Prior exposure to stress exacerbates neuroinflammation and causes long-term behavior changes in sepsis.

Background: Neuroinflammation can occur during sepsis and is now regarded as the main mechanism underlying various related central nervous system (CNS) disorders. Another well-known factor causing neuroinflammation is psychological stress. In the current study, we examined the effects of prior exposure to stress on sepsis-induced neuroinflammation and CNS symptoms. Experimental procedure: Balb/c mice were subjected to wet bedding stress for 2 days, then lipopolysaccharide (LPS) was intraperitoneally administered. For examining the neuroinflammation, the expression of proinflammatory cytokines and NF-κB activity in the brain was analyzed by RT-PCR and ELISA-based assay. Additionally, immunohistochemical study using Iba-1 was performed. Finally, behavior tests were examined one month after LPS treatment. Result and conclusion: Stress exposure induced the upregulation of IL-1ß, IL-6 and TNFα mRNA in the cerebral cortex 4 h after LPS administration. Suggesting an underlying mechanism, LPS-induced NF-κB activation was significantly upregulated with stress in the brain. Histologically, microglia in the cerebral cortex were reactive and became more abundant with stress, while these effects were further increased with LPS injection. Behavioral analysis conducted showed a significant increase of anxiety-like behaviors in the stressed mice. These results suggest that prior exposure to stress exacerbates neuroinflammation during sepsis and induces long-term behavior changes.

Additional Wide Resection of Infantile Dermatofibrosarcoma Protuberans after Unplanned Excision: A Case Report.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive intermediate soft tissue neoplasm that occurs in the dermis. DFSP generally occurs in young to middle-aged adults and rarely in infancy. Because of its extreme rarity, DFSP is difficult to diagnose and treat, especially when it occurs in infancy. In this paper, we reported a case of infantile DFSP in which we performed additional wide resection with a 3-cm horizontal margin for a mass that had previously undergone unplanned excision. No tumor recurrence has been seen for 3 years postoperatively. We suggest that the possibility of DFSP should always be considered when an enlarging superficial mass is identified on the trunk, even in an infant. Additionally, radical local treatment is as important for DFSP in infancy as it is for DFSP in adults, even after unplanned excision.

Sepsis-associated neuroinflammation in the spinal cord.

Septic patients commonly present with central nervous system (CNS) disorders including impaired consciousness and delirium. Today, the main mechanism regulating sepsis-induced cerebral disorders is believed to be neuroinflammation. However, it is unknown how another component of the CNS, the spinal cord, is influenced during sepsis. In the present study, we intraperitoneally injected mice with lipopolysaccharide (LPS) to investigate molecular and immunohistochemical changes in the spinal cord of a sepsis model. After LPS administration in the spinal cord, pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha mRNA were rapidly and drastically induced. Twenty-four-hour after the LPS injection, severe neuronal ischemic damage spread into gray matter, especially around the anterior horns, and the anterior column had global edematous changes. Immunostaining analyses showed that spinal microglia were significantly activated and increased, but astrocytes did not show significant change. The current results indicate that sepsis induces acute neuroinflammation, including microglial activation and pro-inflammatory cytokine upregulation in the spinal cord, causing drastic neuronal ischemia and white matter edema in the spinal cord.

Non-invasive ventilation using a novel ventilator and non-vented full-face mask for patients with respiratory failure during the COVID-19 pandemic: Report of three cases.

The Japanese government's latest manual on COVID-19 management mentions non-invasive ventilation (NIV). Before this version, we experienced three cases in which COVID-19 was a concern. Each case had one of the following conditions: obesity hypoventilation syndrome, amyotrophic lateral sclerosis, acute heart failure with acute kidney injury with hypercapnia. The guidelines indicate that patients with these diseases are good candidates for NIV. NIV was used in a negative pressure room with staff in personal protective equipment. We describe the use of NIV instruments with anti-viral filters and a non-vented mask, including a new NIV machine for COVID-19 respiratory care.

Successful lung-protective ventilatory management during the VV-ECMO in a severe COVID-19 pneumonia patient with extensive pneumomediastinum and subcutaneous emphysema: a case report.

BACKGROUND: Ventilatory management of respiratory failure with pneumomediastinum/subcutaneous emphysema is not established. Herein, we report a case of severe COVID-19 pneumonia with extensive pneumomediastinum/subcutaneous emphysema, rescued by thorough lung-protective ventilatory management after applying the VV-ECMO. CASE PRESENTATION: A 68-year-old male with no medical history was admitted to a local hospital and diagnosed with COVID-19 pneumonia. His pulmonary parameters worsened during invasive ventilation due to the development of pneumomediastinum/subcutaneous emphysema, and then he was transferred to our hospital. On arrival, we immediately decided to apply VV-ECMO and switch to ultraprotective ventilation. After maintaining the initial ventilation with a neuromuscular blocking agent for 2 days, we gradually increased PEEP while limiting PIP to 25 cmH2O. The patient was weaned off VV-ECMO on day 10; he was transferred to the medical ward after extubation. CONCLUSIONS: Lung-protective ventilatory management should be performed thoroughly during VV-ECMO in severe COVID-19 pneumonia with pneumomediastinum/subcutaneous emphysema.

Preliminary Clinical Outcome of One-level Mobi-C Total Disc Replacement in Japanese Population.

INTRODUCTION: In 2018, the first Mobi-CⓇ total disk replacement (TDR) case was performed in Japan. In this study, we examined the preliminary clinical outcome of Mobi-CⓇ for degenerative cervical spine disease. METHODS: We examined 24 consecutive patients who underwent 1-level TDR after 2018 and followed up for more than 6 months after surgery. The evaluation criteria included age, gender, diagnosis, follow-up period, surgical level, implant size, surgery time, intraoperative bleeding volume, complications, revision surgery, imaging findings, JOA score, and various questionnaires. RESULTS: The mean age was 52.7 years, 13 males and 11 females. There were 15 cases of cervical disk herniation and 9 cases of cervical spondylosis. The mean follow-up period was 17.4 months. Surgical levels were C3/4 in 4 cases, C4/5 in 2 cases, C5/6 in 16 cases, and C6/7 in 2 cases. The mean operation time was 138.5 minutes, the amount of intraoperative bleeding was 32.1 ml, and there were no serious intraoperative complications. The range of motion of the affected level increased significantly, from 6.6 degrees preoperatively to 12.2 degrees at final follow-up. No patients required revision surgery at final follow-up, and there were no cases of heterotopic ossification or adjacent segment disease. One patient exhibited radiculopathy due to mild subsidence 1 year after surgery, and 1 had asymptomatic contact of device plates. Preoperative and final JOA scores improved from 11.7 to 15.8 points, and NRS improved from 4.3 to 1.3 points for neck pain and 4.3 to 1.7 points for arm pain. Preoperative and final NDI improved from 39.7% to 14.0%, and EQ-5D improved from 0.602 to 0.801. CONCLUSIONS: The short-term treatment outcomes of Mobi-CⓇ TDR were generally favorable. Spine surgeons should comply with guidelines when introducing this procedure and strive to adopt this new technology in Japan.

Successful treatment of COVID-19-related acute respiratory distress syndrome with a rare blood type: A case report.

Extracorporeal membrane oxygenation is indispensable for critically severe COVID-19 patients. However, it would be inapplicable to patients with a rare blood type or blood transfusion refusal. In that case, severely conservative fluid management with the sacrifice of renal functions and hydrocortisone therapy should be considered for better oxygenation.

The inhibitory effects of Orengedokuto on inducible PGE2 production in BV-2 microglial cells.

BACKGROUND AND AIM: Reactive microglia has been associated with neuroinflammation caused by the production of proinflammatory molecules such as cytokines, nitric oxide, and prostaglandins. The overexpression of these molecules may provoke neuronal damage that can cause neurodegenerative diseases. A traditional herbal medicine, Orengedokuto (OGT), has been widely used for treating inflammation-related diseases. However, how it influences neuroinflammation remains poorly understood. EXPERIMENTAL PROCEDURE: This study investigated the effects of OGT on inflammatory molecule induction in BV-2 microglial cells using real-time RT-PCR and ELISA. An in vivo confirmation of these effects was then performed in mice. RESULTS AND CONCLUSION: OGT showed dose-dependent inhibition of prostaglandin E2 (PGE2) production in BV-2 cells stimulated with lipopolysaccharide (LPS). To elucidate the mechanism of PGE2 inhibition, we examined cyclooxygenases (COXs) and found that OGT did not suppress COX-1 expression or inhibit LPS-induced COX-2 upregulation at either the transcriptional or translational levels. In addition, OGT did not inhibit COX enzyme activities within the concentration that inhibited PGE2 production, suggesting that the effect of OGT is COX-independent. The inhibitory effects of OGT on PGE2 production in BV-2 cells were experimentally replicated in primary cultured astrocytes and mice brains. OGT can be useful in the treatment of neuroinflammatory diseases by modulating PGE2 expression.

[One-stage Radical Surgery for Aortoesophageal Fistula after Graft Replacement of Descending Aorta].

A 31-year-old woman was referred to our institution because of aortoesophageal fistula (AEF) six months after the descending aortic replacement for acute aortic dissection. We operated one-stage repair of the AEF. Thoracoscopic esophagectomy was firstly performed in prone position from right thoracic cavity, and then the esophagus was reconstructed with gastric conduit via posterior mediastinal route with omental flap. Secondly, graft replacement of the descending aorta using lateral oblique straight incision was performed and the graft was covered with omental flap simultaneously. The postoperative course was uneventful, and she started oral intake on the 13th day after surgery. Although the one-stage surgery for the AEF is highly invasive, it could be a good option for selected cases.

A case of left ventricular free wall rupture after insertion of an IMPELLA® left ventricular assist device diagnosed by transesophageal echocardiography.

BACKGROUND: The IMPELLA® is a minimally invasive left ventricular assist device. We report a case in which transesophageal echocardiography (TEE) was useful in diagnosis of left ventricular rupture after IMPELLA® insertion. CASE PRESENTATION: A 75-year-old man presented to the emergency room with chest pain and underwent percutaneous coronary intervention for 100% stenosis of the left anterior descending branch #7. An IMPELLA® was inserted to stabilize the circulation, but hypotension persisted. Transthoracic echocardiography revealed increased pericardial effusion and suspicion of free wall left ventricular rupture, leading to emergency surgery. TEE revealed the IMPELLA® straying into the left ventricle apical wall and cardiac tamponade. Hemorrhage was observed from the thinning free wall and the tip of the IMPELLA® was palpable. The IMPELLA® was removed and the left ventricular wall was repaired. CONCLUSIONS: The IMPELLA® requires implantation of the tip in the left ventricle, but it should be noted that a fragile ventricular wall can be easily perforated.

Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development.

Most clinically used general anesthetics have demonstrated neurotoxicity in animal studies, but the related mechanisms remain unknown. Previous studies suggest that anesthetics affect neuronal development through neuroinflammation, and significant effects of neuroinflammation on neurogenesis and neuronal disease have been shown. In the present study, we treated pregnant mice with 2% sevoflurane for 3 h at gestational day 15.5 and analyzed the expression of proinflammatory cytokines, including IL-6 and IL-17, in fetal mice brains. Sevoflurane induced IL-6 mRNA significantly, but did not upregulate IL-17. Other volatile anesthetics, including isoflurane, enflurane, and halothane, induced IL-6 mRNA in fetal brains as well as sevoflurane, but propofol did not. Sevoflurane and isoflurane showed the same effects in cultured microglia and astrocytes, but not in neurons. Because IL-6 induction in fetal brains may affect neuronal precursor cells (NPCs), numbers of NPCs in the subventricular zone were studied, revealing that maternal sevoflurane treatment significantly increases NPCs in offspring at 8 weeks after birth (p8wk). But this effect was absent in IL-6 knockout mice. Finally, behavioral experiments also revealed that maternal sevoflurane exposure causes learning impairments in p8wk offspring. These findings collectively demonstrate that maternal exposure to volatile anesthetics upregulates IL-6 in fetal mice brains, and the effects could result in long-lasting influences on neuronal development.

Effect of propofol on androgen receptor activity in prostate cancer cells.

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells.

Relationship Between Intraoperative Hypotension and Acute Kidney Injury After Living Donor Liver Transplantation: A Retrospective Analysis.

OBJECTIVE: Acute kidney injury (AKI) is common after liver transplantation (LT) and has a significant impact on outcomes. Although several risk factors for post-LT AKI have been identified, the effect of intraoperative hemodynamic status on post-LT AKI remains unknown. Therefore, the authors aimed to investigate the relationship between hemodynamic parameters during LT and postoperative AKI. DESIGN: A retrospective observational study. SETTING: University hospital. PARTICIPANTS: Patients who underwent living donor LT (n = 231). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Severe AKI (stages 2-3 according to recent guidelines) was the primary outcome. Multivariable logistic regression analysis was used to control for confounding variables to obtain the independent relationship between intraoperative hemodynamic parameters (mean arterial pressure [MAP] and cardiac index) and severe AKI. The prevalence of severe AKI was 30.7%. Nadir MAP during the surgery was independently predictive of severe AKI (adjusted odds ratio, 2.11 [95% confidence interval, 1.32-3.47] per 10-mmHg decrease; p = 0.002). Subgroup analyses based on various patient or operative variables and extensive sensitivity analyses showed substantially similar results. Severe hypotension (MAP<40 mmHg), even for fewer than 10 minutes, was related significantly to severe AKI (adjusted odds ratio, 3.80 [95% confidence interval, 1.17-12.30]; p = 0.026). In contrast, nadir cardiac index was not related significantly to severe AKI. CONCLUSIONS: The authors found an independent relationship between degree of intraoperative hypotension and risk of severe AKI in living donor LT recipients. Severe hypotension, even for a short duration, was related significantly to severe AKI.

Off-Pump Bilateral Cadaveric Lung Transplantation Is Associated With Profound Intraoperative Hypothermia.

OBJECTIVES: Changes in body temperature (BT) during lung transplantation never have been reported. The authors investigated the time-dependent changes in BT during lung transplantation and compared them between off-pump lung transplantation and lung transplantation using extracorporeal membrane oxygenation (ECMO). DESIGN: A retrospective observational study. SETTING: University hospital. PARTICIPANTS: Patients who underwent cadaveric lung transplantation (15 bilateral lung transplantation [BLT] and 31 single-lung transplantation [SLT]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients received multimodal therapy to prevent intraoperative hypothermia, including increased environmental temperature, intravenous fluid warming, and the use of forced-air and circulating water warmers. Data of BT during the surgery were collected, and the time course and the extent of BT decrease during the surgery were analyzed. ECMO support during the surgery was necessary for 66.7% of BLT patients and 35.5% of SLT patients; patient characteristics were comparable between off-pump and ECMO-supported lung transplantation. In patients undergoing off-pump BLT, BT decreased continuously to 32.9°C when reperfusion was completed and gradually recovered thereafter. The decrease in BT was significantly larger during off-pump BLT compared with ECMO-supported BLT (3.5°C±0.5°C compared with 0.6°C±0.5°C, p = 0.002) and was≥3°C in all patients. Patients undergoing off-pump SLT had a similar time trend for their BTs (continuous decrease until reperfusion and subsequent recovery), but the extent of BT decrease was much smaller than that in off-pump BLT patients (1.0°C±0.5°C). CONCLUSIONS: Patients undergoing off-pump BLT were at high risk of profound intraoperative hypothermia despite multimodal preventive therapy.

[Difficult Ventilation Requiring Emergency Endotracheal Intubation during Awake Craniotomy Managed by Laryngeal Mask Airway].

We report a case of difficult ventilation requiring emergency endotracheal intubation during awake craniotomy managed by laryngeal mask airway (LMA). A 45-year-old woman was scheduled to receive awake craniotomy for brain tumor in the frontal lobe. After anesthetic induction, airway was secured using ProSeal LMA and patient was mechanically ventilated in pressure-control mode. Patient's head was fixed with head-pins at anteflex position, and the operation started. About one hour after the start of the operation, tidal volume suddenly decreased. We immediately started manual ventilation, but the airway resistance was extremely high and we could not adequately ventilate the patient. We administered muscle relaxant for suspected laryngospasm, but ventilatory status did not improve; so we decided to conduct emergency endotracheal intubation. We tried to intubate using Airwayscope or LMA-Fastrach, but they were not effective in our case. Finally trachea was intubated using transnasal fiberoptic bronchoscopy. We discuss airway management during awake craniotomy, focusing on emergency endotracheal intubation during surgery.

Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system.

Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1α and HIF-2α proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.

Preoperative Hypercapnia as a Predictor of Hypotension During Anesthetic Induction in Lung Transplant Recipients.

OBJECTIVE: To determine the incidence and predisposing factors of hypotension during anesthetic induction in lung transplant recipients. DESIGN: Retrospective study. SETTING: University hospital. PARTICIPANTS: Patients who underwent lung transplantation between 2008 and 2013 (n = 68). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors analyzed the mean arterial pressure (MAP) from administration of anesthetic drugs to 10 minutes after endotracheal intubation (ie, the anesthetic induction) among participants who underwent lung transplantation. Patients were considered to have clinically significant hypotension (CSH) when the following criteria were fulfilled: An MAP decrease of>40% from baseline and MAP of<60 mmHg. Overall, 41.2% of patients experienced CSH during the induction of anesthesia. The preoperative partial pressure of carbon dioxide (PaCO2) was significantly higher in patients who experienced CSH during anesthetic induction than in those who did not (p = 0.005). Preoperative PaCO2 predicted the development of CSH during anesthetic induction (area under the curve = 0.702; p = 0.002), with an optimal cut-off point of 55 mmHg determined by maximizing the Youden index. The incidences of CSH during anesthetic induction for patients with (PaCO2 ≥ 55) and without (PaCO2<55) preoperative hypercapnia were 75.0% (95% confidence interval [CI] [53.8-89.2]) and 30.8% (95% CI 26.4-37.3), respectively. After adjustment for known predicting factors, the odds ratio for the relationship between preoperative hypercapnia and CSH during anesthetic induction was 12.54 (95% CI 3.10-66.66). CONCLUSIONS: Hypotension during anesthetic induction is common in lung transplant recipients, and is independently predicted by preoperative hypercapnia.

The clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation.

PURPOSE: We examined the clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation (post-HSCT), focusing on ventilatory management. We aimed to determine the incidence of oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction in post-HSCT lung transplant recipients, and to explore factors associated with their development. METHODS: Nineteen consecutive patients who underwent lung transplantation post-HSCT at Kyoto University Hospital (Japan) were retrospectively studied. Data regarding patient characteristics, preoperative examination, and clinical course during anesthetic induction were analyzed. RESULTS: The incidence of oxygen desaturation (SpO2 < 90 %) during anesthetic induction and severe respiratory acidosis (pH < 7.2) after anesthetic induction were 21.1 and 26.3 %, respectively. Reduced dynamic compliance (Cdyn) during mechanical ventilation was significantly associated with oxygen desaturation during anesthetic induction (p = 0.01), as well as severe respiratory acidosis after anesthetic induction (p = 0.01). The preoperative partial pressure of carbon dioxide in arterial blood (PaCO2; r = -0.743, p = 0.002) and body mass index (BMI; r = 0.61, p = 0.021) significantly correlated with Cdyn, and multivariate analysis revealed that both PaCO2 and BMI were independently associated with Cdyn. CONCLUSIONS: Oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction frequently occur in post-HSCT lung transplant recipients. Low Cdyn may, at least partially, explain oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction. Moreover, preoperative hypercapnia and low BMI were predictive of low Cdyn.

The volatile anesthetic isoflurane differentially suppresses the induction of erythropoietin synthesis elicited by acute anemia and systemic hypoxemia in mice in an hypoxia-inducible factor-2-dependent manner.

Erythropoietin (EPO) is a glycoprotein hormone essential for the regulation of erythroid homeostasis. Although EPO production is prominent in the kidney and liver, its production in the central nervous system has also been detected. Tissue hypoxia due to systemic or local hypoxemia and acute anemia due to blood loss occurs frequently during various clinical settings, leading to a high possibility of elevated plasma EPO levels. However, it is largely unknown whether volatile anesthetic agents affect EPO production elicited by acute hypoxia in vivo. Male C57BL/6N CrSlc mice were exposed to a hypoxic insult as a result of bleeding-related anemia or hypoxemia while they were under anesthetized using various concentrations of isoflurane. EPO protein concentrations were assessed by enzyme-linked immunosorbent assay and mRNA levels were measured by quantitative real-time reverse transcriptase-polymerase chain reaction. Plasma EPO concentration was induced as early as 3h following acute anemic and hypoxemic hypoxia and suppressed by clinically relevant doses of isoflurane in a dose-dependent manner. Anemic hypoxia induced EPO mRNA and protein synthesis in the kidney. In the kidney, isoflurane inhibited EPO induction caused by anemia but not that caused by hypoxemia. On the other hand, in the brain hypoxemia-induced EPO production was suppressed by isoflurane. Finally, qRT-PCR studies demonstrate that isoflurane differentially inhibit HIF-1α and HIF-2α mRNA expression in brain and kidney, indicating the involvement of HIF-2 in the hypoxia-induced EPO expression and inhibition of the induction by isoflurane.