Objective To explore the effect and potential mechanism of CYP2C19 gene polymorphism on the blood minimum concentration of voriconazole in children with invasive pulmonary fungal infection. Methods The clinical data of 58 children, who used voriconazole for treatment and prevention of invasive fungal infection in the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University from September 2013 to September 2021, were collected and analyzed retrospectively, including demographic information, glutamic-pyruvic transaminase (ALT), C-reactive protein (CRP) and interleukin-6 (IL-6). The CYP2C19 genotype of children was detected by gene chip method, and the blood drug concentration was detected by high performance liquid chromatography. According to the drug concentration, the children were divided into low concentration group and normal concentration group. The difference of blood drug concentration in patients with different genotypes was compared. Binary logistic regression analysis was performed to analyze the factors affecting the blood concentration of voriconazole in children. Results Four of the 58 children refused to make gene test, the rest 54 patients including 35 males and 19 females; Among the six CYP2C19 genotypes, most children were with *1/*1 (636 GG, 681 GG) genotype (30 cases); The others were *1/*2 (636 GG, 681 GA) genotype (20 cases), *1/*3 (636 GA, 681 GG) genotype (2 cases), and *2/*3 (636 GA, 681 GA) genotype (2 cases), children without *2/*2 (636 GG, 681 AA) genotype and *3/*3 (636 AA, 681 GG) genotype. Among the gene phenotypes, extensive metabolizer type was the highest (30 cases), followed by intermediate metabolizer type and poor metabolizer type (22 cases and 2 cases, respectively). The frequency of allele CYP2C19*1 was the highest (82 cases), followed by the allele CYP2C19*2 and CYP2C19*3 (22 cases and 4 cases, respectively). Genotype and allele were significantly correlated with voriconazole minimum concentration. Compared with intermediate metabolizer and poor metabolizer, extensive metabolizer significantly reduced voriconazole minimum concentration. Compared with CYP2C19*2 and CYP2C19*3 alleles, CYP2C19*1 allele significantly reduced the concentration of voriconazole. Binary logistic regression analysis demonstrated that BMI, CRP, IL-6 and genotype can significantly affect the blood minimum concentration of voriconazole. Conclusions The genotype of CYP2C19 is mainly *1/*1 (636 GG, 681 GG), the extensive metabolizer genotype is the most, and the allele of CYP2C19*1 is the most common. Inflammatory factors, BMI and genotype significantly affected voriconazole metabolism.

Objective To investigate the effect and potential mechanism of angiopoietin 1 (Ang1) on choroidal neovascularization (CNV) of rats. Methods A total of 30 Norwegian (BN) rats aged 6-8 weeks were randomized into three groups (n=10/group): normal group, model group, and Ang1 treatment group. The normal group was not processed, but the other two groups used multi-wavelength krypton laser to model the eyes of BN rats. We then performed fundus fluorescein angiography 14 days post-surgery. After confirming the success of the surgery, on the next day, the Ang1 treatment group received 200 μg/L Ang1 20 μl through vitreous cavity injection, while the other two groups received an equal volume of saline. After another 10-day, we performed Fundus fluorescein angiography examination, measured the CNV area through choroidal patching using FITC-labeled dextran (FITC-dextran) cardiac perfusion, and observed the retinal-choroidal structure changes of rats by Hematoxylin-eosin staining (HE) staining. We also detected the expression of Ang1, Rap1, GAPRap1, and vascular endothelial-cadherin (VE-cadherin) in the retinal-choroidal-sclera complex by Western blotting. Next, we cultured the rat choroidal vascular endothelial cells (RCVECs). When the cells were in the logarithmic growth phase, we stimulated these cells with vascular endothelial growth factor (VEGF) and cultured them for 24 hours, and divided into negative control group (siRNA-NC group), GAPRap1-siRNA group and GAPRap1-siRNA+Ang1 group. We further transfected cells with siRNA-NC (siRNA-NC group) or GAPRap1 small interfering RNA (GAPRap1-siRNA group and GAPRap1-siRNA+Ang1 group). In the GAPGAPRap1 small interfering RNA transfected cells, 6 hours after transfection, we set aside some cells coculture with 200 μg/L Ang1 (GAPRap1-siRNA+Ang1 group). After another 24 hours, we extracted and quantified the expression levels of GAPRap1, Rap1, and VE-cadherin by Western blotting. We detected the expression of VE-cadherin using immunofluorescence. Results Compared with normal group, in model group, the neovascular leakage area and choroidal damage degree significantly increased (P<0.01), the expression of GAPRap1 and VE-cadherin proteins significantly reduced (P<0.05), and the expression of Rap1 had no significant change (P>0.05). Compared with model group, in the Ang1 treatment group the neovascular leakage area and choroidal damage degree were significantly reduced (P<0.01), the expression of GAPRap1 and VE-cadherin proteins in the choroid and cells significantly increased (P<0.01), the expression of Rap1 had no statistical change (P>0.05). In choroidal tissue, the expression of Ang1 protein in Ang1 treatment group was significantly higher than that in the other two groups (P<0.01). In the cell experiment, the expressions of GAPRap1 and VE-cadherin in GAPRap1-siRNA group were significantly lower than those in the GAPRap1-siRNA+Ang1 group and the siRNA-NC group (P<0.01), while the expression of Rap1 had no significant change (P>0.05). The immunofluorescence results showed that the fluorescence of VE-cadherin in the GAPRap1-siRNA group was significantly lower than that in the GAPRap1-siRNA+Ang1 group and siRNA-NC group (P<0.001). Conclusion Ang1 can reduce the leakage of choroidal neovascularization in rats, which has an inhibitory effect on CNV growth, and its mechanism may be related to the enhancement of cell adhesion through the GAPRap1-VE-cadherin pathway.

Objective To investigate the predictive value of serum C-reactive protein/albumin ratio (CAR) with other inflammatory parameters for in-hospital adverse events in patients with acute ST segment elevation myocardial infarction (STEMI) undergoing emergency percutaneous coronary intervention (PCI). Methods A total of 340 patients with STEMI who underwent emergency PCI in 904 Hospital of PLA Joint Logistics Support Force from January 2016 to December 2020 were consecutively included in this retrospective analysis. Patients with STEMI were divided into two groups according to the presence or absence of adverse cardiovascular events during their hospital stay after emergent PCI: patients with major adverse cardiovascular events (MACEs, n=92) and non-MACEs (n=248). Serum C-reactive protein (CRP), white blood cells, neutrophils, lymphocytes, and other indicators were measured in both groups, and inflammatory parameters such as CAR, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) were calculated. Univariate and multivariate logistic regression analyses were used to screen the independent risk factors correlated with the occurrence of MACEs during the hospitalization after PCI in STEMI patients. Correlations between each inflammatory parameter and MACEs were analyzed by Spearman correlation analysis. Receiver operating characteristic (ROC) curve to evaluate the efficacy size of each inflammatory parameter in predicting the occurrence of MACEs during PCI hospitalization in patients with STEMI. Results Comparison of general data between the two groups revealed that patients in MACEs group had a higher frequency of age, history of diabetes mellitus, polydactyly, and serum composite inflammatory parameters (CAR, NLR, PLR, MLR, and SII) than those in non-MACEs group, the univariate and multivariate results showed that CAR was a risk factor for the occurrence of MACEs during the hospitalization after PCI in patients with STEMI. Spearman correlation analysis showed that CAR was significantly correlated with the occurrence of MACEs during hospitalization, such as cardiogenic shock (r=0.134, P<0.05), heart failure (r=0.436, P<0.05), and all-cause death (r=0.185, P<0.05). The results of ROC curves showed that CAR (AUC=0.751, 95%CI 0.691-0.811, P<0.001) had better predictive value for the occurrence of MACEs after PCI than NLR (AUC=0.643, 95%CI 0.576-0.711, P<0.001), PLR (AUC=0.598, 95%CI 0.530-0.665, P=0.006) and other inflammatory parameters. Conclusion Compared with traditional inflammatory parameters, CAR has better predictive efficacy for the occurrence of MACEs during hospitalization in STEMI patients undergoing emergency PCI, and can better guide the clinic.

Objective To explore the effect and mechanism of acid-sensitive ion channel 3 (ASIC3) expression on visceral sensitivity in irritable bowel syndrome (IBS) rats and the possible regulatory mechanisms of signalling pathways. Methods From the 2nd day postpartum, 6 neonatal rats and their mother were kept in their original cages as control group; the rest of the neonatal rats were separated from their mother to make IBS models. After the neonatal rats grow into rats, use abdominal withdrawal reflex (AWR) score to screen 16 rats that were successful in IBS modeling, and they were randomly divided into neonatal maternal separation (NMS) group and NMS+APETx2 group, with 8 rats in each group. NMS+APETx2 group was given the ASIC3-specific blocker APETx2 100 μg/kg intraperitoneally for 1 week while NMS group and control group were intraperitoneally injected with same amount of normal saline. Visceral pain response was measured by abdominal withdraw reflex (AWR) score, the intestinal transmission rate was measured by ink staining, the 5-hydroxytrgptamine (5-HT) level in colonic tissue was measured by enzyme-linked immunosorbent assay (ELISA), and the expression levels of 5-HT4 receptor and ASIC3 in colonic tissue were measured by immunohistochemistry. Results Compared with control group, rats in NMS group showed significantly increased AWR scores at colorectal pressures of 40, 60, 80 mmHg, decreased intestinal transmission rate, intestinal 5-HT, ASIC3 and 5-HT4 receptor expression increased, all with statistically significant differences (P<0.01). There was no significant difference in AWR score and intestinal propulsion rate in NMS+APETx2 group compared with control group (P>0.05), but the expression levels of 5-HT, ASIC3 and 5-HT4 receptors increased compared with control group with significant difference (P<0.01). Compared with NMS group, the application of ASIC3-specific blocker APETx2 in NMS+APETx2 group resulted in lower AWR scores, enhanced intestinal transmission rate, and the expression levels of 5-HT, ASIC3 and 5-HT4 receptor decreased, and the differences were statistically significant (P<0.05 or P<0.01). Conclusion ASIC3 expression takes part in the generation of high sensitivity in viscera of IBS rat, which may be related to the enhance of 5-HT pathway activation.

Parkinson's disease (PD) is a common neurodegenerative disease, and its incidence increases with age. The incorrect folding and abnormal aggregation of α-synuclein are the key neuropathological markers of PD. Recent studies have shown that exosomes may also promote the pathological α-synuclein spreads in brain through their transport and transfer functions, further promoting the development of PD, thus participating in the pathogenesis of PD. Exosomes are nanoscale extracellular vesicles, the advantage of its smaller diameter is expected to play a significant role in treatment of PD. This article reviews the related research progress on the role of exosome and its potential clinical application in PD.

Objective To investigate the value of nomogram based on lactate-to-albumin ratio (L/A) combined with neutrophil-to-lymphocyte ratio (NLR) for predicting the early prognosis of patients with acute respiratory distress syndrome (ARDS). Methods A total of 115 patients with ARDS admitted in the Department of Critical Care Medicine of the Second Hospital of Lanzhou University from March 2018 to June 2022 were retrospectively analyzed, and divided into survival group (n=62) and death group (n=53) depending on their clinical outcomes at 28 days after treatment. The general clinical data, blood routine, serum albumin, blood gas analysis, sequential organ failure (SOFA) score, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, Murray lung injury (Murray) score, number of organ failure, cause of ARDS, ICU stay, mechanical ventilation time, 28-day mortality were collected within 24 hours of ICU admission. At the same time, the L/A and NLR were calculated. Univariate and multivariate logistic regression analysis were performed to screen the independent risk factors affecting the prognosis of ARDS and to construct a clinical prediction model. The nomogram was drawn to visualize the clinical model. Finally, receiver operating characteristic (ROC) curve and calibration curve were used to verify the accuracy of the nomogram, a decision curve analysis was also performed to evaluate the clinical usefulness of the nomogram. Results The age, APACHE II, SOFA, and Murray scores, number of organ failure, proportion of pulmonary ARDS, neutrophil count (NEU), NLR, L/A, and blood lactate level in death group were significantly higher than those in survival group, the oxygenation index (PaO₂/FiO₂), proportion of extra pulmonary ARDS, lymphocyte count (LYM), and platelet count (PLT) were significantly lower than those in survival group (P<0.05). Univariate analysis and multivariate logistic regression analysis showed that age, SOFA score, the cause of ARDS, NLR and L/A were the independent risk factors for prognosis of ARDS (P<0.05). In addition, ROC curve analysis showed that the area under the ROC curve (AUC) of age, SOFA score, cause of ARDS, NLR and L/A in predicting the 28-day prognosis of ARDS patients were 0.651, 0.777, 0.579, 0.727 and 0.753, respectively. But the AUC of ARDS cause combined with age and SOFA score was 0.830, which was significantly higher than that of age (P=0.000) and ARDS cause (P=0.000), but there was no significant difference in SOFA score (P=0.064). The nomogram based on all these five independent risk factors was constructed, which was defined as Model 1. At the same time, the combined model constructed by age, cause of ARDS and SOFA was defined as Model 2. The ROC comparison between the two showed that Model 1 had a higher ability to predict the prognosis of ARDS (AUC: 0.889 vs. 0.830), and the calibration curve and decision curve analysis showed that Model 1 had better accuracy and potential application value in predicting the prognosis of ARDS patients. Conclusion The nomogram constructed based on L/A combined with NLR can predict the early prognosis of patients with ARDS, and has high predictive efficiency and clinical benefit.

Objective To investigate the central mechanism of glial cells of the dorsal reticular nucleus (DRt) in the modulation of chronic orofacial pain after removal of experimental occlusal interference(EOI) in rats. Methods Twenty-four male SD rats (180-200 g) were randomly divided into three groups (8 in each group): sham group, EOI hyperalgesia maintaining group (occlusal interference appliance removed on day 8 after wearing 0.4 mm thick crowns), EOI hyperalgesia maintaining+DRt damage group (EOI hyperalgesia maintaining rats were injected with ibotenic acid to damage DRt). The non-reflexive behaviors of the three groups were evaluated by using orofacial operant test on 7, 10, 14 d after model establishment. Nine male SD rats were randomly divided into three groups (3 in each group): sham group, EOI hyperalgesia maintaining group (day 8 after wearing 0.4 mm thick crowns, before removal of EOI), EOI hyperalgesia maintaining group 6 d (6 days after EOI removed on day 8). DRt sections were obtained and processed for immunofluorescence staining for glai fibrillary acidic protein (GFAP) and OX-42. The levels of expression were hemi-quantitatively analyzed to evaluate the fluorescence area and fluorescence intensity of astrocytes and microglia. Results EOI hyperalgesia maintaining group and EOI hyperalgesia maintaining+DRt damage group exhibited lower feeding time in orofacial operant test, which implied hyperalgesia (P<0.05). The hyperalgesia in EOI hyperalgesia maintaining group persisted after the removal of EOI, and the difference was statistically significant at 10 d and 14 d compared with sham group (P<0.05), while the hyperalgesia in the EOI hyperalgesia maintaining+DRt damage group showed a rebound trend, and the difference was not statistically significant at 10 d and 14 d compared with sham group (P>0.05). The total feeding time at 14 d significant longer compared with the EOI hyperalgesia maintaining group (P<0.05). Semi-quantitative analysis of immunofluorescence staining showed that the fluorescence area and fluorescence intensity of GFAP and OX-42 in EOI hyperalgesia maintaining group did not show any increase compared with that of sham group (P>0.05), whereas the fluorescence area and fluorescence intensity of GFAP as well as the fluorescence area of OX-42 in EOI hyperalgesia maintaining group 6 d were significantly higher (P<0.05). The fluorescence area and fluorescence intensity of GFAP and OX-42 in EOI hyperalgesia maintaining group did not show any increase compared with that of EOI hyperalgesia maintaining group 6 d (P>0.05). Conclusion DRt was involved in the persistent maintenance of hyperalgesia in the EOI model after removal of occlusal interference, in which astrocyte and microglia activation in DRt were the central mechanisms for the maintenance of hyperalgesia.

Esophagogastric variceal bleeding in cirrhotic patients is associated with high mortality if not adequately managed. Standardized treatment of esophagogastric variceal bleeding includes adequate resuscitation maneuvers, restrictive transfusion policy, antibiotic prophylaxis, pharmacologic therapy, and endoscopic therapy. After this initial treatment, the most appropriate therapy to prevent both early and late rebleeding must be instituted following a risk stratification strategy. Placing a preemptive transjugular intrahepatic portosystemic shunt in high-risk patients, as soon as possible after admission, to achieve early control of bleeding has proved to improve survival. The present review will focus on the initial management of patients with acute esophagogastric variceal bleeding, including general management and assessment, pharmacotherapy, as well as the available endoscopic, interventional and salvage treatments, trying to provide reference for standardizing the treatment process of such patients, in order to improve their survival rate.

Objective To investigate the clinical diagnostic value of peripheral white blood cell count (WBC) and neutrophil-to-lymphocyte ratio (NLR) in obesity with gastroesophageal reflux disease (GERD). Methods The clinical data of 118 patients of obesity admitted to People's Hospital of Xinjiang Uygur Autonomous Region from January 2020 to January 2022 were retrospectively analyzed. Based on the medical history and examination results, the patients were divided into obesity with GERD group (n=57) and obesity without GERD group (n=61). Univariate and multivariate logistic regression were used to analyze the risk factors of obesity combined with GERD. Receiver operating characteristic (ROC) curve was used to evaluate the clinical diagnostic value of peripheral WBC and NLR testing alone vs. combined testing for obesity combined with GERD. Results The obesity with GERD group had a higher proportion of smoking history (31.6% vs. 14.8%, P=0.030), family history of GERD (43.9% vs. 24.6%, P=0.027), and WBC of peripheral blood [(10.25±1.81)×10⁹/L vs. (8.72±2.11)×10⁹/L, P<0.001], NLR (3.55±0.71 vs. 3.00±0.64, P<0.001), and fasting plasma glucose [(6.39±2.21) mmol/L vs. (5.76±0.85) mmol/L, P=0.041] were higher in obesity without GERD group. The results of multivariate logistic regression analysis showed that peripheral WBC and NLR were independent risk factors for the obesity combined with GERD (P<0.05). ROC curve analysis showed that peripheral WBC (AUC=0.707) and NLR (AUC=0.722) had high clinical diagnostic values for obesity combined with GERD (P<0.001), and the combination of them improved the diagnostic efficacy (AUC=0.786). Conclusion Peripheral WBC and NLR are independent risk factors for the obesity combined with GERD, and are of great diagnostic value for obesity combined with GERD, and the combination of the two can improve the diagnostic efficacy and have a certain clinical value.

Pyroptosis is a caspase-dependent, gasdermin protein mediated inflammatory programmed cell death mode, which is involved in the occurrence and development of a variety of diseases. Mesenchymal stem cells (MSCs) are adult pluripotent stem cells derived from the mesoderm and widely distributed in various tissues of human body and show strong secretory capacity. Exosomes, microvesicles, cytokines and other substances secreted by MSCs can regulate microglia phenotypic transformation, promote mitochondrial autophagy, protect mitochondrial function, regulate endoplasmic reticulum stress and calcium homeostasis, thereby inhibiting the pyroptosis mediated by inflammasome and improving the progression and prognosis of related diseases. In addition, pyroptosis has also been reported in MSCs itself. In present paper, the research progress has been reviewed on the role and mechanism of MSCs in regulating pyroptosis, so as to deepen people's understanding on the relationship between MSCs and cell pyroptosis.