Published papers

© The Japanese Society for Immunology. 2015. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) is known as a mouse model of acute respiratory distress syndrome; however, the function of T-cell-derived cytokines in ALI has not yet been established. We found that LPS challenge in one lung resulted in a rapid induction of innatetype pro-inflammatory cytokines such as IL-6 and TNF-α, followed by the expression of T-cell-type cytokines, including IL-17, IL-22 and IFN-γ. We discovered that IL-23 is important for ALI, since blockage of IL-23 by gene disruption or anti-IL-12/23p40 antibody treatment reduced neutrophil infiltration and inflammatory cytokine secretion into the bronchoalveolar lavage fluid (BALF). IL-23 was mostly produced from F4/80+CD11c+ alveolar macrophages, and IL-23 expression was markedly reduced by the pre-treatment of mice with antibiotics, suggesting that the development of IL-23-producing macrophages required commensal bacteria. Unexpectedly, among T-cell-derived cytokines, IL-22 rather than IL-17 or IFN-γ played a major role in LPS-induced ALI. IL-22 protein levels were higher than IL-17 in the BALF after LPS instillation, and the major source of IL-22 was memory Th17 cells. Lung memory CD4+ T cells had a potential to produce IL-22 at higher levels than IL-17 in response to IL-1ß plus IL-23 without TCR stimulation. Our study revealed an innate-like function of the lung memory Th17 cells that produce IL-22 in response to IL-23 and are involved in exaggeration of ALI.

© 2016, © The Author(s) 2016. Background: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. Methods: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. Results: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. Conclusion: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

© 2016 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. Background and Aim: Because neutrophil gelatinase-associated lipocalin (NGAL) is known to provide significant bacteriostatic effects during infectious conditions, we tested the hypothesis that this protein is up-regulated and secreted into the intraluminal cavity of the gut under critically ill conditions and is thus responsible for the regulation of bacterial overgrowth. Methods: With our institutional approval, male C57BL/6J mouse (6-7weeks) were enrolled and applied for lipopolysaccharide or peritonitis model compared with naïve control. We assessed NGAL protein concentrations in intestinal lumen and up-regulation of NGAL expression in intestinal tissues in in vivo as well as ex vivo settings. Simultaneously, we examined the effects of NGAL protein administration on the growth of Escherichia coli (E.coli) in in vivo and in vitro experimental settings. The localization of NGAL in intestinal tissues and lumen was also assessed by immunohistological approach using NGAL antibody. Results: Both lipopolysaccharide and peritonitis insults evoked the marked up-regulation of NGAL mRNA and protein levels in gut tissues such as crypt cells. In addition, the administration of NGAL protein significantly inhibited the outgrowth of enteric E.coli under both in vitro and in vivo conditions, accompanied by histological evidence. Conclusion: Neutrophil gelatinase-associated lipocalin protein accompanied by apparent bacteriostatic action accumulated in the intestinal wall and streamed into the mucosal layer during critically ill state, thereby possibly shaping microbiota homeostasis in the gut.

© 2019 IPSJ. Electronic anesthesia record data have been accumulated, and efforts to solve medical problems using data analysis methods and machine learning have been conducted. Post-induction hypotension frequently occurred after induction of anesthesia. Intraoperative hypotension is associated with various adverse events such as myocardial infarction and cerebral infarction. In a related study, eight machine learning methods were used to construct hypotension prediction models and evaluated by area under the curve (AUC), using data collected from an institution in the United States. Nevertheless, it was not focused on improving prediction power. This paper aims to predict post-induction hypotension with high prediction power using 1,626 electronic anesthesia record data. Our hypotension prediction model using a stacking method is introduced. F-measure 0.60 was achieved by using our method through the evaluation.

© 2019 IPSJ. Post-induction hypotension frequently occurred after anesthesia induction. Avoiding post-induction hypotension is important as it is associated with postoperative adverse outcomes. Related studies have shown that the dose of anesthetic induction drugs affects the post-induction hypotension. The purpose of this study is to propose an anesthetic dose that does not cause post-induction hypotension according to the patient's condition. A model for predicting the optimal dose of an anesthetic induction drug is constructed using a regression model which is one of machine learning methods by focusing on electronic anesthesia records. The prediction coefficient of determination 0.5008 was achieved by adjusting the explanatory variables and parameters and using ridge regression.

© 2017 European Pain Federation - EFIC® Background: This prospective study was designed to examine the associations of demographic, clinical, psychological and neuroendocrine factors with acute and chronic post-operative pain following partial mastectomy. Methods: Sixty-four female patients scheduled for partial mastectomy were enrolled. Pre-operative anxiety/depression was assessed, using the Hospital Anxiety and Depression Scale (HADS). Pre-operative 24-h urinary cortisol levels were measured 2 days before surgery. Post-operative pain was examined using a visual analog scale (VAS) for acute pain on 0–2 post-operative day (POD), and a short-form McGill Pain Questionnaire for chronic pain at 6 months after surgery. In the last 29 subjects, post-operative 24-h urinary cortisol levels were also measured on 0 POD and were subjected to correlation analysis. Results: Multivariate logistic regression analysis revealed that lower pre-operative cortisol secretion and greater pre-operative anxiety were significantly associated with an increased risk of moderate to severe acute post-operative pain [Odds Ratio (95% Confidence Interval); 0.96 (0.92–0.98), and 1.24 (1.04–1.54)], and that patients with greater pre-operative anxiety and moderate to severe acute pain were more likely to develop chronic post-operative pain [OR (95% CI); 1.63 (1.23–2.40), and 5.07 (1.30–24.6)]. Correlational analysis demonstrated that the post-operative cortisol level was inversely correlated with pre-operative anxiety and the intensity of acute post-operative pain (r = −0.40, p < 0.05, and r = −0.50, p < 0.01), but not with the intensity of chronic pain. Conclusions: This study confirms that pre-operative anxiety is associated with both acute and chronic post-operative pain after partial mastectomy. It also suggests that lower perioperative cortisol secretion might be associated with greater acute post-operative pain. Significance: Although the associations between psychological stress/stress hormone levels and chronic post-operative pain remain to be determined, pre-operative psychological stress and perioperative cortisol levels are correlated with acute post-operative pain.

© 2020, Japanese Society of Anesthesiologists. Ringer's ethyl pyruvate solution (REPS) has been protective against experimental renal, intestinal, and spinal ischemia and may be useful for organ protection in major vascular surgery. The purpose of this study was to investigate whether REPS attenuates organ injury in a rabbit model of supraceliac aortic cross-clamp that simulates thoracoabdominal aortic surgery. Following the Institutional Animal Care and Use Committee’s approval, 20 rabbits were undergone cross-clamping of the supraceliac thoracic aorta for 30 min, and observed for 180 min after reperfusion. Either REPS (33 mg/kg/h of ethyl pyruvate) or Ringer's lactate solution were infused throughout the study period. Arterial pressure and aortic blood flow were continuously monitored. Blood lactate concentration, serum transaminase levels, neutrophil activation, and urinary N-acetyl-beta-glucosaminidase (NAG) activity were evaluated. After reperfusion, supraceliac aortic blood flow was significantly higher, and urinary NAG was significantly lower in animals that received REPS, while the other parameters were not significantly different. In conclusion, REPS attenuated the reduction of aortic blood flow and urinary NAG elevation after the cross-clamp of supraceliac aorta.

© 2020, Japanese Society of Anesthesiologists. Purpose: Remimazolam, an ultra-short-acting benzodiazepine sedative is equally effective as propofol in induction and maintenance of general anesthesia with improved hemodynamic stability in American Society of Anesthesiologists (ASA) Class I and II patients. This trial investigated remimazolam’s efficacy and safety in vulnerable patients (ASA Class III) undergoing elective general surgery. Methods: A multicenter, randomized, double-blind, parallel-group trial in 67 adult surgical patients undergoing general anesthesia with two remimazolam induction doses (6 mg kg−1 h−1—group A and 12 mg kg−1 h−1—group B) has been conducted in 6 trials sites in Japan. Remimazolam was infused up to 2 mg kg−1 h−1 for maintenance of anesthesia in both groups. Results: The functional anesthetic capability of the investigated drug was 100% in both arms. The mean time to loss of consciousness (LoC) was significantly shorter in group B (81.7 s) compared to group A (97.2 s), p = 0.0139. The mean bispectral index (BIS) value during maintenance of anesthesia ranged from 46.0 to 68.0 and from 44.7 to 67.5 in group A and B, respectively. There was no statistically significant difference between the remimazolam arms concerning the incidence of blood pressure (BP) decrease (67.7% in group B vs. 54.8% in group A), recovery profile or the incidence or severity of adverse events (AEs) or adverse drug reactions (ADRs). Conclusion: Both induction regimens (6 and 12 mg kg−1 h−1) were equally efficacious and safe in surgical patients ASA Class III. A significantly shorter time to LoC was observed with the higher remimazolam dosage. Clinical trial registration This trial is registered with the Japan Pharmaceutical Information Center—Clinical Trials Information (JapicCTI). JapicCTI number: 121977.

© 2017 The Author(s). Despite recent advances in medical care, mortality due to sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains high. Fluid resuscitation and vasopressors are the first-line treatment for sepsis in order to optimize hemodynamic instability caused by vasodilation and increased vascular permeability. However, these therapies, aimed at maintaining blood pressure and blood flow to vital organs, could have deleterious cardiac effects, as cardiomyocyte damage occurs in the early stages of sepsis. Recent experimental and clinical studies have demonstrated that a number of factors contribute to sepsis-induced cardiac dysfunction and the degree of cardiac dysfunction is one of the major prognostic factors of sepsis. Therefore, strategies to prevent further cardiomyocyte damage could be of crucial importance in improving the outcome of sepsis. Among many factors causing sepsis-induced cardiac dysfunction, sympathetic nerve overstimulation, due to endogenous elevated catecholamine levels and exogenous catecholamine administration, is thought to play a major role. β-adrenergic blockade therapy is widely used for ischemic heart disease and chronic heart failure and in the prevention of cardiovascular events in high-risk perioperative patients undergoing major surgery. It has also been shown to restore cardiac function in experimental septic animal models. In a single-center randomized controlled trial, esmolol infusion in patients with septic shock with persistent tachycardia reduced the 28-day mortality. Furthermore, it is likely that β-adrenergic blockade therapy may result in further beneficial effects in patients with sepsis, such as the reduction of inflammatory cytokine production, suppression of hypermetabolic status, maintenance of glucose homeostasis, and improvement of coagulation disorders. Recent accumulating evidence suggests that β-adrenergic blockade could be an attractive therapy to improve the prognosis of sepsis. We await a large multicenter randomized clinical trial to confirm the beneficial effects of β-adrenergic blockade therapy in sepsis, of which mortality is still high.

© 2017 American Society for Microbiology. Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxiainducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.

© 2019 Ihara et al. Chronic neck pain (CNP), a global health problem, involves a large amount of psychological and socioeconomic burdens. Not only physical causes but also behavioral disorders such as a fear-avoidance belief (FAB) can associate with the chronicity of neck pain. However, functional brain mechanisms underlying CNP and its related behavioral disorders remain unknown. The aim of the current resting-state functional magnetic resonance imaging (fMRI) study was to explore how the functional brain networks differed between CNP patients and age- and sex-matched healthy, pain-free controls (HCs). We also investigated whether these possible brain network changes in CNP patients were associated with fear avoidance belief (FAB) and the intensity of pain. We analyzed the resting-state fMRI data of 20 CNP patients and 20 HCs. FAB and the intensity of pain were assessed by Tampa Scale for Kinesiophobia (TSK) and Visual Analog Scale (VAS) of pain. The whole brain analysis showed that CNP patients had significant different functional connectivity (FC) compared with HCs, and the right dorsolateral prefrontal cortex (DLPFC) was a core hub of these altered functional networks. Furthermore, general linear model analyses showed that, in CNP patients, the increased FC between the right DLPFC and the right anterior insular cortex (aIC) significantly associated with increased TSK (p = 0.01, statistical significance after Bonferroni correction: p<0.025), and the FC between the right DLPFC and dorsal posterior cingulate cortex had a trend of inverse association with VAS (p = 0.04). Our findings suggest that aberrant FCs between the right DLPFC and aIC associated with CNP and its related FAB.

© 2019, The Author(s). Chronic pain (CP) is a global problem extensively associated with an unhealthy lifestyle. Time discounting (TD), a tendency to assign less value to future gains than to present gains, is an indicator of the unhealthy behaviors. While, recent neuroimaging studies implied overlapping neuro mechanisms underlying CP and TD, little is known about the specific relationship between CP and TD in behavior or neuroscience. As such, we investigated the association of TD with behavioral measures in CP and resting-state brain functional network in both CP patients and healthy subjects. Behaviorally, TD showed a significant correlation with meaningfulness in healthy subjects, whereas TD in patients only correlated with pain intensity. We identified a specific network including medial and dorsolateral prefrontal cortex (PFC) in default mode network (DMN) associated with TD in healthy subjects that showed significant indirect mediation effect of meaningfulness on TD. In contrast, TD in patients was correlated with functional connectivity between dorsolateral PFC (DLPFC) and temporal lobe that mediated the effect of pain intensity on TD in patients. These results imply that TD is modulated by pain intensity in CP patients, and the brain function associated to TD is shifted from a medial to lateral representation within the frontal regions.

© 2015 Signa Vitae. All rights reserved. It remains unknown whether application of nasal high flow (NHF) is effective after liberation from non-invasive ventilation (NIV). This study was aimed at investigating the effect of NHF in patients ready for weaning from NIV. With institutional ethic committee approval, patients receiving NIV due to hypoxemic respiratory failure for more than 24 hours were enrolled. After passing the weaning criteria with continuous positive airway pressure (CPAP) mode [fraction of inspiratory oxygen (FIO2) ≦0.5, positive end expiratory pressure (PEEP) 4 cmH2O], patients received NHF (Flow 50 L/min, FIO2 ≦0.5) immediately after liberation from NIV. Before the initiation of the study, eight sequential patients who received oxygen via face mask after NIV treatment, served as the historical control. Respiratory parameters [partial pressure of arterial oxygen (PaO2) to FIO2 ratio (P/F ratio), respiratory rate (RR)] 1 hour after liberation from NIV were evaluated with those during NIV as the primary outcome. The frequency of rescue NIV therapy, intubation, and respiratory failure were also recorded. Nine eligible patients received NHF therapy after liberation from NIV. P/F ratio and RR did not change significantly compared with those during NIV (231 ± 43.6 versus 250.7 ± 34.2 mmHg, 20.8 ± 2.3 versus 21 ± 1.6/min), while P/F ratio decreased significantly in the historical control group (194.3 ± 20.1 versus 255.9 ± 58.1 mmHg, p=0.013). Rescue NIV therapy, intubation, and respiratory failure never occurred in the NFH group, although two patients received NIV rescue therapy, of whom one was intubated in the historical control. NHF after liberation from NIV might be effective in patients recovering from hypoxemic respiratory failure. Registration number: UMIN000014133 (UMIN-CTR).

© 2019 Takeshi Suzuki et al. Lymphocyte cell death contributes to sepsis-induced immunosuppression, leading to poor prognosis. This study examined whether sepsis severity and beta-blocker therapy could affect the degree of T-lymphocyte cell death in a mouse model of sepsis. In the first control study, 20 animals were allocated to 4 groups: control group with sham operation (group C, n = 5) and 3 groups with cecum ligation and puncture (CLP) performed at 3 different sites: proximal, middle, and distal cecum (groups CLP-P, CLP-M, and CLP-D, respectively; n = 5 in each group). Their spleens were resected under general anesthesia 24 hours after CLP, and the total number of normal splenic T lymphocytes per mouse and the percentage of apoptotic T lymphocytes were evaluated using flow cytometry. In the second experimental study, the effect of the beta-blocker esmolol was examined in CLP-P (group CLP-PE vs. CLP-P; n = 5 in each group). The total normal splenic T-lymphocyte numbers per mouse significantly decreased in proportion to CLP severity (group C, 18.6 × 106 (15 × 106-23.6 × 106); CLP-D, 9.2 × 106 (8.8 × 106-9.8 × 106); CLP-M, 6.7 × 106 (6.3 × 106-7.0 × 106); and CLP-P, 5.3 × 106 (5.1 × 106-6.8 × 106)). Beta-blocker therapy restored T-lymphocyte numbers (group CLP-PE vs. CLP-P; 6.94 ± 1.52 × 106 vs. 4.18 ± 1.71 × 106; p=0.027) without affecting apoptosis percentage. Beta-blocker therapy might improve sepsis-induced immunosuppression via normal splenic T-lymphocyte preservation.

© 2018 Kokuseido Publishing Co. Ltd. All rights reserved. Background: Few prospective study examined the optimal postoperative opioid dose setting for chronically opioid consuming patients. We prospectively investigated whether postoperative pain control based on the equianalgesic conversion of the preoperative opioid dose is a safe and adequate way of relieving postoperative pain in patients with chronic opioid use. Methods: The patients were allocated into the high dose group (HG) or the low dose group (LG) according to their preoperative doses of opioid. After surgery, the patients received intravenous morphine using a patient-controlled analgesia (PCA) pump which was set based on their preoperative opioid dose. The numerical rating scale (NRS) pain score, 24 hr cumulative morphine consumption, and the incidence of adverse events were compared between the groups. Results: A total of seventeen patients (HG I n=9, LG; n=8) were enrolled. The worst NRS pain score was significantly higher in HG than in LG. No serious adverse events due to overdose occurred in either group. Conclusions: Our PCA regimen appears to be safe overall; however it is still inadequate for relieving postoperative pain in patients taking high preoperative opioid doses.

© 2018 Kokuseido Publishing Co. Ltd. All rights reserved. Despite recent advances in surgical techniques and perioperative management, the rate of perioperative complications after esophagectomy, one of major surgical interventions, remains high compared to those of other surgical procedures. Respiratory complications are often observed and sometimes serious and life-threatening unless treated appropriately. Thus, certain prevention and adequate treatment of perioperative respiratory complications during perioperative periods are imperative to improve the outcome of patients with esophageal cancer. Prior to surgery, smoking cessation is extremely important to reduce the risk of respiratory complications. Moreover, preoperative oral care has been shown to prevent postoperative pneumonia During surgery, lung protective strategy and goal-directed fluid management have been reported to prevent the development of acute lung injury and to reduce postoperative respiratory complications. Postoperatively, sufficient analgesia and early mobilization therapy could promote recovery of respiratory function after esophagectomy. Compared with conventional oxygen therapy, nasal high-flow therapy might promote better recovery of respiratory functions owing to clearance of tracheal secretions, additional positive end-expiratory pressure, and reduced work of breathing.