The emerging role of nuclear receptor coactivator 4 in health and disease: a novel bridge between iron metabolism and immunity.

Nuclear receptor coactivator 4 (NCOA4) has recently been recognized as a selective cargo receptor of ferritinophagy participating in ferroptosis. However, NCOA4 is also a coactivator that modulates the transcriptional activity of many vital nuclear receptors. Recent novel studies have documented the role of NCOA4 in healthy and pathogenic conditions via its modulation of iron- and non-iron-dependent metabolic pathways. NCOA4 exhibits non-ferritinophagic and iron-independent features such as promoting tumorigenesis and erythropoiesis, immunomodulation, regulating autophagy, and participating in DNA replication and mitosis. Full-length human-NCOA4 is composed of 614 amino acids, of which the N-terminal (1-237) contains nuclear-receptor-binding domains, while the C-terminal (238-614) principally contains a ferritin-binding domain. The exploration of the protein structure of NCOA4 suggests that NCOA4 possesses additional significant and complex functions based on its structural domains. Intriguingly, another three isoforms of NCOA4 that are produced by alternative splicing have been identified, which may also display disparate activities in physiological and pathological processes. Thus, NCOA4 has become an important bridge that encompasses interactions between immunity and metabolism. In this review, we outline the latest advances in the important regulating mechanisms underlying NCOA4 actions in health and disease conditions, providing insights into potential therapeutic interventions.

FASN regulates STING palmitoylation via malonyl-CoA in macrophages to alleviate sepsis-induced liver injury.

STING (stimulator of interferon genes) is a critical immunoregulatory protein in sepsis and is regulated by various mechanisms, especially palmitoylation. FASN (fatty acid synthase) is the rate-limiting enzyme to generate cellular palmitic acid (PA) via acetyl-CoA and malonyl-CoA and participates in protein palmitoylation. However, the mechanisms underlying the interaction between STING and FASN have not been completely understood. In this study, STING-knockout mice were used to confirm the pivotal role of STING in sepsis-induced liver injury. Metabolomics confirmed the dyslipidemia in septic mice and patients. The compounds library was screened, revealing that FASN inhibitors exerted a significant inhibitory effect on the STING pathway. Mechanically, the regulatory effect of FASN on the STING pathway was dependent on palmitoylation. Further experiments indicated that the upstream of FASN, malonyl-CoA inhibited STING pathway possibly due to C91 (palmitoylated residue) of STING. Overall, this study reveals a novel paradigm of STING regulation and provides a new perspective on immunity and metabolism.

Smart microgrid construction in abandoned mines based on gravity energy storage.

The share of new energy in China's energy consumption structure is expanding, posing serious challenges to the national grid's stability and reliability.As a result, it is critical to construct large-scale reliable energy storage infrastructure and smart microgrids. Based on the spatial resource endowment of abandoned mines' upper and lower wells and the principle characteristics of the gravity energy storage system, an intelligent microgrid system model for abandoned mines based on gravity energy storage is proposed, and the system's feasibility and key influencing factors are discussed and analyzed from the standpoint of economic benefits. The gravity energy storage system principle, system structure, subsurface powerhouse, underground storage, and transit system are all examined and analyzed.The viability of establishing intelligent microgrid systems in abandoned mines is proved using the resource conditions, technical conditions, economic advantages, and social benefits of Panyidong Mine in Huainan Coal Mine.The findings indicate that the project concept has good economic and social benefits as well as practical viability.Next, from the perspectives of technology, policy, and the ecological environment, several recommendations for the development of a smart microgrid system based on gravity energy storage power station are made. This study presents a novel concept for the advancement of energy storage technology and the reuse of abandoned mine resources, which is critical to the long-term development of abandoned mine resources and the advancement of energy storage technology.

RIPK3-MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis.

BACKGROUNDS: The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. METHODS AND RESULTS: Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT-29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL-mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro-necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA-induced intestinal injury and sepsis. CONCLUSIONS: These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING-driven inflammatory diseases.

The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages.

The discovery of STING-related innate immunity has recently provided a deep mechanistic understanding of immunopathy. While the detrimental effects of STING during sepsis had been well documented, the exact mechanism by which STING causes lethal sepsis remains obscure. Through single-cell RNA sequence, genetic approaches, and mass spectrometry, we demonstrate that STING promotes sepsis-induced multiple organ injury by inducing macrophage ferroptosis in a cGAS- and interferon-independent manner. Mechanistically, Q237, E316, and S322 in the CBD domain of STING are critical binding sites for the interaction with the coiled-coil domain of NCOA4. Their interaction not only triggers ferritinophagy-mediated ferroptosis, but also maintains the stability of STING dimers leading to enhanced inflammatory response, and reduces the nuclear localization of NCOA4, which impairs the transcription factor coregulator function of NCOA4. Meanwhile, we identified HET0016 by high throughput screening, a selective 20-HETE synthase inhibitor, decreased STING-induced ferroptosis in peripheral blood mononuclear cells from patients with sepsis and mortality in septic mice model. Our findings uncover a novel mechanism by which the interaction between STING and NCOA4 regulates innate immune response and ferroptosis, which can be reversed by HET0016, providing mechanistic and promising targets insights into sepsis.

Post-Translational Modifications of STING: A Potential Therapeutic Target.

Stimulator of interferon genes (STING) is an endoplasmic-reticulum resident protein, playing essential roles in immune responses against microbial infections. However, over-activation of STING is accompanied by excessive inflammation and results in various diseases, including autoinflammatory diseases and cancers. Therefore, precise regulation of STING activities is critical for adequate immune protection while limiting abnormal tissue damage. Numerous mechanisms regulate STING to maintain homeostasis, including protein-protein interaction and molecular modification. Among these, post-translational modifications (PTMs) are key to accurately orchestrating the activation and degradation of STING by temporarily changing the structure of STING. In this review, we focus on the emerging roles of PTMs that regulate activation and inhibition of STING, and provide insights into the roles of the PTMs of STING in disease pathogenesis and as potential targeted therapy.

Experimental Study of Adsorption Characteristics and Deformation of Coal for Different Gases.

Coal seam deformation due to gas adsorption affects the stability of the underground structure. Natural coal blocks of the Shanxi Formation were selected to study the dynamic adsorption characteristics of coal samples subjected to CO2, CH4, and N2 gas injections under coaxial pressure and confining pressure (7 MPa), as well as the displacement of CH4 with CO2 and N2 under the same conditions. The results show that, under the same conditions, the strain in the coal samples first increased, followed by a rapid increase along with the increase in pressure, with the transverse strain being always higher than the axial strain. The amount of gas adsorption varied from high to low as CO2 > CH4 > N2, and the final adsorption strains and equilibrium times were different for each gas. Based on the increase in gas pressure, the gas adsorption strain curve can be divided into two stages. The displacement of N2 only uses partial pressure to achieve the desorption of CH4 in the coal sample, leading to shrinkage deformation of the coal sample. In contrast, the displacement of CO2 has the dual effects of competitive adsorption and partial pressure reduction on CH4, leading to the swelling deformation of the coal sample.

Current Practice of Acute Appendicitis Diagnosis and Management in China (PANDA-C): A National Cross-Sectional Survey.

Background: The aim of this study was to describe and analyze the current status of the diagnosis and management of acute appendicitis in China. Patients and Methods: An online record system was used to collect data retrospectively from 52 medical centers in mainland China. All patients with acute appendicitis who were first treated at the hospital in 2017 were included and followed up for one year. Propensity score matching (PSM) was used to exclude the potential confounders and analyze the difference in outcomes between the non-operative management (NOM) and surgical groups. Results: A total of 10,187 patients were enrolled, of whom 5,517 (54.2%) were males. A total of 2,056 (20.2%) cases received NOM. The one-year recurrence rate of appendicitis in the NOM group was 19.3%. On PSM analysis, we found that the NOM group had a lower complication rate (2% vs. 4.2%; p = 0.001) and an acceptable success rate (96.8% vs. 100%; p < 0.001) compared with the operative group in patients with non-complicated acute appendicitis. However, in the complicated acute appendicitis population, the in-hospital complication rate in the NOM group was higher (10.8% vs. 5.8%; p = 0.048) and the success rate was lower (95.4% vs. 100%; p < 0.001) than the operative group. The recurrence rate was lower in patients with non-complicated acute appendicitis than in those with complicated acute appendicitis (17.3% vs. 30.8%; p = 0.010). In the operative group, pre-operative antimicrobial prophylaxis-covered anaerobes could reduce the surgical site infection (SSI) rate compared with that in the non-covered anaerobes group in non-complicated patients (0.9% vs. 1.9%; p = 0.020). Conclusions: Appendectomy is currently the most effective treatment for acute appendicitis. However, NOM is an alternative treatment for non-complicated acute appendicitis but not for complicated acute appendicitis because of the lower complication rate, considerable success rate, and recurrence rate.

Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury.

The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

Experimental study on the characteristics of train-induced vibration in a new structure of metro depot.

In order to improve the utilization rate of expensive and very limited urban land, a new structure system, underground metro depot, has been developed and applied in several cities in China. The underground metro depot, which is built underground, can be multiple stories, and allows other developments on top, has become increasingly popular in recent years. Since there are other developments on top, the vibration induced by the trains frequently entering and exiting the depot cannot be ignored. To better understand the characteristics of the train-induced vibration in the underground metro depot, a series of field tests were conducted on a two-story underground depot which is the largest underground metro depot in Asia. The results show that the main frequency components of vibration source are between 50 and 200 Hz and the level of that in the first floor underground is larger than that in the second floor underground due to the train floor structure interaction when the train running on the first floor underground. The vibration in the top platform decreases linearly with the distance from the measuring point to the center line of the track. When the train is running on the track at the edge area, the linear attenuation rate was about 0.2dB/m. It is easy to excite the vibration mode of the floor structure when the train is running on the first floor underground, so the vibration in the top platform induced by the train running on the first floor underground was much larger than the train running on the second floor underground. In the future design, if the underground depot has more than one floor, the structural dynamic behavior of over-track buildings induced by the train running on the floor slab underground should be the focus. The throat area has many rail joints and turnouts which can lead to a larger vibration level, the level easy to exceed the limit given for human vibration comfort. If developments are proposed on top of the throat area, the vibration level should be carefully checked in the area within 30 m from the track to avoid potential later vibration problem.

Iron homeostasis and disorders revisited in the sepsis.

Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.

STING-dependent induction of lipid peroxidation mediates intestinal ischemia-reperfusion injury.

Stimulator of interferon genes (STING) is essential for the type I interferon response against DNA pathogens. Recent evidence has indicated that STING also plays a critical role in various diseases such as systemic lupus erythematous, nonalcoholic fatty liver disease, and cancer. However, the exact function and mechanism of STING in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. In the current study, we evaluated the contribution of STING to the intestinal I/R progression. The data indicate a robust STING activation, specifically in the reperfusion period, with the evidence of interferon response and NF-κB pathway activation. The intestinal I/R injury and distant organ damage was absent in STING-/- mice. Mechanically, this detrimental effect relies on excess level of lipid peroxidation, which was proved by the level of 4-hydroxynonenal (4-HNE) and the malondialdehyde (MDA). Additionally, bone marrow derived macrophage (BMDM) was stimulated with mtDNA or STING agonist showed a dose- and time-dependent lipid peroxidation and cell death, which could be reverse by STING-/- or pretreatment of lipid peroxidation inhibitor. Liproxstatin-1 could also ameliorate injury I/R induced multiple-organ damage. Similar results were also identified in the GSE96733 database, which indicated that STING activation was associated with the disbalance of lipid peroxidation and antioxidant system. Collectively, our results indicate a novel role for STING activation in the regulation of lipid peroxidation is closely associated with intestinal I/R injury, and that anti-lipid peroxidation is a unique and effective mechanistic approach for intestinal I/R injury and STING activation associated damage prevention and treatment.

mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion.

Intestinal ischemia reperfusion (I/R) injury is the important pathogenesis for acute intestinal barrier disruption. The STING signaling is associated with gut homeostasis and barrier integrity. However, the biological function and regulation of STING signaling in intestinal I/R injury are not yet fully understood. As the ligand of STING signaling, the mitochondrial DNA (mtDNA) has been found to be associated with necroptosis. It still remains unknown whether mtDNA-STING signaling triggers intestinal necroptosis in intestinal I/R injury. We found that circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury in critically ill patients with intestinal injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. To explore the relationship between mtDNA and intestinal necroptosis, mice were treated with the intraperitoneal injection of mtDNA, and necroptosis signaling was remarkably activated and the inhibition of necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated intestinal necroptosis. In intestinal I/R injury, mtDNA was released from IECs and necroptosis was also triggered, companied with a significant decrease of RIPK3 in the intestine. STING knockout mice markedly attenuated intestinal necroptosis and intestinal I/R injury. Finally, we found that mtDNA-mediated STING signaling triggered necroptosis through synergistic IFN and TNF-α signaling in primary IECs. Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC necroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis.

Biomimetic enzyme barrier for preventing intestine-derived LPS induced diseases.

Biomimetic enzyme barrier (BEB) encapsulated microcapsules with alginate shells were in situ fabricated with a microfluidic electrospray approach for preventing intestine-derived LPS induced diseases. As the alginate shells could protect the contents in gastric juice and release them in the intestine, the inner BEB could form a consecutive immune barrier on the surface of the intestine during the release. Through combining BEB with alkaline phosphatase, the immune barrier could degrade and prevent the permeation of lipopolysaccharide, which enhanced the intestinal barrier function. Thus, the BEB microcapsules were imparted with outstanding ability in preventing intestine-derived LPS induced diseases. Based on an in vivo study, we demonstrated that this BEB microcapsule could effectively protect organ function, restore intestinal barrier integrity, prevent the permeation of LPS and alleviate inflammation. Therefore, the generated microcapsules have potential for clinical applications.

Polymicrobial Bacteremia Involving Klebsiella pneumoniae in Patients with Complicated Intra-Abdominal Infections: Frequency, Co-Pathogens, Risk Factors, and Clinical Outcomes.

Background: Klebsiella pneumoniae has gained notoriety because of its high antibiotic resistance and mortality. We compared the clinical features and outcomes of polymicrobial bacteremia involving K. pneumoniae (PBKP). Patients and Methods: A retrospective observational study of patients with polymicrobial and monomicrobial bacteremia involving K. pneumoniae from January 2012 to December 2016 was performed. The expression of resistance and virulence genes of 27 strains was also compared by polymerase chain reaction (PCR). Results: Among the polymicrobial group, the most common accompanying micro-organism was Escherichia coli. No differences in the expression of resistance and virulence genes was found among the 27 strains collected from the group. The analysis of the outcomes revealed that the patients with PBKP were more likely to have recurrent blood stream infections (p = 0.038), longer intensive care unit (ICU) lengths of stay (p = 0.043), and a higher total hospitalization cost (p = 0.045). However, no substantial differences in mortality were found between the two groups. The multivariable analysis revealed that a longer hospital stay prior to the onset of bacteremia (>20 days) was an independent risk factor for PBKP (p = 0.034), and the Sequential Organ Failure Assessment (SOFA) score upon onset of infection (p = 0.013), the adequacy of source control (p < 0.001), and iron supplementation (p = 0.003) were identified as independent predictors of mortality in patients with KP bacteremia. Conclusions: The development of septic shock and the concomitant use of iron supplementation are associated with higher mortality in patients with KP bacteremia, and PBKP did not increase the mortality of these patients, possibly because of the ability of K. pneumoniae to obscure the effects of other bacteria. Thus, adequate source control is more important than high-dose antibiotic therapy and is linked to higher survival.

[Status of diagnosis and management of acute appendicitis in 2017: a national multi-center retrospective study].

OBJECTIVE: To analyze the current status of diagnosis and management of acute appendicitis (AA) in China. METHODS: Questionnaire survey was used to retrospectively collect data of hospitalized patients with AA from 43 medical centers nationwide in 2017 (Sort by number of cases provided: Jinling Hospital of Medical School of Nanjing University, The First Affiliated Hospital of Xinjiang Medical University, Lu'an People's Hospital, Tengzhou Central People's Hospital, Dalian Central Hospital, The Affiliated Hospital of Xuzhou Medical University, Dongying People's Hospital, Jinjiang Hospital of Traditional Chinese Medicine, Huangshan Shoukang Hospital, Xuyi People's Hospital, Nanjing Jiangbei People's Hospital, Lanzhou 940th Hospital of PLA, Heze Municipal Hospital, The First College of Clinical Medical Science of China Three Gorges University, Affiliated Jiujiang Hospital of Nanchang University, The Second People's Hospital of Hefei, Affiliated Central Hospital of Shandong Zaozhuang Mining Group, The Third People's Hospital of Kunshan City, Xuzhou First People's Hospital, The 81st Group Army Hospital of PLA, Linyi Central Hospital, The General Hospital of Huainan Eastern Hospital Group, The 908th Hospital of PLA, Liyang People's Hospital, The 901th Hospital of Joint Logistic Support Force, The Third Affiliated Hospital of Chongqing Medical University, The Fourth Hospital of Jilin University, Harbin Acheng District People's Hospital, The First Affiliated Hospital of Zhengzhou University, Nanjing Luhe People's Hospital, Taixing Municipal People's Hospital, Baotou Central Hospital, The Affiliated Hospital of Nantong University, Linyi People's Hospital, The 72st Group Army Hospital of PLA, Zaozhuang Municipal Hospital, People's Hospital of Dayu County, Taixing City Hospital of Traditional Chinese Medicine, Suzhou Municipal Hospital, Beijing Guang'anmen Hospital, Langxi County Hospital of Traditional Chinese Medicine, Nanyang Central Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University).The diagnosis and management of AA were analyzed through unified summary. Different centers collected and summarized their data in 2017 and sent back the questionnaires for summary. RESULTS: A total of 8 766 AA patients were enrolled from 43 medical centers, including 4 711 males (53.7%) with median age of 39 years and 958 (10.9%) patients over 65 years old. Of 8 776 patients, 5 677 cases (64.6%) received one or more imaging examinations, and the other 3 099 (35.4%) did not receive any imaging examination. A total of 1 858 (21.2%) cases received medical treatment, mainly a combination of nitroimidazoles (1 107 cases, 59.8%) doublet regimen, followed by a single-agent regimen of non-nitroimidazoles (451 cases, 24.4%), a nitroimidazole-free doublet regimen (134 cases, 7.2%), a triple regimen of combined nitroimidazoles (116 cases, 6.3%), nitroimidazole alone (39 cases, 2.1%) and nitroimidazole-free triple regimen (3 cases, 0.2%). Of the 6 908 patients (78.8%) who underwent surgery, 4 319 (62.5%) underwent laparoscopic appendectomy and 2589 (37.5%) underwent open surgery. Ratio of laparotomy was higher in those patients under 16 years old (392 cases) or over 65 years old (258 cases) [15.1%(392/2 589) and 10.0%(258/2 589), respectively, compared with 8.5%(367/4 316) and 8.0%(347/4 316) in the same age group for laparoscopic surgery, χ²=91.415, P<0.001; χ²=15.915,P<0.001]. Patients with complicated appendicitis had higher ratio of undergoing open surgery as compared to those undergoing laparoscopic surgery [26.7%(692/2 589) vs. 15.6%(672/4 316), χ²=125.726, P<0.001].The cure rates of laparoscopic and open surgery were 100.0% and 99.8%(2 585/2 589) respectively without significant difference (P=0.206). Postoperative complication rates were 4.5%(121/2 589) and 4.7%(196/4 316) respectively, and the difference was not statistically significant (χ²=0.065, P=0.799). The incidence of surgical site infection was lower (0.6% vs. 1.7%, χ²=17.315, P<0.001), and hospital stay was shorter [6(4-7) days vs. 6(5-8) days, U=4 384 348.0, P<0.001] in the laparoscopic surgery group, while hospitalization cost was higher (median 12 527 yuan vs. 9 342 yuan, U=2 586 809.0, P<0.001). CONCLUSIONS: The diagnosis of acute appendicitis is still clinically based, supplemented by imaging examination. Appendectomy is still the most effective treatment at present. Laparoscopic appendectomy has become the main treatment strategy, but anti-infective drugs are also very effective.

Hypermucoviscous Klebsiella pneumoniae infections induce platelet aggregation and apoptosis and inhibit maturation of megakaryocytes.

INTRODUCTION: Different Klebsiella pneumoniae strains carry different virulence factors and antibiotic resistance and may cause thrombocytopenia. This study aimed to investigate the effects of different infections caused by K. pneumoniae on platelets. METHODS: Two hypermucoviscous K. pneumoniae strains and two classic strains were collected from clinical blood culture, and in both groups, there was a carbapenem-resistant strain and a carbapenem-sensitive strain. Mouse infection models were constructed by intraperitoneally injecting different strains, and mice injected with phosphate-buffered saline served as a control. Count, aggregation rate and apoptosis proportion of platelets within 12 h were examined. CD41 expression was measured in bone marrow cells to determine the maturation of megakaryocytes. The concentrations of lipopolysaccharides and related signaling molecules were also measured. RESULTS: The platelet aggregation rate was much significantly higher in the two hypermucoviscous groups, while it showed no difference in the classic groups compared to the control group. All infections induced apoptosis of platelets, among which the highest apoptosis proportions were observed in infections caused by the hypermucoviscous carbapenem-sensitive strain. In both hypermucoviscous groups the CD41 mean fluorescence intensity was much lower than that in the control group, indicating that the maturation of megakaryocytes in the hypermucoviscous groups was significantly inhibited. Lipopolysaccharides were significantly higher and TLR4/Myd88 and JNK/MAPK pathways were strongly activated in hypermucoviscous groups. CONCLUSIONS: The results indicate that hypermucoviscous K. pneumoniae can reduce platelet count by several pathways. Although antibiotic resistance is rapidly emerging worldwide, it has little influence on the decrease in platelets.

Released Mitochondrial DNA Following Intestinal Ischemia Reperfusion Induces the Inflammatory Response and Gut Barrier Dysfunction.

Ischemia-reperfusion (I/R) injury is a challenging clinical problem, especially injuries involving the gastrointestinal tract. Mitochondrial DNA (mtDNA) is released upon cell death and stress, and can induce the inflammatory response. We aimed to investigate the role of mtDNA in the pathogenesis of intestinal I/R. Intestinal I/R model was established with clamping of the superior mesenteric artery, and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury. Using in vitro models, H/R up-regulated oxidative stress, disrupted mitochondrial activity and the mitochondrial membrane potential, induced apoptosis and elevated the mtDNA levels in the supernatant of intestinal epithelial cells, and the co-culture of mtDNA with human primary dendritic cells significantly elevated TLR9-MyD88 expression and enhanced the production of inflammatory cytokines and chemokines. MtDNA was also released in a mouse model of intestinal I/R and was associated with the increased secretion of inflammatory cytokines and increased gut barrier injury compared with that of the sham group. We concluded that mtDNA contributes to I/R injury and may serve as a biomarker of intestinal I/R. We further suggest that oxidized mtDNA originated from IECs during intestinal I/R exacerbates the acute proinflammatory process by eliciting the production of proinflammatory cytokines and chemokines.

A New Scoring System to Predict Blood Stream Infections in Patients with Complicated Intra-Abdominal Infections: Experience from a Tertiary Referral Hospital in China.

BACKGROUND: This purpose of this study was to investigate the effects of blood stream infections (BSIs) on the prognosis of patients with complicated intra-abdominal infections (IAIs) and to make predictions based on patients' characteristics on admission. PATIENTS AND METHODS: One hundred eighty-seven patients with complicated IAI in 2014 and 2015 were included in our retrospective analysis, except for those diagnosed with central line-associated blood stream infections (CLABSIs). Patients with BSIs were compared with patients without BSIs. Multivariable logistic regression was applied to identify factors associated with BSIs and also the subtypes of BSIs. The predictive score systems were established further. RESULTS: Seventy-four patients (39.6%) with complicated IAIs developed BSIs after admission. Four factors evaluated on admission were associated independently with BSIs including alanine aminotransferase (ALT) ≥66 U/L (two scores), insensitivity to initial empirical antibiotic agents (IIEA; three scores), Sepsis-Related Organ Failure Assessment (SOFA) score of two or more (three scores), and generalized peritonitis (four scores). A total score of five or more was regarded as the critical value in the combined test to predict BSIs, with a sensitivity of 0.78 and a specificity of 0.73. Blood stream infections were further divided as secondary BSIs and non-secondary BSIs. The risk factors of secondary BSIs included IIEA (three scores), SOFA score of two or more (five scores), and generalized peritonitis (eight scores), where a total score of nine or more was regarded as the critical value in the combined test, with a sensitivity of 0.68 and a specificity of 0.87, whereas the risk factors of non-secondary BSIs included IIEA (three scores), SOFA score of two or more (three scores) and procalcitonin (PCT) ≥0.43 mcg/L (three scores), where a total score of six or more was regarded as the critical value in the combined test, with a sensitivity of 0.75 and a specificity of 0.70. Moreover, BSIs were linked with the worse clinical outcomes in organ functions, hospitalization costs, and mortality. CONCLUSIONS: Our new scoring methods may have potential advantages on the early prediction and recognition of BSIs in patients with complicated IAIs.