Haploinsufficiency of Cnot3 Aggravates Acid-Induced Acute Lung Injury Likely Through Transcriptional and Post-Transcriptional Upregulation of Pro-Inflammatory Genes.

Background: Acute lung injury (ALI) is caused by a variety of illnesses, including aspiration pneumonia and sepsis. The CCR4-NOT complex is a large multimeric protein complex that degrades mRNA through poly(A) tail shortening, whereas it also contributes to regulation of transcription and translation. Cnot3 is a scaffold component of the CCR4-NOT complex and is essential for the integrity of the complex; loss of Cnot3 leads to depletion of whole complex. While the significance of cytokine mRNA degradation in limiting inflammation has been established, the roles of CCR4-NOT complex-mediated in ALI remain elusive. Methods: The effects of Cnot3 haploinsufficiency in the pathology and cytokine expression were analyzed in the mouse lungs of acid aspiration-induced acute lung injury. The decay rate and transcription activity of cytokine mRNAs under Cnot3 heterozygous deletion were analyzed in lipopolysaccharide (LPS) -stimulated mouse embryonic fibroblasts (MEFs). Results: Tamoxifen-induced heterozygous deletion of Cnot3 in adult mice (Cnot3 Hetz) did not show body weight loss or any apparent abnormality. Under acid aspiration-induced acute lung injury, Cnot3 Hetz mice exhibited increased pulmonary edema, worse lung pathologies and more severe inflammation compared with wild type mice. mRNA expression of pro-inflammatory genes Il1b and Nos2 were significantly upregulated in the lungs of Cnot3 Hetz mice. Consistently, mRNA expression of Il1b and Nos2 was upregulated in LPS-stimulated Cnot3 Hetz MEFs. Mechanistically, while heterozygous depletion of Cnot3 stabilized both Il1b and Nos2 mRNAs, the nascent pre-mRNA level of Il1b was upregulated in Cnot3 Hetz MEFs, implicating Cnot3-mediated transcriptional repression of Il1b expression in addition to destabilization of Il1b and Nos2 mRNAs. PU.1 (Spi1) was identified as a causative transcription factor to promote Il1b expression under Cnot3 haploinsufficient conditions. Conclusion: CNOT3 plays a protective role in ALI by suppressing expression of pro-inflammatory genes Il1b and Nos2 through both post-transcriptional and transcriptional mechanisms, including mRNA stability control of Spi1.

Impact of right ventricular and pulmonary vascular characteristics on Impella hemodynamic support in biventricular heart failure: A simulation study.

BACKGROUND: Impella (Abiomed, Danvers, MA, USA) is a percutaneous ventricular assist device commonly used in cardiogenic shock, providing robust hemodynamic support, improving the systemic circulation, and relieving pulmonary congestion. Maintaining adequate left ventricular (LV) filling is essential for optimal hemodynamic support by Impella. This study aimed to investigate the impact of pulmonary vascular resistance (PVR) and right ventricular (RV) function on Impella-supported hemodynamics in severe biventricular failure using cardiovascular simulation. METHODS: We used Simulink® (Mathworks, Inc., Natick, MA, USA) for the simulation, incorporating pump performance of Impella CP determined using a mock circulatory loop. Both systemic and pulmonary circulation were modeled using a 5-element resistance-capacitance network. The four cardiac chambers were represented by time-varying elastance with unidirectional valves. In the scenario of severe LV dysfunction (LV end-systolic elastance set at a low level of 0.4 mmHg/mL), we compared the changes in right (RAP) and left atrial pressures (LAP), total systemic flow, and pressure-volume loop relationship at varying degrees of RV function, PVR, and Impella flow rate. RESULTS: The simulation results showed that under low PVR conditions, an increase in Impella flow rate slightly reduced RAP and LAP and increased total systemic flow, regardless of RV function. Under moderate RV dysfunction and high PVR conditions, an increase in Impella flow rate elevated RAP and excessively reduced LAP to induce LV suction, which limited the increase in total systemic flow. CONCLUSIONS: PVR is the primary determinant of stable and effective Impella hemodynamic support in patients with severe biventricular failure.

CHANGES OF HISTIDINE-RICH GLYCOPROTEIN LEVELS IN CRITICALLY ILL SEPTIC PATIENTS.

ABSTRACT: Background: Histidine-rich glycoprotein (HRG), a potential prognostic factor in sepsis, lacks clarity regarding its relevance in septic-induced shock, disseminated intravascular coagulation (DIC), and acute respiratory distress syndrome (ARDS) pathogenesis. This study investigated the association between HRG concentrations and these critical conditions. Methods: Blood samples were collected from 53 critically ill patients on days 1, 3, 5, and 7 after ICU admission at the Kyushu University Hospital. Daily clinical and laboratory data were recorded, and patient survival was assessed 28 days after ICU admission. Results: Serum HRG concentrations were significantly reduced on days 3, 5, and 7 in patients with septic shock and DIC but not in those with ARDS. While initial HRG levels on day one were not correlated with survival, nonsurvivors displayed decreased HRG levels, notably on days 3, 5, and 7 post-ICU admissions. The HRG levels remained stable in survivors. A progressive decrease was associated with higher mortality rates, particularly on days 5 and 7. On day 5, an HRG level with a cutoff of 25.5 µg/mL showed a sensitivity of 0.77 and a specificity of 0.75, indicating significantly lower survival rates (log-rank test, P < 0.05). Conclusion: HRG presents a potential intervention for critically ill sepsis patients, providing a novel strategy to enhance outcomes. Further research is needed to explore the therapeutic potential of HRG in sepsis management.

Anesthetic management in pregnant women with Fontan circulation: a case series.

BACKGROUND: Given the advances in medicine, women with Fontan circulation are now reaching childbearing age. However, data on the mode of delivery and anesthetic management of these patients are limited. We report the cases of five pregnant women with Fontan circulation. CASE PRESENTATION: The mean age at delivery was 28 ± 3 years, and the mean gestational period was 34 weeks and 3 days. Anticoagulation therapy was switched from warfarin and aspirin to continuous intravenous heparin. The modes of delivery were scheduled cesarean section (C/S) in one, emergency C/S in three, and vaginal delivery with epidural labor analgesia in one patient. Three patients underwent C/S under regional anesthesia; one received general anesthesia. The perinatal complications were heart failure, worsening valve regurgitation, and postoperative hematoma in three, four, and two patients, respectively. CONCLUSIONS: For C/S in women with Fontan circulation, regional anesthesia should be considered. Epidural labor analgesia can help prevent the decrease in pulmonary blood flow due to straining. We initiated labor analgesia or C/S with regional anesthesia at the appropriate time in four patients.

Successful radiofrequency thermocoagulation of the mandibular nerve for intractable pain associated with medication-related osteonecrosis of the jaw: a case report.

BACKGROUND: Bisphosphonates may cause serious adverse events, including osteonecrosis of the jaw. This article describes a case of successful application of radiofrequency thermocoagulation for pain caused by osteonecrosis of the jaw. CASE PRESENTATION: An 86-year-old woman who had received alendronate sodium hydrate for osteoporosis was diagnosed with osteonecrosis of the right mandible after dental treatment. Despite repeated conservative and debridement treatments, the patient could not eat due to intractable pain; accordingly, her condition was debilitated. The patient was referred to our pain management clinic for radiofrequency thermocoagulation of the right mandibular nerve. Immediately after the procedure, her pain drastically improved and she could eat; moreover, the pain has not recurred for 3 years. CONCLUSION: Our findings demonstrate that minimally invasive radiofrequency thermocoagulation may have long-term effects in patients with chronic pain caused by osteonecrosis of the jaw that is refractory to conservative treatment.

The impact of ECPELLA on haemodynamics and global oxygen delivery: a comprehensive simulation of biventricular failure.

BACKGROUND: ECPELLA, a combination of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) and Impella, a percutaneous left ventricular (LV) assist device, has emerged as a novel therapeutic option in patients with severe cardiogenic shock (CS). Since multiple cardiovascular and pump factors influence the haemodynamic effects of ECPELLA, optimising ECPELLA management remains challenging. In this study, we conducted a comprehensive simulation study of ECPELLA haemodynamics. We also simulated global oxygen delivery (DO2) under ECPELLA in severe CS and acute respiratory failure as a first step to incorporate global DO2 into our developed cardiovascular simulation. METHODS AND RESULTS: Both the systemic and pulmonary circulations were modelled using a 5-element resistance‒capacitance network. The four ventricles were represented by time-varying elastances with unidirectional valves. In the scenarios of severe LV dysfunction, biventricular dysfunction with normal pulmonary vascular resistance (PVR, 0.8 Wood units), and biventricular dysfunction with high PVR (6.0 Wood units), we compared the changes in haemodynamics, pressure-volume relationship (PV loop), and global DO2 under different VA-ECMO flows and Impella support levels. RESULTS: In the simulation, ECPELLA improved total systemic flow with a minimising biventricular pressure-volume loop, indicating biventricular unloading in normal PVR conditions. Meanwhile, increased Impella support level in high PVR conditions rendered the LV-PV loop smaller and induced LV suction in ECPELLA support conditions. The general trend of global DO2 was followed by the changes in total systemic flow. The addition of veno-venous ECMO (VV-ECMO) augmented the global DO2 increment under ECPELLA total support conditions. CONCLUSIONS: The optimal ECPELLA support increased total systemic flow and achieved both biventricular unloading. The VV-ECMO effectively improves global DO2 in total ECPELLA support conditions.

Delayed Emergence from Total Intravenous Anesthesia Following Posterior Spinal Correction and Fusion for Scoliosis: A Case Report.

BACKGROUND Postoperative acute liver failure, a complication following spine surgery, can cause delayed emergence from total intravenous anesthesia. Here, we report a case of acute severe postoperative liver failure following posterior spinal correction and fusion in a patient with congenital scoliosis. CASE REPORT A girl's congenital scoliosis worsened, and posterior spinal correction and fusion was scheduled. General anesthesia was induced with sevoflurane, fentanyl, target-controlled-infusion with propofol, and rocuronium. General anesthesia was maintained using target-controlled-infusion with propofol and remifentanil. The operation was completed with no remarkable complications. The operative time was 516 min and the anesthesia time was 641 min in the prone position. Emergence from anesthesia was poor, and it took 68 min to remove the tracheal tube after discontinuation of the anesthetic agents. The patient was drowsy and was transferred to her room in a general ward without reporting any pain, nausea, or dyspnea. On postoperative day 1, the results of laboratory investigations were suggestive of acute liver failure; contrast-enhanced computed tomography revealed a poorly enhanced area in the umbilical portion of the left liver lobe portal vein, indicating ischemic liver damage. Although no additional treatment was administered for acute liver failure, the patient recovered over time, and laboratory values normalized. No other postoperative complications were observed, and the patient was discharged on postoperative day 1. CONCLUSIONS Delayed emergence from general anesthesia may be due to acute liver failure following posterior spinal correction and fusion. There are several possible causes of postoperative liver failure, including anesthetics, prone position, and spinal surgery.

Autonomic nervous system function assessed by heart rate variability and the presence of symptoms affecting activities of daily living in community-dwelling residents with chronic pain: The Hisayama Study.

BACKGROUND: Autonomic nervous system dysfunction has been reported to be associated with impaired activities of daily living (ADL) among patients with chronic pain, but the association has not been fully addressed in general populations. This study cross-sectionally investigated the association between autonomic nervous system function and the presence of subjective symptoms affecting ADL in community-dwelling residents with chronic pain. METHODS: A total of 888 residents with chronic pain, aged 40-79 years, who underwent a health examination in 2017-2018 were included. Based on heart rate variability measured by fingertip pulse wave, the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR interval differences (RMSSD), low frequency (LF) power, and high frequency (HF) power were calculated. Symptoms affecting ADL were defined as those scoring ≥1 on the modified Rankin Scale. Odds ratios (ORs) and their 95% confidence intervals (CIs) for symptoms affecting ADL were estimated using a logistic regression analysis. RESULTS: The overall prevalence of symptoms affecting ADL was 39.4%. The ORs for symptoms affecting ADL increased significantly per 1-standard-deviation decrement in log-transformed SDNN (OR 1.23 [95% CI 1.06-1.44]), RMSSD (1.25 [1.08-1.45]), LF power (1.29 [1.11-1.52]), and HF power (1.29 [1.11-1.51]) after adjusting for age, sex, education, hypertension, diabetes, serum total cholesterol level, body mass index, past medical history, current smoking, current drinking, exercise, depressive symptoms, and pain intensity. CONCLUSIONS: Decreased heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. SIGNIFICANCE: Decrease in heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. This article could help scientists understand the significance of autonomic nervous system dysfunction in the pathology of chronic pain. Approaches that target autonomic nervous system dysfunction may be an option to relieve or prevent symptoms affecting ADL for chronic pain sufferers.

Associations between ondansetron and the incidence of postoperative nausea and vomiting and food intake in Japanese female undergoing laparoscopic gynecological surgery: a retrospective study.

PURPOSE: Prevention of postoperative nausea and vomiting (PONV) is important to achieve DREAM (drinking, eating, mobilization). Ondansetron inhibits PONV, but its effects on postoperative food intake have not been investigated. This study aimed to examine associations between ondansetron and PONV incidence, and postoperative food intake. METHODS: This retrospective study included adult patients (n = 632) who underwent laparoscopic gynecological surgery at Kyushu University Hospital between January 2017 and June 2023. Outcomes were PONV on the day of surgery, PONV up to the day after surgery, and food intake, which was assessed for breakfast and lunch on the day after surgery. Odds ratios (ORs) for PONV incidence and postoperative no-food intake were calculated between those with and without ondansetron during surgery. Multivariable-adjusted analysis was performed using possible confounding factors for PONV. Synergistic effects of combining ondansetron with dexamethasone or total intravenous anesthesia (TIVA) were assessed. RESULTS: Multivariable-adjusted ORs for PONV on the day of surgery and up to the day after surgery were 0.56 (95% confidence interval, 0.32-0.99, p = 0.04) and 0.52 (0.30-0.93, p = 0.03), respectively, in the ondansetron group (n = 84) compared with the non-ondansetron group (n = 548). In contrast, multivariable-adjusted ORs for no-food intake of breakfast and lunch the day after surgery in the ondansetron group compared with the non-ondansetron group were not significant. Analysis of synergistic effects on PONV showed no significant interaction between ondansetron and dexamethasone or ondansetron and TIVA combinations. CONCLUSION: Ondansetron administration during surgery was significantly associated with decreased PONV risk but was not associated with food intake the day after surgery.

Recovery of memory retention after anesthesia with remimazolam: an exploratory, randomized, open, propofol-controlled, single-center clinical trial.

PURPOSE: Remimazolam, a newly developed ultra-short-acting benzodiazepine, provides early recovery of consciousness but its effects on memory recovery are unclear. This study examined memory recovery after emergence from general anesthesia using remimazolam. METHODS: Seventy-four patients undergoing breast surgery between October 2021 and March 2022 were enrolled and randomly assigned to receive propofol (control group) or remimazolam as general anesthetic during surgery. The primary endpoint was the number of posters patients remembered 24 h after surgery (among four posters shown after recovering from anesthesia) as an assessment of memory retention. The secondary endpoints were the recall of a numeric character patients had been shown just before anesthetic induction, as an assessment of retrograde amnesia 24 h after surgery. RESULTS: Sixty-six patients (propofol, 32; remimazolam, 34) were assessed. Patients in the remimazolam group remembered significantly fewer posters shown to them after surgery than those in the propofol group (0 [0 - 2] vs. 2 [1 - 3], p < 0.001). In the remimazolam group, the patients who received flumazenil remembered a higher number of posters than those who did not receive flumazenil (3 [1 - 4] vs. 0 [0 - 0], p < 0.001). All patients remembered all events that occurred during the preoperative period as well as the numeric character. CONCLUSION: Patients recovering from remimazolam anesthesia without receiving flumazenil do not remember events after regaining consciousness. IRB: Kyushu University School of Medicine Hospital Institutional Review Board (IRB) (approval number: 20212006). TRIAL REGISTRATION: This clinical trial was registered with the University Hospital Medical Information Network (UMIN) Center on September 28, 2021 (UMIN-CTR: UMIN000045593). IMPLICATION STATEMENT: Memory recovery is slower following emergence from remimazolam than from propofol anesthesia.

Perineural treatment with anti-TNF-α antibody ameliorates persistent allodynia and edema in novel mouse models with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is an intractable chronic pain syndrome with various signs and symptoms including allodynia/hyperalgesia, edema, swelling, and skin abnormalities. However, a definitive therapeutic treatment for CRPS has not been established. In CRPS patients, inflammatory cytokines such as TNF-α and IL-1ß have been shown to increase in affected areas, suggesting that these molecules may be potential therapeutic targets for CRPS. Here, we first created a novel CRPS mouse model (CRPS-II-like) via sciatic nerve injury and cast immobilization, which was characterized by mechanical allodynia, local edema, and skin abnormalities, to evaluate the pathophysiology and pharmacotherapy of CRPS. When an anti-TNF-α antibody was consecutively administered near the injured sciatic nerve of CRPS model mice, persistent allodynia and CRPS-related signs in the ipsilateral hindpaw were markedly attenuated to control levels. Perineural administration of anti-TNF-α antibody also suppressed the upregulation of inflammatory cytokines as well as the activation of macrophages and Schwann cells in the injured sciatic nerve. These findings indicate that persistent allodynia and CRPS-related signs in CRPS models are primarily associated with TNF-α-mediated immune responses in injured peripheral nerves, suggesting that perineural treatment with anti-TNF-α antibody might be therapeutically useful.

Safety and utility of ultrasound-guided superior cervical ganglion block for headaches and orofacial pain: a retrospective, single-center study of 10 patients.

BACKGROUND: Several new ultrasound-guided superior cervical ganglia blocks (U-SCGBs) have been proposed to overcome the shortcomings of conventional superior cervical ganglia blocks; however, their clinical utility and practicality have not yet been demonstrated. The aim of this study was to evaluate the safety and utility of a new method of U-SCGB. METHODS: We retrospectively collected data on patients who underwent U-SCGB for the treatment of headaches and orofacial pain at a single center. U-SCGB was performed by injecting 2-3 mL of 1% mepivacaine posterior to the internal carotid artery, just above the bifurcation. The Wilcoxon signed-rank test was used to compare pain scores. Numerical data are expressed as the mean ± standard error. RESULTS: The total number of U-SCGB procedures was 43. All procedures were accompanied by Horner's sign. The numerical rating scale score for pain (possible scores, 0-10) was reduced predominantly from 7.0 ± 0.7 before treatment to 4.5 ± 0.7 at the follow-up (p = 0.014). CONCLUSION: U-SCGB was considered a clinically useful and accurate treatment for headaches and orofacial pain in this study.

Anesthetic management of pheochromocytoma and paraganglioma for patients with Fontan circulation: a case series.

BACKGROUND: Anesthetic management of pheochromocytoma and paraganglioma with Fontan circulation is challenging for physicians, with attention to cardiovascular physiology. CASE PRESENTATION: We performed anesthetic management for pheochromocytoma and paraganglioma in three patients with Fontan circulation. We maintained intraoperative central venous pressure at preoperative level under fluid infusion and administrating nitric oxide to decrease pulmonary arterial resistance. We administered noradrenaline or vasopressin if low blood pressure was present despite adequate central venous pressure. Although noradrenaline is prevalent for the case of noradrenaline-secreting tumor especially after resection, we could maintain blood pressure to administrate vasopressin without increasing central venous pressure. Retroperitoneal laparoscopic approach which could avoid intra-abdominal adhesions might be selectable as case 3. CONCLUSIONS: Sophisticated management is required for pheochromocytoma and paraganglioma with Fontan circulation.

Redistributional Hypothermia Prevention by Prewarming with Forced-Air: Exploratory, Open, Randomized, Clinical Trial of Efficacy.

Avoiding redistributional hypothermia that decreases core temperature by 0.5-1.5°C within the 1st hour of surgery is difficult. The efficacy of prewarming using a forced-air warming (FAW) device with a lower-body blanket on redistribution hypothermia during epidural procedures have not been investigated. After ethics approval, 113 patients undergoing laparoscopic surgery under general anesthesia combined with epidural anesthesia were enrolled. Intervention (prewarming) group patients who were warmed from operating room entry, including during epidural anesthesia, was compared with the control group that was warmed from just before surgery started. In total, 104 patients (52, control; 52, prewarming) were analyzed. In the prewarming group, compared to the control group, the core temperature 20 minutes after anesthesia induction (36.9 ± 0.4 vs. 37.1 ± 0.4°C, p < 0.02) was significantly higher. The core temperature was higher in the prewarming group than in the control group until 3 hours after the surgery. In the prewarming group, compared to the control group, the core temperature-time integral below baseline till 180 minutes after surgery start (65.1 ± 64.0 vs. 8.1 ± 18.6°C/min, p < 0.0001) or 30 minutes after anesthesia induction (5.3 ± 6.2 vs. 2.0 ± 4.7°C/min, p < 0.0001) were significantly smaller. Postoperative shivering was comparable between the groups. Prewarming during epidural catheter insertion with a FAW device could safely prevent a core temperature decrease induced by redistribution or heat loss without additional preparation, effort, space, or time requirements.

Identification of Spinal Inhibitory Interneurons Required for Attenuating Effect of Duloxetine on Neuropathic Allodynia-like Signs in Rats.

Neuropathic pain is a chronic pain condition that occurs after nerve damage; allodynia, which refers to pain caused by generally innocuous stimuli, is a hallmark symptom. Although allodynia is often resistant to analgesics, the antidepressant duloxetine has been used as an effective therapeutic option. Duloxetine increases spinal noradrenaline (NA) levels by inhibiting its transporter at NAergic terminals in the spinal dorsal horn (SDH), which has been proposed to contribute to its pain-relieving effect. However, the mechanism through which duloxetine suppresses neuropathic allodynia remains unclear. Here, we identified an SDH inhibitory interneuron subset (captured by adeno-associated viral (AAV) vectors incorporating a rat neuropeptide Y promoter; AAV-NpyP+ neurons) that is mostly depolarized by NA. Furthermore, this excitatory effect was suppressed by pharmacological blockade or genetic knockdown of α1B-adrenoceptors (ARs) in AAV-NpyP+ SDH neurons. We found that duloxetine suppressed Aß fiber-mediated allodynia-like behavioral responses after nerve injury and that this effect was not observed in AAV-NpyP+ SDH neuron-selective α1B-AR-knockdown. These results indicate that α1B-AR and AAV-NpyP+ neurons are critical targets for spinal NA and are necessary for the therapeutic effect of duloxetine on neuropathic pain, which can support the development of novel analgesics.

Anesthetic management of hepatectomy for the patient with Fontan circulation: a case series.

BACKGROUND: Hepatectomy for patients with Fontan circulation consists of high central venous pressure and low pulmonary vascular resistance, and is challenging for physicians. CASE PRESENTATION: We performed anesthetic management for hepatectomy in three patients with Fontan circulation. Massive bleeding and transfusion as well as careful management were needed. Open abdominal surgery had to be conducted instead of laparoscopic surgery for controlling bleeding in one case. We successfully performed general anesthesia using nitric oxide and inotropes while monitoring arterial pressure and central venous pressure in all the cases. CONCLUSIONS: To maintain Fontan circulation during hepatectomy, it is important to manage central venous pressure and ensure appropriate circulatory volume.

Impact of Antithrombin Activity Levels Following Recombinant Antithrombin Gamma Therapy in Patients with Sepsis-Induced Disseminated Intravascular Coagulation.

Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels <70% were treated with rAT between May 2018 and December 2020. The recovery rates from DIC were 32.2% and 63.3% on day 3 and 5 post administration, respectively. Recovery and survival rates were significantly higher in patients who achieved AT activity ≥70% or 80% on day 3 post administration. Receiver operating characteristic curve analysis revealed that the cutoff values of post-treatment AT activity on day 3 for 28-day survival and 5-day recovery from DIC were 79.5% and 81.5%, respectively. Patients who did not achieve AT activity ≥80% on day 3 presented a lower base level of AT activity and lower dose supplementation. Our results suggest that targeted AT activity should be at least 70%, and ideally 80%, and sufficient doses to maintain this activity are required to achieve better outcomes.