The clinical trajectory of peripheral blood immune cell subsets, T-cell activation, and cytokines in septic patients.

OBJECTIVE AND DESIGN: Changes in the immune status of patients with sepsis may have a major impact on their prognosis. Our research focused on changes in various immune cell subsets and T-cell activation during the progression of sepsis. METHODS AND SUBJECTS: We collected data from 188 sepsis patients at the First Affiliated Hospital of Zhejiang University School of Medicine. The main focus was on the patient's immunocyte subset typing, T-cell activation/Treg cell analysis, and cytokine assay, which can indicate the immune status of the patient. RESULTS: The study found that the number of CD4+ T cells, CD8+ T cells, NK cells, and B cells decreased early in the disease, and the decrease in CD4+ and CD8+ T cells was more pronounced in the death group. T lymphocyte activation was inhibited, and the number of Treg cells increased as the disease progressed. T lymphocyte inhibition was more significant in the death group, and the increase in IL-10 was more significant in the death group. Finally, we used patients' baseline conditions and immunological detection indicators for modeling and found that IL-10, CD4+ Treg cells, CD3+HLA-DR+ T cells, and CD3+CD69+ T cells could predict patients' prognosis well. CONCLUSION: Our study found that immunosuppression occurs in patients early in sepsis. Early monitoring of the patient's immune status may provide a timely warning of the disease.

Mid-to-late stage diquat accumulation in the central nervous system: A severe case of oral poisoning.

A 54-year-old woman in good health was admitted to our hospital with diquat poisoning. The patient drank an unknown dose of diquat, and acute kidney injury developed early. However, there were no obvious pulmonary abnormalities and no signs of central nervous system toxicity in the early stage. The woman underwent active treatment, which resulted in a significant decrease in blood diquat levels, but her lung condition progressively worsened and neurological symptoms developed. Fortunately, the patient survived after intensive hemoperfusion combined with continuous renal replacement therapy (CRRT), intracranial pressure reduction, and anti-infective treatment. This case report highlights the importance of being aware of the development of delayed pulmonary symptoms and neurologic complications when caring for patients poisoned with diquat, even in those with low diquat blood concentrations. Interestingly, we also detected the concentration of diquat in the cerebrospinal fluid (CSF) of patients with diquat poisoning, and found that the rate of decrease of diquat concentration in the CSF was considerably slower than that in the blood.Notably, a specific correlation was observed between the concentration of diquat in the CSF, rather than in the blood, and both the intracranial pressure (ICP) and the severity of cerebral edema in this patient.

Structural basis of AlpA-dependent transcription antitermination.

AlpA positively regulates a programmed cell death pathway linked to the virulence of Pseudomonas aeruginosa by recognizing an AlpA binding element within the promoter, then binding RNA polymerase directly and allowing it to bypass an intrinsic terminator positioned downstream. Here, we report the single-particle cryo-electron microscopy structures of both an AlpA-loading complex and an AlpA-loaded complex. These structures indicate that the C-terminal helix-turn-helix motif of AlpA binds to the AlpA binding element and that the N-terminal segment of AlpA forms a narrow ring inside the RNA exit channel. AlpA was also revealed to render RNAP resistant to termination signals by prohibiting RNA hairpin formation in the RNA exit channel. Structural analysis predicted that AlpA, 21Q, λQ and 82Q share the same mechanism of transcription antitermination.

Severe liver injury and clinical characteristics of occupational exposure to 2-amino-5-chloro-N,3-dimethylbenzamide: A case series.

BACKGROUND: The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and pharmaceuticals. However, no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in humans. This study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. METHODS: This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July 2022. The entire course of the incidents was described in detail. Blood 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass spectrometer. Hematoxylin and eosin staining was performed to assess liver injury, and immunofluorescence was used to evaluate hepatic mitophagy. RESULTS: The 2-amino-5-chloro-N,3-dimethylbenzamide powder (99% purity) entered the human body mainly via the skin and respiratory tract due to poor personal protective measures. The typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency, rash, fever, organic damage, and recovery phases in accordance with the clinical evolution. Rash and fever may be the important premonitory symptoms for further organ injuries. The chemical was detected in the blood of all patients and caused multiple organ injuries, predominantly liver injury, including kidney, myocardium, and microcirculation. Three patients recovered smoothly after comprehensive treatments, including artificial liver therapy, continuous renal replacement therapy, glucocorticoids, and other symptomatic and supportive treatments. One patient survived by liver transplantation. The postoperative pathological findings of the removed liver showed acute liver failure, and immunofluorescence staining confirmed the abundance of mitophagy in residual hepatocytes. CONCLUSIONS: This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. The chemical enters the body through the respiratory tract and skin during industrial production. The 2-amino-5-chloro-N,3-dimethylbenzamide poisoning causes multiple-organ dysfunction with a predominance of liver injury. Liver transplantation may be an effective option for patients with severe liver failure. The mechanisms of liver injury induced by 2-amino-5-chloro-N,3-dimethylbenzamide might involve abnormal mitochondrial function and mitophagy.

Tripterygium wilfordii Hook.f. ameliorates paraquat-induced lung injury by reducing oxidative stress and ferroptosis via Nrf2/HO-1 pathway.

Paraquat (PQ) poisoning can induce acute lung injury and fibrosis and has an extremely high mortality rate. However, no effective treatments for PQ poisoning have been established. In this study, the potential efficacy of Tripterygium wilfordii Hook.f. (TwHF) in alleviating PQ-induced lung injury and fibrosis was investigated in a mouse model. Mice were randomly assigned to the control, PQ, PQ + TwHF1 (pretreatment before inducing poisoning), and PQ + TwHF2 (treatment after poisoning) groups. The mice in the PQ + TwHF1 group were pretreated with TwHF for 5 days before receiving one dose of PQ (120 mg/kg) and then received a daily oral gavage of the indicated dosages of TwHF until sacrifice. The mice in the PQ + TwHF2 group were treated with TwHF 2 h after PQ exposure until sacrifice. The pathological analysis and Fapi PET/CT showed that treatment with TwHF attenuated lung injury. And TwHF reduced pulmonary oxidative stress, as indicated by the reduction in, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels, as well as by the increase in superoxide dismutase (SOD) levels. Accordingly, the Perls DAB staining showed increased iron concentrations and western blotting revealed a decreased GPX4 expression after PQ exposure, as well as the mitigation of the overexpression of Nrf2 and HO-1 induced by PQ. In conclusion, our study demonstrated the potential of TwHF as a treatment for PQ-induced lung injury and fibrosis. The protective mechanism of this medicinal herb may involve the regulation of ferroptosis.

The characteristics of liver injury induced by Amanita and clinical value of α-amanitin detection.

BACKGROUND: Amanita poisoning as a foodborne disease has raised concerning mortality issues. Reducing the interval between mushroom ingestion and medical intervention could greatly influence the outcomes of Amanita poisoning patients, while treatment is highly dependent on a confirmed diagnosis. To this end, we developed an early detection-guided intervention strategy by optimizing diagnostic process with performing α-amanitin detection, and further explored whether this strategy influenced the progression of Amanita poisoning. METHODS: This study was a retrospective analysis of 25 Amanita poisoning patients. Thirteen patients in the detection group were diagnosed mainly based on α-amanitin detection, and 12 patients were diagnosed essentially on the basis of mushroom consumption history, typical clinical patterns and mushroom identification (conventional group). Amanita poisoning patients received uniform therapy, in which plasmapheresis was executed once confirming the diagnosis of Amanita poisoning. We compared the demographic baseline, clinical and laboratory data, treatment and outcomes between the two groups, and further explored the predictive value of α-amanitin concentration in serum. RESULTS: Liver injury induced by Amanita appeared worst at the fourth day and alanine aminotransferase (ALT) rose higher than aspartate aminotransferase (AST). The mortality rate was 7.7% (1/13) in the detection group and 50.0% (6/12) in the conventional group (P = 0.030), since patients in the detection group arrived hospital much earlier and received plasmapheresis at the early stage of disease. The early detection-guided intervention helped alleviate liver impairment caused by Amanita and decreased the peak AST as well as ALT. However, the predictive value of α-amanitin concentration in serum was still considered limited. CONCLUSIONS: In the management of mushroom poisoning, consideration should be given to the rapid detection of α-amanitin in suspected Amanita poisoning patients and the immediate initiation of medical treatment upon a positive toxin screening result.

Role of routine check-up in the prognosis of patients with pancreatic cancer: A puzzling phenomenon.

BACKGROUND: The high coverage of annual routine health check-up in China is a unique phenomenon throughout the world. However, its clinical value is controversial. In this cohort study, we chose pancreatic cancer as a disease model to explore the role of routine check-up in the prognosis of patients with pancreatic cancer. METHODS: Data from 157 patients who were diagnosed with pancreatic cancer between January 2010 and April 2014 were collected. Patients were divided into two groups depending on how their disease was detected. Group A (n = 85): Patients were diagnosed with pancreatic cancer in clinic visits. Group B (n = 72): Patients were diagnosed with pancreatic cancer in routine check-ups. We compared their prognosis. RESULTS: The tumor stage in group B was earlier than that in group A. The 1-year survival rate in group B was significantly higher than that in group A (74.6% vs. 42.4%, P < 0.001), while the 3- and 5-year survival rates of the two groups showed no significant difference (P > 0.05). The difference of overall survival time between the two groups was not significant (22.0 vs. 9.0 months, P = 0.078). CONCLUSIONS: The stage of pancreatic cancer diagnosed in routine check-ups was earlier and therefore, the intervention was earlier which improved short-term survival rate. However, early intervention did not improve overall survival in the long-term.

Early Changes of Peripheral Blood Lymphocyte Subpopulations in Patients with Occupational 2,4-dinitrophenol Poisoning.

2,4-dinitrophenol (DNP), an organic compound which frequently used in industry, is considered to have high toxicity. This study aimed to investigate the early changes of lymphocyte subpopulations in patients with occupational 2,4-DNP poisoning. Totally 9 patients with acute occupational 2,4-DNP poisoning and 30 healthy volunteers as control were enrolled. The patients received immediately comprehensive supportive treatments, including large-dose glucocorticoid and repeated hemoperfusion (HP). The ratio of CD4+/CD8+ T cells were significantly higher in patients upon admission compared to healthy controls (P < 0.01); however, counts of total lymphocytes, CD3+, CD3+CD4+, CD3+CD8+, B (CD19+), and natural killer (NK) cells (CD16+CD56+) were significantly reduced (all P < 0.001). The NK cell count was negatively correlated with initial plasma 2,4-DNP concentration (r = -0.750, P = 0.026). Thus, acute occupational 2,4-DNP poisoning was accompanied by immediate complex immune cell reactions, especially NK cells might play important role in severe 2,4-DNP poisoning.

An Epistaxis Emergency Associated with Multiple Pollutants in Elementary Students.

Emergencies of epistaxis in students caused by environmental pollution have rarely been reported to date. This study aimed to explore the cause of an emergency of epistaxis in elementary students by using a field epidemiological investigation. Twenty-two epistaxis cases from a single school with differences in gender, age, and classroom, were diagnosed within a period of 7 days. The air concentration of chromic acid mist (Cr6+) in the electroplating factory area, new campus, and residential area exceeded the limit of uncontrolled emissions. The emission of HCL and H2SO4 was also observed. Formaldehyde levels in the classrooms exceeded the limits of indoor air quality. Abnormal nasal mucosa was significantly more frequent in the case group (93.3%) and control group 1 (of the same school) (66.7%) than in control group 2 (from a mountainous area with no industrial zone) (34.8%; P < 0.05 and P < 0.01, respectively). On the basis of the pre-existing local nasal mucosal lesions, excessive chromic acid mist in the school's surrounding areas and formaldehyde in the classrooms were considered to have acutely irritated the nasal mucosa, causing epistaxis. Several lessons regarding factory site selection, eradication of chemical emissions, and indoor air quality in newly decorated classrooms, should be learned from this emergency.

Machine learning models for early prediction of potassium lowering effectiveness and adverse events in patients with hyperkalemia.

The aim of this study was to develop a model for early prediction of adverse events and treatment effectiveness in patients with hyperkalemia. We collected clinical data from patients with hyperkalemia in the First Hospital of Zhejiang University School of Medicine between 2015 and 2021. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to analyze the predictors on the full dataset. We randomly divided the data into a training group and a validation group, and used LASSO to filter variables in the training set. Six machine learning methods were used to develop the models. The best model was selected based on the area under the curve (AUC). Shapley additive exPlanations (SHAP) values were used to explain the best model. A total of 1074 patients with hyperkalemia were finally enrolled. Diastolic blood pressure (DBP), breathing, oxygen saturation (SPO2), Glasgow coma score (GCS), liver disease, oliguria, blood sodium, international standardized ratio (ISR), and initial blood potassium were the predictors of the occurrence of adverse events; peripheral edema, estimated glomerular filtration rate (eGFR), blood sodium, actual base residual, and initial blood potassium were the predictors of therapeutic effect. Extreme gradient boosting (XGBoost) model achieved the best performance (adverse events: AUC = 0.87; therapeutic effect: AUC = 0.75). A model based on clinical characteristics was developed and validated with good performance.

Effect of hypertonic versus isotonic saline resuscitation on heme oxygenase-1 expression in visceral organs following hemorrhagic shock in rats.

To compare the early effects of hypertonic and isotonic saline resuscitation on heme oxygenase-1 (HO-1) expression in organs of rats with hemorrhagic shock. Rats were randomly divided into hypertonic saline resuscitation (HTS), normal saline resuscitation (NS) and sham groups. HO-1 mRNA, protein expression and apoptosis were evaluated in organs. In the HTS group, significant difference was noted in HO-1 protein in small intestinal mucosa and liver compared with the NS and sham groups, and in HO-1 mRNA in liver and kidney compared with the sham group. The apoptosis of small intestinal mucosa, liver, heart, and lung was significantly lower in the HTS group than that in the NS group. In this study, small volume resuscitation with HTS can efficiently up-regulate the expression level of HO-1 in small intestinal mucosa and liver, which may be one of the mechanisms alleviating organ damage.

[Effects of hemoperfusion on the patients with acute toxication of 2, 4-dinitrophenol].

OBJECTIVE: To explore the management strategies of acute toxication of 2, 4-dinitrophenol by hemoperfusion. METHODS: A total of 14 patients with acute toxication of 2, 4-dinitrophenol were admitted on September 14, 2009. And they were divided into severe and mild groups according to the severity of clinical manifestation. All patients in both groups received 2-hour blood perfusion within 2 hour post-admission. Their clinical manifestations, laboratory parameters and 2, 4-dinitrophenol levels were carefully observed before and after each perfusion. And oxygenation, intravenous use of furosemide, corticosteroids and symptomatic therapies were simultaneously given to improve general conditions. RESULTS: In serious group, the levels of before and after the first perfusion were 28.21(15.56-45.23) and 16.11(10.10-27.52) mg/L (P < 0.05), respectively. In both groups, all levels of 2, 4-dinitrophenol were significantly reduced before and after each perfusion (all P < 0.05). The patients in severe group would get relieved after 3 vs 2 perfusions in mild group. In severe group, there was a remarked decrease in neutrophil and platelet count after perfusion than those in mild group. The liver enzymes and blood lipids in both groups after therapy significantly elevated than those before therapy (all P < 0.05). CONCLUSION: Crucial for managing acute toxication of 2, 4-dinitrophenol, early hemoperfusion reduces mortality.

Serum creatinine in predicting mortality after paraquat poisoning: A systematic review and meta-analysis.

Although the prognostic value of blood creatinine levels in patients with paraquat (PQ) poisoning has been studied for a long time, the results are still controversial. Therefore, we performed the first meta-analysis to comprehensively assess the value of blood creatinine in predicting the prognosis of patients with PQ poisoning. We searched PubMed, EMBase, Web of Science, ScienceDirect, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, and China Online Journals to identify all relevant papers published up to June 2022. Data were extracted for pooled analysis, heterogeneity testing, sensitivity analysis, publication bias analysis, and subgroup analysis. Ultimately, 10 studies involving 862 patients were included. The I2 of diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of this study were all greater than 50%, which showed the existence of heterogeneity in this study, and a random effects model was used for the combination of the above five effect sizes. Pooled analysis showed a high predictive value of blood creatinine for prognosis of PQ poisoning [pooled DOR:22.92, 95% confidence interval (CI):15.62-33.65, P < 0.001]. The combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 86% (95% CI: 0.79-0.91), 78% (95% CI: 0.69-0.86), 4.01 (95% CI: 2.81-5.71), and 0.17 (95% CI: 0.12-0.25), respectively. Deeks publication bias test revealed there was publication bias. Sensitivity analysis showed no significant differences in the estimates of impact. Serum creatinine is an effective predictor of mortality in patients with PQ poisoning.

Development and validation of a predictive model for the assessment of potassium-lowering treatment among hyperkalemia patients.

BACKGROUND: Hyperkalemia is common among patients in emergency department and is associated with mortality. While, there is a lack of good evaluation and prediction methods for the efficacy of potassium-lowering treatment, making the drug dosage adjustment quite difficult. We aimed to develop a predictive model to provide early forecasting of treating effects for hyperkalemia patients. METHODS: Around 80% of hyperkalemia patients (n=818) were randomly selected as the training dataset and the remaining 20% (n=196) as the validating dataset. According to the serum potassium (K+) levels after the first round of potassium-lowering treatment, patients were classified into the effective and ineffective groups. Multivariate logistic regression analyses were performed to develop a prediction model. The receiver operating characteristic (ROC) curve and calibration curve analysis were used for model validation. RESULTS: In the training dataset, 429 patients had favorable effects after treatment (effective group), and 389 had poor therapeutic outcomes (ineffective group). Patients in the ineffective group had a higher percentage of renal disease (P=0.007), peripheral edema (P<0.001), oliguria (P=0.001), or higher initial serum K+ level (P<0.001). The percentage of insulin usage was higher in the effective group than in the ineffective group (P=0.005). After multivariate logistic regression analysis, we found age, peripheral edema, oliguria, history of kidney transplantation, end-stage renal disease, insulin, and initial serum K+ were all independently associated with favorable treatment effects. CONCLUSION: The predictive model could provide early forecasting of therapeutic outcomes for hyperkalemia patients after drug treatment, which could help clinicians to identify hyperkalemia patients with high risk and adjust the dosage of medication for potassium-lowering.

Structural basis of λCII-dependent transcription activation.

The CII protein of bacteriophage λ activates transcription from the phage promoters PRE, PI, and PAQ by binding to two direct repeats that straddle the promoter -35 element. Although genetic, biochemical, and structural studies have elucidated many aspects of λCII-mediated transcription activation, no precise structure of the transcription machinery in the process is available. Here, we report a 3.1-Å cryo-electron microscopy (cryo-EM) structure of an intact λCII-dependent transcription activation complex (TAC-λCII), which comprises λCII, E. coli RNAP-σ70 holoenzyme, and the phage promoter PRE. The structure reveals the interactions between λCII and the direct repeats responsible for promoter specificity and the interactions between λCII and RNAP α subunit C-terminal domain responsible for transcription activation. We also determined a 3.4-Å cryo-EM structure of an RNAP-promoter open complex (RPo-PRE) from the same dataset. Structural comparison between TAC-λCII and RPo-PRE provides new insights into λCII-dependent transcription activation.

Assessment of pulmonary fibrosis induced by paraquat using Al18F-NODA-FAPI-04 PET/CT.

The lack of a highly sensitive method to evaluate paraquat (PQ)-induced pulmonary fibrosis and predict disease progression remains an unresolved clinic issue. Fibroblast activation protein (FAP) may play an important role in the pathogenesis of PQ-induced pulmonary fibrosis. We aimed to evaluate the role of FAP in the PQ-induced pulmonary fibrosis and the utility of fibroblast activation protein inhibitor (FAPI) for positron emission tomography (PET) imaging in PQ-induced pulmonary fibrosis. In our study, two cases of PQ poisoning were presented and FAPI PET/CT was performed as a novel imaging technique. The uptake of FAPI increased in both cases of PQ poisoning. Animal experiments were then performed to validate the findings in the patients. Physiological FAPI lung uptake was higher in mice of the PQ group than in the control group. The results of histological analysis and Western blot were consistent with the findings of PET/CT imaging. The pulmonary fibrosis animal model was developed by intragastric gavage of PQ. PET/CT imaging was performed after injection of FAPI. Lung tissues of mice were collected for fibrosis assessment after imaging. Immunohistochemistry for FAP, histology and Western blot for collagen were performed to further validate the imaging findings. In conclusion, FAPI was involved in the pathogenesis of fibrosis induced by PQ, and PET/CT with FAPI could detect lung fibrogenesis, making it a promising tool to assess early disease activity and predict disease progression.

Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells.

Ferroptosis is a form of programmed cell death that was only recognized in 2012. Until recently, numerous researchers have turned their attention to the mechanism and function of ferroptosis. A large number of studies have shown potential links between cell ferroptosis and infection, inflammation, and tumor. At the same time, immune cells are vital players in these above-mentioned processes. To date, there is no comprehensive literature review to summarize the relationship between ferroptosis and immune cells. Therefore, it is of great significance to explore the functional relationship between the two. This review will attempt to explain the link between ferroptosis and various immune cells, as well as determine the role ferroptosis plays in infection, inflammation, and malignancies. From this, we may find the potential therapeutic targets of these diseases.

Serum vitamin D levels and acute kidney injury: a systemic review and meta-analysis.

Numerous researches have evaluated the prevalence and clinical outcome of vitamin D deficiency in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). But the quantitative vitamin D status in acute kidney injury (AKI) patients and its relationship with prognosis remains controversial. We conducted this systemic review and meta-analysis to assess the quantitative difference of vitamin D status, including serum 25(OH) D and 1,25(OH)2D levels, between AKI patients and non-AKI controls, and further explore whether vitamin D status can be clearly correlated with the mortality of AKI. Major databases, including PubMed, Web of Science and EBSCO, were searched until 1st September 2021. All published observational studies related to vitamin D and AKI According to predefined inclusion and exclusion criteria were extracted. Meta-analyses were performed using Review Manager 5.3.5. Four studies including five cohorts were included with a total of 413 patients. The serum 25(OH)D levels showed no statistically significant difference in AKI patients and non-AKI controls. On the other hand, the serum 1,25(OH)2D levels were significant lower in AKI patients than in non-AKI controls (MD = - 17.79, 95% CI = - 32.73 to - 2.85, P = 0.02). As for the relationship between serum vitamin D status and AKI patients' mortality, we were unable to give a consistent conclusion based on current limited and conflict study results. Our meta-analysis suggested that serum 1,25(OH)2D levels, rather than 25(OH)D, is significantly lower in AKI patients. The relationship between vitamin D status and clinical outcome of AKI remains controversial based on current evidence. Future comprehensive studies are required to confirm these relations and to elucidate potential mechanisms.