Remimazolam anaphylaxis in a patient not allergic to brotizolam: a case report and literature review.

BACKGROUND: Remimazolam is a recently developed, ultrashort-acting benzodiazepine that is used as a general anesthetic. Some cases of remimazolam anaphylaxis have been reported, but its characteristics are not fully understood. We present an interesting case report and review of the literature to better understand remimazolam anaphylaxis. CASE PRESENTATION: A 75-year-old man scheduled for robot-assisted gastrectomy was administered remimazolam for the induction of general anesthesia. After intubation, low end-expiratory CO2, high airway pressure and concurrent circulatory collapse were observed. Bronchoscopy revealed marked tracheal and bronchial edema, which we diagnosed as anaphylaxis. The patient suffered cardiac arrest after bronchoscopy but recovered immediately with intravenous adrenaline administration and chest compressions. We performed skin prick tests for the drugs used during induction except for remimazolam, considering the high risk of systemic adverse reactions to remimazolam. We diagnosed remimazolam anaphylaxis because the skin prick test results for the other drugs used during anesthesia were negative, and these drugs could have been used without allergic reactions during the subsequent surgery. Furthermore, this patient had experienced severe anaphylactic-like reactions when he underwent cardiac surgery a year earlier, in which midazolam had been used, but it was not thought to be the allergen at that time. Based on these findings, cross-reactivity to remimazolam and midazolam was suspected. However, the patient had previously received another benzodiazepine, brotizolam, to which he was not allergic, suggesting that cross-reactivity of remimazolam may vary among benzodiazepines. In this article, we reviewed the 11 cases of remimazolam anaphylaxis that have been described in the literature. CONCLUSIONS: Remimazolam is an ultrashort-acting sedative; however, it can cause life-threatening anaphylaxis. In addition, its cross-reactivity with other benzodiazepines is not fully understood. To increase the safety of this drug, further research and more experience in its use are needed.

Neuraminidase inhibition promotes the collective migration of neurons and recovery of brain function.

In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell-cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning.

Peripheral neuropathy in the pre-diabetic state of the type 2 diabetes mouse model (TSOD mice) involves TRPV1 expression in dorsal root ganglions.

Peripheral neuropathy, which is a complication of diabetes mellitus (DM), is thought to occur in the pre-DM state, being known as impaired glucose tolerance (IGT) neuropathy, although its pathogenesis is unknown. Since it is reversible, an effective treatment at the pre-DM stage could stop the progression of peripheral neuropathy and improve patients' quality of life and reduce medical costs. We investigated the hypersensitivity to mechanical and thermal stimuli during the pre-DM state in Tsumura Suzuki Obese Diabetes (TSOD) mice, a type 2 DM mouse model. The expression pattern of the Transient Receptor Potential Vanilloid 1 (TRPV1)-positive cells in the dorsal root ganglia (DRG) was examined in TSOD mice, which showed a pre-DM state at 5-12 weeks of age and decreased mechanical and thermal nociceptive thresholds. Additionally, the size of TRPV1-positive cells in TSOD mice increased compared with that in non-diabetic controls (Tsumura Suzuki Non-Obesity; TSNO). Furthermore, the expression of TRPV1 on myelinated nerve fibers (neurofilament heavy-positive cells) had significantly increased. Thus, TSOD mice in the pre-DM state at 5-12 weeks of age could be a useful animal model of IGT neuropathy. We also hypothesized that the development of IGT neuropathy may involve a switch in TRPV1 expression from small, unmyelinated neurons to large, myelinated neurons in the DRG.

Trends and patterns in the practice of pediatric sedation for magnetic resonance imaging in Japan: A longitudinal descriptive study from 2012 to 2019.

BACKGROUND: Worldwide, pediatric sedation for magnetic resonance imaging is a standard practice; however, there are few studies on its trends and patterns. AIMS: This study aimed to investigate the trends and patterns of pediatric sedation for magnetic resonance imaging in Japan and determine the incidence of and risk factors for adverse events/interventions. METHODS: This longitudinal descriptive study assessed children (age < 15 years) who underwent sedation for magnetic resonance imaging between April 2012 and December 2019 in Japan using a nationwide claims database. We assessed the patients' demographic characteristics, time trends in sedatives, sedative patterns by age, and adverse events/interventions within two post-sedation days. Further, we used multivariable logistic regression models to explore factors related to the incidence of adverse events/interventions. RESULTS: We identified 29 187 cases (median age, 2.0 years; 55.2% males). The most common sedative was triclofos sodium (n = 18 812, 51.7%). There was an increasing trend in barbiturate use (17.0% [2012] to 25.0% [2019]) and decreasing trends in the use of triclofos sodium (56.4% [2012] to 47.7% [2019]) and chloral hydrate (15.6% [2012] to 10.8% [2019]). We identified 534 adverse events/interventions in 460 cases (1.5%). Multivariable logistic regression analyses revealed that the incidence of adverse events/interventions mainly increased with the number of sedatives (≥3; adjusted odds ratio, 5.10; 95% confidence interval, 3.67-7.10) and unscheduled setting (adjusted odds ratio, 6.28; 95% confidence interval, 4.85-8.61); further, it decreased with high hospital procedure volume (adjusted odds ratio, 0.62; 95% confidence interval, 0.49-0.78). CONCLUSIONS: Based on a Japanese real-world setting, there is an increasing trend in barbiturate use and decreasing trends in the use of triclofos sodium and chloral hydrate in pediatric sedation for magnetic resonance imaging. Low hospital procedure volumes were associated with an increased risk of adverse events/interventions.

General Anesthetic Management of a Child With Horseshoe Lung and Left Lung Hypoplasia for Cheiloplasty: A Case Report.

Horseshoe lung is an extremely rare congenital malformation in which the right and left lungs are fused due to stenosis of the lung parenchyma. In anesthetic management, it is important to avoid hypoxemia and hypercapnia caused by a decline in lung capacity and functional residual capacity. A 3-year-old boy with horseshoe lung and left lung hypoplasia was scheduled to undergo cheiloplasty. Regarding respiratory management, to prevent hypoxemia and hypercapnia, we avoided intraoperative peripheral airway obstruction with positive end-expiratory pressure, set a long inspiratory phase time for sufficient alveolar expansion, and maintained sufficient gas exchange in lungs with low reserve capacity.

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA.

Throughout life, new neurons generated in the ventricular-subventricular zone take the long journey to the olfactory bulb. The intracellular mechanisms that precisely control the neurons' migration speed, enabling their well-organized movement, remain unclear. Rho signalling is known to affect the morphology and movement of various cell types, including neurons. Here we identify Gem-interacting protein (Gmip), a RhoA-specific GTPase-activating protein, as a key factor in saltatory neuronal migration. RhoA is activated at the proximal leading process of migrating neurons, where Gmip is also localized and negatively regulates RhoA. Gmip controls the saltatory movement of neurons that regulate their migration speed and 'stop' positions in the olfactory bulb, thereby altering the neural circuitry. This study demonstrates that Gmip serves as a brake for the RhoA-mediated movement of neuronal somata, and highlights the significance of speed control in the well-organized neuronal migration and the maintenance of neuronal circuits in the postnatal brain.

Rac1-mediated indentation of resting neurons promotes the chain migration of new neurons in the rostral migratory stream of post-natal mouse brain.

New neurons generated in the ventricular-subventricular zone in the post-natal brain travel toward the olfactory bulb by using a collective cell migration process called 'chain migration.' These new neurons show a saltatory movement of their soma, suggesting that each neuron cycles through periods of 'rest' during migration. Here, we investigated the role of the resting neurons in chain migration using post-natal mouse brain, and found that they undergo a dynamic morphological change, in which a deep indentation forms in the cell body. Inhibition of Rac1 activity resulted in less indentation of the new neurons in vivo. Live cell imaging using a Förster resonance energy transfer biosensor revealed that Rac1 was activated at the sites of contact between actively migrating and resting new neurons. On the cell surface of resting neurons, Rac1 activation coincided with the formation of the indentation. Furthermore, Rac1 knockdown prevented the indentation from forming and impaired migration along the resting neurons. These results suggest that Rac1 regulates a morphological change in the resting neurons, which allows them to serve as a migratory scaffold, and thereby non-cell-autonomously promotes chain migration.

Proteomic analysis of Girdin-interacting proteins in migrating new neurons in the postnatal mouse brain.

Neural stem cells continuously generate new neurons in the ventricular-subventricular zone (V-SVZ) of the postnatal and adult mammalian brain. New neurons born in the rodent V-SVZ migrate toward the olfactory bulb (OB), where they differentiate into interneurons. To reveal novel intracellular molecular mechanisms that control postnatal neuronal migration, we performed a global proteomic search for proteins interacting with Girdin, an essential protein for postnatal neuronal migration. Using GST pull-down and LC-MS/MS shotgun analysis, we identified cytoskeletal proteins, cytoskeleton-binding proteins, and signal-transduction proteins as possible participants in neuronal migration. Our results suggest that Girdin and Girdin-interacting proteins control neuronal migration by regulating actin and/or microtubule dynamics.

[Reappraisal of current practice of preoperative fasting in Japan].

BACKGROUND: The American Society of Anesthesiologists (ASA) published a clinical practice guideline of preoperative fasting in 1999. A nationwide survey conducted in Japan in 2003 reveals that many hospitals have a much longer fasting period. We conducted a similar survey in three limited areas in Japan to assess the changes in fasting practice. METHODS: A written questionnaire for preoperative fasting was sent to 50 hospital in 3 prefectures. RESULTS: The duration of fasting for liquids tends to be shorter than those in the 2003 survey. The rates of application of the ASA guideline, however, are still low specifically in adults (4.2%), which is significantly lower than those in children (17.7%), or in infants (39.0%). The reasons for noncompliance are mainly due to organizational problems associated with scheduling of operation. Most hospitals aspire to have Japanese guideline about preoperative fasting periods. CONCLUSIONS: Longer preoperative fasting periods are still common practice in Japanese hospitals.

Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain.

In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed "chain migration." The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin's C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell-cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.

Pretreatment of macrophages with the combination of IFN-gamma and IL-12 induces resistance to Leishmania major at the early phase of infection.

Interferon (IFN)-gamma is essential but not sufficient to control leishmaniasis. It is known that IFN-gamma is one of the major macrophage-activating cytokines, and the activated macrophages are a principal source of interleukin (IL)-12, which induces autocrine macrophage activation. In this study, the combined effect of IFN-gamma and IL-12 on the susceptibility of macrophages to Leishmania major infection was evaluated. Macrophages pretreated with IFN-gamma and/or IL-12 were infected with the parasites. Four hr post-infection (p.i.), the levels of infection and parasite load in the macrophages treated with the combination of IFN-gamma and IL-12 (IFN-gamma/IL-12) were significantly lower than those in the nontreated cells. However, the macrophages treated with either IFN-gamma or IL-12 did not show resistance to L. major infection. In addition, 72 hr p.i., the IFN-gamma/IL-12-treated and IFN-gamma-treated macrophages showed significantly lower levels of infection and parasite load than the nontreated cells, and higher levels of resistance was observed in the IFN-gamma/IL-12-treated macrophages than in the IFN-gamma-treated macrophages. Although IFN-gamma/IL-12 treatment of macrophages prior to the infection led to the induction of resistance, as described above, this resistance was not induced when these cytokines and the parasites were added simultaneously to the macrophage culture. These results suggest that IFN-gamma/IL-12 treatment prior to the infection restricts the early phase of the infection.

A fusion protein of IgG fc and mouse-derived antigen on the surface of pseudorabies virus particles does not accelerate production of harmful auto-reactive antibodies.

Previously we reported that immunization with pseudorabies virus (PRV), harboring chimeric Fc on the surface of the virus particles (PRV/Fc), induced higher immune responses than normal PRV particles. The chimeric Fc was fused with mouse transferrin receptor of transmembrane domain (mTR) and the Fc region of immunoglobulin G1. Since it has been reported that some chimeric protein of Fc and self-antigen induce auto-reactive antibodies, in this present study, we examined whether PRV/Fc induces auto-reactive antibodies that react with mTR. PRV/Fc immunized mice produced higher levels of anti-PRV antibodies and antibodies that reacted with mouse-derived 3T3/A31 cells (A31 cell), compared to normal PRV immunized mice. However, antibodies that reacted with mTR in A31 cells were not detected in both Western blot analyses and indirect immunofluorescence assay. The antibodies reacted with an antigen of approximately 16 kDa in A31 cells, but this antigen has a different molecular mass from that of mTR. The antibody also reacted with the antigen of approximately 16 kDa in RK13 cells in which the virus had been propagated. In addition, antibodies induced by immunization with normal PRV also reacted with the same antigen in A31 and RK13 cells. Moreover, neither kidney disorders, in which high levels of mTR were expressed, nor clinical symptoms of autoimmune diseases were observed in mice immunized with either PRV or PRV/Fc. These results indicated that the antibodies were not induced by mTR-Fc, but were instead induced by trace amounts of RK13 derived antigens contained in PRV or PRV/Fc preparations, and cross-reacted with equivalent molecules in mouse derived A31 cells. Therefore, this study confirmed that immunization with PRV/Fc did not induce harmful auto-reactive antibodies.

Ventilator weaning using a fenestrated tracheostomy tube with a speaking valve.

We describe two patients with tracheostomies who showed difficulty in weaning from mechanical ventilation, but were eventually weaned after use of a fenestrated tracheostomy tube with a speaking valve. The first patient underwent mechanical ventilation after pulmonary bleeding, while the second needed ventilator support because of tracheomalacia. Both patients needed only slight ventilator support but developed respiratory distress when it was discontinued. When the standard tracheostomy tube was replaced by a fenestrated tracheostomy tube with a speaking valve, each patient was easily weaned from mechanical ventilation. With a valved tube, vocal cords can exert part of their original function during expiration. The valved tube allowed the first patient to control breath-holding, and the second to avoid tracheal collapse. Regaining vocal cord function improved their pulmonary mechanics, which was demonstrated by dramatic improvement of findings on chest x-ray and computed tomography. A fenestrated tracheostomy tube is usually used to improve daily activities of patients with tracheostomies, but might be worth trying for difficult ventilator weaning.

Cell surface expression of a chimeric protein containing mouse immunoglobulin G1 Fc domain and its immunological property.

Recently we reported that a chimeric molecule containing mouse transferrin receptor and immunoglobulin G1 (IgG1) Fc, mTR-Fc, induced higher immune responses and can be used as a vaccine adjuvant. In this study, the immunological property of the molecule was investigated. Although, the mTR-Fc did not activate complement classical pathway, it was recognized by activated macrophage as like intact IgG Fc, which is recognized by macrophage via Fcgamma receptor. In addition, we found that splenocyte simultaneously exposed to lipopolysaccaride (LPS) and mTR-Fc produced higher amount of interleukin-10, comparing to that exposed to only LPS. These results suggest that the mTR-Fc molecules conserved the IgG Fc property to biasing immune responses via modulation of cytokine production by antigen presenting cell.

Immunization with pseudorabies virus harboring Fc domain of IgG makes a contribution to protection of mice from lethal challenge.

To enhance the efficacy of an inactivated vaccine against pseudorabies virus (PRV), we evaluated the adjuvant properties of Fc domain of IgG. A cell line expressing mouse IgG Fc chimera on its surface was established. We found that when PRV was propagated in the cells expressing the Fc chimera, PRV virion incorporated the Fc. Immunization of BALB/c mice with inactivated PRV harboring Fc, which had been propagated in the cells expressing Fc on its surface, induced higher antibody production against PRV and protected mice more effectively from lethal challenge of virulent strain, comparing to the immunization with normal inactivated virus. Virus harboring Fc has a great potential as a new inactivated vaccine.