Nucleic acid-based nanotherapeutics for treating sepsis and associated organ injuries.

In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future.

Autoinflammatory Contributors to Cytokine Storm.

Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.

Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome.

There is extensive overlap of clinical features among familial or primary HLH (pHLH), reactive or secondary hemophagocytic lymphohistiocytosis (sHLH) [including macrophage activation syndrome (MAS) related to rheumatic diseases], and hyperferritinemic sepsis-induced multiple organ dysfunction syndrome (MODS); however, the distinctive pathobiology that causes hyperinflammatory process in each condition requires careful considerations for therapeutic decision-making. pHLH is defined by five or more of eight HLH-2004 criteria [1], where genetic impairment of natural killer (NK) cells or CD8+ cytolytic T cells results in interferon gamma (IFN-γ)-induced hyperinflammation regardless of triggering factors. Cytolytic treatments (e.g., etoposide) or anti-IFN-γ monoclonal antibody (emapalumab) has been effectively used to bridge the affected patients to hematopoietic stem cell transplant. Secondary forms of HLH also have normal NK cell number with decreased cytolytic function of varying degrees depending on the underlying and triggering factors. Although etoposide was uniformly used in sHLH/MAS in the past, the treatment strategy in different types of sHLH/MAS is increasingly streamlined to reflect the triggering/predisposing conditions, severity/progression, and comorbidities. Accordingly, in hyperferritinemic sepsis, the combination of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC) reflects reticuloendothelial system dysfunction and defines sepsis-associated MAS. It is demonstrated that as the innate immune response to infectious organism prolongs, it results in reduction in T cells and NK cells with subsequent lymphopenia even though normal cytolytic activity continues (Figs. 30.1, 30.2, 30.3, and 30.4). These changes allow free hemoglobin and pathogens to stimulate inflammasome activation in the absence of interferon-γ (IFN-γ) production that often responds to source control, intravenous immunoglobulin (IVIg), plasma exchange, and interleukin 1 receptor antagonist (IL-1Ra), similar to non-EBV, infection-induced HLH.

Towards better mortality prediction in cancer patients in the ICU: a comparative analysis of prognostic scales: systematic literature review.

OBJECTIVE: To evaluate the predictive ability of mortality prediction scales in cancer patients admitted to intensive care units (ICUs). DESIGN: A systematic review of the literature was conducted using a search algorithm in October 2022. The following databases were searched: PubMed, Scopus, Virtual Health Library (BVS), and Medrxiv. The risk of bias was assessed using the QUADAS-2 scale. SETTING: ICUs admitting cancer patients. PARTICIPANTS: Studies that included adult patients with an active cancer diagnosis who were admitted to the ICU. INTERVENTIONS: Integrative study without interventions. MAIN VARIABLES OF INTEREST: Mortality prediction, standardized mortality, discrimination, and calibration. RESULTS: Seven mortality risk prediction models were analyzed in cancer patients in the ICU. Most models (APACHE II, APACHE IV, SOFA, SAPS-II, SAPS-III, and MPM II) underestimated mortality, while the ICMM overestimated it. The APACHE II had the SMR (Standardized Mortality Ratio) value closest to 1, suggesting a better prognostic ability compared to the other models. CONCLUSIONS: Predicting mortality in ICU cancer patients remains an intricate challenge due to the lack of a definitive superior model and the inherent limitations of available prediction tools. For evidence-based informed clinical decision-making, it is crucial to consider the healthcare team's familiarity with each tool and its inherent limitations. Developing novel instruments or conducting large-scale validation studies is essential to enhance prediction accuracy and optimize patient care in this population.

The evaluation of cytokines in predicting the organ injury of critically pediatric patients: a retrospective study.

Background: The current early warning model for organ damage in critically ill patients has certain limitations. Based on the pathological mechanism, the establishment of an early warning system for organ damage in critically ill children using cytokines profile has not been explored. The aim of this study is to explore the predicting value of cytokines in critically ill patients. Methods: There were 200 critically pediatric patients and 49 general patients between August 22, 2018 and April 28, 2023 from Children's Hospital of Soochow University enrolled in this study. The clinical information was retrospectively collected and analyzed. The cytokine profiles of these patients were detected by flow cytometry. Receiver operating characteristic (ROC) curves were plotted to determine the association between the cytokines and organ injury. Results: There were no statistically significant differences in gender, age and underlying disease between critically ill patients and general patients. The interleukin (IL)-6 (P<0.001), IL-10 (P<0.001), IL-17A (P=0.001), tumor necrosis factor-α (TNF-α) (P=0.02) and interferon-γ (IFN-γ) (P=0.02) level in the critically patients were significantly higher than those in the general patients. The results showed that the incidence of acute gastrointestinal injury (AGI) and acute kidney injury (AKI) in critically ill patients was 39% and 23.5%, respectively. Moreover, there were 4% and 3.5% patients with the occurrence of cardiac arrest and acute live injury. The IFN-γ level was increased in these patients with acute liver injury compared to those without these organ injuries, but reduced in the patients with AGI compared to those without. The patients with AKI showed a significant increase in IL-10 in contrast to those without. The IL-2, IL-4, IL-6, IL-10 and IL-17A were higher in patients with acute liver failure (ALF), but TNF-α was reduced, compared to those without. The IL-2, IL-4, IL-6 and IL-10 were significantly increased in the patients with cardiac arrest compared to those without. When IL-10 was higher than 279.45 pg/mL, the sensitivity and specificity for predicting cardiac arrest were 0.875 and 0.927, respectively. While the sensitivity and specificity of IL-6 (more than 1,425.6 pg/mL) were 0.625 and 0.844, respectively. However, no synergistic effect of IL-6 and IL-10 was observed for predicting cardiac arrest. Additionally, the IL-17A (more than 21.6 pg/mL) was a good predictor for the incidence of ALF (sensitivity =0.714, specificity =0.876). Conclusions: The cytokines profile was different between critically ill patients with organ injury and those without organ injury. The IL-6 and IL-10 levels were good predictors for cardiac arrest in critically ill patients. Additionally, higher IL-17A predicted the incidence of ALF of the critically ill patients.

Impact of interleukin 6 levels on acute lung injury risk and disease severity in critically ill sepsis patients.

BACKGROUND: Sepsis is a life-threatening condition characterized by a dysregulation of the host response to infection that can lead to acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Interleukin 6 (IL-6) is a pro-inflammatory cytokine that plays a crucial role in the pathogenesis of sepsis and its complications. AIM: To investigate the relationship among plasma IL-6 levels, risk of ALI, and disease severity in critically ill patients with sepsis. METHODS: This prospective and observational study was conducted in the intensive care unit of a tertiary care hospital between January 2021 and December 2022. A total of 83 septic patients were enrolled. Plasma IL-6 levels were measured upon admission using an enzyme-linked immunosorbent assay. The development of ALI and MODS was monitored during hospitalization. Disease severity was evaluated by Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. RESULTS: Among the 83 patients with sepsis, 38 (45.8%) developed ALI and 29 (34.9%) developed MODS. Plasma IL-6 levels were significantly higher in patients who developed ALI than in those without ALI (median: 125.6 pg/mL vs 48.3 pg/mL; P < 0.001). Similarly, patients with MODS had higher IL-6 levels than those without MODS (median: 142.9 pg/mL vs 58.7 pg/mL; P < 0.001). Plasma IL-6 levels were strongly and positively correlated with APACHE II (r = 0.72; P < 0.001) and SOFA scores (r = 0.68; P < 0.001). CONCLUSION: Elevated plasma IL-6 levels in critically ill patients with sepsis were associated with an increased risk of ALI and MODS. Higher IL-6 levels were correlated with greater disease severity, as reflected by higher APACHE II and SOFA scores. These findings suggest that IL-6 may serve as a biomarker for predicting the development of ALI and disease severity in patients with sepsis.

Homograft Aortic Root Replacement for Destructive Prosthetic Valve Endocarditis: Results in the Current Era.

Background: Destructive aortic prosthetic valve endocarditis portends a high morbidity and mortality, and requires complex high-risk surgery. Homograft root replacement is the most radical and biocompatible operation and, thus, the preferred option. Methods: A retrospective analysis was conducted on 61 consecutive patients who underwent a cardiac reoperation comprising homograft aortic root replacement since 2010. The probabilities of survival were calculated with the Kaplan-Meier method, whereas multivariable regression served to outline the predictors of adverse events. The endpoints were operative/late death, perioperative low cardiac output and renal failure, and reoperations. Results: The operative (cumulative hospital and 30-day) mortality was 13%. The baseline aspartate transaminase (AST) and associated mitral procedures were predictive of operative death (p = 0.048, OR [95% CIs] = 1.03 [1-1.06]) and perioperative low cardiac output, respectively (p = 0.04, OR [95% CIs] = 21.3 [2.7-168.9] for valve replacement). The latter occurred in 12 (20%) patients, despite a normal ejection fraction. Survival estimates (±SE) at 3 months, 6 months, 1 year, and 3 years after surgery were 86.3 ± 4.7%, 82.0 ± 4.9%, 75.2 ± 5.6, and 70.0 ± 6.3%, respectively. Survival was significantly lower in the case of AST ≥ 40 IU/L (p = 0.04) and aortic cross-clamp time ≥ 180 min (p = 0.01), but not when excluding operative survivors. Five patients required early (two out of the five, within 3 months) or late (three out of the five) reoperation. Conclusions: Homograft aortic root replacement for destructive prosthetic valve endocarditis can currently be performed with a near 90% operative survival and reasonable 3-year mortality and reoperation rate. AST might serve to additionally stratify the operative risk.

Extracerebral multiple organ dysfunction and interactions with brain injury after cardiac arrest.

Cardiac arrest and successful resuscitation cause whole-body ischemia and reperfusion, leading to brain injury and extracerebral multiple organ dysfunction. Brain injury is the leading cause of death and long-term disability in resuscitated survivors, and was conceptualized and treated as an isolated injury, which has neglected the brain-visceral organ crosstalk. Extracerebral organ dysfunction is common and is significantly associated with mortality and poor neurological prognosis after resuscitation. However, detailed description of the characteristics of post-resuscitation multiple organ dysfunction is lacking, and the bidirectional interactions between brain and visceral organs need to be elucidated to explore new treatment for neuroprotection. This review aims to describe current concepts of post-cardiac arrest brain injury and specific characteristics of post-resuscitation dysfunction in cardiovascular, respiratory, renal, hepatic, adrenal, gastrointestinal, and neurohumoral systems. Additionally, we discuss the crosstalk between brain and extracerebral organs, especially focusing on how visceral organ dysfunction and other factors affect brain injury progression. We think that clarifying these interactions is of profound significance on how we treat patients for neural/systemic protection to improve outcome.

Predictive value of lactate/albumin ratio for death and multiple organ dysfunction syndrome in patients with sepsis.

Background: Multiple organ dysfunction syndrome (MODS) is common after sepsis and increases mortality. Lactate (Lac) can assess the prognosis of patients. Albumin (Alb) is closely associated with inflammatory response in sepsis patients. This work evaluated the predictive value of Lac/Alb for prognosis of sepsis patients. Methods: Data of 160 sepsis patients were retrospectively collected. Lac and Alb levels were measured upon admission, at 24 hours and 48 hours later. Using 0.45 as the cutoff value for Lac/Alb, patients were rolled into high-level (HL) and low-level (LL) groups. MODS rates and mortality rates were analyzed. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive value of 48-hour Lac/Alb for patient prognosis. Correlation between Lac/Alb and APACHE II and SOFA scores was assessed. Results: The 12-month follow-up revealed 52 deaths (32.5%), and MODS occurred in 49 cases (30.6%) on the 7th day. The MODS group possessed elevated Lac and Lac/Alb and decreased Alb to the N-MODS group (P<0.05), and similar results were observed by comparison the survival and death group (P<0.05). The sensitivity, specificity, and area under the ROC curve (AUC) of Lac/Alb in predicting MODS were 81.63%, 85.59%, and 0.89, respectively, while those in predicting death were 94.23%, 88.89%, and 0.91, respectively. Lac/Alb was positively correlated with APACHE II and SOFA scores (r=0.718 and 0.808, respectively). Conclusions: Lac/Alb was linked to MODS and mortality in sepsis patients and can be based to predict adverse outcomes.

[A case of intravenous injection of mercury poisoning].

There are few reports of poisoning caused by high-dose intravenous injection of mercury. Its clinical manifestations are diverse and the risk of mortality is high. Currently, the pathogenesis is not clear and the treatment experience is insufficient, leading to difficulties in clinical diagnosis and treatment. In this article, the data of a case of mercury poisoning caused by intravenous self-administration was analyzed and summarized. The patient developed multiple organ dysfunction syndrome after intravenous injection of high-dose mercury. After comprehensive treatment, such as mercury removal, organ support, and infection prevention, the condition was improved. This case suggests that intravenous injection of mercury can cause damage to the functions of multiple organs, such as the heart, lungs, and kidneys. Early treatment and intervention can bring benefits.

Serum from patients with cirrhosis undergoing liver transplantation induces permeability in human pulmonary microvascular endothelial cells ex vivo.

Introduction: Patients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo. Methods: Adults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts. Results: Liver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability. Discussion: Serum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Endothelial dysfunction: Pathophysiology and therapeutic targets for sepsis-induced multiple organ dysfunction syndrome.

Sepsis and septic shock are critical medical conditions characterized by a systemic inflammatory response to infection, significantly contributing to global mortality rates. The progression to multiple organ dysfunction syndrome (MODS) represents the most severe complication of sepsis and markedly increases clinical mortality. Central to the pathophysiology of sepsis, endothelial cells play a crucial role in regulating microcirculation and maintaining barrier integrity across various organs and tissues. Recent studies have underscored the pivotal role of endothelial function in the development of sepsis-induced MODS. This review aims to provide a comprehensive overview of the pathophysiology of sepsis-induced MODS, with a specific focus on endothelial dysfunction. It also compiles compelling evidence regarding potential small molecules that could attenuate sepsis and subsequent multi-organ damage by modulating endothelial function. Thus, this review serves as an essential resource for clinical practitioners involved in the diagnosing, managing, and providing intensive care for sepsis and associated multi-organ injuries, emphasizing the importance of targeting endothelial cells to enhance outcomes of the patients.

Systemic inflammation in midlife is associated with late-life functional limitations.

Systemic inflammation generally coexists with functional limitations that seriously affect quality of life. This study aimed to investigate the association between systemic inflammation in midlife and the risk of functional limitations in late-life. A total of 10,044 participants with an average age of 53.9 ± 5.7 years at baseline were included in a cohort study. At the last follow-up, the prevalence of impaired activities of daily living (ADLs), instrumental activities of daily living (IADLs), and lower extremity function (LEF) was 14.7%, 21.6%, and 50.3%, respectively. The values of four inflammatory biomarkers were used to calculate the inflammation composite score. Compared with the participants in the lowest quartile of the inflammation composite score (Q1), those in the highest quartile (Q4) exhibited an odds ratio (OR) of 1.589 and a 95% confidence interval (CI) of 1.335-1.892 for impaired ADLs, an OR of 1.426 and a 95% CI of 1.228-1.657 for impaired IADLs, and an OR of 1.728 and a 95% CI of 1.526-1.957 for impaired LEF. The association between systemic inflammation and functional limitations was partly mediated by cardiac and brain function. The present study provides evidence that systemic inflammation in midlife is associated with a higher risk of late-life functional limitations. Protecting vital organ functions in midlife may have a positive impact on reducing the risk of future functional limitations.Trial registration: www.clinicaltrials.gov ; Unique identifier: NCT00005131.

Prediction of adverse drug reactions in geriatric patients admitted to intensive care units. / [Artículo traducido] Predicción de reacciones adversas a medicamentos en pacientes geriátricos ingresados en unidades de cuidados intensivos.

INTRODUCTION: Intensive Care Units (ICUs) pose challenges in managing critically-ill patients with polypharmacy, potentially leading to Adverse Drug Reactions (ADRs), particularly in the elderly. OBJECTIVE: To evaluate whether the severity and clinical prognosis scores used in ICUs correlate with the prediction of ADRs in aged patients admitted to an ICU. METHODS: A cohort study was conducted in a Brazilian University Hospital ICU. APACHE II and SAPS 3 assessed clinical prognosis, while GerontoNet ADR Risk Score and BADRI evaluated ADR risk at ICU admission. Severity of the patients' clinical conditions was evaluated daily based on the SOFA score. Adverse Drug Reaction (ADR) screening was performed daily through the identification of ADR triggers. RESULTS: 1295 triggers were identified (median 30 per patient, IQR = 28), with 15 suspected ADRs. No correlation was observed between patient severity and ADRs at admission (p=0.26), during hospitalization (p=0.91), or at follow-up (p=0.77). There was also no association between death and ADRs (p=0.28) or worse prognosis and ADRs (p>0.05). Higher BADRI scores correlated with more ADRs (p=0.001). CONCLUSIONS: The data suggest that employing the severity and clinical prognosis scores used in Intensive Care Units is not sufficient to direct active pharmacovigilance efforts, which are therefore indicated for critically ill patients.

Heat stroke: Pathogenesis, diagnosis, and current treatment.

Recently, the incidence of heat-related illnesses has exhibited a steadily upward trend, which is closely associated with several environmental factors such as climate change and air pollution. The progression of heat-related illnesses is a continuous process and can progress to the terminal period when it transforms into heat stroke, the most severe form. Heat stroke is markedly by a core body temperature above 40°C and central nervous system dysfunction. Current knowledge suggests that the pathogenesis of heat stroke is complex and varied, including inflammatory response, oxidative stress, cell death, and coagulation dysfunction. This review consolidated recent research progress on the pathophysiology and pathogenesis of heat stroke, with a focus on the related molecular mechanisms. In addition, we reviewed common strategies and sorted out the drugs in various preclinical stages for heat stroke, aiming to offer a comprehensive research roadmap for more in-depth researches into the mechanisms of heat stroke and the reduction in the mortality of heat stroke in the future.

Cerebral venous sinus thrombosis accompanied by cerebral venous infarction and multiorgan dysfunction after wasp stings, A case report.

Introduction: The high incidence of wasp stings have been causing a variety of injuries in China, but systemic complications are rarely reported. Case presentation: A 59-year-old man was severely attacked by wasps. He developed an acute onset of right hemiplegia and chest distress and was admitted to our emergency department 13 hours after being attacked. Various abnormal signals were found by biochemical tests. Magnetic resonance venography of head demonstrated that the superior sagittal sinus was not visible, indicating cerebral venous sinus thrombosis. Magnetic resonance imaging showed abnormal signals in the left frontal lobe, parietal lobe, and thalamus, indicating venous cerebral infarction and hemorrhage, coupled with subarachnoid hemorrhage. The patient was diagnosed with a rare combination of cerebral venous sinus thrombosis, cerebral venous infarction, and multi-organ dysfunction following hornet stings. After undergoing systematic treatment including blood perfusion, blood dialysis, anti-inflammatory hormone therapy, antiallergic medication, antibiotic use, and anticoagulation treatment, the patient showed significant improvement in limb muscle strength and dizziness symptoms. However, the patient developed irreversible kidney damage and is currently dependent on renal replacement therapy. Conclusions: This case highlights the serious systemic consequences that can occur following multiple wasp stings, including rare complications such as venous sinus thrombosis leading to cerebral infarction and renal failure. Early intervention with blood perfusion, hemodialysis, and plasmapheresis, in addition to general treatment, may help prevent permanent organ damage in patients with a large number of wasp stings.

Effects of anesthesia with sevoflurane on outcome parameters in murine experimental studies.

PURPOSE: Multiple murine studies modelling the immuno-pathophysiological consequences of trauma, shock, burn or sepsis were performed during the last decades. Almost every animal model requires anesthesia for practical and ethical reasons. Furthermore, often, corresponding control groups involve untreated animals without or with a limited exposure to anesthetics. However, the influences of anesthetic drugs on immuno-pathophysiological reactions remain insufficiently investigated. Therefore, we aimed to closer characterize the anesthetic impact exemplified by sevoflurane on the organ performance in mice and thereby investigate the influence of anesthesia itself on major outcome parameters in animal studies. METHODS: C57/BL6 mice were subjected either to 270 min of sevoflurane narcosis or directly euthanized. Plasma, BAL-fluids, lungs, kidneys, liver and intestine were collected and examined for immunological, functional and morphological changes. RESULTS: Systemic levels of the cytokine keratinocyte chemoattractant (KC) were raised in the narcosis group, while concentrations of high mobility group box protein 1 (HMGB-1) as a major inflammatory marker were reduced. In the lungs, levels of HMGB-1 and interleukin 6 (IL-6) were reduced. In contrast, systemic concentrations of intestinal fatty acid binding-protein (i-FABP) as an intestinal damage marker were elevated. Furthermore, liver-type fatty acid binding-protein (L-FABP) levels were lower in the narcosis animals, and inflammatory markers were reduced in liver tissues. Anesthesia also ameliorated the inflammatory reaction in renal tissues, while plasma levels of urea and creatinine were elevated, reflecting either dehydration and/or impaired renal function. CONCLUSION: As anesthesia with sevoflurane exhibited distinct effects in different organs, it is difficult to predict its specific impact on targets of interest in in vivo studies. Therefore, further studies are required to clarify the effects of different anesthetic drugs. Overall, the inclusion of a control group subjected to the same anesthesia protocol as the experimental groups of interest seems helpful to precisely define the inherent impact of the anesthetic when investigating immuno-pathophysiologic conditions in vivo.

Heat stress-induced platelet dysfunction is associated with loss of fibrinogen and is improved by fibrinogen supplementation.

INTRODUCTION: Heatstroke is a critical heat-related condition characterized by coagulopathy and multiple organ dysfunction. One of the most severe complications of heatstroke is disseminated intravascular coagulation. This condition manifests as excessive clot formation and bleeding that are primarily due to platelet depletion and dysfunction. Fibrinogen plays a crucial role in hemostasis because it links integrin αIIbß3 on adjacent platelets, thereby promoting the platelet activation and aggregation necessary for clot formation. However, reduced fibrinogen levels may impair the formation of the initial platelet plug and increase the risk of bleeding. The current study explored the effect of fibrinogen on platelet dysfunction in a heatstroke model. MATERIALS AND METHODS: Male Wistar rats were subjected to heat stress, and subsequent changes in hemodynamic, biochemical, and coagulation parameters were analyzed. Platelet viability, aggregation, adhesion, spreading and fibrin clot retraction were assessed. RESULTS: The rats with heatstroke exhibited a variety of clinical symptoms, including hypotension, tachycardia, multiple organ dysfunction, and coagulopathy. Platelet viability in the heatstroke group was comparable to that in the healthy control group. However, the heatstroke group exhibited significant reductions in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and fibrin clot retraction. Notably, fibrinogen supplementation markedly augmented the aggregation responses of platelets in the heatstroke group. The impairment of platelet adhesion, spreading, and fibrin clot retraction in the rats with heatstroke was partially ameliorated by fibrinogen supplementation. CONCLUSIONS: An early use of fibrinogen replacement may serve as a therapeutic intervention to alleviate platelet hyporeactivity and prevent the complications in patients with heatstroke.

The Relationship Between Acute Kidney Injury in Sepsis Patients and Coagulation Dysfunction and Prognosis.

Purpose: The aim of this study was to investigate the relationship between ARF and coagulopathy in patients with sepsis and to explore the prognostic value of these conditions. Patients and Methods: The data of 271 patients with sepsis-associated coagulopathy admitted from June 2021 to June 2022 were reviewed. The patients were divided into a survival group and a nonsurviving group according to patient prognosis. Independent sample t tests were utilized to compare laboratory parameters within 24 hours of admission, as well as the APACHE II and SOFA scores, between the two patient groups. According to the sepsis-associated coagulation dysfunction (SAC) grading criteria for grading, Spearman correlation analysis was used to study the relationship between blood creatinine and SAC grading and assignment scores, and receiver operating characteristic (ROC) curves and Cox's proportional risk regression model were used to explore the factors affecting the prognosis of SAC patients. Results: Spearman correlation analysis revealed strong associations between serum creatinine (Scr) concentration, SAC classification, and SAC score, with coefficients above 0.7. SAC classification outcomes varied significantly with severity: mild severity had a 77.6% survival rate versus 22.4% mortality; moderate severity had 21.5% survival versus 78.5% mortality; and severe cases had a 0.7% survival rate versus 99.3% mortality (P<0.01 for all). Multivariate analysis revealed significant predictors of outcome, including multiple organ dysfunction syndrome (MODS), with an OR of 2.070 (P=0.019); the SOFA score (OR=1.200, P<0.01); the international normalized ratio (INR) (OR=0.72, P=0.013); and the Scr level (OR=0.995, P<0.01). The areas under the ROC curves for the SOFA score, APACHE II score, and SAC classification were >0.8, all P < 0.05. Conclusion: In patients with sepsis, SAC grade 3 or a SAC score of 4 or higher is associated with poorer prognosis, and the interaction of acute kidney injury exacerbates the degree of SAC, consequently affecting prognosis.

To investigate the relationship between acute renal dysfunction and coagulation dysfunction in patients with sepsis and to explore the prognostic value of these conditions. We collected information and laboratory indicators from 271 patients, classified these two groups of patients according to the grading criteria for sepsis-associated coagulation dysfunction (SAC), and compared the differences between them. We utilized Spearman correlation analysis to investigate the relationship between blood creatinine and the severity of sepsis-associated coagulation dysfunction (SAC). Additionally, we employed a Cox proportional hazards regression model to study the factors influencing the prognosis of SAC patients. This study revealed a significant positive correlation between blood creatinine levels and SAC grade. Furthermore, the presence of MODS, INR, blood creatinine, and SOFA score can serve as independent predictive factors for mortality. We can infer that there is a significant correlation between coagulation function parameters and blood creatinine levels, which play a crucial role in the diagnosis and prognostic analysis of sepsis. In patients with sepsis, a higher grade of SAC or an SAC score of 4 or higher indicates a poorer prognosis. Additionally, the interaction with acute kidney injury exacerbates the severity of SAC, thereby impacting patient prognosis.

Heat acclimation with probiotics-based ORS supplementation alleviates heat stroke-induced multiple organ dysfunction via improving intestinal thermotolerance and modulating gut microbiota in rats.

Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.