RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that induces cytokine hypersecretion. Receptor activity-modifying protein (RAMP) 1, a subunit of the calcitonin gene-related peptide (CGRP) receptor, regulates the production of cytokines. This study examined the role of RAMP1 signaling during lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS administration to wild-type (WT) mice depleted alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) and neutrophils. RAMP1-deficient (RAMP1-/-) mice exhibited higher lung injury scores, cytokine levels, and cytokine-producing neutrophil infiltration. RAMP1-deficient AMs produced more cytokines in response to LPS than WT AMs. Adoptive transfer of RAMP1-deficient AMs to RAMP1-/- mice increased cytokine levels and neutrophil accumulation compared to the transfer of WT AMs. RAMP1-/- mice had reduced MDM recruitment and lower pro-inflammatory and reparative macrophage profiles. Cultured bone marrow (BM)-derived RAMP1-deficient macrophages stimulated with LPS showed decreased expression of pro-inflammatory and pro-repairing genes. CGRP administration to WT mice reduced cytokine production and neutrophil accumulation. These findings indicate that RAMP1 signaling mitigates LPS-induced ALI by inactivating AMs and promoting inflammatory and repair activities of MDMs. Targeting RAMP1 signaling presents a potential therapeutic approach for the treatment of ARDS.

Airway Management for Massive Anterior Mediastinal Tumor Resection in an Infant: A Strategy Involving Spontaneous Breathing-Preserving Endotracheal Intubation under Intravenous Anesthesia.

Tracheal intubation under sedation in uncooperative infants is challenging. The case of a 4-month-old infant with a massive anterior mediastinal tumor and upper respiratory tract symptoms, for whom effective preoxygenation was provided with a high-flow nasal cannula (HFNC), allowing for safe tracheal intubation in combination with a supraglottic device and local anesthetic, is reported. With careful planning of anesthesia and creative problem solving, airway management for anterior mediastinal tumors can be performed safely with the selection of an appropriate airway device. This may be a good airway management strategy for infants with mediastinal tumors or who may be expected to have ventilation difficulties.

Ultraearly Hematoma Evacuation (<12 Hours) Associated with Better Functional Outcome in Patients with Symptomatic Spontaneous Spinal Epidural Hematoma.

BACKGROUND: Early decompressive surgery within 24 hours improves the functional outcome of patients with traumatic spinal cord injury; however, little is known about the effect of early surgery for spontaneous spinal epidural hematoma (SSEH). In this study, we aimed to investigate the effectiveness of ultraearly hematoma evacuation (<12 hours) for SSEH. METHODS: Patients with SSEH treated with surgical hematoma evacuation at our institution between January 2000 and July 2021 were retrospectively analyzed. Neurologic function was evaluated using the American Spinal Injury Association Impairment Scale (AIS). AIS grades A-C were defined as severe, and grades D and E as mild. AIS grades D and E at the final follow-up were considered favorable outcomes. Preoperative status and postoperative treatment results were compared between patients who had hematoma evacuation within 12 hours of onset and those who underwent surgery after 12 hours. RESULTS: Twenty-five consecutive patients were included in the analysis. Preoperatively, 23 patients (92.0%) had severe AIS. Fourteen (56.0%) patients underwent early surgery. At the final follow-up, 21 patients (84.0%) achieved favorable outcomes. Patients treated with ultraearly surgery had significantly better outcomes (100% vs. 63.6%, P = 0.03). Additionally, the time from onset to surgery was significantly shorter in patients with AIS improvement by 2 or more grades than that in patients with AIS improvement of 1 or less (median 8 hours vs. 14 hours, P = 0.0001). CONCLUSIONS: Ultraearly surgery within 12 hours for SSEH was associated with better functional outcomes.

General anesthesia for treating scoliosis with congenital myasthenia syndrome: a case report.

BACKGROUND: Congenital myasthenia syndrome is a heterogeneous disease with impaired neuromuscular transmission. CASE PRESENTATION: This report describes a 13-year-old child with congenital myasthenia syndrome who underwent surgery for scoliosis under general anesthesia. We used a small dose of rocuronium, neuromuscular transmission monitoring, and non-invasive positive pressure ventilation for postoperative respiratory management. There were no respiratory complications during the perioperative period. CONCLUSION: As there are only a few reports on the anesthetic management of patients with congenital myasthenia syndrome, we applied the principles of managing autoimmune myasthenia gravis. The postoperative management described herein can prevent respiratory complications in patients with congenital myasthenia syndrome.

Effects of General Anesthesia on Ocular Refraction.

PURPOSE: General anesthesia alters the autonomic nervous system. This study aimed to investigate the effects of general anesthesia on objective ocular refraction. METHODS: A total of 57 patients (112 eyes) under 15 years of age who underwent strabismus surgery under general anesthesia were included in this study. Objective refraction values, corneal refraction values, and pupil diameter were measured using a HandyRef-K, a hand-held refractive keratometer, in the operating room before and during general anesthesia before strabismus surgery. RESULTS: The spherical power of the myopic eye increased from -0.75 D to -2.29 D (diopter); the cylindrical power increased from -0.90 D to -1.39 D (p < .01 for all). The corneal refractive power decreased by an average of 0.25 D (p < .01). The spherical refractive power was negatively correlated with the age and the amount of change between cycloplegia before general anesthesia and during general anesthesia (r = -0.32, p < .05). CONCLUSIONS: General anesthesia resulted in manifestation of myopia as noted by the objective refraction values. Corneal refractive values flatten under the same conditions, suggesting that the contraction of the ciliary muscles was the main cause of myopia. We speculate that this change was due to parasympathetic dominance and contraction of the ciliary muscles during general anesthesia.

Serum concentration of oral midazolam as pediatric preanesthetic medication and factors related to the sedation level.

BACKGROUND: Preanesthetic medication is important to eliminate surgical anxiety in pediatric patients and facilitate their smooth transfer to the operating room. Midazolam is the most commonly used preanesthetic medication. However, it has been reported that the sedative effect varies from patient to patient. In this study, the pharmacokinetics of midazolam were examined, and the aim was to assess the factors affecting the quality of sedation. METHODS: The participants were children ranging in age from 6 months to 8 years scheduled for surgery. Midazolam 0.5 mg/kg was administered orally 30 min before entering the operating room, and the sedation level was evaluated at the time of mask application. Blood was collected after slow induction, and the serum concentration of midazolam was measured using high-performance liquid chromatography. RESULTS: A total of 98 patients were registered. There was no difference in serum concentrations between the effective sedation group and the ineffective sedation group (48.0 vs. 49.1 ng/mL), regardless of the effect of midazolam. Percentages of ineffective sedation by age (0 to 7 years) were 66.6%, 60%, 33.3%, 11.1%, 0%, 0%, 12.5%, and 0%, respectively. On multivariate logistic regression analysis, siblings (OR = 3.9, CI: 1.1-14.0, p = .03) and age (OR = 3.2, CI:1.2-8.5, p = .02) were related to an insufficient sedative effect. CONCLUSION: The serum concentration of oral midazolam reached effective levels even in patients in whom the sedative effect was inadequate. It is important to manage the perioperative period with appropriate concurrent premedication taking into account patient age and social background characteristics. CLINICAL TRIAL REGISTRATION: Clinical trial registry: UMIN R000052504.

Roles of Thromboxane Receptor Signaling in Enhancement of Lipopolysaccharide-Induced Lymphangiogenesis and Lymphatic Drainage Function in Diaphragm.

[Figure: see text].

Six-Minute Walk Test Predicts Postoperative Delirium After Transcatheter Aortic Valve Replacement.

OBJECTIVE: This study investigated the incidence and risk factors of postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR) and to evaluate the association between preoperative conditions, particularly frailty, and POD. DESIGN: Observational, case-control study. SETTING: Single-center university hospital. PARTICIPANTS: The study comprised 124 patients who underwent TAVR and were divided into the following two groups: group D (patients diagnosed with POD) and group C (patients without POD). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients (21.7%) developed POD (95% confidence interval 14.9%-30.1%). POD was defined as a diagnosis of delirium using the Confusion Assessment Method for Intensive Care Unit scale during the patients' intensive care unit stay. Preoperative and postoperative data of patient characteristics were obtained from their medical records. A multivariate logistic regression analysis was performed using variables associated with POD incidence. Frailty scores were significantly higher in group D than in group C. The distance covered in the six-minute walk test (6MD) was significantly shorter in group D than in group C. The risk of developing POD was significantly higher in patients with a 6MD shorter than 220 m. Multivariate logistic regression analysis showed that a shorter 6MD was an independent risk factor for POD (odds ratio 5.66; p = 0.004). CONCLUSION: In the present study, POD was seen in 21.7% of the patients who underwent TAVR. A 6MD shorter than 220 m was an independent preoperative risk factor for POD. For patients at high risk of POD, more careful management in the perioperative period may reduce POD.

Risk factors associated with prolonged intensive care unit stay after posterior spinal fusion for Duchenne muscular dystrophy.

BACKGROUND: The perioperative complication rate for spinal fusion in Duchenne muscular dystrophy (DMD) remains high and sometimes prolonged perioperative intensive care is needed. We investigated preoperative and intraoperative risk factors associated with prolonged intensive care unit (ICU) stay after posterior spinal fusion. METHODS: We reviewed the records of 49 consecutive DMD patients who underwent posterior spinal fusion. Instrumentation was performed from T4 to L5 (46 cases) or to the ilium (3 cases). We recorded the preoperative Cobb angle and perioperative clinical data from patient records. Patients were divided into two groups (ICU stay 0 or 1 day, 2 days or longer). Chi-square and t tests were used for univariate analysis. Factors with p < 0.05 in the univariate analysis were entered into a multilevel logistic regression analysis. RESULTS: The average age of patients at surgery was 14.2 years (range 11-20 years). Their preoperative Cobb angle was 79.2° (range 40°-154°). Average operative time was 325.3 min (range 225-507 min). The average estimated blood loss (EBL) was 1673.0 ml (range 500-3785 ml). Eight patients stayed in the ICU for 2 days or longer for postoperative monitoring and treatment. Univariate analysis found statistical difference between the two groups in preoperative Cobb angle, Thoracolumbar kyphosis, %VC, operation time, and EBL during surgery. After multiple logistic regression analysis, Cobb angle and EBL was identified as an independent factor. The patients with a larger Cobb angle and greater EBL had a higher rate of prolonged ICU stay in interquartile range-based comparison. CONCLUSIONS: The present study suggests the preoperative Cobb angle and intraoperative EBL could be predictors for postoperative course in posterior spinal fusion for DMD patients.

RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis.

Calcitonin gene-related peptide (CGRP) regulates inflammation via signaling through receptor activity-modifying protein (RAMP) 1. Here, we investigated the role of RAMP1 signaling in growth of lymphatic vessels during inflammation. Lymphangiogenesis in the diaphragm of RAMP1-deficient (-/-) mice or their wild-type (WT) counterparts was induced by repeated intraperitoneal injection of lipopolysaccharide (LPS). Compared with WT mice, LPS-induced lymphangiogenesis in RAMP1-/- mice was suppressed. This was accompanied by the reduced expression of vascular endothelial growth factor (VEGF)-C and VEGF-D. The number of CD4+ cells in diaphragm tissue from WT mice was greater than RAMP1-/- mice. Removing CD4+ cells attenuated lymphangiogenesis and expression of VEGF-C and VEGF-D. CD4+ cells isolated from RAMP1-/- mice exhibited reduced expression of VEGF-C and VEGF-D. The number of CD11b+ cells from RAMP1-/- mice was higher than WT mice and was associated with the upregulated expression of genes related to pro-inflammatory macrophage phenotype and downregulation of reparative macrophage phenotype-related expression. When fluorescein isothiocyanate (FITC)-dextran was injected into the peritoneal cavity, the amount of residual FITC-dextran in WT mice was lower than that in RAMP1-/- mice. The present results suggest that RAMP1 signaling in immune cells plays a critical role in inflammation-related lymphangiogenesis; therefore, it represents a novel target for controlling lymphangiogenesis.

Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model.

AIMS: Lymphangiogenesis is frequently observed during inflammation, and this inflammation-induced lymphangiogenesis (IL) is a phenomenon actively involved in the pathophysiology of inflammation. We explored the roles of an inducible prostaglandin E synthase, mPGES-1, in IL elicited by lipopolysaccharide (LPS). MAIN METHODS: Peritonitis was induced in mice by intraperitoneal injection of LPS (E. coli 0111-B4; 25µg/mouse every 2days), and IL was evaluated by LYVE-1 immunostaining of whole-mount diaphragm tissues. KEY FINDINGS: Compared to vehicle-treated wild-type (WT) mice, lymphatics in the diaphragms of mice injected with LPS were widened and the number of LYVE-1-positive ladder-structured lymphatics increased temporally. This increase in lymphangiogenesis was accompanied by increased expression of vascular endothelial growth factor (VEGF)-C/D in the diaphragms. In mice treated with celecoxib, a cyclooxygenase-2 inhibitor, IL was suppressed with reduced expression of VEGF-C/D. This was also observed in mPGES-1 knockout mice (KO). Immunoreactive COX-2 and mPGES-1 were detected in both CD11b-positive and CD3ε-positivecells in the diaphragm. When FITC-dextran was injected into the peritoneal cavities, the amount of residual FITC-dextran was reduced significantly in WT mice injected with LPS, and this reduction was significantly decreased in mPGES-1 KO mice. SIGNIFICANCE: The present results suggest that mPGES-1 plays a significant role in lymphangiogenesis during inflammation, and represents a novel target for controlling IL.

[Total intravenous anesthesia for a patient with Fukuyama congenital muscular dystrophy undergoing scoliosis surgery].

We described the anesthetic management of a 17-year-old male patient with Fukuyama congenital muscle dystrophy (FCMD) who underwent surgical repair for scoliosis under total intravenous anesthesia. The patient had severe constructive lung disease (%VC 18.6%). Left ventricular wall motion was reduced (left ventricular ejection fraction 40%). Propofol and remifentanil were continuously infused to maintain anesthesia, but we did not use any muscle relaxant throughout the course. We used arterial pressure-based cardiac output and stroke volume variation as a guide for circulatory management. We could not find any congestion on chest X-ray after the surgery. The emergence and recovery from the anesthesia was rapid and muscle strength was enough, and we could extubate the patient just after the end of the surgery. No respiratory and cardiac complications occurred during the postoperative period. Even though he was in the young age in FCMD, respiratory and cardiac complications were severely impaired. For successful anesthetic management in FCMD patient, we should take care of rapid emergence from anesthesia and also we should not impair muscle strength for good postoperative respiratory function. Appropriate hemodynamic monitoring to avoid postoperative cardiac congestion is also required.

[Prominent elevation of liver enzymes after Fontan operation].

It is known that acute liver dysfunction is one of the complications after Fontan operation. We tend to overlook it because their laboratory abnormalities are typically mild and hepatic dysfunction is an uncommon complication in children after cardiac surgery. However, this complication is likely to be an important indicator of poor prognosis. We report a patient who showed a prominent elevation of liver enzymes after Fontan operation. A year and 5 month old boy was scheduled for Fontan operation due to hypoplastic left heart syndrome. We used arterial pressure, central venous pressure and rSO2 probes (INVOS 5100, Somanetics Corp., USA) attaching on his head, abdomen and leg for circulatory management. The operation was performed with the heart beating. The blood removal tubes were inserted to the superior vena cava and inferior vena cava and the blood sending tube was inserted to the innominate artery when Norwood stage 1 was performed. After making an extracardiac conduit and a fenestration, we tried to take off the oxygenator with dopamine 5 microg x kg(-1) x min(-1), dobutamine 3 microg x kg(-1) x min(-1), isosorbide 2.5 microg x kg(-1) x min(-1). The central venous pressure was increased to 22-25 mmHg and systematic arterial pressure was unstable around 50 mmHg. We suggested the surgeons to expand the fenestration because the low flow through it was found on TEE examination, and introduced 15 ppm of nitric monoxide (NO) to decrease pulmonary vascular resistance and to control the central venous pressure at the same time. rSO2 was decreased to 50 temporarily when the oxygenator was taken off, however it was returned to 70 just after expanding the fenestration. On the first postoperative day, the patient showed marked elevations in GOT 17,305 U x l(-1), GPT 8,110 U x l(-1), gradually peaking out to GOT 105 U x l(-1), GPT 1,348 U x l(-1) by the seventh postoperative day. Hepatic dysfunction is related mainly to hemodynamic disturbances and is also related to the abdominal rSO2 and the high central venous pressure.

Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice.

Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor (CLR) to produce the receptor for calcitonin gene-related peptide (CGRP). CGRP, a 37-aa neuropeptide, is widely distributed in neuronal tissues and exerts its biological effects via CLR/RAMP1; however, the pathophysiological roles of CLR/RAMP1 remain to be clarified. To study the functions of CLR/RAMP1, we generated RAMP1-knockout (RAMP1(-/-)) mice. Compared with those of wild-type (WT) mice, wound healing and wound-induced angiogenesis were significantly suppressed in RAMP1(-/-) mice, with reduced expression of vascular endothelial growth factor (VEGF)-A. Formation of the lymphatic vessels that drain interstitial fluids was also suppressed in RAMP1(-/-) mice, with reduced expression of VEGF-C and VEGFR-3 in wound granulation tissues. RAMP1 was expressed in endothelial cells (ECs) in the preexisting skin blood vessels, but was not observed in ECs in newly formed blood or lymphatic vessels. Macrophages in the wound granulation tissues expressed RAMP1 and produced substantial amounts of VEGF-C in response to CGRP in vitro. RAMP1(-/-) bone marrow chimeric mice showed delayed wound healing with reduced angiogenesis/lymphangiogenesis in wound granulation tissues. These findings suggest that RAMP1 plays a crucial role in wound healing and wound-induced angiogenesis and lymphangiogenesis and that it is a promising target for controlling angiogenesis and lymphangiogenesis.

On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN).

Nitric oxide (NO) physiologically regulates numerous cellular responses through S-nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S-nitrosylated proteins. Using this combination of techniques, we found that phosphatase with sequence homology to tensin (PTEN) is selectively S-nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S-nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S-nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S-nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S-nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S-nitrosylation, resulting in an "on-off" pattern of control of Akt signaling.

[Case of anesthesia for laparoscopic cholecystectomy in a patient with a history of frequent anaphylaxis].

Idiopathic anaphylaxis is a rare disease that induces anaphylactic shock without extrinsic incentive. We had a patient with such frequent episodes undergoing laparoscopic cholecystectomy. Steroid was administered both at preoperative and intraoperative periods. Epidural anesthesia and general anesthesia by inhalation anesthesia, which are low risk for anaphylaxis, were used to reduce perioperative stress and restricted usage of drugs even in postoperative period. Consequently, we can safety manage anesthesia without episode of anaphylactic shock. To prepare for anaphylaxis we prepared usual therapeutic drugs for shock and measured serum tryptase, which has longer half-life than that of histamine.