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Introduction: Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy., Methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed., Results: A total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae., Conclusion: The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role., (© 2024. The Author(s).)

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = - 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28-30, 2024, in Estoril, Lisbon, Portugal., (© 2024. The Author(s).)

Background/objective Cordyceps enhances animal survival against influenza by boosting the immune system. In animal studies, it also had anti-inflammatory and preventive properties. Cordyceps stimulates the immune system by increasing the activity and production of various immune cells. Some studies have shown the role of Cordyceps in the novel SARS-CoV-2 virus responsible for the COVID-19 pandemic, in addition to other respiratory diseases caused by the Picorna viruses, SARS-CoV, MERS-CoV, and Influenza viruses. However, it remains unknown whether this food supplement is safe and has anti-inflammatory effects in patients with COVID-19. Therefore, the objectives of this study were to evaluate the use and efficacy of Cordyceps capsules as an adjunct to standard treatment in patients with mild (symptomatic) to moderate COVID-19 infection. Methods A randomised, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of Cordyceps capsules (a food supplement) 500 mg as adjuvant therapy in patients with COVID-19. The rationale for dose selection was as per the existing evidence from toxicity studies. The inclusion criteria were patients with either a mild or moderate COVID-19 infection. Clinical features suggestive of dyspnoea or hypoxia, fever, and cough, including SpO 2 <94% (range 90-94%) on room air and a respiratory rate ≥24 per minute, were also included. Results Sixty-five patients were recruited for the study, with 33 in the Cordyceps group and 32 in the placebo group. Out of 58 evaluable patients, 33 recovered on day 5, 49 on day 10, and 58 on days 16 and 30. The recovery of patients steadily increased from 56.9% on day 5 to 100% on day 30. The time to clinical recovery was shorter in the Cordyceps group than in the placebo group (mean 6.6 vs. 7.3 days; p > 0.05) overall and for mild disease. However, there was no difference in the time to recovery (time from day 1 to the resolution of all symptoms) for moderate disease. A lower frequency of normal chest X-rays on day 1 and a higher number on day 16 in the treatment group than in the placebo group suggest an improvement in the number of normal chest X-rays with Cordyceps. Significant changes were seen in biomarkers MCPIP, CxCL10, and IL-1β for overall (both mild and moderate patients) on days 5 and 10 as compared to baseline, and in biomarkers CRP and CxCL10 in moderate category patients on days 5 and 10, respectively. There were no statistically significant changes in IL-6, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), or D-dimer levels between baseline and day 5/10 in patients taking Cordyceps capsules and also between the treatment and placebo groups. Conclusion Cordyceps capsules administered at a dose of 500 mg three times a day along with supportive treatment showed effectiveness in patients with mild to moderate COVID-19 infection, as evidenced by the proportionately higher number of recoveries on day 5, the relatively shorter time for improvement of clinical symptoms, and the proportionately higher number of patients showing negative RT-PCR tests on day 10. Thus, Cordyceps appears to be a safe immunological adjuvant for the treatment of patients with mild-to-moderate COVID-19. Future studies with a larger sample size would shed more light on the evidence, as there are limitations in the generalizability of the results from the present study due to the small sample size., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Dubhashi et al.)

Objective: To determine differences in plasma sex hormone levels in male and female coronavirus disease 2019 (COVID-19) patients and healthy volunteers (HVs) because cell entry of severe acute respiratory syndrome coronavirus 2 occurs via the angiotensin-converting enzyme 2 receptor which is downregulated by 17β-estradiol., Patients and Methods: Citrated plasma samples were collected from 101 patients with COVID-19 upon presentation to the emergency department and from 40 HVs between November 1, 2020, and May 30, 2021. Plasma 17β-estradiol and 5α-dihydrotestosterone (DHT) levels were measured using enzyme-linked immunosorbent assay (pg/mL). Data are presented as median and quartiles (IQR). Wilcoxon rank sum test with a P value less than .05 was considered significant., Results: Patients with COVID-19 (median age, 49 years) included 51 males and 50 females (25 postmenopausal). Hospital admission was required for 58.8% of male patients (n = 30) and 48.0% of female patients (n = 24) (66.7% postmenopausal, n = 16) Healthy volunteers (median age, 41 years) included 20 males and 20 females (9 postmenopausal). Female patients with COVID-19 were found to have decreased 17β-estradiol levels (18.5 [IQR, 10.5-32.3] pg/mL; 41.4 [IQR, 15.5-111.0] pg/mL, P=.025), and lower 17β-estradiol to DHT ratios (0.073 [IQR, 0.052-0.159] pg/mL; 0.207 [IQR, 0.104-0.538] pg/mL, P=.015) than female HVs. Male patients with COVID-19 were found to have decreased DHT levels (302.8 [IQR, 249.9-470.8] pg/mL; 457.2 [IQR, 368.7-844.3] pg/mL, P=.005), compared with male HVs. Levels of DHT did not differ between female patients with COVID-19 and female HVs, whereas 17β-estradiol levels did not differ between male patients with COVID-19 and male HVs., Conclusion: Sex hormone levels differ between patients with COVID-19 and HVs, with sex-specific patterns of hypogonadism in males and females. These alterations may be associated with disease development and severity., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis., (© 2022. The Author(s).)

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.

Background: Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO 4 ) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS., Methods: All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO 4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation)., Results: A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO 4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO 4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO 4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO 4 or Placebo administration., Conclusions: EE-3-SO 4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies., (© 2021. The Author(s).)

Abstract: In cancer patients, surgical removal of the primary tumor is one of the major steps within a multimodal therapy concept toward eliminating the disease and limiting further progression. In this respect, surgical trauma can have potent effects on the patient's immune system. Intraoperative blood loss associated with major surgical trauma leads to reduced blood flow, regional hypoxia, metabolic, and microenvironmental alterations stimulating an inflammatory response characterized by the release of pro-inflammatory cytokines (i.e., TNF-α, IL-6) and acute-phase proteins. The inflammatory state is accompanied by and intertwined with a counter-regulatory anti-inflammatory response reflected in the rise of anti-inflammatory cytokines (i.e., transforming growth factor-β) and prostaglandins (i.e., prostaglandin E2) which can lead to a depression of cell-mediated immunity and systemic immunosuppression. This results in a highly vulnerable state with concurrent expression of pro- and anti-inflammatory cytokines alternately predominating. The immunosuppressive state is characterized by a reduced antigen-presentation capacity of macrophages, alterations in lymphocyte proliferation, and activation as well as a shift of the Th1/Th2 (T helper cells 1 and 2) balance toward Th2 and a decrease in natural killer cell activity. The severity of the immunosuppression thereby correlates with the extent and the duration of the surgical procedure. Growing evidence suggests that the immunosuppressive state following hemorrhage and surgical trauma might not only be a risk factor for postoperative complications but also facilitate tumor proliferation, metastatic growth, and recurrence. This article provides an overview of the cascade of events and underlying mechanisms resulting in immunosuppression and describes the impact of hemorrhage and major surgical trauma on tumor growth and recurrence. Attempts to control for perioperative inflammation thereby reducing the adverse effects of postoperative immunosuppression could have positive effects on tumor growth, metastasis formation, and recurrence., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Introduction: The pathology resulting from concurrent traumatic brain injury (TBI) and hemorrhagic shock (HS; TBI+HS) are leading causes of mortality and morbidity worldwide following trauma. However, the majority of large animal models of TBI+HS have utilized focal/contusional injuries rather than incorporating the types of brain trauma (closed-head injury caused by dynamic acceleration) that typify human injury., Objective: To examine survival rates and effects on biomarkers from rotational TBI with two levels of HS., Methods: Twenty-two sexually mature Yucatan swine (30.39 ± 2.25 kg; 11 females) therefore underwent either Sham trauma procedures (n = 6) or a dynamic acceleration TBI combined with either 55% (n = 8) or 40% (n = 8) blood loss in this serial study., Results: Survival rates were significantly higher for the TBI+40% (87.5%) relative to TBI+55% (12.5%) cohort, with the majority of TBI+55% animals expiring within 2 h post-trauma from apnea. Blood-based neural biomarkers and immunohistochemistry indicated evidence of diffuse axonal injury (increased NFL/Aβ42), blood-brain barrier breach (increased immunoglobulin G) and inflammation (increased glial fibrillary acidic protein/ionized calcium-binding adaptor molecule 1) in the injured cohorts relative to Shams. Invasive hemodynamic measurements indicated increased shock index and decreased pulse pressure in both injury cohorts, with evidence of partial recovery for invasive hemodynamic measurements in the TBI+40% cohort. Similarly, although both injury groups demonstrated ionic and blood gas abnormalities immediately postinjury, metabolic acidosis continued to increase in the TBI+55% group ∼85 min postinjury. Somewhat surprisingly, both neural and physiological biomarkers showed significant changes within the Sham cohort across the multi-hour experimental procedure, most likely associated with prolonged anesthesia., Conclusion: Current results suggest the TBI+55% model may be more appropriate for severe trauma requiring immediate medical attention/standard fluid resuscitation protocols whereas the TBI+40% model may be useful for studies of prolonged field care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, comorbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1β, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.

Introduction: Rapid diagnosis accompanied by appropriate treatment is essential in the therapy of sepsis. However, there is no blood marker available, which reliably predicts sepsis and associated mortality. Therefore, the aim of the present study was to evaluate presepsin and endotoxin in comparison with established blood markers in patients undergoing emergency visceral surgery for abdominal infection., Patients and Methods: This prospective study included 31 patients with abdominal infection undergoing emergency surgery between March and August 2014. The Sepsis-2 and Sepsis-3 definitions of sepsis were used. Blood markers (presepsin, endotoxin, C-reactive protein, procalcitonin (PCT), interleukin 6 (IL-6), white blood count) were analyzed preoperatively and correlated with the clinical course and mortality. Additionally, a combination of the three markers, which performed best, was tested., Results: Twenty patients (64.5%) in the analyzed cohort developed sepsis from an abdominal focus according to the latest sepsis definition. Out of the analyzed blood markers, presepsin exhibited the highest area under the curve, sensitivity, and specificity for the prediction of the development of sepsis. Moreover, presepsin had the highest predictive value for mortality as opposed to both endotoxin and previously established blood markers (i.e., PCT, IL-6). The multimarker approach, which included PCT, IL-6, and presepsin, showed no additional predictive value over presepsin alone., Conclusion: The present study suggests that presepsin is a novel predictor of sepsis and mortality from sepsis in patients undergoing surgery for intra-abdominal infections. The findings of the present study should be validated in a larger cohort.

As outlined in the "International Guidelines for Management of Sepsis and Septic Shock: 2016," initial fluid resuscitation and administration of antibiotics are key steps in the early management of sepsis and septic shock. However, such clear guidelines do not exist for preclinical sepsis models. To address these shortcomings, the Wiggers-Bernard conference on preclinical sepsis models was held in Vienna in May 2017. The participants reviewed 260 of the most highly cited papers between 2003 and 2012 that used sepsis models. The review demonstrated that over 70% of experiments either did not use or failed to report resuscitation and/or antibiotic treatment. This information served as the basis to create a series of recommendations and considerations for preclinical sepsis models; this Part III report details the recommendations for fluid resuscitation and antibiotic treatment that should be addressed in sepsis models. Similar to human sepsis, fluid resuscitation is recommended in the experimental setting unless part of the study. Iso-osmolar crystalloid solutions are preferred. The administration route and its timing should be adjusted to the specific requirements of the model with preference given to dynamic rather than static hemodynamic monitoring. Predefined endpoints for fluid resuscitation and avoidance of fluid overload should be considered. Preclinical sepsis studies display serious inconsistencies in the use of antimicrobial protocols. To remedy this, antimicrobials are recommended for preclinical studies, with choice and dose adjusted to the specific sepsis model and pathogen (s). Ideally, the administration of antimicrobials should closely mimic clinical practice, taking into account the drug's pharmacokinetic profile, alterations in absorption, distribution and clearance, and host factors such as age, weight, and comorbidities. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

Despite efforts in prevention and intensive care, trauma and subsequent sepsis are still associated with a high mortality rate. Traumatic injury remains the main cause of death in people younger than 45 years and is thus a source of immense social and economic burden. In recent years, the knowledge concerning gender medicine has continuously increased. A number of studies have reported gender dimorphism in terms of response to trauma, shock and sepsis. However, the advantageous outcome following trauma-hemorrhage in females is not due only to sex. Rather, it is due to the prevailing hormonal milieu of the victim. In this respect, various experimental and clinical studies have demonstrated beneficial effects of estrogen for the central nervous system, the cardiopulmonary system, the liver, the kidneys, the immune system, and for the overall survival of the host. Nonetheless, there remains a gap between the bench and the bedside. This is most likely because clinical studies have not accounted for the estrus cycle. This review attempts to provide an overview of the current level of knowledge and highlights the most important organ systems responding to trauma, shock and sepsis. There continues to be a need for clinical studies on the prevailing hormonal milieu following trauma, shock and sepsis.

Preclinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of preclinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling was held in Vienna in May, 2017. The goal of the conference was to identify limitations of preclinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Preclinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models. A total of 31 experts from 13 countries participated and were divided into six thematic Working Groups: Study Design, Humane modeling, Infection types, Organ failure/dysfunction, Fluid resuscitation, and Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013). Overall, the participants reached consensus on 29 points; 20 at "recommendation" and nine at "consideration" strength. This Executive Summary provides a synopsis of the MQTiPSS consensus. We believe that these recommendations and considerations will serve to bring a level of standardization to preclinical models of sepsis and ultimately improve translation of preclinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. To encourage its wide dissemination, this article is freely accessible on the Intensive Care Medicine Experimental and Infection journal websites. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection, and Intensive Care Medicine Experimental.

Corilagin, a component of Phyllanthus urinaria extract, possesses antioxidant, thrombolytic, antiatherogenic, and hepatoprotective properties, but the mechanism underlying these effects remains unclear. Previous studies showed that the Akt (protein kinase B) signaling pathway exerts anti-inflammatory and organ protective effects. The aim of this study was to investigate the mechanism of action of corilagin and determine whether these effects are mediated through the Akt-dependent pathway in a trauma-hemorrhagic shock-induced liver injury rodent model. Hemorrhagic shock was induced in male Sprague-Dawley rats; mean blood pressure was maintained at 35 mm Hg to 40 mm Hg for 90 min, followed by fluid resuscitation. During resuscitation, three doses of corilagin alone (1 mg/kg, 5 mg/kg, or 10 mg/kg, intravenously) were administered. Furthermore, a single dose of corilagin (5 mg/kg) with and without Wortmannin (1 mg/kg, PI3K inhibitor), Wortmannin alone, or vehicle was administered. Twenty-four hours after resuscitation, plasma alanine aminotransferase and aspartate aminotransferase concentration and hepatic parameters were measured. One-way ANOVA was used for statistical analysis. Hepatic myeloperoxidase activity and the concentrations of plasma alanine aminotransferase and aspartate aminotransferase, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) and CINC-3 increased following hemorrhagic shock. These parameters were significantly attenuated in corilagin-treated rats following hemorrhagic shock. Hepatic phospho-Akt expression was also higher in corilagin-treated rats than in vehicle-treated rats. The elevation of phospho-Akt was abolished by combined treatment with Wortmannin and corilagin. Our results suggest that corilagin exerts its protective effects on hemorrhagic shock-induced liver injury, at least, via the Akt-dependent pathway., Competing Interests: The authors report no conflicts of interest.

Several lines of evidence indicate that female sex is a protective factor in trauma and hemorrhage. In both clinical and experimental studies, proestrus females have been shown to have better chances of survival and reduced rates of posttraumatic sepsis. Estrogen receptors are expressed in a variety of tissues and exert genomic, as well as nongenomic effects. By improving cardiac, pulmonary, hepatic, and immune function, estrogens have been shown to prolong survival in animal models of hemorrhagic shock. Despite encouraging results from experimental studies, retrospective clinical studies have not clearly pointed to advantages of estrogens following trauma-hemorrhage, which may be due to insufficient study design. Therefore, this review aims to give an overview on the current evidence and emphasizes on the importance of further clinical investigation on estrogens following trauma.

Estrogen plays an important role as a neuroprotector in the central nervous system (CNS), directly interacting with neurons and regulating physiological properties of non-neuronal cells. Here we evaluated estrogen sulfate (E2-SO4) for traumatic brain injury (TBI) using a Sprague-Dawley rat model. TBI was induced via lateral fluid percussion (LFP) at 24 h after craniectomy. E2-SO4 (1 mg/kg BW in 1 mL/kg BW) or saline (served as control) was intravenously administered at 1 h after TBI (n=5/group). Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (pbtO2) were measured for 2 h (from 23 to 25 h after E2-SO4 injection). Brain edema and diffuse axonal injury (DAI) were assessed by diffusion tensor imaging (DTI), and cerebral glycolysis was measured by (18)F-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging, at 1 and 7 days after E2-SO4 injection. E2-SO4 significantly decreased ICP, while increasing CPP and pbtO2 (p<0.05) as compared with vehicle-treated TBI rats. The edema size in the brains of the E2-SO4 treated group was also significantly smaller than that of vehicle-treated group at 1 day after E2-SO4 injection (p=0.04), and cerebral glycolysis of injured region was also increased significantly during the same time period (p=0.04). However, E2-SO4 treatment did not affect DAI (p>0.05). These findings demonstrated the potential benefits of E2-SO4 in TBI.

As with sharks and horseshoe crabs, some designs of nature need only minor evolutionary adjustments during the millennia to remain superbly adapted. Such is the case at the molecular level for the nuclear receptors (NRs), which seem to have originated concomitantly with the earliest metazoan lineage of animals. A wide array of NRs persists today throughout all animal phyla with many different functions, yet they share a highly conserved protein structure, a testament to their having evolved through numerous gene duplications. Of particular interest for this readership are the estrogen-related receptors (ERRs), which have significant supportive roles in energy creation and regulation, mitochondrial function and biogenesis, development, tissue repair, hypoxia, and cancer. Thus, placed at the nexus of energetics and homeostasis, ERR (in association with the coregulatory molecules peroxisome proliferator-activated receptor-γ coactivator-1α and -β) can facilitate repair from injury and adaptations to stressful environments. Whereas it is curious that ERRs and some other NRs exist as "orphans" by virtue of having no known cognate ligand, increasing interest in the estrogen receptor has led to the development of synthetic ligands and screening for naturally occurring molecules, either capable of modulating ERR activity. Thus, what is needed now is a nomenclature update for the ERR to focus the mind on energetics and metabolism, the most compromised and crucial systems after trauma and shock.

Casodex (bicalutamide), an androgen receptor antagonist, is used for the treatment of prostate cancer. Recent evidences show that Akt signaling pathway exerts organ-protective effects after injury. The aim of this study was to investigate whether Akt plays any role in the casodex-mediated attenuation of hepatic injury after trauma-hemorrhagic shock. Male Sprague-Dawley rats underwent trauma hemorrhage (mean blood pressure kept at approximately 35-40 mm Hg for 90 min), followed by fluid resuscitation. During resuscitation, a single dose of casodex (5 mg/kg, intravenous) with and without a phosphatidylinositol 3-kinase inhibitor wortmannin (1 mg/kg, intravenous), wortmannin or vehicle was administered. Plasma aspartate aminotransferase and alanine aminotransferase levels and various hepatic parameters were measured at 24 h after resuscitation. One-way analysis of variance and the Tukey test were used for statistical analysis. These results showed that trauma hemorrhage increased hepatic myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, and plasma aspartate aminotransferase and alanine aminotransferase concentrations. In the trauma hemorrhage rats treated with casodex, these parameters were significantly improved. Casodex treatment also increased hepatic phospho-Akt expression compared with vehicle-treated trauma hemorrhaged rats. Coadministration of wortmannin with casodex abolished the casodex-induced advantageous effects on the aforementioned parameters and hepatic injury. Our results suggest that the protective effect of casodex administration on attenuation of hepatic injury after trauma hemorrhage, which is, at least in part, through Akt-dependent pathway.

Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Severe hemorrhage leads to decreased blood flow to tissues resulting in decreased oxygen and nutrient availability affecting mitochondrial function. A mitoscriptome profiling study demonstrated alteration in several genes related to mitochondria, consistent with the mitochondrial functional decline observed after trauma hemorrhage (T-H). Our experiments led to the identification of sirtuin 1 (SIRT1) as a potential target in T-H. Administration of resveratrol (a naturally occurring polyphenol and activator of SIRT1) after T-H improved left ventricular function and tissue ATP levels. Our hypothesis was that mitochondrial function after T-H depends on SIRT1 activity. In this study, we evaluated the activity of SIRT1, a mitochondrial functional modulator, and the mitochondrial-glycolytic balance after T-H. We determined the changes in protein levels of pyruvate dehydrogenase kinase (PDK)-1 and nuclear c-Myc, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and NF-E2-related factor (NRF)2 after T-H and after treatment with resveratrol or a combination of sirtinol (a SIRT1 inhibitor) and resveratrol. We have also tested the activity of mitochondrial complex 1. SIRT1 enzyme activity was significantly decreased after T-H, whereas resveratrol treatment restored the activity. We found elevated PDK1 and c-Myc levels and decreased PGC-1α, NRF2 and mitochondrial complex I activity after T-H. The reduced SIRT1 activity after T-H may be related to declining mitochondrial function, since resveratrol was able to reinstate SIRT1 activity and mitochondrial function. The elevated level of PDK1 (an inhibitor of pyruvate dehydrogenase complex) after T-H indicates a possible shift in cellular energetics from mitochondria to glycolysis. In conclusion, SIRT1 modulation alters left ventricular function after T-H through regulation of cellular energetics.

During sepsis, a complex network of cytokine, immune, and endothelial cell interactions occur and disturbances in the microcirculation cause organ dysfunction or even failure leading to high mortality in those patients. In this respect, numerous experimental and clinical studies indicate sex-specific differences in infectious diseases and sepsis. Female gender has been demonstrated to be protective under such conditions, whereas male gender may be deleterious due to a diminished cell-mediated immune response and cardiovascular functions. Male sex hormones, i.e., androgens, have been shown to be suppressive on cell-mediated immune responses. In contrast, female sex hormones exhibit protective effects which may contribute to the natural advantages of females under septic conditions. Thus, the hormonal status has to be considered when treating septic patients. Therefore, potential therapies could be derived from this knowledge. In this respect, administration of female sex hormones (estrogens and their precursors) may exert beneficial effects. Alternatively, blockade of male sex hormone receptors could result in maintained immune responses under adverse circulatory conditions. Finally, administration of agents that influence enzymes synthesizing female sex hormones which attenuate the levels of pro-inflammatory agents might exert salutary effects in septic patients. Prospective patient studies are required for transferring those important experimental findings into the clinical arena.

Abstract Traumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17β-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously 1 hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5 mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER.

A recent large civilian randomized controlled trial on the use of tranexamic acid (TXA) for trauma reported important survival benefits. Subsequently, successful use of TXA for combat casualties in Afghanistan was also reported. As a result of these promising studies, there has been growing interest in the use of TXA for trauma. Potential adverse effects of TXA have also been reported. A US Department of Defense committee conducted a review and assessment of knowledge gaps and research requirements regarding the use of TXA for the treatment of casualties that have experienced traumatic hemorrhage. We present identified knowledge gaps and associated research priorities. We believe that important knowledge gaps exist and that a targeted, prioritized research effort will contribute to the refinement of practice guidelines over time.

The aim of this study was to examine the role of estrogen on hepatic gene expression profiles at an early time point following trauma-hemorrhage in rats. Groups of injured and sham controls receiving estrogen or vehicle were killed 2 h after injury and resuscitation, and liver tissue was harvested. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. A large number of genes were differentially expressed at the 2-h time point in injured animals with or without estrogen treatment. The upregulation or downregulation of a cohort of 14 of these genes was validated by reverse transcription-polymerase chain reaction. This large-scale microarray analysis shows that at the 2-h time point, there is marked alteration in hepatic gene expression following trauma-hemorrhage. However, estrogen treatment attenuated these changes in injured animals. Pathway analysis demonstrated predominant changes in the expression of genes involved in metabolism, immunity, and apoptosis. Upregulation of low-density lipoprotein receptor, protein phosphatase 1, regulatory subunit 3C, ring-finger protein 11, pyroglutamyl-peptidase I, bactericidal/permeability-increasing protein, integrin, αD, BCL2-like 11, leukemia inhibitory factor receptor, ATPase, Cu transporting, α polypeptide, and Mk1 protein was found in estrogen-treated trauma-hemorrhaged animals. Thus, estrogen produces hepatoprotection following trauma-hemorrhage likely via antiapoptosis and improving/restoring metabolism and immunity pathways.