Activated clotting time value as an independent predictor of postoperative bleeding and transfusion.

OBJECTIVES: Activated clotting time (ACT) is commonly used to monitor anticoagulation during cardiac surgeries. Final ACT values may be essential to predict postoperative bleeding and transfusions, although ideal values remain unknown. Our aim was to evaluate the utility of ACT as a predictor of postoperative bleeding and transfusion use. METHODS: Retrospective study (722 patients) submitted to surgery between July 2018-October 2021. We compared patients with final ACT < basal ACT and final ACT ≥ basal ACT and final ACT < 140 s with ≥140 s. Continuous variables were analysed with the Wilcoxon rank-sum test; categorical variables using Chi-square or Fisher's exact test. A linear mixed regression model was used to analyse bleeding in patients with final ACT < 140 and ≥140. Independent variables were analysed with binary logistic regression models to investigate their association with bleeding and transfusion. RESULTS: Patients with final ACT ≥ 140 s presented higher postoperative bleeding than final ACT < 140 s at 12 h (P = 0.006) and 24 h (**P = 0.004). Cardiopulmonary bypass (CPB) time [odds ratio (OR) 1.009, 1.002-1.015, 95% confidence interval (CI)] and masculine sex (OR 2.842,1.721-4.821, 95% CI) were significant predictors of bleeding. Patients with final ACT ≥ 140 s had higher risk of UT (OR 1.81, 1.13-2.89, 95% CI; P = 0.0104), compared to final ACT < 140 s. CPB time (OR 1.019,1.012-1.026, 95% CI) and final ACT (OR 1.021,1.010-1.032, 95% CI) were significant predictors of transfusion. Female sex was a predictor of use of transfusion, with a probability for use of 27.23% (21.84-33.39%, 95% CI) in elective surgeries, and 60.38% (37.65-79.36%, 95% CI) in urgent surgeries, higher than in males. CONCLUSIONS: Final ACT has a good predictive value for the use of transfusion. Final ACT ≥ 140 s correlates with higher risk of transfusion and increased bleeding. The risk of bleeding and transfusion is higher with longer periods of CPB. Males have a higher risk of bleeding, but females have a higher risk of transfusion.

Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.

INTRODUCTION: Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host-pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose-response trial is necessary to assess the potential harm of this drug in this new indication. METHODS AND ANALYSIS: Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05033808.

The impact of cardiopulmonary bypass time on the Sequential Organ Failure Assessment score after cardiac surgery.

OBJECTIVES: Postoperative organ dysfunction is common after cardiac surgery, particularly when cardiopulmonary bypass (CPB) is used. The Sequential Organ Failure Assessment (SOFA) score is validated to predict morbidity and mortality in cardiac surgery. However, the impact of CPB duration on postoperative SOFA remains unclear. METHODS: This is a retrospective study. Categorical values are presented as percentages. The comparison of SOFA groups utilized the Kruskal-Wallis chi-squared test, complemented by ad hoc Dunn's test with Bonferroni correction. Multinomial logistics regressions were employed to evaluate the relationship between CPB time and SOFA. RESULTS: A total of 1032 patients were included. CPB time was independently associated with higher postoperative SOFA scores at 24 h. CPB time was significantly higher in patients with SOFA 4-5 (**P = 0.0022) or higher (***P < 0.001) when compared to SOFA 0-1. The percentage of patients with no/mild dysfunction decreased with longer periods of CPB, down to 0% for CPB time >180min (50% of the patients with >180m in of CPB presented SOFA ≥ 10). The same trend is observed for each of the SOFA variables, with higher impact in the cardiovascular and renal systems. Severe dysfunction occurs especially >200 min of CPB (cardiovascular system >100 min; other systems mainly >200 min). CONCLUSIONS: CPB time may predict the probability of postoperative SOFA categories. Patients with extended CPB durations exhibited higher SOFA scores (overall and for each variable) at 24 h, with higher proportion of moderate and severe dysfunction with increasing times of CPB.

CLOCK gene circannual expression in cluster headache.

BACKGROUND: Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The CLOCK gene has a central role in regulating circadian rhythms. Here, we investigate the circannual CLOCK expression in a population of cluster headache patients in comparison to matched controls. METHODS: Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of CLOCK was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS: This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. CLOCK expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in CLOCK expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to CLOCK expression. CONCLUSIONS: We observed that CLOCK expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence CLOCK expression.

Physiologic disruption and metabolic reprogramming in infection and sepsis.

Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.

Ketogenesis favors oxidative phosphorylation to promote disease tolerance.

Pseudomonas aeruginosa is an opportunistic pathogen of great medical relevance, although the mechanisms involved in chronic P. aeruginosa infection are unclear. Tomlinson et al. have now shown that systemic and local pathogen-induced ketone bodies (KBs) select strains that preserve respiratory integrity by failing to substantially increase glycolysis, which drives immunopathology resulting from resistance mechanisms.

Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

Eosinophil Granule Proteins Involvement in Acute Appendicitis-An Allergic Disease?

Several pieces of evidence point to an allergic component as a trigger of acute appendicitis. As the Th2 immune response is characterized by eosinophil mobilization to the target organ and release of their cationic granule proteins, it is reasonable to investigate if the degranulation of eosinophils could be associated with the local injury. The primary aim of this study is to evaluate the participation of eosinophils granules proteins in acute appendicitis, both at local and systemic levels and the secondary aim is to evaluate the diagnostic accuracy of eosinophils granules proteins for the detection of acute appendicitis, as well as for distinguishing between complicated and uncomplicated acute appendicitis. Eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and eosinophil peroxidase (EP) are the most well-known eosinophil granule proteins. From August 2021 to April 2022, we present a prospective single-center study to evaluate the EDN, ECP, and EP concentrations simultaneously in appendicular lavage fluid (ALF) and the serum of 22 patients with acute phlegmonous appendicitis (APA), 24 with acute gangrenous appendicitis (AGA), and 14 normal controls. Concerning EDN, no differences were found between groups. ECP concentrations in ALF and serum were significantly higher in the histologically confirmed acute appendicitis compared to the control groups (p < 0.0001 and p < 0.0001, respectively). In ALF, no differences were found between ECP levels in APA: 38.85 ng/mL (IQR 26.50-51.77) and AGA 51.55 ng/mL (IQR 39.55-70.09) groups (p = 0.176). In the serum, no difference was found between ECP levels at APA: 39 ng/mL (IQR 21.30-56.90) and AGA: 51.30 ng/mL (IQR 20.25-62.59) (p = 0.100). For EP, the concentrations in ALF (p < 0.001) and serum (p < 0.001) were both higher in acute appendicitis compared to the control. In ALF, no difference was found between APA: 240.28 ng/mL (IQR 191.2-341.3) and AGA: 302.5 (IQR 227.7-535.85) (p = 0.236). In the serum, no differences were found between APA: 158.4 ng/mL (IQR 111.09-222.1) and AGA: 235.27 (IQR 192.33-262.51) (p = 0.179). Globally, the ALF concentrations were higher than serum concentrations, reflecting an intense inflammatory local reaction in AA. The optimal ECP cut-off for discriminating between acute appendicitis and the controls was >11.41 ng/mL, with a sensitivity of 93.5%, but with a specificity for identifying appendicitis of 21.4%, good discriminative power (AUC = 0.880). For EP, the optimal cut-off was >93.20 ng/mL, with a sensitivity of 87%, but with a specificity of 14.3% (AUC = 0.901), excellent discriminative power. For the diagnosis of perforated AA, the discriminative power of ECP and EP serum concentrations are weak (AUC = 0.562 and AUC = 0.664, respectively). Concerning the presence of peritonitis, the discriminative power of ECP and EP serum concentrations is acceptable, respectively: AUC = 0.724 and AUC = 0.735. Serum levels of EDN (p = 0.119), ECP (p = 0.586) and EP (p = 0.08) in complicated appendicitis were similar to uncomplicated appendicitis. Serum concentrations of ECP and EP can be added to decision-making AA diagnosis. A Th2-type immune response is present in AA. These data bring forward the role of an allergic reaction in the pathogenesis of acute appendicitis.

Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis.

OBJECTIVE: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. METHODS: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. RESULTS: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to repress the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism. CONCLUSIONS: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

DNA damage independent inhibition of NF-κB transcription by anthracyclines.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.

IL-5 Serum and Appendicular Lavage Fluid Concentrations Correlate with Eosinophilic Infiltration in the Appendicular Wall Supporting a Role for a Hypersensitivity Type I Reaction in Acute Appendicitis.

Appendicitis is the most common abdominal surgical emergency, but its aetiology is not fully understood. We and others have proposed that allergic responses play significant roles in its pathophysiology. Eosinophils and Interleukin (IL)-5 are involved in a hypersensitivity type I reaction. Eosinophil infiltration is common in the allergic target organ and is dependent on IL-5. In the presence of an allergic component, it is expected that the eosinophil count and IL-5 local and systemic concentrations become elevated. To address this hypothesis, we designed a prospective study that included 65 patients with acute appendicitis (grouped as acute phlegmonous or gangrenous according to the histological definition) and 18 patients with the clinical diagnosis of acute appendicitis, but with normal histological findings (control group) were enrolled. Eosinophil blood counts and appendicular wall eosinophil infiltration were determined. IL-5 levels in blood and appendicular lavage fluid were evaluated. Appendicular lavage fluid was collected by a new methodology developed and standardized by our group. Appendicular wall eosinophil infiltration was higher in acute phlegmonous appendicitis than in gangrenous appendicitis (p = 0.000). IL-5 blood levels were similar in both pathologic and control groups (p > 0.05). In the appendicular lavage fluid, the higher levels of IL-5 were observed in the phlegmonous appendicitis group (p = 0.056). We found a positive correlation between the appendicular wall eosinophilic infiltration and the IL-5 concentrations, in both the blood and the appendicular lavage fluid, supporting the IL-5 reliance in eosinophil local infiltration. We observed the highest presence of eosinophils at phlegmonous appendicitis walls. In conclusion, the present data are compatible with a hypersensitivity type I allergic reaction in the target organ, the appendix, during the phlegmonous phase of appendicitis.

Role of Omega-6 Fatty Acid Metabolism in Cardiac Surgery Postoperative Bleeding Risk.

Cardiac surgery is frequently associated with significant postoperative bleeding. Platelet-dysfunction is the main cardiopulmonary bypass (CPB)-induced hemostatic defect. Not only the number of platelets decreases, but also the remaining are functionally impaired. Although lipid metabolism is crucial for platelet function, little is known regarding platelet metabolic changes associated with CPB-dysfunction. Our aim is to explore possible contribution of metabolic perturbations for platelet dysfunction after cardiac surgery. DESIGN: Prospective cohort study. SETTING: Tertiary academic cardiothoracic-surgery ICU. PATIENTS: Thirty-three patients submitted to elective surgical aortic valve replacement. INTERVENTIONS: Samples from patients were collected at three time points (preoperative, 6- and 24-hr postoperative). Untargeted metabolic analysis using high-performance liquid chromatography-tandem mass spectrometry was performed to compare patients with significant postoperative bleeding with patients without hemorrhage. Principal component analyses, Wilcoxon matched-pairs signed-rank tests, adjusted to FDR, and pairwise comparison were used to identify pathways of interest. Enrichment and pathway metabolomic complemented the analyses. MEASUREMENTS AND MAIN RESULTS: We identified a platelet-related signature based on an overrepresentation of changes in known fatty acid metabolism pathways involved in platelet function. We observed that arachidonic acid (AA) levels and other metabolites from the pathway were reduced at 6 and 24 hours, independently from antiagreggation therapy and platelet count. Concentrations of preoperative AA were inversely correlated with postoperative chest tube blood loss but were not correlated with platelet count in the preoperative, at 6 or at 24 hours. Patients with significant postoperative blood-loss had considerably lower values of AA and higher transfusion rates. Values of postoperative interleukin-6 were strongly correlated with AA variability. CONCLUSIONS AND RELEVANCE: Our observations suggest that an inflammatory-related perturbation of AA metabolism is a signature of cardiac surgery with CPB and that preoperative levels of AA may be more relevant than platelet count to anticipate and prevent postoperative blood loss in patients submitted to cardiac surgery with CPB.

Tetracyclines: four rings to rule infections through resistance and disease tolerance.

Several classes of antibiotics have long been known for protective properties that cannot be explained through their direct antimicrobial effects. However, the molecular bases of these beneficial roles have been elusive. In this issue of the JCI, Mottis et al. report that tetracyclines induced disease tolerance against influenza virus infection, expanding their protection potential beyond resistance and disease tolerance against bacterial infections. The authors dissociated tetracycline's disease-resistance properties from its disease-tolerance properties by identifying potent tetracycline derivatives with minimal antimicrobial activity but increased capacity to induce an adaptive mitochondrial stress response that initiated disease tolerance mechanisms. These findings have potential clinical applications in viral infections.

Sequential Organ Failure Assessment Score in the ICU As a Predictor of Long-Term Survival After Cardiac Surgery.

OBJECTIVES: The Sequential Organ Failure Assessment (SOFA) score is a predictor of mortality in ICU patients. Although it is widely used and has been validated as a reliable and independent predictor of mortality and morbidity in cardiac ICU, few studies correlate early postoperative SOFA with long-term survival. DESIGN: Retrospective observational cohort study. SETTING: Tertiary academic cardiac surgery ICU. PATIENTS: One-thousand three-hundred seventy-nine patients submitted to cardiac surgery. INTERVENTIONS: SOFA 24 hours, SOFA 48 hours, mean, and highest SOFA scores were correlated with survival at 12 and 24 months. Wilcoxon tests were used to analyze differences in variables. Multivariate logistic regressions and likelihood ratio test were used to access the predictive modeling. Receiver operating characteristic curves were used to assess accuracy of the variables in separating survivor from nonsurvivors. MEASUREMENTS AND MAIN RESULTS: Lower SOFA scores have better survival rates at 12 and 24 months. Highest SOFA and SOFA at 48 hours showed to be better predictors of outcome and to have higher accuracy in distinguishing survivors from nonsurvivors than initial SOFA and mean SOFA. A decreasing score during the first 48 hours had mortality rates of 4.9%, while an unchanged or increased score was associated with a mortality rate of 5.7%. CONCLUSIONS: SOFA score in the ICU after cardiac surgery correlated with survival at 12 and 24 months. Patients with lower SOFA scores had higher survival rates. Differences in survival at 12 months were better correlated with the absolute value at 48 hours than with its variation. SOFA score may be useful to predict long-term outcomes and to stratify patients with higher probability of mortality.

MCL1 alternative polyadenylation is essential for cell survival and mitochondria morphology.

Alternative polyadenylation in the 3' UTR (3' UTR-APA) is a mode of gene expression regulation, fundamental for mRNA stability, translation and localization. In the immune system, it was shown that upon T cell activation, there is an increase in the relative expression of mRNA isoforms with short 3' UTRs resulting from 3' UTR-APA. However, the functional significance of 3' UTR-APA remains largely unknown. Here, we studied the physiological function of 3' UTR-APA in the regulation of Myeloid Cell Leukemia 1 (MCL1), an anti-apoptotic member of the Bcl-2 family essential for T cell survival. We found that T cells produce two MCL1 mRNA isoforms (pA1 and pA2) by 3' UTR-APA. We show that upon T cell activation, there is an increase in both the shorter pA1 mRNA isoform and MCL1 protein levels. Moreover, the less efficiently translated pA2 isoform is downregulated by miR-17, which is also more expressed upon T cell activation. Therefore, by increasing the expression of the more efficiently translated pA1 mRNA isoform, which escapes regulation by miR-17, 3' UTR-APA fine tunes MCL1 protein levels, critical for activated T cells' survival. Furthermore, using CRISPR/Cas9-edited cells, we show that depletion of either pA1 or pA2 mRNA isoforms causes severe defects in mitochondria morphology, increases apoptosis and impacts cell proliferation. Collectively, our results show that MCL1 alternative polyadenylation has a key role in the regulation of MCL1 protein levels upon T cell activation and reveal an essential function for MCL1 3' UTR-APA in cell viability and mitochondria dynamics.

Increased IgE Deposition in Appendicular Tissue Specimens Is Compatible with a Type I Hypersensitivity Reaction in Acute Appendicitis.

BACKGROUND: IgE mediates type I hypersensitivity reaction and can be found in the mucosa of organs affected by allergy. Acute appendicitis (AA) is a common disease, but its etiology remains poorly understood. Here, we investigated IgE deposition in histological sections of AA samples to test the hypothesis that an allergic reaction may substantially contribute to the pathophysiology of AA. MATERIALS AND METHODS: In a retrospective study, we assessed the presence of IgE in appendicular specimens of histologically confirmed appendicitis and in the control group, comprised of negative appendicitis and incidental appendectomies, using a monoclonal antibody against human IgE. Samples from 134 appendectomies were included: 38 phlegmonous and 27 gangrenous appendicitis from the study group and 52 incidental appendectomies and 17 negative appendicitis from the control group. The slides were visualized by light microscopy, and a standard procedure was used to manually count the positive IgE staining cells. RESULTS: IgE staining was present in the cells of all but 5 appendicular specimens. We found a significantly increased number of IgE-positive cells in phlegmonous AA (median = 28) when compared to incidental appendectomy (median = 17) (p = 0.005; p < 0.0001 when adjusted for age and gender). No difference was found for gangrenous appendicitis. Discussion. The presence of IgE supports the contribution of an allergic reaction for the pathophysiology of phlegmonous appendicitis. The reduced number of IgE staining cells in gangrenous appendicitis can be due to tissue destruction, or, as been claimed by others, gangrenous appendicitis is a distinct entity, with different etiology. CONCLUSION: In this study, phlegmonous appendicitis had the highest number of IgE-positive appendicular cells. These findings suggest that an allergic reaction can contribute to the pathophysiology of AA, opening a novel possibility for preventive measures in a disease that typically requires surgery.

Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis.

Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor. Here, we show that defects in the glucocorticoid receptor signaling pathway aggravate sepsis pathophysiology by lowering lactate clearance and sensitizing mice to lactate-induced toxicity. The latter is exerted via an uncontrolled production of vascular endothelial growth factor, resulting in vascular leakage and collapse with severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In conclusion, sepsis leads to glucocorticoid receptor failure and hyperlactatemia, which collectively leads to a lethal vascular collapse.

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15-/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.