Acute Organ Injury Research Articles

Arginine-Rich Peptides Regulate the Pathogenic Galectin-10 Crystallization and Mitigate Crystallopathy-Associated Inflammation.

Protein self-assembly into a crystal in vivo triggers acute or chronic organ injury that can lead to intractable diseases lacking specific treatment options. In this study, we report the discovery of ionic arginine-rich peptides to disrupt the pathogenic galectin-10 (gal-10) crystallization, where the aberrant deposition of gal-10 crystals in airways causes the activation of IL-1β-dependent inflammation and the stimulation of epithelial cells to produce TNF-α. Gal-10 crystals show susceptibility to pH changes and charged residue substitutions at the protein packing interfaces, manifesting the role of charge-charge attractions across protein-protein interaction interfaces in governing gal-10 crystallization. To dissolve the gal-10 crystal, the ionic peptides R9 and R12Y8 were identified to eliminate the interprotein charge-charge interactions. The efficacy of R12Y8 in mitigating the gal-10 crystallopathy in vivo was assessed in a crystal-induced lung inflammation mice model. The mice intratracheally administrated by R12Y8 exhibited a downregulated release of proinflammatory cytokines and reduced infiltration of inflammatory cells in the lungs. Our study demonstrates that the pathogenic gal-10 crystallization is readily eliminated by R-rich peptides, which may display translational potentials for the treatment of gal-10 crystallopathy.

Discovery and optimization of 1,2,4-triazole derivatives as novel ferroptosis inhibitors.

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid ROS accumulation, which is associated with various diseases, including acute organ injury, neurodegenerative disorders, and cancer. Pharmacological inhibition of ferroptosis has great potential for the treatment of these diseases. However, the clinical translation of many ferroptosis inhibitors is hindered by their inadequate activity or suboptimal pharmacokinetic profiles. In this study, several 1,2,4-triazole derivatives were identified as novel ferroptosis inhibitors through phenotypic screening of our in-house compound library. Among these compounds, NY-26 was found to significantly inhibit RSL3-induced ferroptosis in 786-O cells with nanomolar level (EC50=62nM). The antiferroptotic activity of NY-26 was further validated across multiple cell lines. Mechanistic studies revealed that NY-26 inhibits ferroptosis through its intrinsic free radical-trapping antioxidant capacity. Additional results demonstrated that the triazole derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Taken together, NY-26, tethering a novel 1,2,4-triazole scaffold, could be an effective ferroptosis inhibitor with great therapeutic potential for further investigation.

Persistent Neutrophilic Inflammation is Associated with Delayed Toxicity of Phenylarsine Oxide in Lungs.

Phenyl arsine oxide (PAO) is a vesicant, similar to Lewisite, a potential chemical warfare agent and an environmental contaminant. PAO-induced skin burns can trigger acute organ injury, including lungs. We have recently demonstrated that PAO burns can also has a delayed toxicity, although the specific mechanism/s remain to be determined. A single cutaneous exposure to PAO resulted in inflammatory acute lung injury at 6 and 24 hours. While acute injury subsiding by 1 week, we observed a significant airway remodeling at 10 weeks post-PAO exposure. The mechanism of prolonged PAO toxicity was associated with the influx of neutrophils that produced harmful neutrophil extracellular traps (NETs). We demonstrated that the crosstalk between NET deployments and expression of IL-33, a pro-remodeling mediator was associated with the development of peribronchial fibrosis. In summary, these results suggest that a single cutaneous exposure to PAO causes the acute inflammatory phase followed by NETs/IL-33 feed forward signaling implicated for the persistent neutrophil influx and NETs formation resulting in airway remodeling.

Ultrasmall Black Phosphorus Quantum Dots with Robust Antioxidative Properties for Acute Kidney and Liver Injury Therapy.

Acute organ injuries, such as acute kidney injury (AKI) and acute liver injury (ALI), usually present high morbidity and mortality in patients. However, the current clinical treatments remain limited, especially the lack of effective drug-based treatment. Since these acute injuries are often associated with reactive oxygen species (ROS) overproduction, it is a promising strategy to develop therapeutic agents with potent ROS scavenging ability and excellent biocompatibility for efficient antioxidation therapy. Black phosphorus quantum dots (BPQDs), low-dimensional nanomaterials prepared through a straightforward one-step method and capable of complete controllable biodegradation, offer significant potential. This study comprehensively explores the extensive free-radical scavenging capabilities of BPQDs, underscoring their immense potential in treating ROS-related organ injuries. BPQDs could simultaneously achieve radical scavenging of DPPH, ABTS·, OH·, and O2 -· and exhibit excellent cytoprotective effects against ROS-mediated damage even at extremely low dosages. Besides, the ultrasmall size of BPQDs (≈3-5nm) allows them to effectively penetrate the glomerular filtration barrier (≈6nm), significantly improving the symptoms of AKI and ALI in vivo. The therapeutic efficacy and great biocompatibility of BPQDs facilitate the clinical management of ROS-related diseases, which will broaden the applications of QDs in the field of biomedicine.

The Ambivalent Role of miRNA-21 in Trauma and Acute Organ Injury

Since their initial recognition, miRNAs have been the subject of rising scientific interest. Especially in recent years, miRNAs have been recognized to play an important role in the mediation of various diseases, and further, their potential as biomarkers was recognized. Rising attention has also been given to miRNA-21, which has proven to play an ambivalent role as a biomarker. Responding to the demand for biomarkers in the trauma field, the present review summarizes the contrary roles of miRNA-21 in acute organ damage after trauma with a specific focus on the role of miRNA-21 in traumatic brain injury, spinal cord injury, cardiac damage, lung injury, and bone injury. This review is based on a PubMed literature search including the terms “miRNA-21” and “trauma”, “miRNA-21” and “severe injury”, and “miRNA-21” and “acute lung respiratory distress syndrome”. The present summary makes it clear that miRNA-21 has both beneficial and detrimental effects in various acute organ injuries, which precludes its utility as a biomarker but makes it intriguing for mechanistic investigations in the trauma field.

Total alkaloids of Aconitum carmichaelii Debx alleviate cisplatin-induced acute renal injury by inhibiting inflammation and oxidative stress related to gut microbiota metabolism

BackgroundCisplatin-induced acute kidney injury (AKI) is a complex and serious clinical issue, representing a major cause of hospital-acquired AKI. Alkaloids are the main active constituents of Aconitum carmichaelii Debx, which exhibit protective effects in several kidney disease models and against other acute organ injuries. However, its activity and mechanism of action in AKI treatment remain unclear. PurposeThis study aimed to elucidate the effect of Aconitum carmichaelii Debx (ACA) in a model of cisplain-induced AKI and comprehensively investigate its underlying mechanisms. MethodsThe major alkaloids in ACA were analyzed using high-performance liquid chromatography. Blood urea nitrogen (BUN) and serum creatine levels were measured using automated biochemical instruments. 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, fecal microbiota transplantation (FMT), non-targeted metabolomics, and transcriptomics were performed to systematically identify prospective biomarkers after ACA treatment. Anti-inflammatory and anti-oxidative stress activities were monitored using ELISA and western blotting. ResultsFour main compounds (fuziline, neoline, talatisamine, and songorine) were identified in ACA. ACA significantly alleviated cisplatin-induced AKI by reducing (BUN) and serum creatine levels and improving histopathological scores. Moreover, ACA balanced cisplatin-mediated confoundments in microbial composition and function, including decreasing the levels of Escherichia-Shigella, Clostridium, and Ruminococcus, as well as increasing Ligilactobacillus, Anaerotruncus, Bacteroides and Desulfovibrio levels, accompanied by uremic toxin reduction, and augmenting serum SCFAs. The FMT experiments further confirmed that ACA exerts anti-AKI effects by affecting gut microbiota. A multi-omics study has shown that ACA regulates glutathione and tryptophan metabolism and mediates pathways that trigger inflammatory responses. Finally, ACA reduced serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α), restored enzymes of the antioxidative system (SOD and CAT) and GSH values, and decreased monoester diterpene alkaloid levels in the kidney by inhibiting the expression of NF-κB pathway-related proteins and increasing Nrf2/HO-1 pathway-related protein expression. ConclusionACA protects against cisplatin-induced AKI through its anti-inflammatory and antioxidant functions, which may be associated with the restoration of gut microbiota metabolism. ACA is a potential drug for AKI and other forms of organ damage related to the disruption of the gut microbiota.

Macrophages dying from ferroptosis promote microglia-mediated inflammatory responses during spinal cord injury

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.

The microbiome and acute organ injury: focus on kidneys.

The microbiome of critically ill patients is significantly altered by both effects of the illnesses and clinical interventions provided during intensive care. Studies have shown that manipulating the microbiome can prevent or modulate complications of critical illness in experimental models and preliminary clinical trials. This review aims to discuss general concepts about the microbiome, including mechanisms of modifying acute organ dysfunction. The focus will be on the effects of microbiome modulation during experimental acute kidney injury (excluding septic AKI) and comparison with other experimental acute organ injuries commonly seen in critically ill patients.

FBXW7-Mediated Downregulation of GPX4 Aggravates Acute Kidney Injury Following Ischemia‒Reperfusion.

Acute kidney injury (AKI) is a prevalent and potentially life-threatening complication characterized by a high incidence and mortality. A large number of studies have emphasized the role of ferroptosis in AKI. Moreover, FBXW7, a ubiquitin ligase, has been implicated in acute organ injury. Analysis of the GEO database (GSE98622) revealed increased FBXW7 mRNA levels in the kidney following ischemia‒reperfusion (IR). However, the role of FBXW7 in AKI has not been elucidated. Therefore, this study aimed to investigate the role of FBXW7 in IR-AKI and its underlying mechanisms. Here, we found that IR could induce AKI and increase FBXW7 expression, while the ferroptosis inhibitor Fer-1 alleviated AKI and decreased FBXW7 expression. Furthermore, we treated HK-2 cells with hypoxia for 12h and reoxygenation for 4h (H12R4) to simulate IR-AKI and investigated the impact of modulating FBXW7 expression on ferroptosis by employing ferroptosis-related agonists or inhibitors. Our findings revealed that H12R4 induced HK2 ferroptosis and increased the expression of FBXW7. FBXW7 overexpression in control cells exacerbated erastin-induced ferroptosis, and FBXW7 knockdown inhibited ferroptosis in H12R4-treated cells. Mechanistically, we confirmed that FBXW7 can bind to GPX4, a key molecule that inhibits ferroptosis. The half-life of the GPX4 protein decreased after FBXW7 overexpression, GPX4 ubiquitination increased after H12R4, and GPX4 degradation decreased after FBXW7 knockdown. In conclusion, our results indicated that FBXW7 plays an important role in the development of IR-AKI by promoting ferroptosis through the downregulation of GPX4 expression. This study provides new insight into FBXW7 as a potential target for treating AKI.

Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery

Liberal oxygen (hyperoxia) is commonly administered to patients during surgery, and oxygenation is known to impact mechanisms of perioperative organ injury. To evaluate the effect of intraoperative hyperoxia compared to maintaining normoxia on oxidative stress, kidney injury, and other organ dysfunctions after cardiac surgery. This was a participant- and assessor-blinded, randomized clinical trial conducted from April 2016 to October 2020 with 1 year of follow-up at a single tertiary care medical center. Adult patients (>18 years) presenting for elective open cardiac surgery without preoperative oxygen requirement, acute coronary syndrome, carotid stenosis, or dialysis were included. Of 3919 patients assessed, 2501 were considered eligible and 213 provided consent. Of these, 12 were excluded prior to randomization and 1 following randomization whose surgery was cancelled, leaving 100 participants in each group. Participants were randomly assigned to hyperoxia (1.00 fraction of inspired oxygen [FiO2]) or normoxia (minimum FiO2 to maintain oxygen saturation 95%-97%) throughout surgery. Participants were assessed for oxidative stress by measuring F2-isoprostanes and isofurans, for acute kidney injury (AKI), and for delirium, myocardial injury, atrial fibrillation, and additional secondary outcomes. Participants were monitored for 1 year following surgery. Two hundred participants were studied (median [IQR] age, 66 [59-72] years; 140 male and 60 female; 82 [41.0%] with diabetes). F2-isoprostanes and isofurans (primary mechanistic end point) increased on average throughout surgery, from a median (IQR) of 73.3 (53.1-101.1) pg/mL at baseline to a peak of 85.5 (64.0-109.8) pg/mL at admission to the intensive care unit and were 9.2 pg/mL (95% CI, 1.0-17.4; P = .03) higher during surgery in patients assigned to hyperoxia. Median (IQR) change in serum creatinine (primary clinical end point) from baseline to postoperative day 2 was 0.01 mg/dL (-0.12 to 0.19) in participants assigned hyperoxia and -0.01 mg/dL (-0.16 to 0.19) in those assigned normoxia (median difference, 0.03; 95% CI, -0.04 to 0.10; P = .45). AKI occurred in 21 participants (21%) in each group. Intraoperative oxygen treatment did not affect additional acute organ injuries, safety events, or kidney, neuropsychological, and functional outcomes at 1 year. Among adults receiving cardiac surgery, intraoperative hyperoxia increased intraoperative oxidative stress compared to normoxia but did not affect kidney injury or additional measurements of organ injury including delirium, myocardial injury, and atrial fibrillation. ClinicalTrials.gov Identifier: NCT02361944.

Neutrophils: a key component in ECMO-related acute organ injury.

Extracorporeal membrane oxygenation (ECMO), as an extracorporeal life support technique, can save the lives of reversible critically ill patients when conventional treatments fail. However, ECMO-related acute organ injury is a common complication that increases the risk of death in critically ill patients, including acute kidney injury, acute brain injury, acute lung injury, and so on. In ECMO supported patients, an increasing number of studies have shown that activation of the inflammatory response plays an important role in the development of acute organ injury. Cross-cascade activation of the complement system, the contact system, and the coagulation system, as well as the mechanical forces of the circuitry are very important pathophysiological mechanisms, likely leading to neutrophil activation and the production of neutrophil extracellular traps (NETs). NETs may have the potential to cause organ damage, generating interest in their study as potential therapeutic targets for ECMO-related acute organ injury. Therefore, this article comprehensively summarized the mechanism of neutrophils activation and NETs formation following ECMO treatment and their actions on acute organ injury.

Long wavelength light exposure reduces systemic inflammation coagulopathy and acute organ injury following multiple injuries in mice.

Evidence suggests that variation in light exposure strongly influences the dynamic of inflammation, coagulation, and the immune system. Multiple injuries induce systemic inflammation that can lead to end-organ injury. Here, we hypothesize that alterations in light exposure influence posttrauma inflammation, coagulopathy, and end-organ injury. C57BL/6 mice underwent a validated multiple-injury and hemorrhage model performed following 72 hours of exposure to red (617 nm, 1,700 lux), blue (321 nm, 1,700 lux), and fluorescent white light (300 lux) (n = 6-8/group). The animals were sacrificed at 6 hours posttrauma. Plasma samples were evaluated and compared for proinflammatory cytokine expression levels, coagulation parameters, markers of liver and renal injury, and histological changes (Carstairs staining). One-way analysis of variance statistical tests were applied to compare study groups. Preexposure to long-wavelength red light significantly reduced the inflammatory response at 6 hours after multiple injuries compared with blue and ambient light, as evidenced by decreased levels of interleukin 6, monocyte chemoattractant protein-1 (both p < 0.001), liver injury markers (alanine transaminase, p < 0.05), and kidney injury markers (cystatin C, p < 0.01). In addition, Carstairs staining of organ tissues revealed milder histological changes in the red light-exposed group, indicating reduced end-organ damage. Furthermore, prothrombin time was significantly lower ( p < 0.001), and fibrinogen levels were better maintained ( p < 0.01) in the red light-exposed mice compared with those exposed to blue and ambient light. Prophylactic light exposure can be optimized to reduce systemic inflammation and coagulopathy and minimize acute organ injury following multiple injuries. Understanding the mechanisms by which light exposure attenuates inflammation may provide a novel strategy to reducing trauma-related morbidity.

Meta-analysis of the effects of inert gases on cerebral ischemia–reperfusion injury

Recently, noble gas has become a hot spot within the medical field like respiratory organ cerebral anemia, acute urinary organ injury and transplantation. However, the shield performance in cerebral ischemia–reperfusion injury (CIRI) has not reached an accord. This study aims to evaluate existing evidence through meta-analysis to determine the effects of inert gases on the level of blood glucose, partial pressure of oxygen, and lactate levels in CIRI. We searched relevant articles within the following both Chinese and English databases: PubMed, Web of science, Embase, CNKI, Cochrane Library and Scopus. The search was conducted from the time of database establishment to the end of May 2023, and two researchers independently entered the data into Revman 5.3 and Stata 15.1. There were total 14 articles were enclosed within the search. The results showed that the amount of partial pressure of blood oxygen in the noble gas cluster was beyond that in the medicine gas cluster (P < 0.05), and the inert gas group had lower lactate acid and blood glucose levels than the medical gas group. The partial pressure of oxygen (SMD = 1.51, 95% CI 0.10 ~ 0.91 P = 0.04), the blood glucose level (SMD = − 0.59, 95% CI − 0.92 ~ − 0.27 P = 0.0004) and the lactic acid level (SMD = − 0.42, 95% CI − 0.80 ~ − 0.03 P = 0.03) (P < 0.05). These results are evaluated as medium-quality evidence. Inert gas can effectively regulate blood glucose level, partial pressure of oxygen and lactate level, and this regulatory function mainly plays a protective role in the small animal ischemia–reperfusion injury model. This finding provides an assessment and evidence of the effectiveness of inert gases for clinical practice, and provides the possibility for the application of noble gases in the treatment of CIRI. However, more operations are still needed before designing clinical trials, such as the analysis of the inhalation time, inhalation dose and efficacy of different inert gases, and the effective comparison of the effects in large-scale animal experiments.

MIR-155 PROMOTES ACUTE ORGAN INJURY IN LPS-INDUCED ENDOTOXEMIC MICE BY ENHANCING CCL-2 EXPRESSION IN MACROPHAGES.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Macrophages play important roles in the inflammatory process of sepsis by secreting chemokines. Chemokine (CC-motif) ligand 2 (CCL-2) is one of the main proinflammatory chemokines secreted by macrophages that plays a critical role in the recruitment of more monocytes and macrophages to the sites of injury in sepsis, but the mechanisms that regulate CCL-2 expression in macrophages during sepsis are still unknown. In the present study, by using the LPS-induced endotoxemia model, we found that LPS induced the expression of microRNA (miR)-155 and CCL-2 in endotoxemic mice and RAW264.7 cells. MiR-155 mimics or miR-155 inhibitor treatment experiment suggested that miR-155 was sufficient to increase LPS-induced CCL-2 expression in macrophages, but miR-155 was not the only factor promoting CCL-2 expression. We further demonstrated that miR-155-induced increase of CCL-2 promoted chemotaxis of additional macrophages, which subsequently enhanced lung injury in endotoxemic mice. Serum/glucocorticoid regulated kinase family member 3 (SGK3), a potential target of miR-155, was identified by RNA sequencing and predicted by TargetScan and miRDB. We further confirmed miR-155 regulated SGK3 to increase LPS-induced CCL-2 by using miR-155 mimics and SGK3 overexpression. Thus, our study demonstrates that miR-155 targets SGK3 to increase LPS-induced CCL-2 expression in macrophages, which promotes macrophage chemotaxis and enhances organs injury during endotoxemia. Our study contributed to a better understanding of the mechanisms underlying the inflammatory response during sepsis.

Theaflavin mitigates acute gouty peritonitis and septic organ injury in mice by suppressing NLRP3 inflammasome assembly.

Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 μM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1β (IL-1β). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1β and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.

Longitudinal analysis of electrolyte prolife in intensive care COVID-19 patients

ABSTRACT Introduction According to a substantial body of research, electrolyte abnormalities are a common manifestation in coronavirus disease 2019 (COVID-19) patients and are associated with adverse outcomes. This study aimed to investigate electrolyte imbalances in COVID-19 patients and assess their relation to mortality. Methods Adult COVID-19 patients hospitalized in the Security Forces Hospital in Saudi Arabia from June 8th till August 18th, 2020 were enrolled in this retrospective observational study. We examined baseline characteristics, comorbidities, acute organ injuries, medications, and electrolyte levels including sodium, potassium, chloride, calcium, bicarbonate, phosphate, and magnesium on ICU admission, as well as every following day of ICU stay, until death or discharge. Patients were stratified according to survival, and differences in variables between groups were compared using Mann-Whitney’s U test or Fisher’s exact test. Longitudinal electrolyte profiles were modeled using random intercept linear regression models. Results A total of 60 COVID-19 patients were enrolled. Compared to survivors, non-survivors had significantly higher sodium and phosphate on admission and death, higher potassium and magnesium at death, and significantly lower calcium at death. Abnormalities in admission levels of chloride and bicarbonate were also more frequently observed in non-survivors. Furthermore, in the deceased group, we observed a daily increase in potassium and phosphate levels, and a daily decrease in sodium and chloride. Finally, calcium increased in non-survivors over time, however, not as significantly as in the survivor group. Conclusion Admission levels of electrolytes and changes over the course of ICU stay appear to be associated with mortality in COVID-19 patients.

Academician Nikolay Anatolyevich Maistrenko (to the 70th anniversary of his birthday)

Nikolay Anatolyevich Maistrenko is a prominent specialist in the field of abdominal and endocrine surgery, oncology, and organization of specialized surgical care. For 24 years, he headed the Department and Clinic of Faculty Surgery named after S.P. Fedorov Military Medical Academy of S.M. Kirov. With his direct participation in the clinic, the structural units became modernized, which were equipped with modern equipment to provide high-tech surgical care. Under the direction of Academician of the Russian Academy of Sciences N.A. Maistrenko, the range of scientific research conducted in the clinic and together with other research institutions of Saint Petersburg (i.e., Research Institute of Oncology named after N.N. Petrov, Institute of Physiology named after I.P. Pavlov, and Research Institute of Emergency Medicine named after I.I. Dzhanelidze) has significantly expanded. The main areas of scientific activity of Professor N.A. Maistrenko are the development of organizational, tactical, and technical issues of providing surgical care to patients with gastroenterological profile; study of long-term results of organ-preserving operations and resection interventions for complicated gastric and duodenal ulcers; research on the problem of choledocholithiasis using laparoscopic, endoscopic, and non-surgical methods of its elimination; introduction of new diagnostic and therapeutic technologies in surgical endocrinology; study of the possibilities of laparoscopic interventions in emergency surgery of acute diseases and abdominal organ injuries; development of topical aspects of colorectal surgery using new technologies when performing sphincter-preserving operations; and surgical treatment of chronic pancreatitis. Academician N.A. Maistrenko is the author and co-author of more than 750 scientific papers, including 28 monographs and manuals. Under his direction, 13 doctoral and 19 masters theses were defended. Eighteen teaching aids, workshops, and lectures have been published on various sections of endocrine and abdominal surgery. Nikolay Anatolyevich Maistrenko is a vivid example of how aspiration, diligence, and discipline ensure the achievement of the highest goals, and love for his specialty guarantees great professional success.

The impact of hyperglycaemic crisis episodes on long-term outcomes for inpatients presenting with acute organ injury: A prospective, multicentre follow-up study.

The long-term clinical outcome of poor prognosis in patients with diabetic hyperglycaemic crisis episodes (HCE) remains unknown, which may be related to acute organ injury (AOI) and its continuous damage after hospital discharge. This study aimed to observe the clinical differences and relevant risk factors in HCE with or without AOI. A total of 339 inpatients were divided into an AOI group (n=69) and a non-AOI group (n=270), and their differences and risk factors were explored. The differences in clinical outcomes and prediction models for evaluating the long-term adverse events after hospital discharge were established. The mortality among cases complicated by AOI was significantly higher than that among patients without AOI [8 (11.59%) vs. 11 (4.07%), Q = 0.034] during hospitalization. After a 2-year follow-up, the mortality was also significantly higher in patients with concomitant AOI than in patients without AOI after hospital discharge during follow-up [13 (21.31%) vs. 15 (5.8%), Q < 0.001]. The long-term adverse events in patients with concomitant AOI were significantly higher than those in patients without AOI during follow-up [15 (24.59%) vs. 31 (11.97%), Q = 0.015]. Furthermore, Blood β-hydroxybutyric acid (P = 0.003), Cystatin C (P <0.001), serum potassium levels (P = 0.001) were significantly associated with long-term adverse events after hospital discharge. The long-term prognosis of HCE patients complicated with AOI was significantly worse than that of HCE patients without AOI. The laboratory indicators were closely correlated with AOI, and future studies should explore the improvement of clinical outcome in response to timely interventions.

ODP015 "Malignant" Hypertension in an Older Male

Abstract Background Malignant hypertension connotates extreme elevation of blood pressure with associated acute target organ injury. Secondary causes of hypertension should always be considered in patients presenting with acute organ dysfunction especially when the hypertension is also resistant. Clinical case: A 66-year-old male was transferred to our hospital after two successive admissions to a local hospital with acute confusion. Importantly, he was noted to have acute kidney injury and hypokalemia in the course of those admissions. On review of his records, it was noted that he had been evaluated recently for chest pain with a contrast enhanced chest CT which incidentally detected a left adrenal mass. Biopsy of the mass had been performed and returned positive for adrenocortical carcinoma. Past history was also notable for chronic hypertension, type 2 diabetes and hypothyroidism for which he was on appropriate therapy. On physical examination, the patient was noted to be hypertensive. Other pertinent findings included facial plethora, extensive bruising and supraclavicular fat pad fullness. Abdominal striae were not seen. Laboratory investigations showed hyperglycemia (glucose: 201 mg/dL), hypokalemia (potassium: 3. 0 mmol/L) and metabolic alkalosis (bicarbonate: 30 mmol/L). Endocrine work up showed suppressed aldosterone (&amp;lt;4. 0 ng/dL, n: &amp;lt;21 ng/dL), total testosterone (31 ng/dL, n: 240-950 ng/dL) and ACTH (&amp;lt;5. 0 pg/mL, n: 7.2-63 pg/mL). Dehydroepiandrosterone (474 mcg/dL, n: 12-227 mcg/dL) and androstenedione (219 ng/dL, n: 40-150 ng/dL) levels were elevated. Cortisol levels did not suppress with overnight dexamethasone suppression test (29.8 mcg/dL). A diagnosis of Cushing's syndrome secondary to adrenocortical carcinoma was made. The patient was initiated on chemotherapy with carboplatin and etoposide. He was planned for mitotane therapy but passed away unexpectedly before the drug could be arranged. Conclusion Adrenocortical carcinoma can present with rapid onset of Cushingoid symptoms as well as sudden decompensation of previously controlled chronic hypertension, both of which were seen in this case. Although relatively uncommon, it remains a treatable and yet deadly cause for secondary hypertension, and should be considered in the appropriate clinical and biochemical settings. Presentation: No date and time listed

Respiratory Exposure to Copper Oxide Particles Causes Multiple Organ Injuries via Oxidative Stress in a Rat Model.

IntroductionThe wide application of copper oxide nanoparticles (CuO NPs) in industry, agriculture, environmental remediation, and biomedicine has increased the risk of human exposure to CuO NPs. Recent studies suggested that CuO NPs have genotoxic and cytotoxic effects on various cells. However, little is known about the toxicity of CuO NPs on major peripheral organs after respiratory exposure.Materials and MethodsWe investigated the toxicities of CuO NPs on human bronchial epithelial (BEAS-2B) and human cardiomyocytes (AC16) cells in vitro, and on the lungs, liver, kidneys, and heart of spontaneously hypertensive rats (SHRs) at 24 and 72 h after intrabronchial instillation in vivo.ResultsCuO NPs induced concentration-dependent toxicities in both BEAS-2B and AC16 cells mainly through hierarchical oxidative stress mechanisms, involving generation of reactive oxygen species (ROS), upregulation of heme oxygenase-1 (HO-1), mitochondrial dysfunction, and secretion of proinflammatory and profibrogenic cytokines. Respiratory exposure to CuO NPs induced acute multiple organ injuries in SHRs manifesting through inflammation and fibrosis. However, cardiac injury was relatively less severe than injuries in the lungs, liver, and kidneys. Upregulation of serum C-reaction protein (CRP), tumor necrosis factor α (TNF-α), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1), angiotensin converting enzyme (ACE), and von Willebrand factor (vWF) after exposure to CuO NPs indicated systematic inflammation, endothelial injury, and potential prothrombosis.ConclusionRespiratory exposure to CuO NPs induced acute injuries in main peripheral organs, including the lungs, liver, kidneys, and heart. Individuals with existing cardiovascular diseases were susceptible to exposure to CuO NPs. This study provides a warning about the extensive toxic effects of CuO NPs, especially in the susceptible population.