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.

Development and Validation of a Prediction Model for Acute Hypotensive Events in Intensive Care Unit Patients.

Background: Persistent hypotension in the intensive care unit (ICU) is associated with increased mortality. Predicting acute hypotensive events can lead to timely intervention. We aimed to develop a prediction model of acute hypotensive events in patients admitted to the ICU. Methods: We included adult patients admitted to the Nagoya City University (NCU) Hospital ICU between January 2018 and December 2021 for model training and internal validation. The MIMIC-III database was used for external validation. A hypotensive event was defined as a mean arterial pressure < 60 mmHg for at least 5 min in 10 min. The input features were age, sex, and time-series data for vital signs. We compared the area under the receiver-operating characteristic curve (AUROC) of three machine-learning algorithms: logistic regression, the light gradient boosting machine (LightGBM), and long short-term memory (LSTM). Results: Acute hypotensive events were found in 1325/1777 (74.6%) and 2691/5266 (51.1%) of admissions in the NCU and MIMIC-III cohorts, respectively. In the internal validation, the LightGBM model had the highest AUROC (0.835), followed by the LSTM (AUROC 0.834) and logistic regression (AUROC 0.821) models. Applying only blood pressure-related features, the LSTM model achieved the highest AUROC (0.843) and consistently showed similar results in external and internal validation. Conclusions: The LSTM model using only blood pressure-related features had the highest AUROC with comparable performance in external validation.

Real-time monitoring of cortical brain activity in response to acute pain using wide-area Ca2+ imaging.

Previous human and rodent studies indicated that nociceptive stimuli activate many brain regions that is involved in the somatosensory and emotional sensation. Although these studies have identified several important brain regions involved in pain perception, it has been a challenge to observe neural activity directly and simultaneously in these multiple brain regions during pain perception. Using a transgenic mouse expressing G-CaMP7 in majority of astrocytes and a subpopulation of excitatory neurons, we recorded the brain activity in the mouse cerebral cortex during acute pain stimulation. Both of hind paw pinch and intraplantar administration of formalin caused strong transient increase of the fluorescence in several cortical regions, including primary somatosensory, motor and retrosplenial cortex. This increase of the fluorescence intensity was attenuated by the pretreatment with morphine. The present study provides important insight into the cortico-cortical network during pain perception.

Comparative efficacy of ultrasound guidance or conventional anatomical landmarks for neuraxial puncture in adult patients: a systematic review and network meta-analysis.

BACKGROUND: Preprocedural, real-time, and computer-aided three-dimensional ultrasound has been widely used for neuraxial puncture; however, the optimal guidance is unclear. We examined the comparative efficacy of three ultrasound guidance and anatomical landmarks for neuraxial puncture in adults. METHODS: We searched for randomised controlled studies comparing the efficacy of ultrasound guidance and anatomical landmarks for neuraxial puncture in adults using electronic databases and unpublished studies. The primary outcomes were first-pass success and patient satisfaction. A random-effects network meta-analysis (NMA) was used. RESULTS: We identified 74 eligible studies (7090 patients). Preprocedural ultrasound and real-time ultrasound-guided neuraxial puncture improved first-pass success compared with anatomical landmarks (risk ratio [RR] 1.6; 95% credible interval [CrI] 1.3-1.9; RR 1.9; 95% CrI 1.3-2.9, respectively, moderate confidence). Computer-aided ultrasound-guided neuraxial puncture also increased first-pass success (RR 1.8; 95% CrI 0.97-3.3, low confidence), although estimates were imprecise. However, real-time ultrasound-guided neuraxial puncture resulted in minimal difference in first-pass success compared with preprocedural ultrasound (RR 1.2; 95% CrI 0.8-1.8, moderate confidence). Preprocedural ultrasound improved patient satisfaction slightly compared with anatomical landmark use (standardised mean differences 0.28; 95% CrI 0.092-0.47, low confidence). CONCLUSIONS: This NMA provides evidence supporting ultrasound-guided neuraxial puncture compared with use of anatomical landmarks, including indirect comparisons. Among the three ultrasound guidance methods, preprocedural ultrasound appears to be a better adjunctive option.

Rapid Response System and Limitations of Medical Treatment Among Children With Clinical Deterioration in Japan: A Multicenter Retrospective Cohort Study.

Objective: We investigated the role of rapid response systems (RRSs) in limitations of medical treatment (LOMT) planning among children, their families, and health care providers. Methods: This multicenter retrospective cohort study examined children with clinical deterioration using the Japanese RRS registry between 2012 and 2021. Results: Children (n = 348) at 28 hospitals in Japan who required RRS calls were analyzed. Eleven (3%) of the 348 patients had LOMT before RRS calls and 11 (3%) had newly implemented LOMT after RRS calls. Patients with LOMT were significantly less likely to be admitted to an intensive care unit compared with those without (36% vs. 61%, p < 0.001) and were more likely to die within 30 days (45% vs. 11%, p < 0.001). Conclusions: LOMT issues existed in 6% of children who received RRS calls. RRS calls for clinically deteriorating children with LOMT were associated with less intensive care and higher mortality.

Association between postinduction hypotension and postoperative mortality: a single-centre retrospective cohort study.

PURPOSE: We aimed to elucidate whether postinduction hypotension (PIH), defined as hypotension between anesthesia induction and skin incision, and intraoperative hypotension (IOH) are associated with postoperative mortality. METHODS: We conducted a retrospective cohort study of adult patients with an ASA Physical Status I-IV who underwent noncardiac and nonobstetric surgery under general anesthesia between 2015 and 2021 at Nagoya City University Hospital. The primary and secondary outcomes were 30-day and 90-day postoperative mortality, respectively. We calculated four hypotensive indices (with time proportion of the area under the threshold being the primary exposure variable) to evaluate the association between hypotension (defined as a mean blood pressure < 65 mm Hg) and mortality using multivariable logistic regression models. We used propensity score matching and RUSBoost (random under-sampling and boosting), a machine-learning model for imbalanced data, for sensitivity analyses. RESULTS: Postinduction hypotension and IOH were observed in 82% and 84% of patients, respectively. The 30-day and 90-day postoperative mortality rates were 0.4% (52/14,210) and 1.0% (138/13,334), respectively. Postinduction hypotension was not associated with 30-day mortality (adjusted odds ratio [aOR], 1.03; 95% confidence interval [CI], 0.93 to 1.13; P = 0.60) and 90-day mortality (aOR, 1.01; 95% CI, 0.94 to 1.07; P = 0.82). Conversely, IOH was associated with 30-day mortality (aOR, 1.19; 95% CI, 1.12 to 1.27; P < 0.001) and 90-day mortality (aOR, 1.12; 95% CI, 1.06 to 1.19; P < 0.001). Sensitivity analyses supported the association of IOH but not PIH with postoperative mortality. CONCLUSION: Despite limitations, including power and residual confounding, postoperative mortality was associated with IOH but not with PIH.

RéSUMé: OBJECTIF: Nous avons cherché à déterminer si l'hypotension post-induction (HPI), définie comme une hypotension entre l'induction de l'anesthésie et l'incision cutanée, et l'hypotension peropératoire (HPO) étaient associées à la mortalité postopératoire. MéTHODE: Nous avons mené une étude de cohorte rétrospective de patient·es adultes ayant un statut physique I-IV selon l'ASA et ayant bénéficié d'une chirurgie non cardiaque et non obstétricale sous anesthésie générale entre 2015 et 2021 à l'Hôpital universitaire de la ville de Nagoya. Les critères d'évaluation principal et secondaire étaient la mortalité postopératoire à 30 et 90 jours, respectivement. Nous avons calculé quatre indices d'hypotension (la proportion temporelle de la zone sous le seuil étant la principale variable d'exposition) pour évaluer l'association entre l'hypotension (définie comme une tension artérielle moyenne < 65 mm Hg) et la mortalité à l'aide de modèles de régression logistique multivariée. Nous avons utilisé l'appariement par score de propension et le RUSBoost (sous-échantillonnage et boosting aléatoire), un modèle d'apprentissage automatique pour les données déséquilibrées, pour les analyses de sensibilité. RéSULTATS: Une HPI et une HPO ont été observées chez 82 % et 84 % des patient·es, respectivement. Les taux de mortalité postopératoire à 30 et 90 jours étaient respectivement de 0,4 % (52/14 210) et de 1,0 % (138/13 334). L'hypotension post-induction n'était pas associée à la mortalité à 30 jours (rapport de cotes ajusté [RCa], 1,03; intervalle de confiance [IC] à 95 %, 0,93 à 1,13; P = 0,60) et à la mortalité à 90 jours (RCa, 1,01; IC 95 %, 0,94 à 1,07; P = 0,82). À l'inverse, l'HPO était associée à une mortalité à 30 jours (RCa, 1,19; IC 95 %, 1,12 à 1,27; P < 0,001) et à la mortalité à 90 jours (RCa, 1,12; IC 95 %, 1,06 à 1,19; P < 0,001). Les analyses de sensibilité ont confirmé l'association de l'HPO, mais pas de l'HPI, avec la mortalité postopératoire. CONCLUSION: Malgré les limitations, y compris la puissance et persistance de facteurs confondants, la mortalité postopératoire était associée à l'hypotension peropératoire mais pas à l'hypotension post-induction seule.

Prediction model of postoperative pain exacerbation using an intravenous patient-controlled analgesia device and a wearable electrocardiogram sensor.

There is a need to develop objective and real-time postoperative pain assessment methods in perioperative medicine. Few studies have evaluated the relationship between pain severity and temporal changes of physiological signals in actual postoperative patients. In this study, we developed a machine learning model which was trained from intravenous patient-controlled analgesia (IV-PCA) records and electrocardiogram (ECG) of postoperative patients to predict pain exacerbation. A self-attentive autoencoder (SA-AE) model achieved 54% of sensitivity and a 1.76 times/h of false positive rate.Clinical relevance- We proposed a novel method for evaluating postoperative pain in real time and demonstrated the possibility of predicting pain exacerbation. The proposed method would realize the automatic administration of analgesics and the optimization of opioid doses.

Pericapsular nerve group block for osteoarthritis-related chronic hip joint pain: a case report.

BACKGROUND: Pericapsular nerve group (PENG) block has shown effectiveness for acute hip pain associated with fractures and surgery. Herein, PENG block was performed for osteoarthritis (OA)-related chronic hip joint pain. CASE PRESENTATION: A 65-year-old woman presented left hip pain. She had bilateral hip osteoarthritis that improved with medications; however, a fall resulted in left hip pain. She experienced severe pain on movements, which required walking aids. To alleviate the hip pain, a PENG block was performed under ultrasound guidance. Transient muscle weakness occurred in 2 of 5 times. After 5 blocks, she regained the ability to walk without assistive devices. Pain did not recur even after 6 months. CONCLUSIONS: Repeated PENG blocks of short-acting local anesthetics alone could be an effective pain management technique for chronic hip pain. For safety, the appropriate injection site and local anesthetic dosage must be carefully considered.

Anesthetic Management of Inguinal Hernia Surgery Using a Second-Generation Supraglottic Airway in a Patient With Trisomy 18: A Case Report.

Children with trisomy 18 have abnormal airway anatomy, making their airway management challenging. Only a few papers have comprehensively described and discussed the use of supraglottic airway devices in patients with trisomy 18. We present a case of a 20-month-old boy with trisomy 18 who was scheduled for open repair of the right inguinal hernia. He had micrognathia, a short neck, and an atrial septal defect but was in a clinically stable condition. A supraglottic airway device was inserted under general anesthesia. The patient's respiration was maintained by pressure support ventilation with spontaneous breathing. A right ilioinguinal-iliohypogastric nerve block was performed for perioperative analgesia. The surgery ended without complications. After removing the supraglottic airway device and ensuring proper respiratory parameters, the patient was transferred to the post-anesthesia care unit. In our case, supraglottic airway devices could be effectively used as a primary airway for inguinal hernia repair. The concomitant ilioinguinal-iliohypogastric nerve block was helpful for anesthetic management with spontaneous breathing maintained using pressure support ventilation. A supraglottic airway device may be a potential alternative as a primary airway for superficial surgery in pediatric patients with trisomy 18. For pediatric patients with difficult airways, a second-generation supraglottic airway device with the insertion of a gastric tube to prevent gastric insufflation combining pressure support ventilation and positive end-expiratory pressure may be a beneficial choice for the maintenance of spontaneous breathing.

Incidence and factors associated with newly implemented do-not-attempt-resuscitation orders among deteriorating patients after rapid response system activation: A retrospective observational study using a Japanese multicenter database.

Aim: The rapid response system (RRS) was initially aimed to improve patient outcomes. Recently, some studies have implicated that RRS might facilitate do-not-attempt-resuscitation (DNAR) orders among patients, their families, and healthcare providers. This study aimed to examine the incidence and factors independently associated with DNAR orders newly implemented after RRS activation among deteriorating patients. Methods: This observational study assessed patients who required RRS activation between 2012 and 2021 in Japan. We investigated patients' characteristics and the incidence of new DNAR orders after RRS activation. Furthermore, we used multivariable hierarchical logistic regression models to explore independent predictors of new DNAR orders. Results: We identified 7904 patients (median age, 72 years; 59% male) who required RRS activation at 29 facilities. Of the 7066 patients without pre-existing DNAR orders before RRS activation, 394 (5.6%) had new DNAR orders. Multivariable hierarchical logistic regression analyses revealed that new DNAR orders were associated with age category (adjusted odds ratio [aOR], 1.56; 95% confidence interval, 1.12-2.17 [65-74 years old reference to 20-64 years old], aOR, 2.56; 1.92-3.42 [75-89 years old], and aOR, 6.58; 4.17-10.4 [90 years old]), malignancy (aOR, 1.82; 1.42-2.32), postoperative status (aOR, 0.45; 0.30-0.71), and National Early Warning Score 2 (aOR, 1.07; 1.02-1.12 [per 1 score]). Conclusion: The incidence of new DNAR orders was one in 18 patients after RRS activation. The factors associated with new DNAR orders were age, malignancy, postoperative status, and National Early Warning Score 2.

Malposition of a pulmonary artery catheter in the left ventricle: a case report.

BACKGROUND: Placement of pulmonary artery catheters may be associated with a variety of complications. We present a case where a pulmonary artery catheter was accidentally advanced into the left ventricle by perforating the intraventricular septum. CASE PRESENTATION: A 73-year-old woman underwent mitral valve dysfunction. A pulmonary artery catheter could not pass the tricuspid valve under general anesthesia, which was manually advanced via the right ventricle during surgery. After valve replacement, systolic pulmonary artery pressure was higher than radial arterial blood pressure. Transesophageal echocardiography (TEE) revealed the tip of the catheter in the left ventricle. The catheter was withdrawn and then advanced to the pulmonary artery under monitoring of TEE. Transseptal shunt flow gradually decreased and finally disappeared. The surgery was completed without additional procedures. CONCLUSIONS: Although ventricular septal perforation is rare, it should be recognized as a potential complication of pulmonary artery catheter insertion.

Combined use of the ProSeal laryngeal mask airway and a bronchial blocker vs. a double-lumen endobronchial tube in thoracoscopic surgery: A randomized controlled trial.

STUDY OBJECTIVE: The combined use of the ProSeal laryngeal mask airway and a bronchial blocker may reduce postoperative hoarseness and sore throat. We aimed to test the feasibility and efficacy of this combination technique in thoracoscopic surgery. DESIGN: A single-center, patient-assessor blinded, randomized controlled trial. SETTING: Nagoya City University Hospital (between November 2020 and April 2022). PATIENTS: A total of 100 adult patients undergoing lobectomy or segmentectomy by video- or robotic-assisted thoracoscopic surgery. INTERVENTIONS: Patients were randomly assigned to either group using a combination of the ProSeal laryngeal mask airway and a bronchial blocker (pLMA+BB group) or a double-lumen endobronchial tube (DLT group). MEASUREMENTS: The primary outcome was the hoarseness incidence on 1-3 postoperative days. Secondary outcomes included sore throat, intraoperative complications (hypoxemia, hypercapnia, surgical interruption, malposition of devices, unintended lung expansion, and ventilatory difficulty), lung collapse, device placement-related outcomes, and coughing during emergence. MAIN RESULTS: A total of 100 patients underwent randomization (51 to the pLMA+BB group and 49 to the DLT group). After drop outs, a total of 49 patients in each group were analyzed per-protocol. The incidences of hoarseness in the pLMA+BB and DLT groups were 42.9% and 53.1% (difference, -10.2%; 95% confidence interval, -30.1% to 10.3%; p = 0.419), 18.4% vs. 32.7%, and 20.4% vs. 24.5% on postoperative day 1, 2, and 3, respectively. The incidences of sore throat in the pLMA+BB and DLT groups were 16.3% vs. 34.7% (difference, -18.4%; 95% confidence interval, -35.9% to -0.9%; p = 0.063) on postoperative day 1. In the pLMA+BB group, more intraoperative complications and less coughing during emergence were observed compared to the DLT group. Lung collapse and placement-related outcomes were comparable between the groups. CONCLUSIONS: The combination of ProSeal laryngeal mask airway and bronchial blocker did not significantly reduce hoarseness compared to the double-lumen endobronchial tube.

Efficacy of intravenous dexamethasone on postoperative pain after caesarean delivery under spinal anaesthesia with an intrathecal long-acting opioid: a systematic review and meta-analysis.

PURPOSE: Intravenous dexamethasone is recommended in elective caesarean delivery to decrease postoperative pain. However, the efficacy of spinal anaesthesia with an intrathecal long-acting opioid such as morphine or diamorphine for caesarean delivery has not been systematically investigated. METHODS: We searched all randomized controlled trials (RCTs) of pregnant women undergoing caesarean delivery under spinal anaesthesia with an intrathecal morphine or diamorphine via MEDLINE, CENTRAL, EMBASE, ICTRP, and ClinicalTrials.gov on May 18, 2022. Primary outcomes were time to first rescue analgesia, consumption of oral morphine equivalents, and incidence of drug-related adverse reactions. We evaluated the risk of bias for each outcome using the Risk of Bias 2. We conducted a meta-analysis using a random effects model. We evaluated the certainty of evidence with the GRADE approach. RESULTS: Five RCTs (455 patients) were included. The results of intravenous dexamethasone were as follows: time to first rescue analgesia (mean difference [MD] 0.99 h, 95% confidence interval [CI] - 0.86 to 2.84; very low certainty) and consumption of oral morphine equivalents (MD - 6.55 mg, 95% CI - 17.13 to 4.02; moderate certainty). No incidence of drug-related adverse reactions was reported (very low certainty). CONCLUSION: The evidence was very uncertain about the efficacy of intravenous dexamethasone on time to first rescue analgesia and the incidence of drug-related adverse reactions. Intravenous dexamethasone probably reduces the consumption of oral morphine equivalents. Anaesthesiologists might want to consider intravenous dexamethasone for postoperative pain after caesarean delivery under spinal anaesthesia with an intrathecal long-acting opioid.

3M microfoam™ surgical tape prevents nasal pressure injury associated with nasotracheal intubation: A randomized double-blind trial.

BACKGROUND: 3M microfoam™ surgical tape (3ST: 3M Japan Limited) is used for pressure wound control of medical equipment. It is cushioned and can be fitted to any body part. Here we investigated whether 3ST prevents nasal pressure injury associated with nasotracheal intubation (NTI). METHODS: We conducted a prospective, randomized double-blind study, enrolling 63 patients aged 20 to 70 years, who underwent general anesthesia with NTI. They were divided into 2 groups; those treated with 3ST (group S; n = 31) and control (group C; n = 31). After NTI and before securing the nasotracheal tube, a 35 × 25 mm 3ST was used to protect the nasal wing in group S, and the nasotracheal tube was fixed in place after NTI without protection in group C. The primary outcome was the presence or absence of nasal pressure injury after extubation. The Chi-Square test was used to assess the association between the 2 categorical variables. RESULTS: Nasal pressure injury was observed in 7 and 19 patients from groups S and C, respectively, representing a significant difference between the 2 groups (24.1% vs 67.8%, P = .001). Remarkably, none of the patients developed ulcers. CONCLUSION: 3ST prevents nasal pressure injury associated with NTI.

High preoperative serum strontium levels increase the risk of acute kidney injury after cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgeries. The incidence of AKI after cardiac surgeries using cardiopulmonary bypass (CPB-AKI) is high, emphasizing the need to determine strategies to prevent CPB-AKI. This study investigates the correlation between CPB-AKI and trace metal levels in clinical and animal studies. METHODS: Samples and clinical data were obtained from 74 patients from the Nagoya City University Hospital and Okazaki City Hospital. Blood samples were collected before, immediately after, and 2 h after CPB withdrawal. Trace metal levels were measured using inductively coupled plasma mass spectrometry. Sr or vehicle treatment was orally administered to the rats to determine if Sr was associated with CPB-AKI. After the treatment, ischemia-reperfusion (IR) injury was induced, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. RESULTS: In this clinical study, the incidence of CPB-AKI was found to be 28% (21/74). The body mass index and estimated glomerular filtration rate were significantly different in patients with AKI. The intensive care unit and hospital stay were longer in AKI patients than in non-AKI patients. The Na, Fe, and Sr levels were significantly higher in AKI patients before CPB. Also, Fe and Sr were higher immediately after CPB withdrawal, and Sr was higher 2 h after CPB withdrawal in AKI patients. Animal studies showed that Sr-treated rats had significantly increased SCr and BUN levels than vehicle-treated rats at 24 h post-IR injury. CONCLUSIONS: High preoperative serum Sr levels may be associated with CPB-AKI.

Poly(I:C) promotes neurotoxic amyloid ß accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes.

Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll-like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid ß (Aß) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the main Aß-degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aß degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aß toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aß was markedly delayed in poly(I:C)-treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aß1-42. Altogether, these results suggest that viral infections induce Aß neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aß degradation.

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.