Comparison of Nocifensive Behavior in NaV1.7-, NaV1.8-, and NaV1.9-Channelrhodopsin-2 Mice by Selective Optogenetic Activation of Targeted Sodium Channel Subtype-Expressing Afferents.

Voltage-gated sodium channels, including NaV1.7, NaV1.8, and NaV1.9, play important roles in pain transmission and chronic pain development. However, the specific mechanisms of their action remain unclear, highlighting the need for in vivo stimulation studies of these channels. Optogenetics, a novel technique for targeting the activation or inhibition of specific neural circuits using light, offers a promising solution. In our previous study, we used optogenetics to selectively excite NaV1.7-expressing neurons in the dorsal root ganglion of mice to induce nocifensive behavior. Here, we further characterize the impact of nocifensive behavior by activation of NaV1.7, NaV1.8, or NaV1.9-expressing neurons. Using CRISPR/Cas9-mediated homologous recombination, NaV1.7-iCre, NaV1.8-iCre, or NaV1.9-iCre mice expressing iCre recombinase under the control of the endogenous NaV1.7, NaV1.8, or NaV1.9 gene promoter were produced. These mice were then bred with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain NaV1.7-ChR2, NaV1.8-ChR2, or NaV1.9-ChR2 mice. Blue light exposure triggered paw withdrawal in all mice, with the strongest response in NaV1.8-ChR2 mice. These light sensitivity differences observed across NaV1.x-ChR2 mice may be dependent on ChR2 expression or reflect the inherent disparities in their pain transmission roles. In conclusion, we have generated noninvasive pain models, with optically activated peripheral nociceptors. We believe that studies using optogenetics will further elucidate the role of sodium channel subtypes in pain transmission.

Measuring intraoperative anesthetic parameters during hepatectomy with inferior vena cava clamping.

PURPOSE: Uncontrollable bleeding remained problematic in anatomical hepatectomy exposing hepatic veins. Based on the inferior vena cava (IVC) anatomy, we attempted to analyze the hemodynamic and surgical effects of the combined IVC-partial clamp (PC) accompanied with the Trendelenburg position (TP). METHODS: We prospectively assessed 26 consecutive patients who underwent anatomical hepatectomies exposing HV trunks between 2020 and 2023. Patients were divided into three groups: use of IVC-PC (group 1), no use of IVC-PC (group 2), and use of IVC-PC accompanied with TP (group 3). In 10 of 26 patients (38%), hepatic venous pressure was examined using transhepatic catheter insertion. RESULTS: IVC-PC was performed in 15 patients (58%). Operating time and procedures did not significantly differ between groups. A direct hemostatic effect on hepatic veins was evaluated in 60% and 70% of patients in groups 1 and 3, respectively. Group 1 showed significantly more unstable vital status and vasopressor use (p < 0.01). Blood or fluid transfusion and urinary output were similar between groups. Group 2 had a significantly lower baseline central venous pressure (CVP), while group 3 showed a significant increase in CVP in TP. CVP under IVC-PC seemed lower than under TP; however, not significantly. Hepatic venous pressure did not significantly differ between groups. Systolic arterial blood pressure significantly decreased via IVC-PC in group 1 and to a similar extent in group 3. Heart rate significantly increased during IVC-PC (p < 0.05). CONCLUSION: IVC-PC combined with the TP may be an alternative procedure to control intrahepatic venous bleeding during anatomical hepatectomy exposing hepatic venous trunks.

Changes in TRPV1 Receptor, CGRP, and BDNF Expression in Rat Dorsal Root Ganglion with Resiniferatoxin-Induced Neuropathic Pain: Modulation by Pulsed Radiofrequency Applied to the Sciatic Nerve.

Pulsed radiofrequency (PRF) is a safe method of treating neuropathic pain by generating intermittent electric fields at the needle tip. Resiniferatoxin (RTX) is an ultrapotent agonist of transient receptor potential vanilloid subtype-1 (TRPV1) receptors. We investigated the mechanism of PRF using a rat model of RTX-induced neuropathic pain. After administering RTX intraperitoneally, PRF was applied to the right sciatic nerve. We observed the changes in TRPV1, calcitonin gene-related peptide (CGRP), and brain-derived neurotrophic factor (BDNF) in the dorsal root ganglia by western blotting. Expressions of TRPV1 and CGRP were significantly lower in the contralateral (RTX-treated, PRF-untreated) tissue than in control rats (p<0.0001 and p<0.0001, respectively) and the ipsilateral tissues (p<0.0001 and p<0.0001, respectively). BDNF levels were significantly higher in the contralateral tissues than in the control rats (p<0.0001) and the ipsilateral tissues (p<0.0001). These results suggest that, while TRPV1 and CGRP are decreased by RTX-induced neuronal damage, increased BDNF levels result in pain development. PRF may promote recovery from neuronal damage with concomitant restoration of TRPV1 and CGRP, and exert its analgesic effect by reversing BDNF increase. Further research is required to understand the role of TRPV1 and CGRP restoration in improving mechanical allodynia.

Questionnaire survey of virtual reality experiences of digestive surgery at a rural academic institute: A pilot study for pre-surgical education.

We developed a prototype VR platform, VECTORS L&M (VLM), aiming to enhance the understanding of digestive surgery for students, interns, and young surgeons by limiting costs. Its efficacy was assessed via questionnaires before implementation in surgical education. The VLM provides nine-minute VR views of surgeries, from both 180- and 360-degree angles. It was created with L.A.B. Co., Ltd. and incorporates surgery videos from biliary malignancy patients. Following VLM development, a survey was conducted among surgeons who had experienced it. Twenty-eight participants (32% of observers) responded to the survey. A majority (81%) reported positive experiences with the VR content and showed interest in VR video production, though some reported sickness. Most respondents were experienced surgeons, and nearly all believed VR was important for medical education with a mean score of 4.14 on a scale of up to 5. VR was preferred over 3D printed models due to its application versatility. Participants expressed the desire for future VR improvements, such as increased mobility, cloud connectivity, cost reduction, and better resolution. The VLM platform, coupled with this innovative teaching approach, offers experiential learning in intraabdominal surgery, effectively enriching the knowledge of students and surgeons ahead of surgical education and training.

Epidural Anesthesia and Continuous Epidural Analgesia in a Pediatric Patient With Pelizaeus-Merzbacher Disease: A Case Report.

Pelizaeus-Merzbacher disease (PMD) is a genetic leukodystrophy, which is a progressive and degenerative central nervous system abnormality caused by dysmyelination. Because the incidence of PMD is extremely low, only a few case reports have been published regarding its anesthetic management. In particular, epidural anesthesia has only been reported in one case of general anesthesia combined with caudal anesthesia. We performed general anesthesia combined with epidural anesthesia for the soft-tissue release surgery for bilateral hip subluxation in a six-year-old male patient diagnosed with PMD. General anesthesia was induced with sevoflurane in nitrous oxide and oxygen. Rocuronium was administered to facilitate tracheal intubation. After intubation, general anesthesia was maintained with sevoflurane in the air and oxygen. An epidural catheter was placed from L3/4. For epidural anesthesia and analgesia, 1% mepivacaine was used as needed, and 2 ml/h of 0.2% ropivacaine was started one hour before the end of surgery. During surgery, only epidural analgesia was provided as postoperative analgesia, and the patient did not complain of pain after extubation. Anesthesia lasted three hours and 55 minutes. No significant hemodynamic or respiratory changes occurred. Postoperatively, the patient received continuous epidural analgesia and regular oral acetaminophen, and pain control was good. The epidural catheter was removed on the second postoperative day. The postoperative course was good, and the patient was transferred to a pediatric rehabilitation hospital on the fifth postoperative day. No adverse events occurred and no neurological deficits were observed during hospitalization. In conclusion, anesthesiologists should pay attention to the possibility of perioperative aspiration, spasticity, and seizure, even with mild PMD. Proper preoperative evaluations, intraoperative monitoring, and anesthetic techniques will ensure safe anesthesia for PMD patients. Although regional anesthesia in patients with pre-existing neurologic deficits is controversial, we were able to safely perform epidural anesthesia and postoperative continuous epidural analgesia in a pediatric patient with PMD.

Selective optogenetic activation of NaV1.7-expressing afferents in NaV1.7-ChR2 mice induces nocifensive behavior without affecting responses to mechanical and thermal stimuli.

In small and large spinal dorsal root ganglion neurons, subtypes of voltage-gated sodium channels, such as NaV1.7, NaV1.8, and NaV1.9 are expressed with characteristically localized and may play different roles in pain transmission and intractable pain development. Selective stimulation of each specific subtype in vivo may elucidate its role of each subtype in pain. So far, this has been difficult with current technology. However, Optogenetics, a recently developed technique, has enabled selective activation or inhibition of specific neural circulation in vivo. Moreover, optogenetics had even been used to selectively excite NaV1.8-expressing dorsal root ganglion neurons to induce nocifensive behavior. In recent years, genetic modification technologies such as CRISPR/Cas9 have advanced, and various knock-in mice can be easily generated using such technology. We aimed to investigate the effects of selective optogenetic activation of NaV1.7-expressing afferents on mouse behavior. We used CRISPR/Cas9-mediated homologous recombination to generate bicistronic NaV1.7-iCre knock-in mice, which express iCre recombinase under the endogenous NaV1.7 gene promoter without disrupting NaV1.7. The Cre-driver mice were crossed with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain NaV1.7iCre/+;Ai32/+, NaV1.7iCre/iCre;Ai32/+, NaV1.7iCre/+;Ai32/Ai32, and NaV1.7iCre/iCre;Ai32/Ai32 mice. Compared with wild-type mice behavior, no differences were observed in the behaviors associated with mechanical and thermal stimuli exhibited by mice of the aforementioned genotypes, indicating that the endogenous NaV1.7 gene was not affected by the targeted insertion of iCre. Blue light irradiation to the hind paw induced paw withdrawal by mice of all genotypes in a light power-dependent manner. The threshold and incidence of paw withdrawal and aversive behavior in a blue-lit room were dependent on ChR2 expression level; the strongest response was observed in NaV1.7iCre/iCre;Ai32/Ai32 mice. Thus, we developed a non-invasive pain model in which peripheral nociceptors were optically activated in free-moving transgenic NaV1.7-ChR2 mice.

Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells.

Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.

Effect of cryoprecipitate on an increase in fibrinogen level in patients with excessive intraoperative blood loss: a single-center retrospective study.

BACKGROUND: Cryoprecipitate, which contains fibrinogen and factor VIII in large quantities, is concentrated from fresh frozen plasma, and it has hemostatic effects in severe bleeding. We retrospectively examined the effects of cryoprecipitate on the increase in fibrinogen levels in patients with excessive intraoperative blood loss. METHODS: Ninety-seven patients who were administered cryoprecipitate during surgery between June 2014 and May 2019 were enrolled in our study and categorized according to the volume of intraoperative blood loss as follows: group A, 2000-5000 mL; group B, 5000-10,000 mL; group C, > 10,000 mL. Data were extracted from electronic medical records and electronic anesthesia records. The primary endpoint was an increase in the fibrinogen level after the administration of cryoprecipitate. RESULTS: Nine patients with no fibrinogen data and four patients with a bleeding volume of less than 2000 mL were excluded; thus, 84 patients (A: n = 36, B: n = 37, C: n = 11) were evaluated. The mean intraoperative blood loss (mL) in groups A, B, and C were 3348 ± 791, 6688 ± 1225, and 14,281 ± 5142, respectively. The fibrinogen levels (mg/dL) before cryoprecipitate administration in groups A, B, and C were 189 ± 94, 113 ± 42, and 83 ± 29, respectively (p < 0.05 among the groups). The increase in fibrinogen level (mg/dL) after cryoprecipitate administration in group C was significantly greater than that in group A (84 ± 34 versus 50 ± 36, p < 0.01). CONCLUSIONS: The results of this study indicate that the effect of cryoprecipitate on the increase in fibrinogen level was most apparent in patients with excessive intraoperative blood loss ≥ 10,000 mL. In addition, most patients with intraoperative blood loss ≥ 5000 mL had fibrinogen levels < 150 mg/dL which improved to ≥ 150 mg/dL after cryoprecipitate administration in approximately 70% of patients. Therefore, cryoprecipitate administration should be considered for patients with hypofibrinogenemia (≤ 150 mg/dL) experiencing severe bleeding (e.g., ≥ 5000 mL) and rapid administration of cryoprecipitate is necessary to maximize the hemostatic effect, especially when the bleeding volume exceeds 10,000 ml.

Extracellular signal-regulated kinase phosphorylation enhancement and NaV1.7 sodium channel upregulation in rat dorsal root ganglia neurons contribute to resiniferatoxin-induced neuropathic pain: The efficacy and mechanism of pulsed radiofrequency therapy.

Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.

Rapid response system in Japanese outpatient departments based on online registry: Multicentre observational study.

AIM: The rapid response system (RRS) has become well known as a patient safety system to reduce adverse in-patient events, and it is also required to respond to patients in the outpatient department. However, only few studies have reported on the RRS in the outpatient department. We analysed the current status of the RRS in the outpatient department based on a multicentre online registry in Japan. METHODS: This is a prospective multicentre observational study. Among the cases registered in the RRS online registry from January 2014 to March 2018, cases from the outpatient department, consisting of the general outpatient department, radiation department, dialysis department, endoscope department, rehabilitation department, and the surrounding areas were eligible for this study. RESULTS: A total of 6784 cases were registered, and 1022 cases were included. The main reason for activation was altered mental status (39.1%). Incomplete vital sign recording at activation was 67.0%, whereas body temperature (57.0%) and respiratory rate (36.4%) deficits were frequent. The most common intervention during RRS activation was fluid bolus (38.2%) and oxygen supplementation (30.9%). The general outpatient department accounted for nearly half of the activation locations. The 30-day mortality rate for the location was significantly higher in the dialysis department (P < 0.001). CONCLUSIONS: We have reported the first study of RRSs in outpatient departments at multicentre facilities in Japan. The difference in the mortality rate for the location was clarified. Future tasks will involve clarifying the RRS outcome indicators in the outpatient department and examining the effectiveness thereof.

Relationship between hepatic venous anatomy and hepatic venous blood loss during hepatectomy.

PURPOSE: Predicting increased blood loss based on anatomical intervascular relationships is essential in major hepatectomy. METHODS: We assessed 63 consecutive patients undergoing anatomical hepatectomy exposing the hepatic vein (HV) trunk at two institutes. Correlations between anatomical alterations of the hepatic inferior vena cava (IVC), HV, hepatic IVC, or right atrium (RA) and the blood loss per standard weight (BLSW) or blood transfusion (n = 18) were analyzed. The results of IVC partial clamping (PC) were additionally examined. RESULTS: The BLSW in type V-up anatomical morphology was significantly higher than that in straight type (p < 0.05). The parameters associated with an increased BLSW (> 13.5 mL/kg) were tumor size (> 4 cm), prothrombin activity (< 87%), CVP (> 7 mmHg), area of suprahepatic IVC (< 360 mm2), IVC-RA gap (> 28 mm), longitudinal angle of IVC (< 160°), and axial angle of the MHV (< 55°). A multivariate analysis revealed that a high IVC-RA gap was a significant independent risk factor (odds ratio; 4.32, p < 0.05). Among 25 patients undergoing IVC-PC, only three showed a remarkable decrease in hepatic venous bleeding. No other statistically significant differences in the surgical records were observed in most cases. CONCLUSION: The IVC-RA gap might be a promising novel predictive parameter reflecting increased blood loss leading to blood transfusion in anatomical hepatectomy.

The usefulness of plasma levels of mature and total adrenomedullin as biomarkers indicating the magnitude of surgical stress responses: A single-center, prospective, observational study.

BACKGROUND AND AIM: Adrenomedullin (AM), a vasodilatory peptide, is known for its pleiotropic actions. AM levels are increased under inflammatory conditions such as sepsis and can be useful as a prognostic biomarker. However, there are only a few reports on the physiological actions of AM in the perioperative period. The aim of this single-center, prospective, and observational study was to investigate the changes in the plasma levels of mature AM (mAM) and total AM (tAM) observed during the perioperative period. In addition, we aimed to determine the association between each AM level and immune-inflammatory parameters to explore the usefulness of AM as a biomarker of the magnitude of surgical stress responses. METHODS: The levels of both mAM and tAM, in addition to the levels of presepsin, interleukin-6, procalcitonin, white blood cell, and C-reactive protein, were measured in blood samples obtained during the perioperative period. Other laboratory data, including sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II scores, were obtained from individual clinical records. Correlations between each AM and clinical parameters were determined using Spearman's rank correlation. P<0.05 were considered statistically significant. RESULTS: One hundred and twenty-three perioperative patients scheduled for three types of surgical procedures, including cardiopulmonary bypass surgery, abdominal surgery, and cervical laminoplasty, were included in this study. There was a moderate to strong correlation between each AM and immune-inflammatory parameters, SOFA score, and APACHE II score, as related to surgical trauma. Specifically, the strongest correlation was observed between each AM and SOFA score. CONCLUSIONS: These findings suggest that plasma AM levels may represent the most important inflammatory mediators that are evident in surgical stress responses. RELEVANCE FOR PATIENTS: Since the levels of both tAM and mAM show the same trend, mAM and tAM may be equally used as biomarkers for the evaluation of the physiological status of surgical patients. TRIAL REGISTRATION: This observational study was retrospectively registered with Japanese Clinical Trial Registry "UMIN-CTR" on March 19, 2018, and was given a trial ID number UMIN000031792.

The validation of a Japanese language version of the postoperative quality of recovery scale: a prospective observational study.

BACKGROUND: The Postoperative Quality of Recovery Scale (PostopQRS) is a survey-based tool that measures quality of the postoperative recovery in multiple domains over multiple time periods. The purpose of this study is to validate the Japanese version of the PostopQRS. METHODS: A prospective observational study using bilingual healthy volunteers was conducted in Australia to assess equivalence of the test values between the two languages. To assess the feasibility and discriminant validity of the PostopQRS in a Japanese population, an observational study was conducted on patients undergoing ear-nose-throat and orthopedic surgery in Japan, with measurements performed prior to surgery, 2 h, and 1, 3, and 7 days following surgery. The survey was conducted face-to-face while in hospital and via the telephone following discharge. RESULTS: Sixty-eight volunteers participated in the validation study. The scores in the Japanese version were similar to the English version in all domains at all timepoints. In the cognitive domain, there were no differences between the Japanese and English versions for word recall and word generation tasks. For digits forwards and digits backwards the values were skewed to the maximal value, and although significantly different, the absolute difference was <10% at all timepoints between English and Japanese versions. Fifty-one patients, ear-nose-throat (n=22) and orthopedic (n=29), were included in the clinical study. Orthopedic patients had a significantly worse recovery profile over time in overall recovery (p<0.01), physiological (p=0.02), nociceptive (p=0.03), and activities of daily living (ADL, p<0.01) domains, but was not different for emotive (p=0.30) or cognitive domains (p=0.10). CONCLUSION: The Japanese version of the PostopQRS is similar to the English version and was able to discriminate recovery between different surgery disciplines. TRIAL REGISTRATION: UMIN, UMIN000033268 , Registered 6 August 2018.

Comparison of opioid local anesthetic combination regimens using the number of self-administrated boluses in patient-controlled epidural analgesia after cesarean section: A retrospective single-center study.

ABSTRACT: The aim of this study was to assess the efficacy of combined opioids by comparing four regimens of patient-controlled epidural analgesia (PCEA) after cesarean section.Parturient patients who underwent elective or emergent cesarean section under combined spinal and epidural anesthesia from April 2013 to March 2016 were retrospectively analyzed. Based on PCEA, they were assigned to one of 4 groups: local anesthetic alone (LA), epidural single morphine administration during surgery followed by local anesthetic alone (M), local anesthetic combined with fentanyl 10 µg/h (F10), or local anesthetic combined with fentanyl 20 µg/h (F20). The primary outcome was the number of PCEA boluses used. Secondary outcomes included the use of rescue analgesia, postoperative nausea and vomiting, and postoperative pruritus.A total of 250 parturients were analyzed. Whereas the number of PCEA boluses in the LA group was significantly higher than in the other combined opioid groups on the day of surgery and postoperative day 1 (LA: 3 [1-6] and 7 [4-9] vs M: 2 [0-4] and 4 [0-7] vs F10: 1 [0-4] and 3 [0-6] vs F20: 1 [0-3] and 2 [0-8], P = .012 and 0.010, respectively), within the combined opioid groups, the number was not significantly different. Significantly fewer patients in the F20 group required rescue analgesia on postoperative day 1 and 2 (25 and 55%) than those in the M (66 and 81%) and F10 (62 and 66%) groups (P < .001 and P = .007, respectively). Postoperative nausea and vomiting and pruritus were significantly higher in the M group (P < .008 and P = .024, respectively).The results of the present study suggest that local anesthetic alone after a single administration of morphine, or local anesthetic combined with fentanyl 10 µg/h would generally be adequate for PCEA, whereas local anesthetic combined with fentanyl 20 µg/h would be suitable for conventional epidural analgesia.

The diagnostic and prognostic value of mature and total adrenomedullin for sepsis: a prospective observational study.

INTRODUCTION: Information about biologically active adrenomedullin (mature AM), a potential new biomarker for sepsis and septic shock, is limited. Here, we investigated the value of mature AM for diagnosis and outcome prediction in sepsis. MATERIAL AND METHODS: Patients admitted to the intensive care unit (ICU) were retrospectively cate-gorised into non-sepsis or sepsis groups, according to the Sepsis-3 definitions. Plasma levels of mature and total (the sum of the levels of intermediate and mature forms) AM were measured, and their usefulness was compared with that of other sepsis biomarkers, such as procalcitonin and presepsin. RESULTS: Of the 98 patients analysed, 42 were assigned to the non-sepsis and 56 to the sepsis group. Mature and total AM levels on admission were significantly higher in patients with than in those without sepsis. The areas under the receiver operating characteristic curves (AUCs) of mature and total AM for diagnosing sepsis were 0.85 and 0.88, whereas those of procalcitonin and presepsin were 0.83 and 0.68, respectively. AUCs of mature and total AM for predicting 28-day mortality in patients with sepsis became significant on day 3 after admission. A good correlation between the AM forms was found, indicating that changes in their plasma levels may directly reflect each other. CONCLUSIONS: Because mature and total AM levels increased significantly in patients with sepsis on admission, both forms may be used as reliable and early biomarkers for diagnosing sepsis according to the Sepsis-3 definitions. However, prediction of 28-day mortality in such patients would require several days of ICU stay.

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain.

Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 µg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.

Effectiveness of Soluble Recombinant Human Thrombomodulin in Patients with Severe Acute Pancreatitis Complicated by Disseminated Intravascular Coagulation.

OBJECTIVE: We aimed to evaluate retrospectively the effect of soluble recombinant human thrombomodulin (rTM) on prognosis in patients with severe acute pancreatitis complicated by disseminated intravascular coagulation (DIC). METHODS: Based on Japanese diagnostic criteria of acute pancreatitis and DIC, patients who entered our intensive care unit (ICU) were selected. Comparisons were made between patients treated with rTM (rTM group) and without rTM (control group). RESULTS: A total of 38 patients were selected, and rTM was administered to 13 patients. Mortality on the 60th day after entering the ICU was significantly lower in the rTM group (15%) as compared with the control group (56%) (p=0.036). Although the platelet count was significantly lower in the rTM group at the start of treatment, the reversal rate from DIC was significantly higher than in the control group (rTM 62%, control 24%, p=0.035). According to logistic regression analysis of therapeutics, only rTM contributed to survival on the 60th day (odds ratio, 12.5; 95% confidence interval, 1.80-160; p=0.009). CONCLUSION: In patients with severe acute pancreatitis complicated by DIC, it was suggested that rTM might improve the prognosis of survival, even if the platelet count was markedly reduced.

Intraoperative Single-Dose Intravenous Acetaminophen for Postoperative Analgesia After Skin Laser Irradiation Surgery in Paediatric Patients: A Small Prospective Study.

OBJECTIVE: Acetaminophen is an analgesic that shows efficacy in postoperative pain relief in children. Many drugs such as opioids, non-steroidal anti-inflammatory drugs, and/or acetaminophen have been used in paediatric skin laser irradiation surgery for postoperative pain relief. However, acetaminophen has some advantages over opioids, and opioids are being used less often. We aimed to demonstrate the effectiveness of intravenous (IV) acetaminophen during surgery for postoperative pain in paediatric skin laser irradiation. METHODS: The present study is a small, prospective, double-blinded, randomized controlled trial. Paediatric patients (1-12 years old with an American Society of Anesthesiologists physical Status I and II), scheduled for skin laser irradiation for a nevus or haemangioma between October 2014 and April 2016 were randomized into the acetaminophen (n=9) and placebo (saline, n=8) groups. The observational face scale (FS) and the Behavioural Observational Pain Scale (BOPS) scores were recorded on emergence from anaesthesia, and 1, 2, and 4 hr post-surgery. RESULTS: Patient characteristics were not significantly different except with regard to the irradiation area and surgery time. The observational FS and BOPS scores of the acetaminophen group were lower than those of the placebo group; median (minimum-maximum) at each recording time: 1 (0-2) - 0 (0-2) - 0 (0-1) - 0 (0-2) vs. 2 (0-4) - 0 (0-2) - 0 (0-2) - 0 (0-1) and 1 (0-3) - 1 (0-3) - 1 (0-2) - 0 (0-1) vs. 2 (0-4) - 3 (0-5) - 1 (0-4) - 0 (0-3), p=0.07 and p=0.003, respectively. No differences in post-surgical analgesic use or adverse events were observed. CONCLUSION: In this study, we showed that the IV acetaminophen group had lower observational FS and BOPS scores in the early postoperative period; however, further studies including a large number of patients are required to confirm our findings.