabalin treatment during the early post-operative period can prevent neuroinflammation and memory deficits after surgery. It is likely this occurs through a peripheral and central neuro-immune interaction rather than through direct anti-inflammatory effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: The aim of the present study was to investigate the effects and underlying mechanisms of endotoxin (lipopolysaccharide, LPS) on postoperative pain using a rat model of incisional pain., Main Methods: Animals were assigned to one of four groups using a 2×2 experimental design: a single intraperitoneal injection of 5mg/kg LPS versus vehicle, by plantar incision versus anesthesia alone. Spontaneous pain and mechanical paw withdrawal threshold (PWT) were evaluated using Rat Grimace Scale (RGS) and von Frey fibers, respectively. Analgesic effects of ketoprofen, morphine, and wound infiltration with ropivacaine, as well as the contribution of the Toll-like receptor (TLR) 4 pathway, were also evaluated. In vivo single fiber recordings were performed to assess the nociceptive afferent signals from the surgical site., Key Findings: Systemic administration of LPS significantly increased the pain intensity at 2h after hind paw incision, but did not affect the PWT. The duration of post-incisional pain assessed by both scales did not significantly differ in the presence or absence of LPS. The analgesic efficiency of ketoprofen and morphine was reduced by LPS, while that of wound infiltration with ropivacaine was preserved. On the other hand, in vivo single fiber recording failed to demonstrate any significant effects of LPS on the activity of primary afferents due to mechanical stimuli. Pre-treatment with intrathecal LPS from Rhodobacter sphaeroides, a TLR-4 antagonist, almost completely inhibited LPS-induced exacerbated post-incisional pain, and decreased analgesic responsiveness., Significance: The present results suggested that LPS exacerbates post-incisional pain via the central TLR-4 pathway., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Emerging evidence from case reports suggests that fentanyl may precipitate potentially life-threatening serotonin syndrome in patients taking serotonergic drugs. However, the underlying mechanism of the association between serotonin syndrome and fentanyl remains under investigation. We therefore investigated the pharmacological effects of an analgesic dose of fentanyl (0.2 mg/kg) injected subcutaneously (s.c.) on serotonergic toxicity-like responses in rats. Rats were s.c. injected with 0.75 mg/kg 8-OH-DPAT, a full 5-HT1A agonist, as an animal model of serotonin syndrome. The 8-OH-DPAT-treated rats showed well-characterized serotonin syndrome-like behaviors (low body posture, forepaw treading), hyperlocomotion, and decreased body temperature. Rats injected s.c. with fentanyl alone showed no significant changes in any of the parameters measured, while concomitant administration of fentanyl + 8-OH-DPAT resulted in exaggerated 8-OH-DPAT-induced serototoxic responses. A separate dose-response experiment showed that the serototoxic effect of fentanyl was dose-dependent. Pretreatment with naloxone [2.0 mg/kg, intraperitoneal (i.p.) injection], an opioid receptor antagonist, failed to antagonize the fentanyl-induced exaggerated serotonin syndrome-like behaviors. In contrast, pretreatment with WAY-100653, a serotonin 5-HT1A receptor antagonist (0.5 mg/kg, i.p. injection) completely inhibited all responses. Our findings provide preclinical proof-of-concept that an analgesic dose of fentanyl enhances serotonin toxicity, likely via its serotonin-reuptake inhibitory activity, independently of interaction with the opioid receptors.

Background: Post-herpetic itch (PHI) is a neuropathic itch syndrome following herpes zoster. It has been reported that PHI is occasionally sufficiently severe to compromise patients' quality of life and frequently refractory to treatment. Here, we present a case of severe chronic PHI successfully treated with supraorbital nerve block using a high concentration of tetracaine dissolved in bupivacaine., Case Presentation: An 82-year-old man presented with severe chronic itching in the ophthalmic branch of the left trigeminal nerve dermatome, following acute herpes zoster. The patient's itching was unresponsive to usual medical treatments for PHI including antiepileptic drugs, topical capsaicin cream, and supraorbital nerve radiofrequency thermo-coagulation. Topical lidocaine cream could relieve the itching, but could not provide long-term relief of itching and thus failed to achieve a satisfactory result. After these conventional treatments, left supraorbital nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was conducted. Afterwards, the patient experienced long-lasting resolution of the itching with improvement of sleep disturbance. A transient, mild edema of the eyelids occurred, but there were no other complications., Conclusions: Peripheral nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was beneficial in relieving PHI in the ophthalmic division of the trigeminal nerve.

We report a case of difficult lumbar puncture due to the inability to obtain adequate cerebrospinal fluid (CSF) in a patient later diagnosed with spinal epidural lipomatosis (SEL). A 76-year-old man with a body mass index (BMI) of 24.1 kg/m 2 was scheduled for transurethral resection of a bladder tumor for superficial bladder cancer under spinal anesthesia. The patient had a 3-year history of inhaled steroid use for the management of chronic obstructive pulmonary disease. After placing the patient in the right lateral position, a lumbar puncture was performed via the median approach. However, CSF could not be tapped adequately despite repeated attempts at lumbar puncture, so general anesthetic was administered instead. Subsequently, both anesthesia and surgery proceeded uneventfully. On the first postoperative day, the patient developed mild postdural puncture headache (PDPH), which was treated conservatively. No postoperative neurological complications related to spinal anesthesia were observed. Approximately 2 months after discharge, the patient reported progressive lower back pain and was diagnosed with SEL by magnetic resonance imaging (MRI). A lumbar laminectomy and removal of excessive adipose tissue was performed. After surgery, the patient's symptoms resolved. The pathogenesis of SEL involves excess fat tissue deposition in the spinal canal, which can lead to obliteration of the spinal subarachnoid space. Therefore, in this patient, the SEL was thought to have caused the inability to obtain adequate CSF during lumbar puncture, and was associated with difficult spinal anesthesia.

Perioperative administration of adequate glucose prevents hypercatabolism. However, excessive glucose administration until delivery of a fetus might cause newborn hypoglycemia in cesarean section. In this retrospective study, we investigated whether the administration of 1 % glucose solution during cesarean section influenced neonatal blood glucose concentration. We found 46 consecutive patients between 37 and 41 weeks of gestation who underwent cesarean section under combined epidural and spinal anesthesia. We divided the patients into two groups: those receiving 1 % glucose solution (group A, N = 23) and those receiving a solution without glucose (group B, N = 23) until delivery. We recorded umbilical cord blood glucose on delivery, neonatal blood glucose level 3 h after delivery, and 1- and 5-min Apgar scores. The dose of glucose administered until delivery of fetus in group A was 3.6 ± 1.7 mg/kg/min [mean ± standard deviation (SD)] and that in group B 0 mg/kg/min. Umbilical cord blood glucose concentration on delivery of fetus in group A was significantly higher than that in group B (101 ± 19 vs. 66 ± 10 mg/dl; P < 0.0001). Neonatal blood glucose level 3 h after delivery was not significantly different between groups (90 ± 15 vs. 90 ± 21 mg/dl; P = 0.96). The 1- and 5-min Apgar scores were similar between groups. In conclusion, administration of 1 % glucose solution in cesarean section might contribute to prevention of neonatal hypoglycemia.

Background: The objective of this study was to elucidate gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and human epidermal growth factor receptor (HER) family in the human ovary during luteal growth and regression., Methods: Ovaries obtained from pre-menopausal women were used for immunohistochemistry and semiquantitative RT-PCR analysis., Results: Immunoreactive HB-EGF was not detected in follicles or oocyte, while HB-EGF became apparent in granulosa luteal cells in the early luteal phase, and most abundant in the mid-luteal phase, but less abundant in the late luteal phase. Immunostaining for HER1 was very weak in granulosa luteal cells in the early and mid-luteal phases, and was not detected in the late luteal phase. Immunoreactive HER4 was abundant in the early luteal phase and became less abundant in the mid-luteal phase, whereas it was negative in the late luteal phase. Semiquantitative RT-PCR analysis revealed that HB-EGF and HER1 mRNA levels were high in the mid-luteal phase, whereas HER4 mRNA expression was high in the early luteal phase., Conclusions: HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling.

The histopathological features are reported of surgically excised specimens from five patients with polypoidal choroidal vasculopathy, which had been diagnosed by indocyanine green angiography. On stereomicroscopy, four of the five cases demonstrated large choroidal arterioles with an inner elastic layer. Disruption of the inner elastic layer and arteriosclerotic changes of the vessels were identified by light microscopy. Transmission electron microscopy demonstrated increased deposition of basement membrane-like material, together with collagen fibres, in the arteriolar walls. This study indicates that large choroidal arterioles and venules can be found in excised specimens from patients with polypoidal choroidal vasculopathy and arteriosclerosis is an important pathological feature.

Purpose: To report characteristics of polypoidal choroidal vasculopathy (PCV) of large vascular networks that expand across the retinal vascular arcade., Methods: Among 60 consecutive eyes diagnosed as having PCV by fluorescein and indocyanine green (ICG) angiography, 12 eyes (9 patients) showed large lesions. The clinical and angiographic features of these 12 eyes were studied retrospectively., Results: Cases of large PCV typically showed dilated network vessels, which spread radially, and multiple polypoidal dilations at the end of the network vessels. Most of the polypoidal dilations formed clusters resembling bunches of grapes and caused large serous and/or hemorrhagic pigment epithelial detachments (PEDs). Among the 12 eyes, 5 showed rapid expansion of the lesions and became large PCVs within 3-24 months. In these eyes, ICG angiography revealed mesh-like choroidal vessels beneath the retinal pigment epithelium., Conclusion: PCV with a large vascular network that expands across the vascular arcade is not uncommon. Some of these cases seems to have characteristics of choroidal neovascularization rather than choroidal vasculopathy. It is not easy to distinguish such cases from exudative age-related macular degeneration even though they showed typical findings of PCV on ICG angiography.

Comparative immunostaining with antibodies against gastric mucin and p53 was performed on 6 cases of minimal deviation adenocarcinoma (MDA) of the uterine cervix. The MDAs consisted of predominant areas of glands lined by extremely well-differentiated tall columnar epithelial cells with little cytological atypia and minor foci of less well-differentiated glandular epithelium with a minor degree of nuclear atypia. Immunostaining for gastric mucin with a monoclonal antibody HIK1083 revealed that all the tumors areas of typical MDA were partly immunoreactive for HIK1083, but the coexisting less well-differentiated glands were essentially negative. Four MDAs focally contained cells with p53 positive nuclei that were located exclusively in the less well-differentiated cells that lacked gastric mucin. In the pelvic lymph nodes in 2 cases, most of the metastatic tumor was less differentiated and a positive reaction for HIK1083 was observed only in small foci of typical MDA. No significant overexpression of p53 was observed in the metastases. Immunohistochemical expression of gastric mucin and p53 may be related to the histological differentiation of MDA, and detection of p53 overexpression may help to identify critical steps in the local progression of MDA.