Polyunsaturated fatty acid-derived lipid mediator Resolvin D1 alleviates sepsis-induced disseminated intravascular coagulation via Caspase-1/Gasdermin D pyroptotic pathway.

BACKGROUND & AIMS: Sepsis-induced disseminated intravascular coagulation (DIC) is characterised by abnormal blood clotting resulting from severe infection, contributing to organ dysfunction in sepsis. Resolvin D1 (RvD1) is an endogenous lipid mediator, synthesised from the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) through enzymatic processes involving 15-LOX and 5-LOX. RvD1 is recognised for its protective properties against various inflammatory conditions. This study aims to investigate its potential to modulate coagulation dysfunction in sepsis and to evaluate coagulation disorders in septic patients. METHODS: Sepsis models were established by intraperitoneal injection LPS (20 mg/kg) or cecal ligation and puncture (CLP) followed by injection of RvD1 (10 µg/kg) or saline. The impact of RvD1 on coagulation dysfunction was assessed by clotting time and coagulation indicators such as TAT, D-dimer, PAI-1, and fibrinogen. The activity of the coagulation system in vivo was observed by evaluating dynamic microcirculation, platelets and thrombin in mice using intravital microscopy. The effect of RvD1 on pyroptosis was investigated by measuring NOD-like receptor protein 3 (NLRP3), Caspase-1, Caspase-11, and Gasdermin D (GSDMD) levels via western blot. Caspase-1 knockout mice, GSDMD knockout mice and bone marrow-derived macrophages (BMDMs) were used to elucidate the underlying mechanisms. Lastly, the concentration of RvD1 in plasma from septic patients was quantified to explore its relationship with coagulation and pyroptosis. RESULTS: RvD1 significantly attenuated coagulation dysfunction in septic mice induced by LPS and CLP, and inhibited Caspase-1/GSDMD-dependent pyroptosis in septic mice and bone marrow-derived macrophages. In septic patients, the plasma concentrations of RvD1 was negatively correlated with both coagulation-related indicators and markers of GSDMD activation. CONCLUSION: The results suggest that RvD1 can improve coagulation dysfunction in sepsis by regulating the Caspase-1/GSDMD pyroptotic pathway. Additionally, the concentration of RvD1 in septic patient plasma is related to prognosis and DIC development. RvD1 could be a potential biomarker and a promising therapeutic alternative in sepsis-induced DIC.

RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear. OBJECTIVES: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS. METHODS: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry. RESULTS: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher. CONCLUSIONS: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

Inclusion of frailty improved performance of delirium prediction for elderly patients in the cardiac intensive care unit (D-FRAIL): A prospective derivation and external validation study.

BACKGROUND: The elderly patients admitted to cardiac intensive care unit (CICU) are at relatively high risk for developing delirium. A simple and reliable predictive model can benefit them from early recognition of delirium followed by timely and appropriate preventive strategies. OBJECTIVE: To explore the role of frailty in delirium prediction and develop and validate a delirium predictive model including frailty for elderly patients in CICU. DESIGN: A prospective, observational cohort study. SETTINGS: CICU at China-Japan Friendship Hospital from March 1, 2022 to August 25, 2022 (derivation cohort); CICU at Beijing Anzhen Hospital affiliated to Capital Medical University from March 14, 2023 to May 8, 2023 (external validation cohort). PARTICIPANTS: A total of 236 and 90 participants were enrolled in the derivation and external validation cohorts, respectively. Participants in the derivation cohort were assigned into either the delirium (n = 70) or non-delirium group (n = 166) based on the occurrence of delirium. METHODS: The simplified Chinese version of the Confusion Assessment Method for the Diagnosis of Delirium in the Intensive Care Unit was used to assess delirium twice a day at 8:00-10:00 and 18:00-20:00 until the onset of delirium or discharge from the CICU. Frailty was assessed using the FRAIL scale during the first 24 h in the CICU. Other possible risk factors were collected prospectively through patient interviews and medical records review. After processing missing data via multiple imputations, univariate analysis and bootstrapped forward stepwise logistic regression were performed to select optimal predictors and develop the models. The models were internally validated using bootstrapping and evaluated comprehensively via discrimination, calibration, and clinical utility in both the derivation and external validation cohorts. RESULTS: The study developed D-FRAIL predictive model using FRAIL score, hearing impairment, Acute Physiology and Chronic Health Evaluation-II score, and fibrinogen. The area under the receiver operating characteristic curve (AUC) was 0.937 (95% confidence interval [CI]: 0.907-0.967) and 0.889 (95%CI: 0.840-0.938) even after bootstrapping in the derivation cohort. Inclusion of frailty was demonstrated to improve the model performance greatly with the AUC increased from 0.851 to 0.937 (p < 0.001). In the external validation cohort, the AUC of D-FRAIL model was 0.866 (95%CI: 0.782-0.907). Calibration plots and decision curve analysis suggested good calibration and clinical utility of the D-FRAIL model in both the derivation and external validation cohorts. CONCLUSIONS: For elderly patients in the CICU, FRAIL score is an independent delirium predictor and the D-FRAIL model demonstrates superior performance in predicting delirium.

Polyethylene mulch film-derived microplastics enhance the bioaccumulation of atrazine in two earthworm species (Eisenia fetida and Metaphire guillelmi) via carrier effects.

Microplastics (MPs) may significantly affect the bioavailability of coexisting pollutants in soil by adsorption-desorption behavior. However, the mechanisms underlying these interaction remain unclear. Herein, the influence of unused polythylene mulch film-derived MPs (MFMPs) and farmland residual polyethylene mulch film-derived MPs (MFMPs-aged) on the adsorption-desorption behavior and bioavailability of atrazine (ATZ) in soil were investigated. The adsorption kinetics and the adsorption isotherms of ATZ on soil, MFMPs, and MFMPs-aged fitted well by the pseudo-second-order model and the Langmuir model, respectively. ATZ were easier to desorb from soil, MFMPs, and MFMPs-aged in the simulated earthworm digestive fluid than that in the CaCl2 solution. The adsorption and desorption capacities of MFMPs and MFMPs-aged for ATZ were higher than those of soil, especially for MFMPs-aged. The existence of MPs in soil strengthened the adsorption and desorption capacities of ATZ, and the strengthened effects were promoted by the addition amount and aging process of MPs. Moreover, the occurrence of MPs significantly increased the bioaccumulation of ATZ in earthworms, especially for MFMPs-aged. This study deepens the knowledge of the interaction mechanisms of mulch film-derived MPs and pesticide pollution.

Hemophilia A developing cerebral infarction after surgical treatment of giant hemophilic pseudotumor: a case report.

BACKGROUND: Cerebral infarction (CI) is an unusual complication in patients with bleeding disorders. To our knowledge, this is the first case of postoperative internal border-zone infarction (I-BZI) from Hemophilia A. CASE PRESENTATION: We present a case of Hemophilia A developing I-BZI, after surgical treatment of giant hemophilic pseudotumor. A 36-year-old man was introduced from other hospital by Hemophilia with giant hemophilic pseudotumor in his left thigh. Patient and his relatives did not have a history of thrombophilia. After excluding the relevant surgical contraindications, we performed the operation of pseudotumor resection. Prior to surgery, blood tests revealed hemoglobin of 137 g/L. FVIII activity was 1.5%. Activated partial thromboplastin time (APTT) was 71.50 s and D-dimer was 3.33 mg/L FEU. Immediately before surgery, the patient received an intravenous infusion of FVIII products (Xyntha®) at a dose of 3500 IU for his body weight of 80 kg. Post-operative day two (POD2), patient developed vomiting, decreased response, and dysarthria. Hemoglobin was 54 g/L with blood pressure of 110/70 mmHg. Magnetic resonance imaging of the brain showed there were multiple acute cerebral infarctions in bilateral lateral ventricles (internal border zone) and multiple ischemic foci in the white matter areas and basal ganglia of the bilateral cerebral hemispheres. This case suggested that acute severe anemia can be one of the causes of I-BZI. CONCLUSIONS: For the treatment of I-BZI caused by acute anemia from Hemophilia A, volume expansion, red blood cell supplement and continuous improvement of coagulation with suitable dose of factor VIII (FVIII) should be considered to improve prognosis.

Potential biomarkers for inflammatory response in acute lung injury.

Acute lung injury (ALI) is a severe respiratory disorder occurring in critical care medicine, with high rates of mortality and morbidity. This study aims to screen the potential biomarkers for ALI. Microarray data of lung tissues from lung-specific geranylgeranyl pyrophosphate synthase large subunit 1 knockout and wild-type mice treated with lipopolysaccharide were downloaded. Differentially expressed genes (DEGs) between ALI and wild-type mice were screened. Functional analysis and the protein-protein interaction (PPI) modules were analyzed. Finally, a miRNA-transcription factor (TF)-target regulation network was constructed. Totally, 421 DEGs between ALI and wild-type mice were identified. The upregulated DEGs were mainly enriched in the peroxisome proliferator-activated receptor signaling pathway, and fatty acid metabolic process, while downregulated DEGs were related to cytokine-cytokine receptor interaction and regulation of cytokine production. Cxcl5, Cxcl9, Ccr5, and Cxcr4 were key nodes in the PPI network. In addition, three miRNAs (miR505, miR23A, and miR23B) and three TFs (PU1, CEBPA, and CEBPB) were key molecules in the miRNA-TF-target network. Nine genes including ADRA2A, P2RY12, ADORA1, CXCR1, and CXCR4 were predicted as potential druggable genes. As a conclusion, ADRA2A, P2RY12, ADORA1, CXCL5, CXCL9, CXCR1, and CXCR4 might be novel markers and potential druggable genes in ALI by regulating inflammatory response.

Salidroside regulates inflammatory pathway of alveolar macrophages by influencing the secretion of miRNA-146a exosomes by lung epithelial cells.

The purpose of this study was to explore the investigative mechanism of salidroside (SAL) on LPS-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The exosomes from RLE-6TN are extracted and identified by transmission electron microscopy, particle size analysis and protein marker detection, and co-cultured with NR8383 cells. The ALI/ARDS model of SD rats was established by LPS (10 mg/kg) intratracheal instillation. Following a four-hour intratracheal instillation of LPS, 50 µl of RLE-6TN exosomes were injected through the tail vein. After that, SAL and miR-146a antagomir were injected into the tail vein for 72 h, respectively. As the changes of HE stain, body weight and ALI score are observed. The expression of miR-146a, TLR4, NF-kB, IRAK1, TRAF6 and their related proteins were detected by RT-PCR and Western blot, respectively. TNF-α, IL-6, IL-8 and IL-1 ß inflammatory factors were detected by ELISA. The expression of miR-146a, NF-kB, IRAK, TRAF6 and related inflammatory factors in LPS-induced NR8383 was significantly higher than that in the control group, while SAL has greatly reduced the expression of TLR4 mediated NF-kB inflammatory pathway and related inflammatory factors. SAL can significantly improve the LPS-induced lung morphological abnormalities, slowed down the rate of weight loss in rats, and reducing the ALI score. The expression trend of NF-kB, IRAK, TRAF6 and related inflammatory factors in rats' lung tissues was consistent with that in NR8383 cells. SAL has a protective effect on ALI/ARDS caused by sepsis, which is likely to be developed to a potential treatment for the disease. To sum up, this study provides a new theoretical basis for the treatment of ALI/ARDS with SAL.

Environmental behavior of paclobutrazol in soil and its toxicity on potato and taro plants.

The environmental behavior of paclobutrazol in soil and its toxicity were studied by field investigation and an outdoor pot experiment, and the residue of paclobutrazol was detected by gas chromatography-mass spectrometry. Field investigation has found that the residual paclobutrazol in the former succession crop could severely inhibit the growth of succeeding crops of potato; with migration and transformation of residual paclobutrazol in the soil, the stems of potato were thickened with residual amount of 1.23 mg kg-1, the growth was slow, and the height of potato in soil with residual amount of 1.34 mg kg-1 and the control was significantly different. The degradation dynamics of paclobutrazol fits with the first-order degradation kinetics, although T1/2 of paclobutrazol of the taro planting soil was 30.14-46.21 days and the residual paclobutrazol remained detectable even on day 120 after application. Taro leaves were sensitive to the stress of paclobutrazol pollution; the taro leaf thickness increased, the leaf area decreased, the chlorophyll content per area unit of taro leaf showed an obvious increased trend, and SOD and CAT activities and MDA and proline content increased significantly. Paclobutrazol promoted the tillering of taro, and the taro seedlings were dwarfed by 58.01, 63.27, and 75.88% at different concentrations. It indicated that taro had strong stress response ability under paclobutrazol pollution.

Factors that influence the choice to work in rural township health centers among 4,669 clinical medical students from five medical universities in Guangxi, China.

PURPOSE: To produce competent undergraduate-level medical doctors for rural township health centers (THCs), the Chinese government mandated that medical colleges in Central and Western China recruit rural-oriented, tuition-waived medical students (RTMSs) starting in 2010. This study aimed to identify and assess factors that influence the choice to work in rural township health centers among both RTMSs and other students from five medical universities in Guangxi, China. METHODS: An internet-based self-administered questionnaire survey was conducted with medical students in Guangxi province. Multinomial logistic regression was used to identify factors related to the attitudes toward work in a rural township health center. RESULTS: Among 4,669 medical students, 1,523 (33%) had a positive attitude and 2,574 (55%) had a neutral attitude toward working in THCs. Demographic characteristics, personal job concerns, and knowledge of THCs were associated with the choice of a career in THCs. The factors related to a positive attitude included the following: three-year program, a rural-oriented medical program, being male, an expectation of working in a county or township, a focus on medical career development, some perceived difficulty of getting a job, having family support, sufficient knowledge of THCs, optimism toward THC development, seeking lower working pressure, and a lower expected monthly salary. CONCLUSION: Male students in a three-year program or a rural-oriented tuition-waived medical education program were more likely to work in THCs. Selecting medical students through interviews to identify their family support and intentions to work in THCs would increase recruitment and retention. Establishing favorable policies and financial incentives to improve living conditions and the social status of rural physicians is necessary.

Total protein concentration and total bacterial load as measures of residual interproximal plaque in comparative clinical trials.

AIM: Establish total protein concentration and total bacterial load as quantitative measures of residual interproximal plaque (IPP) in a clinical model designed to evaluate oral hygiene interventions. MATERIAL AND METHODS: This clinical model was a randomized, examiner and laboratory technician-blinded, parallel-design study whereby levels of residual IPP were compared for subjects using a manual toothbrush or a toothbrush+floss. Differences between interventions were compared after 7 and 21 days of use. Protein concentration was measured using 3-(4-carboxybenzoyl) quinoline-2-carboxaldehyde in a fluorescence microplate format and bacterial load was assessed by quantitative real-time PCR with universal primers specific for 16S rRNA and detected by SYBR Green. ancova was used to assess the statistical significance of the differences between interventions while clinical relevance was evaluated by a statistical model described by Man-Son-Hing et al. 2002. RESULTS: Ninety-three subjects completed the study. Significant differences between interventions, using both outcome measures, were observed after 7 and 21 days. The difference between interventions by total protein concentration were further determined to be clinically relevant. CONCLUSIONS: Only total protein concentration provided both statistically significant and clinically relevant differences between two clinically distinct oral hygiene interventions in this clinical model for evaluating IPP.