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Introduction This study investigates the synergistic effect of TGF‐β1 and Nrp‐1 on CD4+CD25+ Tregs' stabilization, and the associated pathways of signal transduction, in vitro models in the presence of LPS. Materials and Methods Spleen CD4+CD25+ Tregs cells of mice models in the presence of LPS, were transfected with an shRNA targeting Nrp‐1, Smad2, or Smad3, may or may not be treated with recombinant TGF‐β1. Followed by subsequent determination of cellular proliferation, rate of apoptosis, observation of the Foxp3, CTLA‐4, and TGF‐β1m+ expression levels, foxp3‐TSDR methylation, secretion levels of the inhibitory cytokines IL‐10 and TGF‐β1, and Smad2/3 of CD4+CD25+ Tregs expression. Results A remarkable stimulation in CD4+CD25+ Tregs' stability is noted after administering recombinant TGF‐β1 in the presence of LPS, and promoted cellular viability, increased Foxp3, CTLA‐4, and TGF‐β1m+ expression, and elevated secretion of IL‐10 and TGF‐β1. This also inhibited the apoptosis and methylation of foxp3‐ TSDR of CD4+CD25+ Tregs. The shRNA transfection silenced Nrp‐1 and Smad3, but not Smad2, resulting in the suppression of the recombinant TGF‐β1‐mediated effects in the presence of LPS. Conclusions According to the results, Nrp‐1 mediates TGF‐β1 to improve the stability of regulatory CD4+CD25+ T cells and maybe a possible therapeutic target with the ability to improve the CD4+CD25+ Tregs associated negative immunoregulation that is related to the TGF‐β1/Smads cell signaling during sepsis., Our results suggest that Nrp‐1 is beneficial for TGF‐β1 to enhance the stability of CD4+CD25+ Tregs, and may represent a novel therapeutic target with the potential to improve the CD4+CD25+ Tregs‐related primary negative immunoregulation associated with the TGF‐β1/Smads signaling pathway in sepsis.

Background There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1–7) affect SIC. Methods Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1–7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1–7) levels, along with the protective function of exogenous Ang-(1–7) on SIC. Results Peripheral plasma Ang II and the Ang II/Ang-(1–7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1–7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1–7), and Ang-(1–7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1–7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. Conclusions Plasma Ang-(1–7), Ang II, and Ang II/Ang-(1–7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1–7), may exert protective roles against myocardial damage.

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

Sepsis is a life-threatening syndrome with a high incidence and a weighty economic burden. The cytokines storm in the early stage and the state of immunosuppression in the late stage contribute to the mortality of sepsis. Immune checkpoints expressed on lymphocytes and APCs, including CD28, CTLA-4, CD80, CD86, PD-1 and PD-L1, CD40 and CD40L, OX40 and OX40L, 4-1BB and 4-1BBL, BTLA, TIM family, play significant roles in the pathogenesis of sepsis through regulating the immune disorder. The specific therapies targeting immune checkpoints exhibit great potentials in the animal and preclinical studies, and further clinical trials are planning to implement. Here, we review the current literature on the roles played by immune checkpoints in the pathogenesis and treatment of sepsis. We hope to provide further insights into this novel immunomodulatory strategy.

Acute myocardial infarction (AMI) is one of the leading causes of death globally, with a mortality rate of over 20%. However, the diagnostic biomarkers frequently used in current clinical practice have limitations in both sensitivity and specificity, likely resulting in delayed diagnosis. This study aimed to identify potential diagnostic biomarkers for AMI and explored the possible mechanisms involved. Datasets were retrieved from the Gene Expression Omnibus. First, we identified differentially expressed genes (DEGs) and preserved modules, from which we identified candidate genes by LASSO (least absolute shrinkage and selection operator) regression and the SVM-RFE (support vector machine-recursive feature elimination) algorithm. Subsequently, we used ROC (receiver operating characteristic) analysis to evaluate the diagnostic accuracy of the candidate genes. Thereafter, functional enrichment analysis and an analysis of immune infiltration were implemented. Finally, we assessed the association between biomarkers and biological processes, infiltrated cells, clinical traits, tissues and time points. We identified nine preserved modules containing 1,016 DEGs and managed to construct a diagnostic model with high accuracy (GSE48060: AUC = 0.923; GSE66360: AUC = 0.973) incorporating two genes named S100A9 and SOCS3. Functional analysis revealed the pivotal role of inflammation; immune infiltration analysis indicated that eight cell types (monocytes, epithelial cells, neutrophils, CD8+ T cells, Th2 cells, NK cells, NKT cells and platelets) were likely involved in AMI. Furthermore, we observed that S100A9 and SOCS3 were correlated with inflammation, variably infiltrated cells, clinical traits of patients, sampling tissues and sampling time points. In conclusion, we suggested S100A9 and SOCS3 as diagnostic biomarkers of AMI and discovered their association with inflammation, infiltrated immune cells and other factors.

Acute kidney injury (AKI) is a clinical syndrome in which kidney function declines sharply due to various reasons. Although the morbidity and mortality of AKI are high, the mechanism of occurrence and development of AKI has not been fully elucidated, and precise prevention and treatment measures are lacking. Epigenetics is a branch of genetics that provides a new perspective to explore the pathophysiology of AKI and renal repair. A large amount of literature shows that the methylation mechanism of H3 in histones is closely related to the development of kidney diseases. The sorting out of histone H3 methylation mechanism in AKI and kidney repair can help understand the pathophysiological process of the disease more deeply. It may also provide new ideas for diagnosing and treating of the disease.

Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. Fish oil rich in omega-3 polyunsaturated fatty acids (PUFAs) in ultralong chains has immunomodulatory effects and can inhibit the production of various critically ill proinflammatory cytokines. Therefore, this study focused on whether ω-3 PUFAs have a protective effect on sepsis-induced cardiomyopathy (SIC).Male 6-8 weeks old C57BL/6 mice were pretreated with 3% special fish oil supplement rat food for seven consecutive days prior to surgery. Cecal ligation and puncture (CLP) was perfromed to induce polymicrobial sepsis.The cardiac function was assessed by echocardiography, apoptosis of cardiomyocyte were detected by TUNEL assay and Western blotting, and the level of TNF-α, IL-6, and IL-1β in plasma was determined 24h after CLP.Pretreatment with omega-3 PUFAs attenuated cardiomyocyte apoptosis, decreased the production of proinflammatory cytokines, attenuated the SIC, and improved the survival rate of septic mice induced by CLP.ω-3 PUFAs alleviate SIC through attenuating cardiomyocyte apoptosis, which provides a new direction for the prevention and treatment of SIC.

Background: The purpose of this study was to investigate the effect of the BOPPPS model (bridge-in, learning objective, pretest, participatory learning, posttest, and summary) with PAL (Peer-assisted learning) and medical humanities methods on Chinese Medical Students in Cardiopulmonary Resuscitation Courses. Methods: Participants were the long-term medical students of Tianjin Medical University who accepted emergency medicine courses from 2015 to 2020. Forward-looking descriptive research and phased CPR curriculum teaching innovation, including the BOPPS with PAL (First Stage), the BOPPS with PAL and medical humanities methods (Second Stage), compared with the traditional teaching model (Basic Stage). Results: The usual and final results improved in First stage compared with Basic stage (↑30.2%, ↑7.5%), the proportion of those with more than 80 points increased in the usual exam, and the proportion of those with 70 points or more increased in the final exam. The usual and final results improved in Second stage compared with First stage (↑12.0%, ↑2.2%), the proportion of those with more than 90 points increased in the usual exam, and the proportion of those with 80 points or more increased in the final exam. Conclusions: The teaching innovation of the CPR curriculum, the application of BOPPPS teaching model, and the peer-assisted learning and medical humanities teaching methods can improve teaching quality of CPR courses in medical colleges.

In previous studies, miR-132 and miR-223 were considered to be involved in cellular and pathological processes of diseases. However, the role of early diagnosis and prognosis evaluation in sepsis-induced cardiomyopathy (SIC) remains unknown. The present study aimed to explore the diagnostic value of combined detection of miR-132 and miR-223 for SIC and their correlation with creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor α (TNF-α), and interleukin-6 (IL)-6. SIC patients (n=80) admitted to Tianjin Medical University General Hospital were assigned to the research group (RG), while 60 healthy participants receiving physical examinations at the same period were assigned to the control group (CG). Serum expression profiles of miR-132 and miR-223 were detected by the RT-qPCR. CK-MB and cTnI were assessed using chemiluminescence assay, and TNF-α and IL-6 by enzyme-linked immunosorbent assay (ELISA). Serum miR-132 and miR-223 levels were significantly lower in the RG than in the CG (P

Myocardial cell injury or cardiomyopathy is associated with excessive inflammatory response and apoptosis of cardiac myocytes during sepsis. MicroRNA-23b (miR-23b) is a multifunctional miRNA that is considered to regulate immunosuppression in sepsis. The aim of this study was to examine the effect of miR-23b on cardiomyopathy induced by sepsis and to explore the potential mechanism involved. Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP), and the level of miR-23b at different time points was measured by quantitative real-time polymerase chain reaction (qPCR). Then, we overexpressed miR-23b in vivo and in vitro. The rats were subjected to CLP 7 days after transfection. Cardiac function, inflammatory response, and heart tissues were examined 3 days thereafter. In an in vitro experiment, H9C2 cardiomyoblasts were stimulated with lipopolysaccharide (LPS) after transfection of miR-23b, following which apoptosis and the level of NF-κB were analyzed. The expression of miR-23b was upregulated during polymicrobial sepsis, and transfection of miR-23b lentivirus improved the outcome of sepsis-induced cardiomyopathy by attenuating inflammatory responses and protecting against histopathological damage. In in vitro experiments, elevated miR-23b inhibited excessive apoptosis of cardiomyocytes, which may be because activation of the NF-κB signaling pathway was inhibited by the decreased levels of TRAF6 and IKKβ. Therefore, miR-23b improved sepsis-induced cardiomyopathy by attenuating the inflammatory response, suppressing apoptosis, and preventing NF-κB activation via targeted inhibition of TRAF6 and IκκB. These results indicated that miR-23b may represent a novel therapeutic approach for clinical treatment of sepsis-induced cardiomyopathy.

Quick Sequential Organ Failure Assessment (qSOFA) was proposed to replace SIRS as a new screening tool for the identification of septic patients at high mortality. However, researches from infected patients outside of ICU especially in Emergency Department (ED) drew contradictory conclusions on the prognostic value of qSOFA. This systematic review evaluated qSOFA as a prognostic marker of infected patients outside of ICU. The primary outcome was hospital mortality or 28- or 30-day mortality. Data were pooled based on sensitivity and specificity. Twenty-four trials with 121,237 participants were included. qSOFA had a poor sensitivity (0.58 [95% CI 0.47–0.67], 0.54 [95% CI 0.43–0.65]) and moderate specificity (0.69 [95% CI 0.48–0.84], 0.77 [95% CI 0.66–0.86]) for prediction of mortality in patients outside of ICU and ED patients only. Studies that used in-hospital mortality showed a higher sensitivity (0.61 [95% CI 0.50–0.71] vs 0.32 [95% CI 0.15–0.49]) and lower specificity (0.70 [95% CI 0.59–0.82] vs 0.92 [95% CI 0.85–0.99]) than studies that used 28 or 30-day mortality. Studies with overall mortality

Objective This study aimed to investigate the predictive value of pulse oximetry plethysmography (POP) for the return of spontaneous circulation (ROSC) in cardiac arrest (CA) patients. Methods This was a multicenter, observational, prospective cohort study of patients hospitalized with cardiac arrest at 14 teaching hospitals cross China from December 2013 through November 2014. The study endpoint was ROSC, defined as the restoration of a palpable pulse and an autonomous cardiac rhythm lasting for at least 20 minutes after the completion or cessation of CPR. Results 150 out-of-hospital cardiac arrest (OHCA) patients and 291 in-hospital cardiac arrest (IHCA) patients were enrolled prospectively. ROSC was achieved in 20 (13.3%) and 64 (22.0%) patients in these cohorts, respectively. In patients with complete end-tidal carbon dioxide (ETCO2) and POP data, patients with ROSC had significantly higher levels of POP area under the curve (AUCp), wave amplitude (Amp) and ETCO2 level during CPR than those without ROSC (all p Conclusion POP may be a novel and effective method for predicting ROSC during resuscitation, with a prognostic value similar to ETCO2 at early stage.

Semaphorin 3A (Sema3A), a member of the Sema family of proteins, appears to serve an important role in sepsis and sepsis‑induced immunosuppression and has been regarded as a crucial regulator involved in cellular immune response. However, the role of Sema3A in CD4+ T cell anergy during sepsis remains to be elucidated. In the present study, the cecal ligation and perforation model and lipopolysaccharide (LPS) were used to simulate sepsis and the role of Sema3A in sepsis‑induced CD4+ T cell anergy was investigated in vivo and in vitro. In vivo, the serum concentration of Sema3A was enhanced and exacerbated sepsis‑induced T cell immunosuppression and multiple organ dysfunction syndromes (MODS). Administration of (‑)‑epigallocatechin‑3‑gallate, an inhibitor of Sema3A, markedly improved sepsis‑induced T cell immunosuppression and MODS. In vitro, both lymphoid and myeloid lineages secreted high concentration of Sema3A in LPS‑induced sepsis, especially in the lymphoid lineage. Inhibition of Sema3A alleviated T cell anergy. The NF‑κB signaling pathway was involved in Sema3A‑mediated autocrine loop aggravating T cell immune dysfunction during LPS‑induced sepsis. Inhibiting Sema3A exerted significant improvement of sepsis‑induced immunosuppression and MODS, which was associated with improvement of CD4+ T cells anergy via regulation of the NF‑κB signaling pathway.

Neuropilin-1 (Nrp-1) contributes to maintaining the stability of CD4+ CD25+ regulatory T cells (Tregs). We investigated the impact of Nrp-1 on the stability of CD4+ CD25+ Tregs, and the underlying signaling pathways, in a model of sepsis. Splenic CD4+ CD25+ Tregs were either treated with anti-Nrp-1, transfected to silence Nrp-1 and inhibitor of NF-κB kinase subunit beta (IKKβ), or administered ammonium pyrrolidine dithiocarbamate (PDTC), followed by recombinant semaphorin 3A (rSema3A), in a simulation of sepsis. After the creation of a sepsis model in mice, anti-Nrp-1 was administered. The expression of the gene encoding forkhead box protein P-3 foxp3-Treg-specific demethylated region (foxp3-TSDR), the apoptosis rate, the expression of Foxp-3, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and transforming growth factor β1 (TGF-β1), interleukin 10 (IL-10) and TGF-β1 secretion, and the NF-κB signaling activity of CD4+ CD25+ Tregs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4+ CD25+ Tregs, including an increase in the expression of Foxp-3, CTLA-4, and TGF-β1, decreases in apoptosis and the methylation of foxp3-TSDR, increases in the secretion of TGF-β1 and IL-10, and an increase in the immunosuppressive effect on CD4+ T lymphocytes. Silencing of Nrp-1 or anti-Nrp-1 treatment abrogated lipopolysaccharide (LPS) stimulation with or without an rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the ratios of phosphorylated IKKβ (p-IKKβ) to IKKβ and p-P65 to P65 in vitro and vivo Silencing of IKKβ expression or PDTC treatment suppressed the stability of CD4+ CD25+ Tregs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4+ CD25+ Tregs by regulating the NF-κB signaling pathway; thus, Nrp-1 could be a new target for immunoregulation in sepsis.

Sudden death refers to death that occurs unexpectedly within 6 h of the onset of symptoms and in a normal state of health before. Mortality from sudden cardiac death (SCD) exceed the combined mortality of all major cancers. SCD mostly occurs outside the hospital, and most of them are asymptomatic before the onset of event. SCD has the characteristics of burstiness and unpredictability. The out-of-hospital cardiac arrest survival chain emphasizes timely identification and call for help, mainly chest compressions, defibrillation as soon as possible, and waiting for the professional team to transfer to the hospital as soon as possible after arriving. The hospital cardiac arrest survival chain emphasizes strengthening monitoring, establishing a rapid response system, and multidisciplinary and multi-team collaboration. SCD prevention should focus on high-risk populations. Efforts are made to help patients remove the etiology, take effective measures to control risk factors, detect changes in the condition of high-risk patients, and reduce the incidence of SCD.

Neuropilin-1 (Nrp-1) contributes to maintaining the stability of CD4(+) CD25(+) regulatory T cells (T(regs)). We investigated the impact of Nrp-1 on the stability of CD4(+) CD25(+) T(regs), and the underlying signaling pathways, in a model of sepsis. Splenic CD4(+) CD25(+) T(regs) were either treated with anti-Nrp-1, transfected to silence Nrp-1 and inhibitor of NF-κB kinase subunit beta (IKKβ), or administered ammonium pyrrolidine dithiocarbamate (PDTC), followed by recombinant semaphorin 3A (rSema3A), in a simulation of sepsis. After the creation of a sepsis model in mice, anti-Nrp-1 was administered. The expression of the gene encoding forkhead box protein P-3 foxp3-T(reg)-specific demethylated region (foxp3-TSDR), the apoptosis rate, the expression of Foxp-3, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and transforming growth factor β1 (TGF-β1), interleukin 10 (IL-10) and TGF-β1 secretion, and the NF-κB signaling activity of CD4(+) CD25(+) T(regs) were determined. Sepsis simulation with or without rSema3A increased the stability of CD4(+) CD25(+) T(regs), including an increase in the expression of Foxp-3, CTLA-4, and TGF-β1, decreases in apoptosis and the methylation of foxp3-TSDR, increases in the secretion of TGF-β1 and IL-10, and an increase in the immunosuppressive effect on CD4(+) T lymphocytes. Silencing of Nrp-1 or anti-Nrp-1 treatment abrogated lipopolysaccharide (LPS) stimulation with or without an rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the ratios of phosphorylated IKKβ (p-IKKβ) to IKKβ and p-P65 to P65 in vitro and vivo. Silencing of IKKβ expression or PDTC treatment suppressed the stability of CD4(+) CD25(+) T(regs) in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4(+) CD25(+) T(regs) by regulating the NF-κB signaling pathway; thus, Nrp-1 could be a new target for immunoregulation in sepsis.

Decreased serum thyroid hormone levels and their prediction of mortality in septic patients are still controversial, especially with the evolution of the definition of sepsis. This study aimed to assess the ability of thyroid hormone disorders to predict the early mortality of patients with septic shock defined by Sepsis-3. Sixty-three adult patients with septic shock admitted to a university hospital emergency intensive care unit (EICU) were studied. Serum free T3 (FT3), free T4 (FT4), thyroid stimulating hormone (TSH), C-reactive protein (CRP), procalcitonin (PCT), and lactate levels were determined and compared with survival status and organ dysfunction. Among the 63 patients studied, lower serum FT3 and FT4 levels were significantly associated with higher sequential organ failure assessment (SOFA) scores. Patients with septic shock with lower levels of FT3 (≤ 1.70 pmol/L) and FT4 (≤ 9.99 pmol/L) had significantly increased 28-day mortality. There was no significant difference in the serum TSH level between the survivor and nonsurvivor groups. The areas under the receiver operating characteristic curves for FT3 and FT4 levels were associated with 28-day mortality (0.92 and 0.89, respectively) and were higher than that for SOFA (0.82), CRP (0.65) and lactate (0.59). The decrease in serum levels of FT3 and FT4 in patients with septic shock is associated with the severity of organ dysfunction and 28-day mortality. Early detection of serum FT3 and FT4 levels could help clinicians to identify patients at high risk of clinical deterioration.

Pneumothorax (PTX) represents accumulation of the air in the pleural space. A large or tension pneumothorax can collapse the lung and cause hemodynamic compromise, a life-threatening disorder. Traditionally, neonatal pneumothorax diagnosis has been based on clinical images, auscultation, transillumination, and chest X-ray findings. This approach may potentially lead to a delay in both diagnosis and treatment. The use of lung US in diagnosis of PTX together with US-guided thoracentesis results in earlier and more precise management. The recommendations presented in this publication are aimed at improving the application of lung US in guiding neonatal PTX diagnosis and management.

Urinary trypsin inhibitor (UTI), also known as ulinastatin, has been reported to protect multiple organs against inflammation- and/or injury-induced dysfunction. In the present study, we aimed to investigate the immunomodulation effects of a recombinant human ulinastatin (urinary trypsin inhibitor, UTI) (rhUTI) on splenic dendritic cells (DCs) in cecal ligation and puncture (CLP)-induced septic mice. CLP mice were treated with rhUTI intramuscularly at 0, 12, and 24 h after procedure. Splenic CD11c+ DCs were isolated and accessed with flow cytometry for apoptotic or phenotypic analysis. Protein markers and cytokines were determined with Western blotting or ELISA. Treatment with rhUTI could markedly upregulate levels of costimulatory molecules (CD80, CD86) and MHC-II on surface of the splenic DC in CLP mice. The apoptotic rate of splenic DCs was decreased in CLP mice after rhUTI treatment. The survival rate of septic mice was increased after treatment with rhUTI. In addition, protein level of markers in endoplasmic reticulum stress (ERS)-related apoptotic pathways (including GRP78, caspase-12, and CHOP) were obviously down-regulated in the rhUTI-treated group when compared with the CLP group. These results indicate that rhUTI protects CLP-induced sepsis in mice by improving immune response of splenic DCs and inhibiting the excessive ERS-mediated apoptosis.

Sepsis is a life-threatening clinical syndrome caused by infection. Its pathogenesis is complex and entails coagulation dysfunction, inflammation, and immune disorders. Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. They can polarize into a multi-dimensional spectrum of phenotypes with different functions relating to immune regulation in response to changes in the microenvironment of specific tissues. We reviewed studies that examined the role of macrophage polarization with a focus on the classical activated (M1-like) and alternative activated (M2-like) macrophages as the two main phenotypes involved in the host immune response to sepsis. A complex regulatory network is involved in the process of macrophage polarization, which is influenced by a variety of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. M1-like macrophages release large quantities of pro-inflammatory mediators, while M2-like macrophages release large quantities of anti-inflammatory mediators. An imbalance between M1-like and M2-like macrophages induces the occurrence and development of sepsis. Therefore, targeted regulation of the process of macrophage polarization could be a useful approach to normalize the immune balance of the host, offering a new treatment modality for different stages of sepsis.

Background: Improving the capacity of health care, disease diagnosis and treatment of primary medical workers was the key to hierarchical diagnosis and treatment services. Electrocardiogram (ECG) played an important role in the diagnosis of cardiac diseases and should be regarded as the most basic tool for primary clinical medical workers in China. Objectives: To investigate the competency of Chinese medical workers in electrocardiographic interpretation skills, especially in the primary care hospitals, to explore the insufficiency of electrocardiographic interpretation skills and the improvement methods. Methods: A cross-sectional questionnaire study was conducted via the internet from March to October 2019. The questionnaire consists of 6 parts: basic information, equipping with an electrocardiograph, operating electrocardiograph, receiving electrocardiographic theory, testing of electrocardiographic interpretation, and improving electrocardiographic interpretation skills. Results: The effective quantity of this questionnaire was 2307, with an effective rate of 96.57%. The overall reliability was α=0.895. There were no significant differences among primary, private and class-Ⅲ hospitals in the aspects of equipping with an electrocardiograph (χ2=3.794, 3.104, P＞0.05), operating the electrocardiograph (χ2=1.857, P＞0.05) and receiving electrocardiographic theoretical study (χ2=6.701, P＞0.05). Medical workers in private and class-Ⅲ hospitals had a stronger interpretation competency of ECG, including common or life-threatening ECGs (P＜0.01). The development of talent echelon in primary hospitals affected the electrocardiographic interpretation skills of medical workers (P＜0.01). In primary hospitals, the age was mainly ≥ 40 years (79.0%), the education background was mainly bachelor and below degree (80.9%), the professional qualification was mainly physician assistant (58.6%) and primary physician (31.4%). The interpretation competency of ECG of medical workers in private or class-Ⅲ hospitals was higher than that in primary hospitals (P＜0.05 or 0.01). Conclusions: In China, the examination of electrocardiograph had been popularized. Due to the unreasonable development of talent echelon in primary hospitals, the electrocardiographic interpretation skills of primary medical workers were worrying. We should improve electrocardiographic teaching methods with the help of the internet, to enhance the electrocardiographic interpretation skills of primary medical workers.

// Yu-Lei Gao 1, * , Mu-Ming Yu 1, * , Song-Tao Shou 1, * , Ying Yao 1 , Yan-Cun Liu 1 , Li-Jun Wang 1 , Bin Lu 1 , Yan-Fen Chai 1 1 Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China * These authors have contributed equally to this work Correspondence to: Yan-Fen Chai, email: chaiyanfen2012@126.com Yu-Lei Gao, email: gaoyulei828@126.com Keywords: sepsis, regulatory T cells, negative immunoregulation, tuftsin, neuropilin-1 Received: June 29, 2016 Accepted: October 28, 2016 Published: November 09, 2016 ABSTRACT Our previous research showed that neuropilin (Nrp) -1 high CD4 + CD25 + Regulatory T cells (Tregs) exhibited primary negative immunoregulation in sepsis induced immune dysfunction. Tuftsin is the typical ligand of Nrp-1. Herein, we investigated the potential therapeutic value and mechanisms of tuftsin in sepsis. Sepsis per se markedly decreased the serum concentration of tuftsin, administration of tuftsin improved the survival rate of septic mice with cecal ligation and puncture (CLP). In vitro study, tuftsin prevented the negative immunoregulation of Nrp-1 high CD4 + CD25 + Tregs, including weakening the expression of forkhead/winged helix transcription factor (Foxp)- 3/cytotoxic T lymphocyte associated antigen (CTLA)-4, inhibiting the secretion of transforming growth factor (TGF)-β, and weakening the immunosuppressive function of Nrp-1 high CD4 + CD25 + Tregs to conventional CD4 + CD25 - T cells. Tuftsin markedly inhibited the demethylation of Foxp3-Tregs specific demethylated region (TSDR) of Nrp-1 high CD4 + CD25 + Tregs. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and associate with preventing the negative immunoregulation of Tregs via Nrp-1.

CD4+CD25+ regulatory T cells (Tregs) play an essential role in the suppression of the immune response and prevention of autoimmune reactions. The activation of TLR4, which provides a critical link between the innate and adaptive immune systems, has been implicated in regulating the function of Tregs. Ulinastatin (UTI) is a broad-spectrum protease inhibitor that has been shown to modulate innate immunity and pro-inflammatory signaling in sepsis. In addition, there are reports that UTI may modulate the functional activity of Tregs to influence the inflammatory response in infectious disease. In the present study, we investigated the effect of UTI on the activity of Tregs, which was assessed by measuring the survival and inflammatory responses of mice with cecal ligation and puncture (CLP)-induced sepsis. In addition, we further explored the cellular and molecular mechanisms involved in these effects. The results showed that UTI could enhance survival and attenuate inflammatory responses during CLP-induced sepsis. Moreover, sepsis-induced increases in the quantity and activity of Tregs were attenuated under UTI treatment, but not in TLR4-/- mice. We also found that the functional changes in Tregs could be attributed to the TLR4/NF-κB signaling pathway. Collectively, our results indicated that UTI could ameliorate inflammatory damage by modulating the quantity and function of Tregs via the TLR4/NF-κB signaling pathway. Our study provides theoretical and experimental evidence for the administration of UTI in the treatment of sepsis and other acute critical illnesses.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome, remain the leading causes of morbidity and mortality in intensive care units. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced sepsis; thus, it is now widely used in the treatment of pancreatitis, sepsis, and septic shock. Toll-like receptor 4 (TLR4), an essential LPS signaling receptor, plays a critical role in the activation of innate immunity. The aim of this study was to investigate whether UTI alleviates ALI by attenuating TLR4 expression and to explore the underlying molecular mechanisms involved. Male C56BL/6 mice were administered UTI intravenously 1 h before and 6 h after exposure to LPS by intratracheal instillation. Human lung epithelial (BEAS-2B) cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect levels of inflammatory cytokines. Western blot analysis was performed to detect changes in TLR4 expression and nuclear factor-κB (NF-κB) activation. UTI significantly protected animals from LPS-induced ALI, decreasing the lung wet/dry weight ratio, ALI score, total cells, neutrophils, macrophages, myeloperoxidase activity, and malondialdehyde content, factors associated with lung histological damage. UTI treatment also markedly attenuated levels of TLR4 and other proinflammatory cytokines. Furthermore, UTI significantly attenuated LPS-induced increases in TLR4 protein expression and NF-κB activation in lung tissues. Similarly, UTI markedly attenuated TLR4 expression and NF-κB activation in LPS-stimulated BEAS-2B cells. These findings indicate that UTI ameliorates LPS-induced ALI by attenuating the TLR4/NF-κB pathway activation.

Background Acute respiratory failure (ARF) is still one of the most severe complications in immunocompromised patients. Our previous systematic review showed noninvasive mechanical ventilation (NIV) reduced mortality, length of hospitalization and ICU stay in AIDS/hematological malignancy patients with relatively less severe ARF, compared to invasive mechanical ventilation (IMV). However, this systematic review was based on 13 observational studies and the quality of evidence was low to moderate. The efficacy of NIV in more severe ARF and in patients with other causes of immunodeficiency is still unclear. We aim to determine the efficacy of the initial ventilation strategy in managing ARF in immunocompromised patients stratified by different disease severity and causes of immunodeficiency, and explore predictors for failure of NIV. Methods and analysis The VENIM is a multicentre randomized controlled trial (RCT) comparing the effects of NIV compared with IMV in adult immunocompromised patients with severe hypoxemic ARF. Patients who meet the indications for both forms of ventilatory support will be included. Primary outcome will be 30-day all-cause mortality. Secondary outcomes will include in-hospital mortality, length of stay in hospital, improvement of oxygenation, nosocomial infections, seven-day organ failure, adverse events of intervention, et al. Subgroups with different disease severity and causes of immunodeficiency will also be analyzed. Discussion VENIM is the first randomized controlled trial aiming at assessing the efficacy of initial ventilation strategy in treating moderate and severe acute respiratory failure in immunocompromised patients. The result of this RCT may help doctors with their ventilation decisions. Trial registration ClinicalTrials.gov NCT02983851 . Registered 2 September 2016.

Sepsis is a lethal syndrome with a high incidence and a weighty economy burden. The pathophysiology of sepsis includes inflammation, immune dysfunction, and dysfunction of coagulation, while sepsis-induced cardiomyopathy (SIC), defined as a global but reversible dysfunction of both sides of the heart induced by sepsis, plays a significant role in all of the aspects above in the pathogenesis of sepsis. The complex pathogenesis of SIC involves a combination of dysregulation of inflammatory mediators, mitochondrial dysfunction, oxidative stress, disorder of calcium regulation, autonomic nervous system dysregulation, and endothelial dysfunction. The treatments for SIC include the signal pathway intervention, Chinese traditional medicine, and other specific therapy. Here, we reviewed the latest literatures on the mechanisms and treatments of SIC and hope to provide further insights to researchers and create a new road for the therapy of sepsis.

Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases.

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo−/− mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25− T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo−/− mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-β (TGF-βm+), and the secretion of inhibitory cytokines [including TGF-β and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo−/− septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression.

Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for CD4+CD25+Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1highCD4+CD25+Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4+CD25+Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Nrp-1highTregs and Nrp-1lowTregs; they were cocultured with CD4+CD25− T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor-β (TGF-βm+), apoptotic rate, and secretive ability [including TGF-β and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4+CD25− T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4+CD25+Tregs. Foxp-3/CTLA-4/TGF-βm+ of Nrp-1highTregs were upregulated by septic challenge. Nrp-1highTregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4+CD25− T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1highTregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis.