Surviving Sepsis After Burn Campaign.

INTRODUCTION: The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes. METHODS: The International Society for Burn Injuries (ISBI) reached out to regional or national burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific "patient/population, intervention, comparison and outcome" (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC participants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create "statements" based on the literature. The "summary statements" were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or "no consensus" was reported. RESULTS: The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as "static" comments but should rather be used as guidelines for future testing of the best treatments for sepsis in burn patients. They should be updated on a regular basis. CONCLUSION: Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients.

Instructor Development Workshops for Advanced Life Support Training Courses Held in a Fully Virtual Space: Observational Study.

BACKGROUND: Various face-to-face training opportunities have been lost due to the COVID-19 pandemic. Instructor development workshops for advanced resuscitation (ie, advanced life support) training courses are no exception. Virtual reality (VR) is an attractive strategy for remote training. However, to our knowledge, there are no reports of resuscitation instructor training programs being held in a virtual space. OBJECTIVE: This study aimed to investigate the learning effects of an instructor development workshop that was conducted in a virtual space. METHODS: In this observational study, we created a virtual workshop space by using NEUTRANS (Synamon Inc)-a commercial VR collaboration service. The instructor development workshop for the advanced life support training course was held in a virtual space (ie, termed the VR course) as a certified workshop by the Japanese Association of Acute Medicine. We asked 13 instructor candidates (students) who participated in the VR course to provide a workshop report (VR group). Reports from a previously held face-to-face workshop (ie, the face-to-face course and group) were likewise prepared for comparison. A total of 5 certified instructor trainers viewed and scored the reports on a 5-point Likert scale. RESULTS: All students completed the VR course without any problems and received certificates of completion. The scores for the VR group and the face-to-face group did not differ at the level of statistical significance (median 3.8, IQR 3.8-4.0 and median 4.2, IQR 3.9-4.2, respectively; P=.41). CONCLUSIONS: We successfully conducted an instructor development workshop in a virtual space. The degree of learning in the virtual workshop was the same as that in the face-to-face workshop.

Efficacy of Body Armor in Protection Against Blast Injuries Using a Swine Model in a Confined Space with a Blast Tube.

The purpose of this study was to clarify whether or not body armor would protect the body of a swine model using a blast tube built at National Defense Medical College, which is the first such blast tube in Japan. Seventeen pigs were divided into two groups: the body armor group and the non-body armor group. Under intravenous anesthesia, the pigs were tightly fixed in the left lateral position on a table and exposed from the back neck to the upper lumbar back to the blast wave and wind with or without body armor, with the driving pressure of the blast tube set to 3.0 MPa. When the surviving and dead pigs were compared, blood gas analyses revealed significant differences in PaO2, PaCO2, and pH in the super-early phase. All pigs injured by the blast wave and wind had lung hemorrhage. All 6 animals in the body armor group and 6 of the 11 animals in the control group survived for 3 hours after injury. Respiratory arrest immediately after exposure to the blast wave was considered to influence the mortality in our pig model. Body armor may have a beneficial effect in protecting against respiratory arrest immediately after an explosion.

Comparison of prognostic models for burn patients: A retrospective nationwide registry study.

BACKGROUND: Prognostic burn index (PBI) is a unique model utilized to predict mortality of burn patients in Japan. In contrast, other prediction models are rarely used in Japan, and their accuracy and predictive value are unknown. The present study aimed to compare commonly used burn prediction models and determine the appropriate model for mortality prediction in Japanese burn patients. METHODS: Japanese burn patients registered in the nationwide burn registry of Japanese Society for Burn Injury between April 1, 2011 and March 31, 2019 were reviewed retrospectively. The prognostic performance of PBI was compared with Baux score, revised Baux score, abbreviated burn severity index (ABSI), Ryan score and Belgian outcome in burn injury score (BOBI). The primary outcome was in-hospital mortality. RESULTS: The study included 7911 acute burn patients. The overall mortality rate was 10.7%, the median age was 52 (interquartile range, 26-72) years, and the median % total body surface area was 7% (interquartile range, 3%-17%). The areas under the receiver operating characteristic curve for PBI, Baux score, ABSI, revised Baux score, Ryan score, and BOBI were 0.940 (95% confidence interval [CI]: 0.931-0.948), 0.943 (95% CI: 0.934-0.951; p=0.002), 0.945 (95% CI: 0.937-0.953; p=0.058), 0.946 (95% CI: 0.937-0.953; p=0.002), 0.859 (95% CI: 0.846-0.870; p<0.001), and 0.896 (95% CI: 0.885-0.905; p<0.001), respectively. CONCLUSION: Although the performance of PBI was good, it was not superior to the Baux score, revised Baux score, and ABSI. These three scores have a high prognostic accuracy. Hence, they are considered as alternative burn prognostic scores in Japan. The Baux score was an optimal prognostic model for patients with burns in Japan.

The benefits of extrinsic ligament release for potentially hemodynamically unstable pancreaticoduodenal arcade aneurysm with median arcuate ligament syndrome: a case report.

BACKGROUND: A pancreaticoduodenal artery aneurysm (PDAA) occurring in close association with median arcuate ligament syndrome (MALS) is rare. A surgical procedure, such as median arcuate ligament (MAL) release, should be considered in such cases, but the operative criteria remain unknown. In this study, we reported an extremely rare case of PDAA with periarteritis nodosa (PAN) and MALS. CASE PRESENTATION: A 60-year-old man was transferred to our department with sudden onset of abdominal pain. We initially diagnosed his condition as a PDAA rupture with MALS based on enhanced computed tomography (CT). We promptly performed transcatheter arterial embolization (TAE) of PDAA, and the angiogram showed stagnant contrast agent in the celiac trunk, indicating total celiac artery occlusion. Follow-up enhanced CT three weeks after the first TAE clearly demonstrated newly formed, multiple aneurysms in the pancreaticoduodenal arcade and the hepatic artery. These findings indicated a systemic disorder, such as PAN or segmental arterial mediolysis, as the underlying cause. Therefore, we started corticosteroid therapy and performed diagnostic angiography to clarify the celiac artery's patency. Contrary to the initial angiography, the second angiography showed sustained blood flow in the celiac artery. Nevertheless, we performed both extrinsic MAL release and consecutive TAE because of the risk of multiple aneurysms rupturing due to an uncontrolled systemic disorder and consequent hepatic ischemia. The patient had no episode of recurrence until one year of follow-up. CONCLUSIONS: It is important to evaluate risk for hemodynamically unstable events to decide the best treatment strategy for MALS.

Fulminant pseudomembranous enterocolitis caused by Klebsiella oxytoca: an autopsy case report.

CASE: We describe a rare case of antibiotic-associated fulminant pseudomembranous enterocolitis caused by Klebsiella oxytoca. A 79-year-old man with a history of antibiotic therapy was admitted to our emergency department, complaining of consciousness disturbance. Initially, we suspected septic shock and diabetic ketoacidosis caused by intestinal infection. Although we administered sufficient extracellular fluid, his blood pressure was not elevated and his abdomen gradually swelled. OUTCOME: The patient died of shock and abdominal compartment syndrome. Autopsy revealed widespread jejunal necrosis in conjunction with colitis, suggesting fulminant pseudomembranous enterocolitis caused by K. oxytoca infection. CONCLUSION: As the clinical features of pseudomembranous enterocolitis caused by K. oxytoca resemble the features of colitis caused by Clostridium difficile, conservative therapy is applied first. However, fulminant pseudomembranous enterocolitis is a lethal disease, necessitating early operation for resection of the necrotic lesion. This report highlights the need for better surgical criteria at an early stage.

OsDRE2 contributes to chitin-triggered response through its interaction with OsRLCK185.

The rice receptor-like cytoplasmic kinase 185 (OsRLCK185) interacts with the chitin receptor complex OsCERK1/CEBiP and positively regulates chitin-induced immune responses including MAP kinase activation, ROS production and defense gene expression. To elucidate the regulatory mechanisms of OsRLCK185-mediated immunity, we searched for interactors of OsRLCK185. OsDRE2a, rice homologs of the yeast Dre2 protein, were identified as novel interactors of OsRLCK185. OsDRE2a interacted with OsRLCK185 at plasma membrane. The conserved cysteine residues in CIAPIN1 domain of OsDRE2a were essential for tight interaction of OsRLCK185. OsDRE2a was phosphorylated by OsRLCK185. The expression of OsDRE2a and OsDRE2b was induced after chitin treatment. Reduction of OsDRE2a and OsDRE2b mRNA levels by RNA interference resulted in the decreased chitin-induced ROS production. Thus, it is likely that OsDRE2 regulates OsRLCK185-mediated immune responses.

The Relationship between Functional Outcome and Prehospital Time Interval in Patients with Cerebral Infarction.

BACKGROUND: When symptoms of cerebral infarction are recognized in a patient, he or she should be transported to a hospital and should be started on the appropriate treatments. The effectiveness of delayed treatment of cerebral infarction with respect to the initial diagnosis or perception of the disease is still unclear. METHODS: We retrospectively investigated whether the functional outcomes would improve if patients with cerebral infarction were transported to the hospital with minimum delay. One-hundred twenty-two patients who were transported to Mishuku Hospital from January 2012 to August 2015 were included. We conducted multiple regression analyses. The criterion variable included the BI at discharge, and the explanatory variables were age, sex, days of hospital stay, the Barthel Index (BI) on admission, time from symptom onset to hospital arrival, time from emergency medical service perception to hospital arrival, recombinant tissue plasminogen activator (rt-PA) treatment, and the occluded artery type. RESULTS: In all 122 cases, the BI at the time of discharge was not related to onset time (P = .453) but was significantly related to perception time (P = .026). BI scores at discharge were high for young patients (P = .002) and for patients with short hospital stays (P <.001). In the rt-PA group (52 cases), BI scores at discharge were also high when the perception time was short (P = .036). CONCLUSIONS: A short interval between perception and hospital arrival improves the functional outcomes for patients with cerebral infarction. Thus, patients with cerebral infarctions must be treated with minimal delay after diagnosis of the condition.

Pharmacokinetic Studies of Orally Administered Magnesium Oxide in Rats.

Magnesium oxide (MgO) tablets are widely used as laxatives in patients with constipation. Recently, the "Revision of Precautions on the Use of Magnesium Oxide" has been issued by the Japanese Pharmaceuticals and Medical Devices Agency, warning against the risk of hypermagnesemia with the use of MgO. However, the majority of physicians continue to administer MgO for constipation without adequately considering its safe use. In the present study, we performed two analyses using an identical lot of MgO tablets and evaluated the risk of hypermagnesemia. Approximately 90% of the MgO tablets dissolved within 120 min in dissolution testing; it was believed to form an absorbable state for magnesium. With orally administered MgO, 15% is absorbed in the body and 85% is excreted via the feces without being detected in pharmacokinetic analysis. Magnesium absorbed into the plasma demonstrated peak concentration 3 h after administration and was excreted via the urine within 48 h.

Effect of Food Thickener on Dissolution and Laxative Activity of Magnesium Oxide Tablets in Mice.

The present study examined the dissolution of magnesium oxide (MgO) from MgO tablets placed in a food thickening agent (food thickener) and its effects on laxative activity. We prepared mixtures of MgO tablets suspended in an aqueous suspension and food thickeners in order to evaluate the dissolution of MgO. The results of the dissolution tests revealed that agar-based food thickeners did not affect the MgO dissolution. In contrast, some xanthan gum-based food-thickener products show dissolution rates with certain mixtures containing disintegrated MgO tablets suspended in a food thickener that decrease over time. However, other xanthan gum-based food-thickener products show dissolution rates that decrease immediately after mixing, regardless of the time they were allowed to stand. In order to investigate the laxative activity of MgO, we orally administered a mixture of MgO suspension and food thickener to mice and observed their bowel movements. The animal experiments showed that when agar-based food thickeners were used, the laxative activity of MgO was not affected, but it decreased when xanthan gum-based food thickeners were used.

[Effect of food thickener on disintegration and dissolution of magnesium oxide tablets].

It has been reported that magnesium oxide tablets are excreted in a non-disintegrated state in the stool of patients when the tablets are administered after being immersed in a food thickener. Therefore we examined whether immersion in a food thickener affects the pharmacological effect in patients taking magnesium oxide tablets, and whether immersion affects its disintegration and solubility. The mean dosage (1705 mg/d) was higher for patients who took tablets after immersion in a food thickener than for those who took non-immersed tablets (1380 mg/d). The disintegration time and dissolution rate of the immersed tablets were lower than those of non-immersed tablets in vitro. Furthermore, components that constitute the food thickener and differences in composition concentrations differentially affect the disintegration and solubility of magnesium oxide tablets. This suggests that commercially available food thickeners are likely to be associated with changes in the degradation of magnesium oxide tablets, and they therefore should be carefully used in certain clinical situations.

Bongkrekic acid analogue, lacking one of the carboxylic groups of its parent compound, shows moderate but pH-insensitive inhibitory effects on the mitochondrial ADP/ATP carrier.

Bongkrekic acid, isolated from Burkholderia cocovenenans, is known to specifically inhibit the mitochondrial ADP/ATP carrier. However, the manner of its interaction with the carrier remains elusive. In this study, we tested the inhibitory effects of 17 bongkrekic acid analogues, derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier. Rough screening of these chemicals, performed by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH-1, KH-7, KH-16, and KH-17, had moderate inhibitory effects. Further characterization of the actions of these 4 analogues on mitochondrial function showed that KH-16 had moderate; KH-1 and KH-17, weak; and KH-7, negligible side effects of both permeabilization of the mitochondrial inner membrane and inhibition of the electron transport, indicating that only KH-7 had a specific inhibitory effect on the mitochondrial ADP/ATP carrier. Although the parental bongkrekic acid showed a strong pH dependency of its action, the inhibitory effect of KH-7 was almost insensitive to the pH of the reaction medium, indicating the importance of the 3 carboxyl groups of bongkrekic acid for its pH-dependent action. A direct inhibitory effect of KH-7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated.

Suppression of rice immunity by Xanthomonas oryzae type III effector Xoo2875.

Xanthomonas oryzae delivers effector proteins into host cells through a type III secretion system to inhibit host immune responses, but how these effectors suppress host immunity is largely unknown. Here we found that Xoo2875, one of the effectors of X. oryzae, strongly inhibited host resistance to X. oryzae. Transgenic rice plants expressing Xoo2875 exhibited semi-dwarfism and a reduction in Brassinolide-dependent laminar inclination, characteristics of brassinosteroid (BR)-insensitive mutants caused by mutations of the BR receptor. A yeast two-hybrid experiment indicated that Xoo2875 interacted with OsBAK1, an essential component of both microbe-associated molecular patterns (MAMPs) and BR receptors, suggesting that the virulent activity of Xoo2875 is mediated by inhibition of OsBAK1. Expression of Xoo2875 in Arabidopsis cells activated host immune responses, suggesting the presence of intracellular immune receptors that recognize Xoo2875. Because Xoo2875 homologs are highly conserved in Xanthomonas species, the development of Xoo2875-induced immunity is probably a useful strategy to avoid pathogen invasion.

[The mechanisms of the release of cytochrome C from mitochondria revealed by proteomics analysis].

Mitochondrial permeability transition (PT) is the phenomenon in which the mitochondrial inner membrane becomes permeable to various solutes and ions. When PT is induced by Ca(2+), cytochrome c is released from mitochondria into the cytosol where it then triggers subsequent steps of programmed cell death, apoptosis. Thus, the proteins that regulate PT and cytochrome c release could become druggable targets for various diseases. However, the mechanisms of PT and the release of cytochrome c have not yet been revealed. We previously showed that valinomycin, a potassium selective ionophore, also caused release of cytochrome c from mitochondria without inducing PT. This result indicates that cytochrome c could be released from mitochondria with or without induction of PT. In this study, to understand the difference of effects of valinomycin and Ca(2+) on mitochondria, we examined what protein species are released from valinomycin- and Ca(2+)-treated mitochondria by LC-MS/MS. As a result, only the proteins located in the intermembrane space were found to be released from valinomycin-treated mitochondria, while those in both the intermembrane space and in the matrix were released from Ca(2+)-treated mitochondria. Furthermore, the protein releases by each reagent occurred not selectively but in a concentration-dependent manner. Based on these results, the permeabilization effects of Ca(2+) and valinomycin on the inner and outer mitochondrial membranes are discussed.

S-15176 and its methylated derivative suppress the CsA-insensitive mitochondrial permeability transition and subsequent cytochrome c release induced by silver ion, and show weak protonophoric activity.

A recent report has described that S-15176 (N-[(3,5-di-tert-butyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3,4-trimethoxybenzyl) piperazine), an anti-ischemic agent, inhibits the mitochondrial permeability transition (PT) induced by not only Ca(2+) and inorganic phosphate, but also by tert-butylhydroperoxide or phenylarsine oxide [Morin et al. (Biochem Pharmacol 72:911-918, 2006)]. In the present study, we tested the effects of S-15176 on the PT induced by Ag(+), PT of which is not suppressed by cyclosporin A or oligomycin. S-15176 was effective in suppressing the PT and the subsequent cytochrome c release induced by Ag(+), and hence, it was concluded to be a more universal PT inhibitor than cyclosporin A or oligomycin. In addition to the PT-suppression activity, S-15176 also showed weak protonophoric activity. Thus, we further tested to investigate whether the hydroxyl group of S-15176 was involved in its PT-suppression or weak protonophoric activities. The methylated derivative of S-15176 also showed both PT suppression and weak protonophoric activities; hence, the hydroxyl group of S-15176 was concluded not to be involved in these activities.

Ca2+-induced permeability transition can be observed even in yeast mitochondria under optimized experimental conditions.

Yeast mitochondria have generally been believed not to undergo the permeability transition (PT) by the accumulation of Ca(2+) within the mitochondrial matrix, unlike mammalian mitochondria. However, the reason why the yeast PT is not induced by Ca(2+) has remained obscure. In this study, we examined in detail the effects of Ca(2+) on yeast mitochondria under various conditions. As a result, we discovered that the PT could be induced even in yeast mitochondria by externally added Ca(2+) under optimized experimental conditions. The 2 essential parameters for proper observation of the PT-inducing effects of Ca(2+) were the concentrations of the respiratory substrate and that of inorganic phosphate (Pi) in the incubation medium. The yeast mitochondrial PT induced by Ca(2+) was found to be insensitive to cyclosporin A and suppressed in the presence of a high concentration of Pi. Furthermore, when the PT was induced in yeast mitochondria by Ca(2+), the release of cytochrome c from mitochondria was also observed.

Distinct behaviors of adenylate kinase and cytochrome c observed following induction of mitochondrial permeability transition by Ca(2+) in the absence of respiratory substrate.

For induction of the mitochondrial permeability transition (PT) by Ca(2+), the addition of a respiratory substrate such as succinate is required. However, earlier studies indicated the possible induction of the mitochondrial PT by Ca(2+) in the absence of a respiratory substrate (Hunter, D.R., and Haworth, R.A. (1979) Arch. Biochem. Biophys. 195, 453-459). In the present study, we obtained clear evidence showing that the mitochondrial PT could be induced by Ca(2+) even in the absence of respiratory substrate. We next examined the protein release from mitochondria that accompanied the induction of PT in the absence of a respiratory substrate. Interestingly, distinct from the ordinary mitochondrial PT induced by Ca(2+) in the presence of a respiratory substrate, which is associated with the release of mitochondrial cytochome c and adenylate kinase, the mitochondrial PT occurring in the absence of a respiratory substrate was associated with release of mitochondrial adenylate kinase but not with that of mitochondrial cytochrome c. This experimental system should be quite useful for understanding the mechanisms of protein release from mitochondria.

VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration in an SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues.

The voltage-dependent anion channel (VDAC) is a pore-forming protein expressed in the outer membrane of eukaryotic mitochondria. Three isoforms of it, i.e., VDAC1, VDAC2, and VDAC3, are known to be expressed in mammals; however, the question as to which is the main isoform in mitochondria is still unanswered. To address this question, we first prepared standard VDACs by using a bacterial expression system and raised various antibodies against them by using synthetic peptides as immunogens. Of the three bacterially expressed VDAC isoforms, VDAC3 showed faster migration in SDS-polyacrylamide gels than VDAC1 and VDAC2, although VDAC2 is longer than VDAC1 and VDAC3, due to a 12-amino acid extension of its N-terminal region. Even with careful structural characterization of the expressed VDACs by LC-MS/MS analysis, serious structural modifications of VDACs causing changes in their migration in SDS-polyacrylamide gels were not detected. Next, immunoreactivities of the raised antibodies toward these bacterially expressed VDAC isoforms were evaluated. Trials to prepare specific antibodies against the three individual VDAC isoforms were not successful except in the case of VDAC1. However, using a synthetic peptide corresponding to the highly conserved region among the three VDACs, we were successful in preparing an antibody showing essentially equal immunoreactivities toward all three VDACs. When mitochondrial outer membrane proteins of various rat tissues were subjected to 2-dimensional electrophoresis followed by immunoblotting with this antibody, six immunoreactive protein spots were detected. These spots were characterized by LC-MS/MS analysis, and the signal intensities among the spots were compared. As a result, the signal intensity of the spot representing VDAC1 was the highest, and thus, VDAC1 was concluded to be the most abundantly expressed of the three VDAC isoforms in mammalian mitochondria.