The utility of the perfusion index as an indicator of anesthetic depth for repeated propofol sedation in children: An observational study.

BACKGROUND: Children receiving proton therapy require repeated sedation. In this study, we aimed to investigate the utility of the perfusion index (PI) for evaluating consciousness level during repeated propofol sedation. METHODS: In this prospective observational study, children aged from birth to 19 years old scheduled for proton therapy under repeated propofol sedation were enrolled. The primary outcome was the equivalence of PI values 5 min after anesthesia induction on consecutive sedation. Total consumption of propofol during sedation, time to reach the University of Michigan sedation scale (UMSS) score 1 after end of proton therapy, and duration of post-anesthesia care unit (PACU) stay were recorded. RESULTS: The PI values measured 5 min after induction of anesthesia were not equivalent to each other in consecutive sedation except for the second versus third (1st vs. 2nd: 97.5% CI: -1.34, 0.91; p = 0.206, 0.034; 2nd vs. 3rd: 97.5% CI: -0.87, 0.94; p = 0.023, 0.036 3rd vs. 4th: 97.5% CI: -2.08, -0.26; p < 0.99, <0.001; 4th vs. 5th: 97.5% CI: 0.21, 2.28; p < 0.001, >0.99; respectively). In consecutive sedation, there was not a significantly different difference in the time to reach UMSS score 1 (p > 0.99, all) for total consumption of propofol, time to reach UMSS score 1 after the end of proton therapy, and duration of PACU stay. CONCLUSIONS: During repeated propofol sedation in children, PI was insufficient to be used as an indicator of consciousness level assessment. However, we suggest that the information related to repeated sedation provided by this study may be helpful in clinical practice.

Correlation between bispectral index and patient state index in children under sevoflurane anesthesia.

BACKGROUND: Because the unanticipated arousal or hemodynamic instability during anesthesia may adversely affect the physical and emotional welfare of children, adequate management of the anesthesia depth is required. We aimed to compare Bispectral Index (BIS) and Patient State Index (PSI) in children during sevoflurane anesthesia and evaluate PSI as depth of anesthesia monitor in children aged 6 months-12 years. METHODS: In this prospective observational study, children aged 6 months-12 years old scheduled for elective surgery under sevoflurane anesthesia were enrolled from November 2018 to June 2019. We monitored BIS and PSI at different sevoflurane concentrations. The primary outcome was the correlation between BIS and PSI. The correlation between BIS and PSI at different sevoflurane concentrations (at 1, 1.5, and 2 MACs) and at different age groups (6 months-2 years, 2-7 years, and 8-12 years) was also investigated. RESULTS: Bispectral index and PSI showed a fair correlation (r = .430; 95% confidence interval [CI], 0.297-0.546; p < .001). Two values were fairly correlated at 1, 1.5, and 2 MAC (r = .544; 95% CI, 0.314-0.716; p < .001, r = .509; 95% CI, 0.283-0.699; p < .001, and r = .315; 95% CI, 0.047-0.522; p = 0.007). BIS and PSI values showed a fair correlation in 6 months - 2 year and 8-12 year groups (r = .696; 95% CI, 0.519-0.813; p < .001 and r = .297; 95% CI, -0.017 to 0.543; p < .021), but there was not significant correlation in 2-7 years group (r = .190; 95% CI, -0.015 to 0.374; p = .052). CONCLUSIONS: There was a fair correlation between BIS and PSI in children under sevoflurane anesthesia. The use of BIS and PSI as an indicator for anesthesia depth by sevoflurane is not reliable in pediatric patients.

Inhibition of ACE2-Spike Interaction by an ACE2 Binder Suppresses SARS-CoV-2 Entry.

The emergence of SARS-CoV-2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID-19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS-CoV-2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS-CoV-2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS-CoV-2 entry into host cells and prevent the development of COVID-19.

Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress-Responsive Activation of PERK Signaling.

Tau protein aggregates are a recognized neuropathological feature in Alzheimer's disease as well as many other neurodegenerative disorders, known as tauopathies. The development of tau-targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell-based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label-free target identification technology, we revealed that the transient enhancement of protein kinase-like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress-responsive SB1617 targets, PDIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies. The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and a mouse model with traumatic brain injury, a tauopathy known to involve ER stress.

Incidence and risk factors of unplanned intubation during pediatric sedation for MRI.

BACKGROUND: It is often difficult for the pediatric patient to cooperate or to remain immobile during MR scans. Therefore, sedation is usually needed for children. PURPOSE: To evaluate the incidence and contributing factors of unanticipated intubation during sedation for MRI scan in children. STUDY TYPE: Retrospective observational study. POPULATION/SUBJECTS: In all, 1165 charts were reviewed retrospectively of patients who had been sedated by anesthesiologists at a single institution from May 2015 to June 2016. ASSESSMENT: Patient's demographics, the region of the MRI scan, total amount of medication, duration of sedation, and any adverse event during MRI were assessed. The adverse events during sedation including airway obstruction, apnea, desaturation, bradycardia, and hypotension were also assessed. STATISTICAL TESTS: Risk factors of unplanned intubation during MRI sedation were identified by univariate and multivariate analysis. Firth's exact logistic regression was used for univariate and multivariate analysis. According to the results from multiple logistic regression, a nomogram was developed to predict the risk. RESULTS: A total of 1165 children aged 7 days to 18 years with sedation used during an MRI scan during the study period showed an incidence of unexpected intubation as ~2% (n = 23, 95% confidence interval [CI]; 0.0123, 0.0295). Multivariate logistic regression revealed the following risk factors of unplanned intubation: American Society of Anesthesiologists (ASA) class III patients (odds ratio [OR] 1.212, P < 0.001), premature birth (OR 2.317, P < 0.001), and the presence of gastroesophageal reflux disease (GERD) (OR 1.474, P < 0.001) or congenital heart disease (OR 1.118, P < 0.001). DATA CONCLUSION: This study identified risk factors of unplanned intubation as follows: ASA class III patients, premature birth, and the presence of GERD or congenital heart disease. The physician should screen risk factors of unexpected intubation and maintain adequate sedation during MRI scans in pediatric patients. Level of Evidence 3. Technical Efficacy Stage 5. J. Magn. Reson. Imaging 2019;49:1053-1061.

Impact of Backbone Pattern and Residue Substitution on Helicity in α/ß/γ-Peptides.

We have evaluated the impact of changes in the chemical structure of peptidic oligomers containing α-, ß-, and γ-amino acid residues (α/ß/γ-peptides) on the propensities of these oligomers to adopt helical conformations in aqueous and alcoholic solutions. These studies were inspired by our previous discovery that α/ß/γ-peptides containing a regular αγααßα hexad repeat adopt an α-helix-like conformation in which the ß and γ residues are aligned in a stripe along one side, and the remainder of the helix surface is defined by the α residues. This helix was found to be most stable when the ß and γ residues were rigidified with specific cyclic constraints. Relaxation of the ß residue constraints caused profound conformational destabilization, but relaxation of the γ residue constraints led to only a moderate drop in helicity. The new work more broadly characterizes the effect of γ residue substitution on helix stability, based on circular dichroism and two-dimensional NMR measurements. We find that even a fully unsubstituted γ residue (derived from γ-aminobutyric acid) supports a moderate helical propensity, which is surprising in light of the strong destabilizing effect of glycine residues on α-helix stability. Additional studies examine the effects of altering sequence in terms of amino acid type, by comparing a prototype with the αγααßα hexad pattern to isomers with irregular arrangements of the α, ß, and γ residues along the backbone. The data indicate that the strong helix-forming propensity previously discovered for α/ß/γ-peptide 12-mers is retained when sequence is varied, with small variations detected across diverse α-ß-γ placements. These structural findings suggest that α/ß/γ-peptide scaffolds represent versatile scaffolds for the design of peptidic foldamers that display specific functions.

Incidence of tolerance in children undergoing repeated administration of propofol for proton radiation therapy: a retrospective study.

BACKGROUND: Propofol is an excellent hypnotic drug for use in repeated radiation procedures in young children. To date, tolerance to propofol generally does not develop in pediatric patients undergoing radiation therapy. However, several studies have suggested that there may be potential for development of tolerance to propofol. The aim of this study was to evaluate the development of a tolerance to propofol used for repeated deep sedation in children undergoing proton radiation therapy (PRT). METHODS: All children undergoing PRT at our institution between December 2015 and January 2018 were eligible for inclusion in this study. Sedation was induced by a bolus dose of propofol (2.0 mg.kg- 1) followed by a continuous infusion of 250 µg.kg- 1.min- 1 via an infusion pump to achieve deep sedation. Sedation was maintained with the propofol infusion of 200 µg.kg- 1.min- 1, which was adjusted in 25 µg.kg- 1.min- 1 increments up or down as necessary to ensure deep sedation. The primary outcome was mean doses of propofol over time. RESULTS: Fifty-eight children were analyzed. The mean (SD) age was 4.5 (2.1) years. The mean (SD) number of treatment sessions was 19 (7). Fifteen patients (26%) developed tolerance to propofol. However, there were no significant differences between the children who developed tolerance and the children who did not develop tolerance in mean propofol dose and awakening time over time (p = 0.887 and P = 0.652, respectively). Age, the number of PRT, and attending anesthesiologists was not significantly associated with the incidence of tolerance to propofol. CONCLUSION: Repeated prolonged deep sedation for PRT elicited multiple times over several weeks in young children using propofol did not develop tolerance in 74% of patients. Although the incidence of 26% tolerance to propofol may still be present, the increase in propofol dose was minimal. Therefore, the use of repeated propofol for children was safe.

A retrospective comparison of propofol to dexmedetomidine for pediatric magnetic resonance imaging sedation in patients with mucopolysaccharidosis type II.

BACKGROUND: Mucopolysaccharidosis type II patients are reported to have an elevated incidence of difficult airway. Propofol is a commonly used sedative for magnetic resonance imaging in pediatric patients, but patients who receive it may exhibit dose-dependent upper airway obstruction and respiratory depression. Dexmedetomidine also provides adequate procedural sedation with a relatively low risk of airway obstruction. Accordingly, we introduced the use of dexmedetomidine in our practice to reduce the risk of airway obstruction during magnetic resonance imaging procedures. AIMS: The aim of this study was to evaluate the incidence of artificial airway interventions in patients sedated with propofol and compare it to that in patients sedated with dexmedetomidine in patients with mucopolysaccharidosis type II during magnetic resonance imaging procedures. METHODS: All mucopolysaccharidosis type II patients undergoing magnetic resonance imaging at our institution between April 2014 and February 2018 were included in this study. The patients were divided into two groups according to whether they were managed before and after the introduction of dexmedetomidine: those who were sedated with propofol (group P) and those who were sedated with dexmedetomidine (group D). RESULTS: Forty-six sedations were performed in 27 patients. Artificial airway interventions were significantly more frequent during propofol-based than dexmedetomidine-based sedation: 14 of 32 (43.8%) in group P and 1 of 14 (7.1%) in group D (odds ratio, 10.11; 95% confidence interval, 1.18-86.85; P = 0.018). Time to awake and time to discharge were similar between groups. Changes in hemodynamic variables also did not significantly differ between groups. CONCLUSION: Dexmedetomidine provides an adequate level of sedation and is associated with lower rates of artificial airway interventions compared to propofol. Therefore, dexmedetomidine may offer advantages for preserving the native airway compared to propofol when administered during magnetic resonance imaging scans in patients with mucopolysaccharidosis type II.

The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts.

Independently of the lipid-lowering effects, statin has been reported to attenuate the development of diabetic cardiomyopathy. However, the effect of statin in glucose-controlled diabetic condition has not been demonstrated. We evaluated the effect of fluvastatin on cardiac function, fibrosis, and angiotensin-converting enzyme-2 (ACE2) expression in glucose-controlled diabetic rats. Male Wistar rats were randomly divided into four groups: control (Group C), diabetes (Group D), diabetes with insulin (Group I), and diabetes with insulin and fluvastatin (Group I+F). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). After 8 weeks, the hearts were extracted following echocardiographic evaluation. Cardiac fibrosis was analyzed using Masson's trichrome stain. Collagens I and III and ACE2 expressions were evaluated by immunohistochemistry and western blot. Group D showed reduced cardiac systolic function compared to the other groups (all P < 0.05). However, diastolic function estimated by E/A ratio was significantly decreased in groups D and I (median: 0.88 and 1.45, respectively) compared to groups C and I+F (2.97 and 2.15) (all P < 0.05). Cardiac fibrosis was more severe in groups D and I than in groups C and I+F (all P < 0.05) on Masson's trichrome stain. On immunohistochemistry, ACE2 expression was significantly decreased only in group D (all P < 0.05). However, collagen I and III showed higher expressions in group D compared to groups C and I+F while no significant difference was observed compared with group I (all P < 0.05). On western blot, collagen I and ACE2 expressions in group D (median: 1.78 and 0.35, respectively) were significantly different from groups C (references: 1) and I+F (0.76 and 1.21) (all P < 0.05), but not from group I (1.19 and 0.92). Our study suggested a combination of fluvastatin and insulin would be more effective than insulin alone in diabetic hearts. However, the exact mechanism remains to be elucidated.

A comparison of the use of propofol alone and propofol with midazolam for pediatric magnetic resonance imaging sedation - a retrospective cohort study.

BACKGROUND: Pediatric MRI sedation performed by a variety of specialists such as sedationists and anesthesiologists commonly uses propofol, which has similar effects to an ideal sedative agent for maintaining deep sedation. However, when propofol is used, adverse airway events are relatively more common than when using other sedative agents. The concomitant administration of midazolam and propofol can reduce the dose of propofol needed for adequate sedation and might also reduce the frequency of airway obstruction without affecting the patient's recovery profile. METHODS: We reviewed the our hospital records of all pediatric MRI sedation patients aged 3 to 16 years who were sedated with either propofol alone or propofol with midazolam between December 2013 and June 2016. RESULTS: Eight hundred ninety-seven pediatric MRI sedation patients were included (n = 897). The frequency of airway intervention was 25/356 (7.0%) in Group P and 15/541 (2.8%) in Group PM (difference in proportions: 4.2%; 95% CI: 1.4-7.6%; p = 0.002). The mean (SD) time to awake was longer in Group PM compared to Group P [21.2 (5.6) minutes vs. 23.0 (7.1) minutes; mean difference, 1.8 min; 95% CI, 0.9-2.9; p < 0.001]. The mean (SD) time to discharge was longer in Group PM compared to Group P [34.5 (6.9) minutes vs. 38.6 (9.4) minutes; mean difference, 4.0 min; 95% CI, 3.0-5.1; p < 0.001]. CONCLUSIONS: The administration of a small dose of midazolam during pediatric MRI sedation using propofol can reduce the frequency of airway complications without prolonging the clinically significant recovery profile.

Readily Accessible and Predictable Naphthalene-Based Two-Photon Fluorophore with Full Visible-Color Coverage.

Herein we report 22 acedan-derived, two-photon fluorophores with synthetic feasibility and full coverage of visible wavelength emission. The emission wavelengths were predicted by computational analysis, which enabled us to visualize multicolor images by two-photon excitation with single wavelength, and to design a turn-on, two-photon fluorescence sensor for endogenous H2 O2 in Raw 264.7 macrophage and rat brain hippocampus ex vivo.

Molecular cloning and characterization of a novel acetylalginate esterase gene in alg operon from Sphingomonas sp. MJ-3.

A novel acetylalginate esterase (AcAlgE) gene was cloned and characterized from the genomic DNA library of Sphingomonas sp. MJ-3. A putative gene encoding AcAlgE protein of 292-residue precursor protein with 20-amino acid signal peptide was identified in the alg operon. The deduced AcAlgE protein has GDSL-like consensus motif and shares a highest sequence identity (51%) with GDSL family lipolytic protein from Pseudoxanthomonas suwonensis. Enzymatic assays with bacterial acetylalginate as the substrate showed that the recombinant AcAlgE protein possesses deacetylation activity. The optimal temperature and pH for the AcAlgE were 22 °C and pH 6.5 (citrate buffer), respectively. The recombinant AcAlgE protein catalyzed deacetylation of acetylalginate with release of acetate. The resulting de-acetylated alginate was readily degraded by alginate lyases, indicating that the recombinant AcAlgE enhanced the subsequent degradation of acetylalginate by alginate lyases. The recombinant AcAlgE can play an important role in the degradation of acetylated alginate such as mucoidal acetylalginate in cystic fibrosis patient.

Effect of pre-warmed intravenous fluids on perioperative hypothermia and shivering after ambulatory surgery under monitored anesthesia care.

PURPOSE: The aim of this study was to evaluate the effects of pre-warmed (approximately 41 °C) intravenous fluids (IV) on perioperative hypothermia and postoperative shivering in female patients undergoing short, ambulatory urological surgery under monitored anesthesia care (MAC). METHODS: Patients between the ages of 35 and 80 years were randomly assigned to either the pre-warmed (n = 27) or the room temperature (n = 26) group. According to group allocation, either pre-warmed IV fluids that had been stored in a warming cabinet for at least 8 h or room temperature IV fluids were administered intraoperatively up to approximately 600-700 ml, including a bolus infusion of 10 ml/kg within 20 min. Perioperative core temperatures at the tympanic membrane, postoperative shivering, subjective thermal comfort, and the use of forced-air warming interventions in the post-anesthesia care unit (PACU) were recorded. RESULTS: Mean core temperatures were significantly higher in the pre-warmed group than they were in the room temperature group after 10 ml/kg preload fluid was administered, at the end of the operation, and on admission to the PACU (p = 0.004, p = 0.02, and p = 0.008, respectively). The incidence of hypothermia (<36 °C) was significantly lower in the pre-warmed group (n = 4) than in the room temperature group (n = 11, p = 0.035) upon PACU admission. The postoperative shivering incidence was also significantly lower in the pre-warmed group (n = 2) than in the room temperature group (n = 8, p = 0.039). CONCLUSIONS: Infusion of pre-warmed IV fluid improved the postoperative recovery profile by decreasing hypothermia and shivering in female patients undergoing short, ambulatory urological surgery under MAC.

Quality and composition of archived nucleic acids after use in SARS-CoV-2 molecular testing.

BACKGROUND: Reverse transcription real-time PCR (rRT-PCR) has been a gold-standard method to detect SARS-CoV-2, for which quality assessment of nucleic acids (NAs) is not needed. In order to prepare for future use, we evaluated NA quality from archived SARS-CoV-2 rRT-PCR samples. METHODS: NA samples were collected in February 2021 and extracted using the QIAamp DSP Virus Spin Kit, (53 SARS-CoV-2-positive and 100 SARS-CoV-2-negative). Quality, quantity, and purity of NA were measured spectrophotometrically or fluorescently. Droplet digital PCR was used to characterize the double strand DNA (dsDNA) origin and composition by quantifying 16S rDNA and RPP30. RESULTS: The RIN and purity were not significantly different between groups (p = 0.3828). RNA quantity was significantly higher than dsDNA in both groups (p < 0.0001); both dsDNA and RNA quantity were significantly higher in positive samples (dsDNA, RNA p = 0.021). For dsDNA, 16S rDNA copies were significantly greater than RPP30 in both groups (p < 0.0001), and RPP30 were significantly higher in positive samples (p < 0.0001). CONCLUSIONS: Archived NA quality after SARS-CoV-2 rRT-PCR was guaranteed for subsequent molecular research using human or bacterial DNA, especially for short targets.

Analgesic effects of ultrasound-guided preoperative posterior Quadratus Lumborum block in laparoscopic hepatectomy: A prospective double-blinded randomized controlled trial.

STUDY OBJECTIVE: To determine if single-injection bilateral posterior quadratus lumborum block (QLB) with ropivacaine would improve postoperative analgesia in the first 24 h after laparoscopic hepatectomy, compared with 0.9% saline. DESIGN: Prospective, double blinded, randomized controlled trial. SETTING: A single tertiary care center from November 2021 and January 2023. PATIENTS: A total of 94 patients scheduled to undergo laparoscopic hepatectomy due to hepatocellular carcinoma. INTERVENTIONS: Ninety-four patients were randomized into a QLB group (receiving 20 mL of 0.375% ropivacaine on each side, 150 mg in total) or a control group (receiving 20 mL of 0.9% saline on each side). MEASUREMENTS: The primary outcome was the cumulative opioid consumption during the initial 24-h post-surgery. Secondary outcomes included pain scores and intraoperative and recovery parameters. MAIN RESULTS: The mean cumulative opioid consumption during the initial 24-h post-surgery was 30.8 ± 22.4 mg in the QLB group (n = 46) and 34.0 ± 19.4 mg in the control group (n = 46, mean differences: -3.3 mg, 95% confidence interval, -11.9 to 5.4, p = 0.457). The mean resting pain score at 1 h post-surgery was significantly lower in the QLB group than in the control group (5 [4-6.25] vs. 7 [4.75-8], p = 0.035). No significant intergroup differences were observed in the resting or coughing pain scores at other time points or in other secondary outcomes. CONCLUSIONS: Preoperative bilateral posterior QLB did not reduce cumulative opioid consumption during the first 24 h after laparoscopic hepatectomy.

Comparison of analgesic effects between programmed intermittent epidural boluses and continuous epidural infusion after cesarean section: a randomized controlled study.

BACKGROUND: This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS). METHODS: Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS. RESULTS: The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference: 2, 95% CI [1, 2], P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest; mean difference [MD]: 37.5, 95% CI [24.6, 50.4], P < 0.001/pain during mobilization; MD: 56.6, 95% CI [39.8, 73.5], P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001). CONCLUSIONS: PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Differential impact of ß and γ residue preorganization on α/ß/γ-peptide helix stability in water.

Cyclic constraints have proven to be very effective for preorganizing ß-amino acid residues and thereby stabilizing ß- and α/ß-peptide helices, but little is known about possible preorganization effects among γ residues. Here we assess and compare the impact of cyclic preorganization of ß and γ residues in the context of a specific α/ß/γ-peptide helix. The results show that ß residue preorganization is critical for helix stability but that γ residue preorganization is less important.

Intra-operative cardiac arrests during liver transplantation - a retrospective review of the first 15 yr in Asian population.

Although many report intra-operative cardiac arrests (ICAs) in liver transplantation (LT), the incidence, major causes, and outcome remain unclear. We aimed to investigate retrospectively, the incidence, nature, and outcome of ICA in Asian population and to identify risk factors for ICA. Consecutive 1071 LTs in an institution during 1996-2011 (adult 920, pediatric 151/living donor liver transplantation, LDLT 841, deceased donor liver transplantation, DDLT 230) were reviewed. ICA occurred in 14 adult LTs (1.5%), but none in pediatrics. ICA occurred 1.0% and 3.3% in LDLT and DDLT, respectively. Stages of ICA incidence were three at pre-anhepatic, one at anhepatic, and 10 at neohepatic stage. Post-reperfusion syndrome (PRS) with hyperkalemia and bleeding were the major causes of ICA. While LDLT showed miscellaneous causes for ICA at various stages, DDLT incurred ICAs at neohepatic stage only. Interestingly, we did not find pulmonary thromboembolism (PTE) to incur ICA. Risk factor analysis showed no association of pre-operative patient condition, donor types, and intra-operative parameters. In this review, the incidence of ICA was low in Asian population with LDLT predominance, and while PTE was not the cause of ICA, the neohepatic stage with PRS and bleeding was the most vulnerable period to anticipate ICA.

A kinetic study on nucleophilic displacement reactions of aryl benzenesulfonates with potassium ethoxide: role of K+ ion and reaction mechanism deduced from analyses of LFERs and activation parameters.

Pseudofirst-order rate constants (k(obsd)) have been measured spectrophotometrically for the nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted benzenesulfonates 4a-f and Y-substituted phenyl benzenesulfonates 5a-k with EtOK in anhydrous ethanol. Dissection of k(obsd) into k(EtO(-)) and k(EtOK) (i.e., the second-order rate constants for the reactions with the dissociated EtO(-) and ion-paired EtOK, respectively) shows that the ion-paired EtOK is more reactive than the dissociated EtO(-), indicating that K(+) ion catalyzes the reaction. The catalytic effect exerted by K(+) ion (e.g., the k(EtOK)/k(EtO(-)) ratio) decreases linearly as the substituent X in the benzenesulfonyl moiety changes from an electron-donating group (EDG) to an electron-withdrawing group (EWG), but it is independent of the electronic nature of the substituent Y in the leaving group. The reactions have been concluded to proceed through a concerted mechanism from analyses of the kinetic data through linear free energy relationships (e.g., the Brønsted-type, Hammett, and Yukawa-Tsuno plots). K(+) ion catalyzes the reactions by increasing the electrophilicity of the reaction center through a cyclic transition state (TS) rather than by increasing the nucleofugality of the leaving group. Activation parameters (e.g., ΔH(‡) and ΔS(‡)) determined from the reactions performed at five different temperatures further support the proposed mechanism and TS structures.

Neuroinflammation-Modulating Agent SB1617 Enhances LC3-Associated Phagocytosis to Mitigate Tau Pathology.

Tau protein aggregation and propagation in neurons and surrounding microglia are well-known risk factors for neurodegenerative diseases. Therefore, emerging therapeutic strategies that target neuroinflammatory activity in microglia have the potential to prevent tauopathy. Here, we explored the microglia-mediated neuroprotective function of SB1617 against tau aggregation. Our study revealed that SB1617-inactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines via translational regulation, and induced microglial polarization toward the M2 phenotype and phagocytic function. Furthermore, we observed that extracellular pathogenic tau aggregates were eliminated via LC3-associated phagocytosis. The in vivo efficacy of SB1617 was confirmed in mice with traumatic brain injury in which SB1617 exerted neuroprotective effects by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicated that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis. This study provides new insights into tauopathies and directions for developing novel therapies for neurodegenerative diseases.