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Ischemia-reperfusion injury is inevitable during donor organ harvest and recipient allograft reperfusion in kidney transplantation, and affects graft outcomes. Dexmedetomidine, an α2-adrenoreceptor agonist, has renoprotective effects against ischemia-reperfusion injury. We investigated the effects of intraoperative dexmedetomidine infusion on renal function and the development of delayed graft function after elective living donor kidney transplantation in a randomized controlled trial.A total of 104 patients were randomly assigned to receive either an intraoperative infusion of dexmedetomidine 0.4 μg·kgThe mean (standard deviation) serum creatinine level on POD 7 was comparable between the groups (dexmedetomidine vs control: 1.11 [0.87] mg·dLIntraoperative dexmedetomidine infusion did not produce any beneficial effects on renal function or delayed graft function in patients undergoing elective living donor kidney transplantation.www.gov (NCT03327389); registered 31 October 2017.RéSUMé: OBJECTIF: Les lésions d’ischémie-reperfusion sont inévitables lors du prélèvement d’organes du donneur et de la reperfusion de l’allogreffe chez le receveur pour une transplantation rénale, et affectent le devenir du greffon. La dexmédétomidine, un agoniste des adrénorécepteurs de type α2, a des effets néphroprotecteurs sur les lésions d’ischémie-reperfusion. Nous avons réalisé une étude randomisée contrôlée afin d’examiner les effets d’une perfusion peropératoire de dexmédétomidine sur la fonction rénale et l’apparition d’un retard de fonctionnement du greffon après une transplantation rénale élective issue de donneurs vivants. MéTHODE: Au total, 104 patients ont été aléatoirement répartis pour recevoir une perfusion peropératoire de 0,4 μg·kg

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged

Background: Postoperative delirium (POD) is associated with adverse outcomes in elderly patients after surgery. Electroencephalography (EEG) is an effective tool for identifying degenerative cerebral dysfunctions, including mild cognitive impairment and dementia. Methods: We included 237 patients aged > 70 years who underwent spinal surgery. We measured the median dominant frequency (MDF), which is a resting-state EEG biomarker involving intrinsic alpha oscillations that reflect an idle cortical state, from the prefrontal regions. Additionally, the mini-mental state examination and Montreal cognitive assessment (MoCA) were performed before surgery as well as 5 days, 1 month, and 1 year after surgery. Results: Forty-eight (20.3%) patients were diagnosed with POD. A multivariable logistic regression analysis that included age, MoCA score, Charlson comorbidity index score > 4, anaesthesia duration > 4 hours, and the MDF as variables revealed that the MDF had a significant odds ratio of 0.4 (95% confidence interval 0.23–0.77). Among the patients with POD, the postoperative neurocognitive disorders could last up to 1 year.Conclusions: In conclusion, a low MDF on preoperative EEG was associated with POD in elderly patients undergoing surgery. Our findings suggest that EEG could be a novel tool for identifying patients at a high risk of POD.

Dexmedetomidine (Dex), widely used as a sedative in surgical procedures and intensive care units, induces sympatholytic, anxiolytic, analgesic, and sedative effects. Postoperative cognitive dysfunction (POCD) is routinely observed in postoperative care following surgery and general anesthesia. The NLRP3 inflammasome complex plays a critical role in innate immune response by detecting pathogenic microorganisms and activating pro-inflammatory cytokines. Although there are numerous protective effects of Dex among the neurological diseases, specific mechanisms including NLRP3 inflammasome-mediated neuroinflammation via oxidative stress response in a POCD model are not fully understood. Here, we investigated whether Dex exhibits neurocognitive effects through the NLRP3 inflammasome signaling in a POCD mouse model using a neurobehavioral test and ELISA analysis. We also confirmed the level of oxidative stress-related response in the in vitro system in the POCD model. Furthermore, we evaluated the NLRP3 inflammasome complex by immunoprecipitation analysis. In summary, the results of the present study indicated that Dex showed a neuroprotective effect in the POCD model by reducing oxidative stress response through NLRP3 inflammasome-mediated neuroinflammation.

Here, we aimed to compare the effects of two anesthetic methods (desflurane inhalation anesthesia vs. propofol-based total intravenous anesthesia (TIVA)] on corrected QT interval (QTc) values during living donor liver transplantation. Altogether, 120 patients who underwent living donor liver transplantation were randomized to either the desflurane or TIVA group. The primary outcome was intraoperative QTc change. Other electrocardiogram, hemodynamic findings and postoperative outcomes were examined as secondary outcomes. QTc values were prolonged intraoperatively in both groups; however, the change was smaller in the TIVA group than in the desflurane group (PGroup × Time 500 ms in the desflurane group than in the TIVA group (63.3% vs. 28.3%, P Group × Time

Background: The incidence of postoperative nausea and vomiting (PONV) remains high. The effects of sufentanil for PONV is not firmly confirmed. The aim of this study was to compare the effect of sufentanil- and fentanyl-based intravenous patient-controlled analgesia (IV-PCA) on the incidence of PONV after laparoscopic nephrectomy. Methods: Eighty-six patients were randomly allocated to receive either the sufentanil (n =43) or fentanyl (n =43). IV-PCA was prepared using either sufentanil 3 µg/kg or fentanyl 20 µg/kg, ramosetron 0.3 mg, and ketorolac 120 mg. The primary outcome of was the incidence of PONV during 24 h after post anesthesia care unit (PACU) discharge. The secondary outcomes were the modified Rhodes index and patient satisfaction scores at 24 h after PACU discharge, need for rescue antiemetics, pain score, need for additional analgesics, and cumulative consumption of IV-PCA Results: The incidence of PONV was comparable between the sufentanil and fentanyl groups (64.3% vs. 65%, p = 0.946; respectively). The number of patients who required antiemetics (p = 0.946) and the modified Rhodes index at 24 h after post-anesthesia care unit discharge (p = 0.668) were also comparable in both groups. No significant differences were found in the secondary outcomes, including the analgesic profiles and adverse events between the groups. Conclusions: In conclusion, sufentanil- and fentanyl-based IV-PCA showed similar incidence of PONV with comparable analgesic effects after laparoscopic nephrectomy. Based on these results, we suggest that sufentanil and fentanyl may provide comparable effects for IV-PCA after laparoscopic nephrectomy.

Background Considering the functional role of red blood cells (RBC) in maintaining oxygen supply to tissues, RBC transfusion can be a life-saving intervention in situations of severe bleeding or anemia. RBC transfusion is often inevitable to address intraoperative massive bleeding; it is a key component in safe perioperative patient management. Unlike general medical resources, packed RBCs (pRBCs) have limited availability because their supply relies entirely on voluntary donations. Additionally, excessive utilization of pRBCs may aggravate prognosis or increase the risk of developing infectious diseases. Appropriate perioperative RBC transfusion is, therefore, crucial for the management of patient safety and medical resource conservation. These concerns motivated us to develop the present clinical practice guideline for evidence-based efficient and safe perioperative RBC transfusion management considering the current clinical landscape. Methods This guideline was obtained after the revision and refinement of exemplary clinical practice guidelines developed in advanced countries. This was followed by rigorous evidence-based reassessment considering the healthcare environment of the country. Results This guideline covers all important aspects of perioperative RBC transfusion, such as preoperative anemia management, appropriate RBC storage period, and leukoreduction (removal of white blood cells using filters), reversal of perioperative bleeding tendency, strategies for perioperative RBC transfusion, appropriate blood management protocols, efforts to reduce blood transfusion requirements, and patient monitoring during a perioperative transfusion. Conclusions This guideline will aid decisions related to RBC transfusion in healthcare settings and minimize patient risk associated with unnecessary pRBC transfusion.

Background Postoperative pain is a common phenomenon after surgery and is closely associated with the development of postoperative cognitive dysfunction (POCD). Persistent pain and systemic inflammation caused by surgery have been suggested as key factors for the development of POCD. Fractalkine (CX3CL1) and its receptor, the CX3C chemokine receptor 1 (CX3CR1), are known to play a key role in pain and inflammation signaling pathways. Recent studies have shown that the regulation of CX3CR1/L1 signaling influences the development of various diseases including neuronal diseases. We determined whether CX3CR1/L1 signaling is a putative therapeutic target for POCD in a mouse model. Methods Adult (9–11 weeks) male mice were treated with neutralizing antibody to block CX3CR1/L1 signaling both before and after surgery. Inflammatory and behavioral responses including pain were assessed postoperatively. Also, CX3CR1 mRNA level was assessed. Hippocampal astrocyte activation, Mao B expression, and GABA expression were assessed at 2 days after surgery following neutralizing antibody administration. Results The behavioral response indicated cognitive dysfunction and development of pain in the surgery group compared with the control group. Also, increased levels of pro-inflammatory cytokines and CX3CR1 mRNA were observed in the surgery group. In addition, increased levels of GABA and increased Mao B expression were observed in reactive astrocytes in the surgery group; these responses were attenuated by neutralizing antibody administration. Conclusions Increased CX3CR1 after surgery is both necessary and sufficient to induce cognitive dysfunction. CX3CR1 could be an important target for therapeutic strategies to prevent the development of POCD.

Additional file 2: Figure S2. Data in Figure 4, analyzed by two-way ANOVA followed by Tukey’s post hoc test. Figure S3. Data in Figure 5, analyzed by two-way ANOVA followed by Tukey’s post hoc test. Figure S4. Data in Figure 7, analyzed by two-way ANOVA followed by Tukey’s post hoc test.

Additional file 1: Figure S1. The expression of Iba-1 in hippocampal tissue.

Background: Dynamic preload indices may predict fluid responsiveness in end-stage liver disease. However, their usefulness in patients with altered vascular compliance is uncertain. This study is the first to evaluate whether dynamic indices can reliably predict fluid responsiveness in patients undergoing liver transplantation with a high femoral-to-radial arterial pressure gradient (PG).Methods: 80 liver transplant recipients were retrospectively categorized as having a normal (n = 56) or high (n = 24, difference in systolic pressure ≥ 10 mmHg and/or mean pressure ≥ 5 mmHg) femoral-to-radial arterial PG, measured immediately after radial and femoral arterial cannulation. The ability of dynamic preload indices (stroke volume variation, pulse pressure variation [PPV], pleth variability index) to predict fluid responsiveness was assessed before the surgery. Fluid replacement of 500 ml of crystalloid solution was performed over 15 min. Fluid responsiveness was defined as ≥ 15% increase in the stroke volume index. The area under the receiver-operating characteristic curve (AUC) indicated the prediction of fluid responsiveness.Results: Fourteen patients in the normal, and eight in the high PG group were fluid responders. The AUCs for PPV in the normal, high PG groups and total patients were 0.702 (95% confidence interval [CI] 0.553–0.851, P = 0.008), 0.633 (95% CI 0.384–0.881, P = 0.295) and 0.667 (95% CI 0.537–0.798, P = 0.012), respectively. No other index predicted fluid responsiveness.Conclusion: PPV can be used as a dynamic index of fluid responsiveness in patients with end-stage liver disease but not in patients with altered vascular compliance.

BackgroundPostoperative delirium is a common neuropsychiatric syndrome resulting in a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium models due to their clinical significance, focusing on systemic inflammation and consequent neuroinflammation playing a key in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium mice model with respect to the neuroinflammatory hypothesis of delirium. MethodsMale C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioural tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1ꞵ, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models.Results Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of the genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. Conclusions The scopolamine-induced delirium mice model successfully showed that analogous neuropsychiatric changes coincide with the neuroinflammatory hypothesis for pathogenesis of delirium.

Perioperative fluid management in kidney transplant recipients is crucial to supporting the fluid, acid-base, and electrolyte balance required for graft perfusion. However, the choice of intraoperative crystalloids in kidney transplantation remains controversial. We conducted a single-center retrospective cohort study to evaluate the impact of intraoperative fluids on acid-base and electrolyte balance and graft outcomes.We included 282 living donor kidney transplant recipients from January 2010 to December 2017. Patients were classified into two groups based on the type of intraoperative crystalloids used (157 patients in the half saline group and 125 patients in the balanced crystalloid solutions group, Plasma-lyte).Compared with the half saline group, the Plasma-lyte group showed less metabolic acidosis and hyponatremia during surgery. Hyperkalemia incidence was not significantly different between the two groups. Changes in postoperative graft function assessed by blood urea nitrogen and creatinine were significantly different between the two groups. Patients in the Plasma-lyte group exhibited consistently higher glomerular filtration rates than those in the half saline group at 1 month and 1 year after transplantation after adjusting for demographic differences.Intraoperative Plasma-lyte can lead to more favorable results in terms of acid-base balance during kidney transplantation. Patients who received Plasma-lyte showed superior postoperative graft function at 1 month and 1 year after transplantation. Further studies are needed to evaluate the superiority of intraoperative Plasma-lyte over other types of crystalloids in relation to graft outcomes.

Activation of the inflammasome complex contributes to the inflammatory response and cell death under pathologic conditions. The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 2 (NLRP2) inflammasome is activated in astrocytes after cerebral ischemia, which can aggravate ischemic damage. Apoptosis signal-regulating kinase 1 (ASK1) is an early activator and immune-regulator after ischemic injury, that can lead to cell death. The objective of the present study was to evaluate the role of ASK1 in controlling NLRP2 inflammasomes in astrocytes after cerebral ischemia. In a mouse model of ischemic stroke, the levels of NLRP2 inflammasome components, and interleukin (IL)-1β and IL-18, were quantified in different brain regions. In addition, an astrocyte cell line was subjected to oxygen-glucose deprivation and reperfusion (OGD/R) injury, and the levels of NLRP2 inflammasome factors, IL-1β and IL-18 were evaluated. Ischemic brain injury activated astrocytes. The levels of NLRP2 inflammasome components, IL-1β and IL-18 productions, and cell death increased in the cortex and striatum after ischemic injury. In cultured astrocytes, NLRP2 inflammasome components, IL-1β and IL-18 levels were upregulated after OGD/R. ASK1 silencing or inhibition efficiently reduced NLRP2 inflammasome components and pro-inflammatory cytokine levels in mice and cultured astrocytes. Our findings identify a key role for ASK1 in regulating astroglial inflammasomes after cerebral ischemia. We suggest ASK1 as one of the main targets for astroglial inflammasomes in ischemic stroke.

Background There are various reports on the effects of the anesthetic method on neurologic complications. A population-based study was conducted to estimate the effect of anesthetic method on the incidence of postoperative delirium in patients that underwent total hip replacement arthroplasty in South Korea. Methods The Korean National Health Insurance claims database was used to retrospectively identify and analyze 24,379 cases of total hip replacement arthroplasty, defined as patients having a claim record with the operation code ‘N0711,’ from January 2008 to December 2017. Patients were divided into two groups, a general anesthesia group (n = 9,921) and a regional anesthesia group (n = 14,458). The incidence of delirium was assessed in cases when patients used medications for delirium, such as haloperidol, chlorpromazine, olanzapine, and risperidone. Results Of the 9,921 patients receiving general anesthesia and 14,458 receiving regional anesthesia, 142 (1.43%) and 209 (0.86%) experienced postoperative delirium after total hip replacement arthroplasty, respectively. There was no significant difference between the groups (P = 0.92). In logistic regression analysis, sex (P = 0.038) and patients with acquired immune deficiency syndrome (P = 0.008) were predictors of postoperative delirium. Conclusions Our results revealed that the anesthetic method was not associated with the incidence of postoperative delirium. In addition, the results suggest that male patients and patients with acquired immune deficiency syndrome undergoing total hip replacement arthroplasty carefully managed for postoperative delirium after surgery.

An increasing number of pediatric patients undergo liver transplantation, and it has become an effective and definitive treatment of choice for pediatric end-stage liver disease patients. However, liver transplantation in pediatric patients differs greatly from that in older individuals with respect to not only surgical techniques, immunosuppression, and post-operative managements, but also to intraoperative anesthetic management. The present review provides an overview of the current development and clinical practices in anesthetic management of pediatric liver transplantation.

Background: Caudal block is commonly administered for postoperative analgesia in children. Although caudal block with 1.5 ml kg −1 local anaesthetic has been reported to reduce cerebral oxygenation in infants, the effect of caudal block on intracranial pressure (ICP) in children has not been well investigated. Optic nerve sheath diameter (ONSD) correlates with degree of ICP. This study aimed to estimate the effects of caudal block on ICP according to volume of local anaesthetic using ultrasonographic measurement of ONSD in children. Methods: Eighty patients, 6- to 48-months-old, were randomly allocated to the high-volume (HV) or low-volume (LV) groups for caudal block with ropivacaine 0.15%, 1.5 ml kg −1 or 1.0 ml kg −1 , respectively. Measurement of ONSD was performed before (T0), immediately after (T1), and 10 min (T2) and 30 min (T3) after caudal block. Results: The two groups exhibited significant differences in ONSD according to time ( P Group x Time =0.003). The HV group exhibited significantly greater changes in ONSD from T0 to T2 and T3 than the LV group. However, in both groups, ONSDs at T1, T2 and T3 were significantly greater compared with those at T0, with the highest values at T2. Conclusions: Caudal block with a high volume of local anaesthetic can cause a greater increase in ICP than caudal block with a low volume of local anaesthetic. However, caudal block with 1.0 ml kg −1 of local anaesthetic can also result in a significant increase in ICP. Clinical trial registration NCT02768493.

Introduction: Perioperative anesthesia and analgesia exacerbate immunosuppression in immunocompromised cancer patients. The natural killer (NK) cell is a critical part of anti-tumor immunity. We compared the effects of two different anesthesia and analgesia methods on the NK cell cytotoxicity (NKCC) in patients undergoing breast cancer surgery. Methods: Fifty patients undergoing breast cancer resection were randomly assigned to receive propofol-remifentanil anesthesia with postoperative ketorolac analgesia (Propofol-ketorolac groups) or sevoflurane-remifentanil anesthesia with postoperative fentanyl analgesia (Sevoflurane-fentanyl group). The primary outcome was NKCC, which was measured before and 24 h after surgery. Post-surgical pain scores and inflammatory responses measured by white blood cell, neutrophil, and lymphocyte counts were assessed. Cancer recurrence or metastasis was evaluated with ultrasound and whole body bone scan every 6 months for 2 years after surgery. Results: The baseline NKCC (%) was comparable between the two groups (P = 0.082). Compared with the baseline value, NKCC (%) increased in the Propofol-ketorolac group [15.2 (3.2) to 20.1 (3.5), P = 0.048], whereas it decreased in the Sevoflurane-fentanyl group [19.5 (2.8) to 16.4 (1.9), P = 0.032]. The change of NKCC over time was significantly different between the groups (P = 0.048). Pain scores during 48 h after surgery and post-surgical inflammatory responses were comparable between the groups. One patient in the Sevoflurane-fentanyl group had recurrence in the contralateral breast and no metastasis was found in either group. Conclusions: Propofol anesthesia with postoperative ketorolac analgesia demonstrated a favorable impact on immune function by preserving NKCC compared with sevoflurane anesthesia and postoperative fentanyl analgesia in patients undergoing breast cancer surgery.

Tissue-type plasminogen activator (tPA) is the only treatment for ischemic stroke. However, tPA could induce the intracranial hemorrhage (ICH), which is the main cause of death in ischemic stroke patient after tPA treatment. At present, there is no treatment strategy to ameliorate tPA-induced brain injury after ischemia. Therefore, we investigated the effect of pre-treated isoflurane, which is a volatile anesthetic and has beneficial effects on neurological dysfunction, brain edema and infarct volume in ischemic stroke model. In this study, we used oxygen/glucose deprivation and reperfusion (OGD/R) condition to mimic an ischemic stroke in vitro. Matrix metalloproteinases (MMP) activity was measured in endothelial cell media. Also, neuronal cell culture was performed to investigate the effect of pretreated isoflurane on the neuronal cell survival after tPA-induced injury during OGD/R. Isoflurane pretreatment prevented tPA-induced MMP-2 and MMP-9 activity and suppressed tPA-triggered LRP/NF-κB/Cox-2 signaling after OGD/R. Neuronal cells, incubated with endothelial cell conditioned medium (EC-CM) after tPA + OGD/R, showed upregulation of pro-apoptotic molecules. However, neurons incubated with isoflurane-pretreated EC-CM showed increased anti-apoptotic molecules. Our findings suggest that isoflurane pretreatment could attenuate tPA-exaggerated brain ischemic injury, by reducing tPA-induced LRP/NF-κB/Cox-2 in endothelial cells, endothelial MMP-2 and MMP-9 activation, and subsequent pro-apoptotic molecule in neurons after OGD/R.

Purpose Children have few small alveoli, which reduce lung compliance; in contrast, their cartilaginous rib cage makes their chest wall highly compliant. This combination promotes lung collapse. Prolonged inspiratory to expiratory (I:E) ratio ventilation is used to optimize gas exchange and respiratory mechanics in surgery. However, the optimal ratio is unclear in children. We hypothesized that, compared to a 1:2 I:E ratio, a 1:1 I:E ratio would improve dynamic compliance and oxygenation, and affect the peak airway pressure in pediatric patients undergoing surgery. Materials and methods Forty-eight patients aged ≤6 years who were scheduled to undergo surgery under general anesthesia with an arterial line were randomly allocated to receive 1:1 (group 1:1) or 1:2 (group 1:2) I:E ratio ventilation. Airway pressure, respiratory system compliance, and arterial blood gas analyses were compared between groups immediately after induction (T0), 30 min after induction (T1), 60 min after induction (T2), immediately after surgery (T3), and on arrival at the post-anesthesia care unit (T4). Results Peak and plateau airway pressures were significantly lower in group 1:1 than in group 1:2 at T1 (p=0.044 and 0.048, respectively). The dynamic and static compliances were significantly higher in group 1:1 than in group 1:2 at T1 (p=0.044 and 0.045, respectively). However, the partial pressure of oxygen did not significantly differ between groups. Conclusion Compared to a 1:2 I:E ratio, a 1:1 I:E ratio improved dynamic compliance and lowered the peak airway pressure without complications in pediatric patients. Nevertheless, our results do not support its use solely for improving oxygenation.

Cognitive symptoms are prevalent in the elderly and are associated with an elevated risk of developing dementia. Disease-driven changes can cause cognitive disabilities in memory, attention, and language. The inflammasome is an innate immune intracellular complex that has a critical role in the host defense system, in that it senses infectious pathogen-associated and endogenous danger-associated molecular patterns. An unbalanced or dysregulated inflammasome is associated with infectious, inflammatory, and neurodegenerative diseases. Due to its importance in such pathological conditions, the inflammasome is an emerging drug target for human diseases. A growing number of studies have revealed links between cognitive symptoms and the inflammasome. Several studies have shown that reducing the inflammasome component mitigates cognitive symptoms in diseased states. Therefore, understanding the inflammasome regulatory mechanisms may be required for the prevention and treatment of cognitive symptoms. The purpose of this review is to discuss the current understanding of the inflammasome and its relationships with cognitive symptoms in various human diseases.

Patients undergoing surgery can suffer from various complications, including post-operative bleeding, local or systematic infection, and neurologic disorders. Major surgery can initiate innate immune responses and trigger overproduction of inflammatory mediators, which can contribute to organ dysfunction. Inflammasomes are innate immune complexes, which are connected to the pathogenesis of various diseases, including atherosclerosis, hemorrhagic brain injury, and Alzheimer's disease. In the present study, we hypothesized that nucleotide-binding oligomerization domain-containing-like receptor protein (NLRP) inflammasomes may have a role in the pathological effects of surgery. Therefore, we designed a protein inhibitor of nuclear factor kappa B (NF-κB) p65 transcripts, called nt-p65-TMD (nuclear transducible (nt) transcription modulated domain (TMD) of RelA (p65)), that can penetrate the nucleus, and evaluated its therapeutic efficacy for dampening surgery-induced inflammasome activation. It was found that the nt-p65-TMD significantly reduced the NLRP1 inflammasome complex components (NLRP1, ASC, and Caspase-1) and interleukin (IL)-1β and IL-18 productions in the spleen after surgery. In the spleen, specific cell population and selective mediators were altered after surgery with/without nt-p65-TMD treatment. Also, we found that treatment of nt-p65-TMD decreased cell death in the spleen after surgery. Therefore, nt-p65-TMD is a potential novel strategy for reducing surgery-induced NLRP1 inflammasome and complications.

Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.

Stroke has become a more common disease worldwide. Despite great efforts to develop treatment, little is known about ischemic stroke. Cerebral ischemia activates multiple cascades of cell type-specific pathomechanisms. Ischemic brain injury consists of a complex series of cellular reactions in various cell types within the central nervous system (CNS) including platelets, endothelial cells, astrocytes, neutrophils, microglia/macrophages, and neurons. Diverse cellular changes after ischemic injury are likely to induce cell death and tissue damage in the brain. Since cells in the brain exhibit different functional roles at distinct time points after injury (acute/subacute/chronic phases), it is difficult to pinpoint genuine roles of cell types after brain injury. Many experimental studies have shown the association of apoptosis signal-regulating kinase 1 (ASK1) with cellular pathomechanisms after cerebral ischemia. Blockade of ASK1, by either pharmacological or genetic manipulation, leads to reduced ischemic brain injury and subsequent neuroprotective effects. In this review, we present the cell type-specific pathophysiology of the early phase of ischemic stroke, the role of ASK1 suggested by preclinical studies, and the potential use of ASK suppression, either by pharmacologic or genetic suppression, as a promising therapeutic option for ischemic stroke recovery.

BACKGROUND In free flap reconstruction for head and neck cancer, achieving a haemodynamic target using excessive fluid infusion is associated with decreased flap survival rates and extended hospital stays. We hypothesized that goal-directed haemodynamic therapy would improve flap survival rates and shorten hospitalization periods. METHODS Patients scheduled for free flap reconstruction were randomly assigned to a goal-directed haemodynamic therapy group (n = 31) or a conventional haemodynamic therapy control group (n = 31). The control group received extra bolus fluid and ephedrine or norepinephrine to maintain a mean arterial pressure ≥ 65 mmHg. The goal-directed haemodynamic therapy group received a colloid solution as the extra bolus fluid to maintain a stroke volume variation < 12%; dobutamine, ephedrine, or norepinephrine was administered to maintain a cardiac index ≥ 2.5 l/min/m2 and mean arterial pressure ≥ 65 mmHg. Enhanced recovery after surgery protocols were not used except for fluid therapy. An otolaryngologist blinded to group assignments assessed flap outcomes and classified them as 'survival,' 'at risk' or 'failure.' RESULTS The hospitalization period was not significantly different between the groups. The goal-directed haemodynamic therapy group had significantly shorter intensive care unit stays and a higher flap survival rate. The crystalloid volume was significantly lower in goal-directed haemodynamic therapy group. Reoperation rates, post-operative complications, and laboratory data including inflammatory markers were similar between the groups. CONCLUSION Compared to conventional haemodynamic therapy, goal-directed haemodynamic therapy does not reduce hospitalization periods; it may, however, reduce the length of intensive care unit stays and increase flap survival rates. Further studies including multi-centre trials with larger sample sizes are warranted.

Sympathetic blockade associated with epidural analgesia was reported to be a risk factor for acute kidney injury (AKI) following liver resection. The purpose of this study was to compare the incidence of AKI after living-donor hepatectomies according to the type of patient-controlled analgesia (PCA).A total of 316 patients after living-donor hepatectomy were retrospectively analyzed; 148 patients in the epidural PCA group and 168 patients in the intravenous (IV) PCA group were evaluated. AKI was defined as an increase in serum creatinine ≥0.3 mg/dL, ie, 1.5-fold from the baseline, or a reduction in the urine output in the first 48 hours after surgery, based on the Acute Kidney Injury Network criteria. Logistic regression analysis was performed to identify the independent risk factors for AKI after living-donor hepatectomy.Baseline characteristics were similar between the 2 groups except the age. Volumes of fluids and colloids administered intraoperatively were greater in the epidural PCA group (P .001 and P = .006, respectively). The incidence of AKI did not show significant differences between the 2 groups (8.1% vs 7.1%; P = .747). In multivariate analysis, preoperative serum alanine transaminase level ≥50 U/L was identified as a risk factor for postoperative AKI. However, epidural PCA failed to be a risk factor for postoperative AKI.The type of PCA did not affect the incidence of postoperative AKI after living-donor hepatectomy. Despite significant differences in the postoperative hemodynamics, the incidence of AKI was similar between 2 groups.

Inflammation is implicated in ischemic stroke and is involved in abnormal homeostasis. Activation of the immune system leads to breakdown of the blood brain barrier (BBB) and, thereby, infiltration of immune cells into the brain. Upon cerebral ischemia, infiltrated macrophages and microglia (resident CNS immune cell) are activated, change their phenotype to M1 or M2 based on the microenvironment, migrate toward damaged tissue, and are involved in repair or damage. Those of M1 phenotype release pro-inflammatory mediators, which are associated with tissue damage, while those of M2 phenotype release anti-inflammatory mediators, which are related to tissue recovery. Moreover, late inflammation continually stimulates immune cell infiltration and leads to brain infarction. Therefore, regulation of M1/M2 phenotypes under persistent inflammatory conditions after cerebral ischemia is important for brain repair. Herein, we focus on apoptosis signal-regulating kinase 1 (ASK1), which is involved in apoptotic cell death, brain infarction, and production of inflammatory mediators under cerebral ischemia. We hypothesized that ASK1 is involved in the polarization of M1/M2 phenotype and the function of microglia and macrophage during the late stage of ischemia/hypoxia. We investigated the effects of ASK1 in mice subjected to middle cerebral artery occlusion and on BV2 microglia and RAW264.7 macrophage cell lines subjected to oxygen-glucose deprivation. Our results showed that ASK1 silencing effectively reduced Iba-1 or CD11b- positive cells in ischemic areas, suppressed pro-inflammatory cytokines, and increased anti-inflammatory mediator levels at 7 days after cerebral ischemia. In cultured microglia and macrophages, ASK1 inhibition, induced by NQDI-1 drug, decreased the expression and release of M1-associated factors and increased those of M2-associated factors after hypoxia/reperfusion (H/R). At the gene level, ASK1 inhibition suppressed M1-associated genes and augmented M2-associated genes. In gap closure assay, ASK1 inhibition reduced the migration rate of microglia and macrophages after H/R. Taken together, our results provide new information that suggests ASK1 controls the polarization of M1/M2 and the function of microglia and macrophage under sustained-inflammatory conditions. Regulation of persistent inflammation via M1/M2 polarization by ASK1 is a novel strategy for repair after ischemic stroke.

Some patients experience impaired cognitive functioning after surgery, a phenomenon referred to as postoperative cognitive dysfunction (POCD). Signs of POCD are closely associated with the development of systemic or hippocampal inflammation. However, the precise pathophysiological mechanisms of prevention/treatment options for POCD still remain unclear. After injury, the transcriptional factor nuclear factor-kappa B (NF-κB) is thought to regulate or stimulate inflammation amplification. Therefore, we designed a cell-penetrating fusion protein called nt-p65-TMD, which inhibits NF-κB p65 activation by translocating into the nucleus. In the present study, we discovered that nt-p65-TMD exerted effects on surgery-induced cognitive impairment in mice. Specifically, nt-p65-TMD exhibited strong immunoregulatory properties that were able to reduce surgery-induced elevations in cerebrovascular integrity impairment, subsequent peripheral immune-cell recruitment, and inflammation amplification, which ultimately lead to cognitive decline. The nt-p65-TMD has the unique ability to regulate and reduce systemic inflammation and inflammation amplification, suggesting a new strategy for preventing development of cognitive decline that occurs in POCD.

Laparoscopic surgery involves the creation of a carbon dioxide (CO2) pneumoperitoneum to facilitate a clear surgical view, which may result in an elevated intracranial pressure (ICP). Depending on the surgical area, steep Trendelenburg positioning may be used as well, further increasing the ICP. The objective of this study was to assess the effects of laparoscopic surgery on changes in ICP assessed by ultrasonographic measurement of optic nerve sheath diameter (ONSD), which is a generally accepted simple, reliable, and non-invasive ICP measurement technique. A computerized literature search was performed in August 2016 to identity prospective studies that measured ONSD to assess ICP changes during laparoscopic surgery. The primary outcome was the change in ONSD during the early (0–30 min) and late (30–120 min) periods after initiating pneumoperitoneum, compared with baseline values measured after anesthesia induction. Mean differences (MDs) with 95% confidence intervals [CIs] were calculated. Nine observational studies and one randomized controlled trial, with a total of 460 subjects, were analyzed. Compared to the baseline value after anesthesia induction, significant increases in ONSD were observed in both the early period (MD 0.46, 95% CI 0.31–0.61, P

Tissue plasminogen activator (tPA) is the only recommended pharmacological treatment for acute ischemic stroke. However, tPA can induce intracerebral hemorrhage by blood–brain barrier breakdown through an increase in matrix metalloproteinases (MMPs). Previously, we showed that isoflurane postconditioning reduced intracranial hemorrhage following tPA treatment after cerebral ischemia. Here, we investigated the mechanism by which isoflurane postconditioning reduces tPA-induced MMP-2 and MMP-9 activation following hypoxia/reoxygenation (H/R) in brain endothelial cells. Mouse brain endothelial cells (bEnd.3) were exposed to 6 h of oxygen-glucose deprivation and 3 h of reoxygenation with tPA. Cells were treated with isoflurane for 1 h of the reoxygenation condition and the effect of isoflurane postconditioning on MMP-2 and MMP-9 activation was assessed. Involvement of low-density lipoprotein receptor-related protein (LRP), which is a receptor for tPA, and the extracellular signal-regulated kinase (ERK) and NF-κB pathway in isoflurane postconditioning was assessed using LRP inhibitor (receptor-associated protein, RAP) and ERK-1/2 inhibitor (PD98059). Isoflurane postconditioning decreased tPA-induced MMP-2 and MMP-9 activation under H/R. tPA treatment under H/R increased expression of LRP and the active form of NF-κB. Isoflurane postconditioning suppressed LRP expression, increased ERK-1/2 activation, and suppressed MMP-2 and MMP-9 activation, comparable to the effect of RAP. Activation of ERK-1/2, inhibition of NF-κB activation, and suppression of MMP-2 and MMP-9 activation by isoflurane postconditioning were abolished with PD98059 treatment. These finding indicate that isoflurane postconditioning inhibits tPA-induced MMP-2 and MMP-9 activation following H/R via the LRP/ERK/NF-κB pathway in bEnd.3.

Emergence agitation is common after nasal surgery. We investigated the effects of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery in adult patients.One hundred patients undergoing nasal surgery were randomized into two groups. The dexmedetomidine group (Group D, n=50) received dexmedetomidine infusion at a rate of 0.4 μg kg(-1) h(-1) from induction of anaesthesia until extubation, while the control group (Group C, n=50) received volume-matched normal saline infusion as placebo. Propofol (1.5-2 mg kg(-1)) and fentanyl (1 μg kg(-1)) were used for induction of anaesthesia, and desflurane was used for maintenance of anaesthesia. The incidence of agitation, haemodynamic parameters, and recovery characteristics were evaluated during emergence. A 40-item quality-of-recovery questionnaire (QoR-40) was provided to patients 24 h after surgery.The incidence of agitation was lower in Group D than Group C (28 vs 52%, P=0.014). Mean arterial pressure and heart rate were more stable in Group D than in Group C during emergence (P0.05). Time to extubation, bispectral index, and respiratory rate at extubation were similar between the groups. Global QoR-40 score at 24 h after surgery was higher in Group D (median [range], 183 [146 -198]) compared with Group C (178 [133-196]) (P=0.041).Intraoperative infusion of dexmedetomidine provided smooth and haemodynamically stable emergence. It also improved quality of recovery after nasal surgery.

Despite the extensive use of propofol in general anesthetic procedures, the effects of propofol on glial cell were not completely understood. In lipopolysaccharide (LPS)-stimulated rat primary astrocytes and BV2 microglial cell lines, co-treatment of propofol synergistically induced inflammatory activation as evidenced by the increased production of NO, ROS and expression of iNOS, MMP-9 and several cytokines. Propofol augmented the activation of JNK and p38 MAPKs induced by LPS and the synergistic activation of glial cells by propofol was prevented by pretreatment of JNK and p38 inhibitors. When we treated BV2 cell culture supernatants treated with LPS plus propofol on cultured rat primary neuron, it induced a significant neuronal cell death. The results suggest that the repeated use of propofol in immunologically challenged situation may induce glial activation in brain.

Aims The combination of adhesion and migration of endothelial cells (ECs) is an integral process for evolution, organization, repair and vessel formation in living organisms. Agmatine, a polycationic amine existing in brain, has been investigated to exert neuroprotective effects. Up to date, there are no studies reporting that agmatine modulates murine brain endothelial (bEnd.3) cells migration. In the present study, we intend to investigate the role of agmatine in bEnd.3 cells migration and the molecular mechanism mediating this action. Main methods The effect of agmatine on the bEnd.3 cells migration was examined by migration assay, and the mechanism involved for this effect was investigated by western blot analysis and NO contents measurements. Key findings Agmatine treatment (50, 100 and 200 μM) significantly accelerated bEnd.3 cells migration in a concentration-dependent manner. Western blotting revealed that agmatine treatment significantly induced vascular endothelial growth factor (VEGF), VEGF receptor 2 (Flk-1/KDR or VEGFR2), phosphatidylinositol 3-kinase (PI3K), Akt/protein kinase B (also known as PKB, PI3K downstream effector protein), endothelial nitric oxide synthase (eNOS) nitric oxide (NO; product by eNOS) and intercellular adhesion molecule 1 (ICAM-1) expressions during bEnd.3 cells migration. The expression of ICAM-1 and migration of bEnd.3 cells, induced by agmatine, were significantly attenuated by treatment of wortmannin, a specific PI3K inhibitor. Significance Taken together, we provide the first evidence that activation of VEGF/VEGFR2 and the consequential PI3K/Akt/eNOS/NO/ICAM-1 signaling pathways are serial events, through which the treatment of agmatine could lead to bEnd.3 cells migration.

Conditions of increased oxidative stress including cerebral ischemia can lead to blood-brain barrier (BBB) dysfunction via matrix metalloproteinase (MMP). It is known that MMP-9 in particular is released from brain endothelial cells is involved in the neuronal cell death that occurs after cerebral ischemia. In the intracellular signaling network, apoptosis signal-regulating kinase 1 (ASK1) is the main activator of the oxidative stress that is part of the pathogenesis of cerebral ischemia. ASK1 also promotes apoptotic cell death and brain infarction after ischemia and is associated with vascular permeability and the formation of brain edema. However, the relationship between ASK1 and MMP-9 after cerebral ischemia remains unknown. Therefore, the aim of the present study was to determine whether blocking ASK1 would affect MMP-9 activity in the ischemic brain and cultured brain endothelial cells. Our results showed that ASK1 inhibition efficiently reduced MMP-9 activity in vivo and in vitro. In endothelial cell cultures, ASK1 inhibition upregulated phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) signals and downregulated cyclooxygenase-2 (Cox-2) signals after hypoxia/reperfusion. Additionally, in neuronal cell cultures, cell death occurred when neurons were incubated with endothelial cell-conditioned medium (EC-CM) obtained from the hypoxia/reperfusion group. However, after incubation with EC-CM and following treatment with the ASK1 inhibitor NQDI-1, neuronal cell death was efficiently decreased. We conclude that suppressing ASK1 decreases MMP-9 activity in brain endothelial cells, and leading to decreased neuronal cell death after ischemic injury.

Background: Endothelial dysfunction associated with diabetes mellitus (DM) may influence arterial vasoreactivity after arterial stimulus, such as cannulation, and cause changes in diameter and blood flow. Despite the frequent use of arterial cannulation during anesthesia and critical care, little information is available regarding vasoreactivity of the radial and ulnar arteries and its influence on underlying DM. Methods: Forty non-DM and 40 DM patients, who required arterial cannulation during general anesthesia, were enrolled. Using duplex Doppler ultrasonography, we measured the patients' arterial diameter, peak systolic velocity, end-diastolic velocity, resistance index, and mean volume flow of both arteries at five different time points. Results: After radial artery cannulation, ulnar arterial diameter and blood flow did not significantly increase in DM group, as they did in non-DM group. Ulnar arterial resistance index significantly increased in both groups, but the degree of decrease in DM group was significantly less than non-DM. Conclusion: Ulnar artery's ability to increase blood flow for compensating the sudden reduction of radial arterial flow in DM patients was significantly less than that in non-DM patients under general anesthesia. Such attenuated vasoreactivity of ulnar artery to compensate the reduced radial arterial flow may have to be considered in radial arterial cannulation for DM patients.

Imatinib mesylate, a Bcr/Abl tyrosine kinase inhibitor, is widely used in treating chronic myeloid leukemia. However, drug-resistance of leukemia cells becomes an emergent problem. Herein, various flavonoids were screened for applicability in leukemia treatment, and 3-hydroxyflavone (3-HF) was found to be most effective in reducing cancer cell viability. The combination of 3-HF and imatinib mesylate resulted in significant apoptotic cell death in imatinib mesylate-resistant leukemia cells. Combined treatment resulted in apparent activation of caspases and decrease of the oncoprotein phosphor-Bcr/Abl in leukemia cells. Our results suggest that this combined treatment is beneficial in imatinib mesylate-resistant chronic myelogenous leukemia.

Δ 9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT 3A receptors (h5-HT 3A Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC 50 values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT 3A Rs. In these cells, CBD and THC did not stimulate specific [ 35 S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT 3A Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT 3A R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT 3A receptors through a mechanism that is dependent on receptor desensitization.

Background Although acetaminophen has been used widely and is well tolerated in children, its efficacy and safety have not been clarified when combined with an opioid in intravenous parent-/nurse-controlled postoperative analgesia. Methods Sixty-three children (aged 6-24 months) who had undergone elective ureteroneocystostomies were enrolled in this prospective, randomized, double-blinded study. After the surgery, an analgesic pump was programmed to deliver fentanyl at a basal infusion rate of 0.25 microg.kg(-1).h(-1) and 0.25 microg/kg bolus after a loading dose of 0.5 microg/kg(-1). In the fentanyl-acetaminophen group, acetaminophen was coadministered as a solution mixture at a basal infusion rate of 1.5 mg.kg(-1).h(-1) and 1.5 mg/kg bolus after a loading dose of 15 mg/kg, whereas saline was administered to the fentanyl group. Results Postoperative pain scores were similar between the two groups. The total dose (micrograms per kilogram per day, mean+/-SD) of fentanyl at postoperative days 1 (8.3+/-3.7 vs. 18.1+/-4.6, P=0.021) and 2 (7.0+/-2.4 vs. 16.6, P=0.042) was significantly less in the fentanyl-acetaminophen group compared with that in the fentanyl group. The incidences of vomiting (16.1 vs. 56.3%, P=0.011) and sedation (9.7 vs. 46.9%, P=0.019) were significantly lower in the fentanyl-acetaminophen group than those in the fentanyl group. Conclusions Acetaminophen has significant fentanyl-sparing effects and reduces side effects when combined with fentanyl in intravenous parent-/nurse-controlled analgesia for postoperative pediatric pain management.

Background: Caudal block is the most common regional technique to provide post-operative analgesia in pediatric infra-umbilical surgery. This study was designed to define how many spinal segments would be covered by the weight-based dosage of caudally administered 0.2% ropivacaine in children using the fluoroscopic method. Methods: After an approval from the institutional human research review board, in 83 ASA I boys undergoing day-case urological surgery, the distribution of ropivacaine mixed with a radioactive dye in relation to the volume injected caudally was studied. Three groups were studied: for perineal surgery 0.5 ml/kg (group C0.5), for inguinal hernia repair 1 ml/kg (group C1.0), and for orchiopexy 1.25 ml/kg (group C1.25). The dose of 0.2% ropivacaine containing radiopaque dye at a ratio of 1 : 4 was injected at a rate of 1 ml 3 s−1. Fluoroscopic examination was performed immediately to define the level of the drug spread within the extradural space. Results: The highest spinal levels [median with ranges] of spread were L2 [L4-T12] in group C0.5, T12 [L1-T8] in group C1.0, and T10 [L2-T7] in group C1.25. Analysis by age distribution (infants: 36 months) revealed a larger spread in younger patients. Conclusions: Based on the fluoroscopic findings, the weight-based doses for caudally administered 0.2% bupivacaine suggested by Armitage are also useful for ropivacaine to block the spinal level required for the different types of surgeries studied.

Summary Although the anatomy of the spinal cord and its associated structures have been well defined, the effects of body position relevant to neuraxial blockade have not been elucidated. This study was designed to determine the effect of body position on the end of the dural sac in children. After induction of anaesthesia, ultrasound examination was performed to evaluate the location of the dural sac end in the lateral position with a straight back and knee, and in the lateral position with the knees, legs, and neck flexed. The level of the end of the dural sac was determined in relation to the vertebrae. Our data demonstrate that the dural sac shifts significantly cephalad in the lateral flexed position used for neuraxial blockade (p

Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs). However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotoningated ion channels (5-HT(3A)) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. With increasing surface receptor expression, the magnitude of AEA inhibition decreased. Consistent with this idea, pretreatment with actinomycin D, which inhibits transcription, decreased the amplitude of current activated by maximal concentrations of 5-hydroxytryptamine (5-HT) and increased the magnitude of AEA inhibition. AEA did not significantly alter 5-HT(3A) receptor trafficking. However, AEA accelerated 5-HT(3A) receptor desensitization time in a concentration-dependent manner without significantly changing receptor activation and deactivation time. The desensitization time was correlated with the AEA-induced inhibiting effect and mean 5-HT current density. Applications of 5-hydroxyindole and nocodazole, a microtubule disruptor, significantly slowed 5-HT(3A) receptor desensitization and reduced the magnitude of AEA inhibition. These observations suggest that 5-HT(3) receptor density at the steady state regulates receptor desensitization kinetics and the potency of AEA-induced inhibiting effect on the receptors. The inhibition of 5-HT(3) receptors by AEA may contribute to its physiological roles in control of pain and emesis.

Study Objective To determine (1) the amount of 8.4% sodium bicarbonate (NaHCO 3 ) to adjust the pH of rocuronium to 7.4 (neutralization), (2) to show whether neutralizing the pH of rocuronium can prevent pain, and (3) to confirm that rocuronium mixed with NaHCO 3 does not change the physical property and efficacy of rocuronium. Design Prospective studies. Setting University medical center. Patients 180 ASA physical status I and II women patients undergoing elective gynecologic surgery. Interventions and Measurements 60 patients were randomly allocated to group 1 (rocuronium only), group 2 (rocuronium 50 mg mixed with 0.9% NaCl 3 mL), and group 3 (rocuronium 50 mg mixed with 8.4% NaHCO 3 3 mL). All patients received mixtures equal to 0.04 mg/kg of rocuronium and were asked to evaluate their pain with visual analog scale (VAS) and pain scores. In other settings, the onset time and duration of action of each group of rocuronium were measured. The dose of rocuronium required to produce a 50% twitch depression (ED 50 ) was calculated. Main Results The amount of 8.4% NaHCO 3 needed to neutralize 50 mg of rocuronium was 3.1 ± 0.3 mL. VAS scores were lower in group 3 than in groups 1 or 2 ( P 50 values among the groups. Conclusions Rocuronium neutralized with NaHCO 3 prevents intravenous injection pain. The physical and pharmacologic properties of rocuronium mixed with NaHCO 3 immediately before administration are not altered.

Recently, the laparoscopic surgical technique has been widely applied to major surgery as it can minimize surgical incision, reduce blood loss, and shorten hospital stay. In this study, we evaluated the effectiveness of the laparoscopic surgery on postoperative micturitional function in comparison to open surgery. Sixty patients undergoing subtotal gastrectomy were assigned to either laparoscopic (L group, n = 30) or open surgery (O group, n = 30) groups. The combined thoracic epidural-general anesthesia was performed on all patients, and epidural patient-controlled analgesia (PCA) using ropivacaine and sufentanil was maintained for two days following surgery. After surgery, visual analog pain score (VAS), levels of sensory and motor block, observer’s assessment of alertness/sedation score (OAA/S), time to first flatus, ambulation and oral intake, and micturition function were assessed. The L group showed much earlier ambulation, flatus and oral intake than the O group. Although the scores of VAS and OAA/S were not significantly different between the two groups, the micturition problem scores of the L group were lower than that of the O group (P

Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration.