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.

Population pharmacokinetics and pharmacodynamic target attainment analysis of cefazolin using total and unbound serum concentration in patients with prostatectomy or nephrectomy.

The aim of this study was to analyze the population pharmacokinetics of total and unbound concentrations of prophylactic cefazolin (CFZ) in patients with prostatectomy or nephrectomy. We also aimed to calculate a pharmacodynamics target unbound concentration that exceeded the minimum inhibitory concentration (MIC), to design an effective dosing regimen. Briefly, 614 total concentration and 610 unbound concentration samples from 152 individuals were evaluated, using a nonlinear mixed-effects model. The obtained pharmacodynamics index target value reflected the probability of maintaining CFZ unbound trough concentrations exceeding MIC90, 0.5 mg/L, and MIC50, and 1.0 mg/L, to account for methicillin-susceptible Staphylococcus aureus (MSSA) or Escherichia coli. Population pharmacokinetics were estimated using a two-compartment model with nonlinear protein binding. Unbound systemic clearance (CL) was significantly associated with creatinine clearance, while the maximum protein-binding constant was significantly associated with albumin levels. The probability of achieving an unbound concentration exceeding the MIC50 for E. coli or MIC90 for MSSA in a patient with normal renal function following a 1 g CFZ infusion over 15 min was above 90% at 3 h after the initial dose. Our findings indicated that population pharmacokinetic parameters are useful for determining unbound CFZ pharmacokinetics and evaluating intraoperative CFZ redosing intervals.

EFA6A, an Exchange Factor for Arf6, Regulates NGF-Dependent TrkA Recycling From Early Endosomes and Neurite Outgrowth in PC12 Cells.

Endosomal trafficking of TrkA is a critical process for nerve growth factor (NGF)-dependent neuronal cell survival and differentiation. The small GTPase ADP-ribosylation factor 6 (Arf6) is implicated in NGF-dependent processes in PC12 cells through endosomal trafficking and actin cytoskeleton reorganization. However, the regulatory mechanism for Arf6 in NGF signaling is largely unknown. In this study, we demonstrated that EFA6A, an Arf6-specific guanine nucleotide exchange factor, was abundantly expressed in PC12 cells and that knockdown of EFA6A significantly inhibited NGF-dependent Arf6 activation, TrkA recycling from early endosomes to the cell surface, prolonged ERK1/2 phosphorylation, and neurite outgrowth. We also demonstrated that EFA6A forms a protein complex with TrkA through its N-terminal region, thereby enhancing its catalytic activity for Arf6. Similarly, we demonstrated that EFA6A forms a protein complex with TrkA in cultured dorsal root ganglion (DRG) neurons. Furthermore, cultured DRG neurons from EFA6A knockout mice exhibited disturbed NGF-dependent TrkA trafficking compared with wild-type neurons. These findings provide the first evidence for EFA6A as a key regulator of NGF-dependent TrkA trafficking and signaling.

Investigation of real-world heparin resistance and anticoagulation management prior to cardiopulmonary bypass: report from a nationwide survey by the Japanese Association for Thoracic Surgery heparin resistance working group.

OBJECTIVE: Heparin resistance is often encountered during cardiopulmonary bypass. Heparin dose and activated clotting time target values for the initiation of cardiopulmonary bypass are not yet universally standardized; further no consensus exists on the management of heparin resistance. This study aimed to investigate the current real-world practice on heparin management and anticoagulant treatment for heparin resistance in Japan. METHODS: A questionnaire survey was conducted at medical institutions nationwide with which The Japanese Society of Extra-Corporeal Technology in Medicine members are affiliated, targeting surgical cases with cardiopulmonary bypass performed from January 2019 through December 2019. RESULTS: Among 69% (230/332) of the participating institutions, the criterion for heparin resistance was defined as "the target activated clotting time value not reached even with an additional dose of heparin administration". Cases of heparin resistance were reported in 89.8% (202/225) of the responded institutions. Of note, 75% (106/141) of the responded institutions reported heparin resistance associated with antithrombin activity ≥ 80%. Antithrombin concentrate was used in 38.4% (238/619 responses) or third dose of heparin in 37.8% (234/619 responses) for advanced heparin resistance treatment. Antithrombin concentrate was found to be effective in resolving heparin resistance in patients having normal, as well as lower antithrombin activity. CONCLUSION: Heparin resistance has occurred in many cardiovascular centers, even among patients with normal antithrombin activities. Interestingly, the administration of antithrombin concentrate resolved heparin resistance, regardless of the baseline antithrombin activity value.

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.

Physiological and Pathological Roles of the Cytohesin Family in Neurons.

The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances in molecular biological techniques and the development of a specific pharmacological inhibitor for cytohesins, SecinH3, have revealed the functional involvement of the cytohesin-Arf pathway in diverse neuronal functions from the formation of axons and dendrites, axonal pathfinding, and synaptic vesicle recycling, to pathophysiological processes including chronic pain and neurotoxicity induced by proteins related to neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we review the physiological and pathological roles of the cytohesin-Arf pathway in neurons and discuss the future directions of this research field.

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.

Timing of re-dosing based on population pharmacokinetic-pharmacodynamics target attainment analysis of cefmetazole in subjects undergoing lower gastrointestinal surgery.

INTRODUCTION: This study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval. METHODS: Serum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae RESULTS: The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr â‰§ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr â‰§ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h. CONCLUSIONS: We evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

Association of serum and fat tissue antibiotic concentrations with surgical site infections in lower gastrointestinal surgery.

BACKGROUND: During surgery, the effectiveness of perioperative prophylactic antibiotic administration against surgical site infections is inferred from serum concentrations and not from tissues where local infections occur. This study aimed to measure the serum and tissue concentrations of cefmetazole in colorectal surgery cases to clarify whether there is an association between the incidence of surgical site infections and antibiotic concentrations. METHODS: This prospective cohort study was performed at a single tertiary care center. The data of 105 patients who underwent colorectal surgery between October 2017 and September 2019 were evaluated. The primary outcome was the incidence of surgical site infections. Univariate analysis was performed to investigate the association between surgical site infections, perioperative factors, and the serum and tissue concentrations of cefmetazole. RESULTS: The incidence of surgical site infections was 13/105 (12.4%). Cefmetazole concentrations were measured at initial incision (serum; 101 vs 93.1 mg/L, P = .75, subcutaneous fat tissue; 2.8 vs 3.7 mg/g, P = .15), intestinal resection (serum; 35.1 vs 36.7 mg/L, P = .63, mesenteric adipose tissue; 1.3 vs 1.7 mg/g, P = .55), and at skin closure (serum; 34.5 vs 44.8 mg/L, P = .18, subcutaneous fat tissue; 1.0 vs 2.2 mg/g, P = .09). In univariate analysis with P ≤ .10, cefmetazole concentration in subcutaneous fat tissue at skin closure was found to be a significant risk factor for surgical site infections. Age, additional intraoperative administration of cefmetazole, and creatinine clearance were also significant risk factors for the occurrence of surgical site infections. CONCLUSION: Low subcutaneous fat cefmetazole concentrations at skin closure during gastrointestinal operations may also be involved in the occurrence of surgical site infections.

Cytohesin-2 mediates group I metabotropic glutamate receptor-dependent mechanical allodynia through the activation of ADP ribosylation factor 6 in the spinal cord.

Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, in the spinal cord are implicated in nociceptive transmission and plasticity through G protein-mediated second messenger cascades leading to the activation of various protein kinases such as extracellular signal-regulated kinase (ERK). In this study, we demonstrated that cytohesin-2, a guanine nucleotide exchange factor for ADP ribosylation factors (Arfs), is abundantly expressed in subsets of excitatory interneurons and projection neurons in the superficial dorsal horn. Cytohesin-2 is enriched in the perisynapse on the postsynaptic membrane of dorsal horn neurons and forms a protein complex with mGluR5 in the spinal cord. Central nervous system-specific cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia in inflammatory and neuropathic pain models. Pharmacological blockade of cytohesin catalytic activity with SecinH3 similarly reduced mechanical allodynia and inhibited the spinal activation of Arf6, but not Arf1, in both pain models. Furthermore, cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia and ERK1/2 activation following the pharmacological activation of spinal mGluR1/5 with 3,5-dihydroxylphenylglycine (DHPG). The present study suggests that cytothesin-2 is functionally associated with mGluR5 during the development of mechanical allodynia through the activation of Arf6 in spinal dorsal horn neurons.

Use of electrical muscle stimulation body massager (EMS-BMs) improves deep venous blood flow.

We investigated whether using electrical muscle stimulation body massagers (EMS-BMs) for the passive contraction of the lower extremity muscles reduces venous stasis in the deep veins of the lower extremities. In this randomized crossover design study of 20 healthy volunteers between November 2018 and February 2019, we measured both the popliteal and femoral vein peak velocities (PV, cm/s) and blood flow volumes (BFV,mL/min), using pulsed-wave Doppler ultrasound at rest (baseline), and at 2 and 10 min after starting EMS-BM use. Two EMS types: types A (two small pads) and B (one large pad) devices respectively, were examined. The PVs of the femoral (A: 23±7, B: 25±8) and popliteal (A: 26±12, B: 27±12) veins and BFV of types A (107±46) and B (141±88) of the femoral vein were significantly increased compared to the baseline (PV of femoral vein: 19±9, PV of popliteal vein: 14±5, BFV of popliteal vein: 81±46) (P<0.01). No significant differences occurred between the devices in the PV or BFV at either 2 or 10 min. Regardless of the type of stimulation or the shape of the pad, contraction of the lower limb muscles by EMS-BM effectively reduces venous stasis in the lower limb.

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.

Correction to: Awake fiberoptic intubation with an epidural catheter in a morbidly obese patient.

In the original publication of the article, the acknowledgment section was not included and provided in this correction.

Awake fiberoptic intubation with an epidural catheter in a morbidly obese patient.

We report successful awake intubation in a morbidly obese patient (body mass index of 61.2) using an epidural catheter inserted through the external forceps channel of the fiberscope for delivery of local anesthetic. Direct application of local anesthetic to the pharyngolaryngeal area and proximal tracheal, through the use of a relatively firm epidural catheter. We conclude that awake intubation can be achieved by this method which spares the subsequent use of any sedative drugs.

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.