OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

Objective:To investigate the related risk factors of surgical appendectomy after endoscopic retrograde appendicitis therapy (ERAT) in children.Methods:From September 2019 to November 2023 at the Children's Hospital Affiliated to Shandong University,the data from all related children with appendectomy after ERAT were analyzed. The general situation and main clinical manifestations of the children were collected. According to the effect of ERAT,the patients were divided into transfer to surgical group and appendicitis recurrence group by the reasons and time of transfer to surgical treatment. The indexes such as ERAT and reoperation process and pathological types of appendix after operation were collected,and the clinical experience was summarized.Results:Among the 242 children who underwent ERAT,32 cases underwent appendectomy again,including 19 males and 13 females,with an average age of（9.16±2.77）years,and the reoperation rate was 13.2%. The clinical manifestation was abdominal pain (32 cases,100.0%),mainly right lower abdominal pain (28 cases,87.5%),and the main duration was less than 3 months (30 cases,93.8%). Abdominal ultrasound or CT before ERAT mainly indicated appendicitis (11 cases,34.4%) and appendicitis complicated with appendiceal calculus (11 cases,34.4%). There were 9 children in transferred to surgical group,of which 5 cases were transferred to surgery because of ERAT intubation failure,and 4 cases were transferred to surgery because of appendix perforation or abscess. Postoperative pathology showed acute suppurative appendicitis in 5 cases and acute gangrenous appendicitis in 4 cases. There were 23 children in appendicitis recurrence group,whose abdominal pain was relieved after ERAT,but their symptoms were repeated after discharge. After clinical evaluation,they were diagnosed as recurrent appendicitis and underwent surgical appendectomy. Most of them were reoperated within 6 months after ERAT (21 cases,91.3%).Postoperative pathology was mainly chronic appendicitis (10 cases,43.5%).Conclusion:Acute suppurative appendicitis and acute gangrenous appendicitis are prone to catheterization or endoscopic failure during ERAT,and there is a high risk of surgical transfer. ERAT may relieve the symptoms of chronic appendicitis in children. If the symptoms are repeated,surgery is still needed to remove the appendix.

Objective To compare screw versus Kirschner wire fixation in the treatment of lateral humeral condyle frac-tures in children.Methods A systematic search was conducted in PubMed,Embase,the Cochrane library,Web of Science,China National Knowledge Internet(CNKI),Wanfang Datebase from in ception to February 2022.Studies comparing screws and Kirschner wire fixation in the treatment of lateral humeral condyle fractures in children were included.Outcome measures included and excluded by a set of inclusion and exclusion criteria and evaluated for their quality,their excellent and good rate of fracture healing,malunion,delayed union or nonunion,infection,limitation of elbow flexion or extension(＞10°)were ex-tracted and analyzed using software Rev Man 5.3.Results A total of 9 retrospective studies involving 647 patients were includ-ed,with 255 patients in the screw fixation group(including screw combined with Kirschner wire)and 392 patients in the Kirschner wire fixation group.Meta analysis showed the following:infection rate in the screw group was significantly lower than that in the Kirschner wire group[OR=0.22,95％CI(0.09,0.56),P=0.001].There were no significant differences between the 2 groups in excellent and good rate of fracture healing,malunion rate(P＞0.05).Subgroup analysis showed that infection rate in the screw-only group was significantly lower than that in the Kirschner wire group[OR=0.18,95％CI(0.05,0.65),P=0.009].Conclusion For lateral humeral condyle fractures,Screw fixation alone had a lower infection rate than kirschner wire fixation and screw combined with Kirschner wire fixation.There were no significant differences in the excellent and good rate of fracture healing,malunion.In terms of postoperative efficacy and safety of internal fixation,orthopaedic surgeons are more like-ly to recommend screws for fixation of lateral humeral condyle fractures in children.

Acute skin failure is a common condition of skin damage in critically ill patients, which seriously affects the prognosis of patients. This article summarizes the evaluation indicators, techniques, and comparison of evaluation indicators and techniques for acute skin failure, in order to provide references for the development of acute skin failure evaluation tools and the formulation of nursing measures.

Field epidemiological investigation and treatment of a human skin anthrax outbreak were performed,including tracing of the infection source,case searching,management of close contacts,sampling and testing,and on-site elimination.Additional training and public outreach,and anthrax prevention and control measures are recommended.This case involved a sporadic outbreak of human skin anthrax,with sick cattle as the source of infection.On July 20,our patient slaughtered a cow at his home without taking any protective measures.Three days earlier,he had been stabbed at the second joint of the middle finger of his right hand,and he became infected with anthrax bacilli through the wound.Fever appeared on the day after expo-sure,and on the fourth day(July 24),a black scab mass of approximately(3X3)cm was visible at the wound site,without rupture or discharge of pus.He was hospitalized with fever at the 164th Regiment Hospital,Tacheng People's Hospital,Tacheng District People's Hospital,and Tacheng Jingcheng Hospital.His stay at the Tacheng District People's Hospital was from the 24th to 25th.He had seven close contacts,none of whom were infected,and no common exposures were identified.On the 27th,the PCR results for smear samples around the black scab were positive,the serum antibody results were positive,and the fecal samples were negative.The PCR test results for five environmental specimens were negative,and the isolation and culture results for bone surface specimens from dead cattle were positive.Strengthened efforts are necessary in training and public education regarding zoonotic disease prevention and control;establishment of local corps integration and joint prevention and control;and detection and mitigation of epi-demics in early stages.

Objective:To evaluate the diagnostic efficacy of the multiparametric MRI (mpMRI) deep learning artificial intelligence (AI) analysis system combined with 68Ga-prostate specific membrane antigen (PSMA) PET for prostate cancer. Methods:Data of 103 patients (age: 45-85 years) who underwent 68Ga-PSMA PET/MR at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from May 2018 to October 2023 for suspected or confirmed prostate cancer were retrospectively collected. ROI was delineated to measure SUV max of primary tumor or prostate, and a deep learning AI system was applied to analyze MR images of the prostate. The diagnostic efficacies of T 2 weighted imaging (WI), diffusion WI (DWI), mpMRI, PET SUV max, and PET/MR for prostate cancer were assessed, with using the pathological results as the gold standard. Results:Among 103 patients, 82 cases (79.61%) were with prostate cancer. PET unimodality demonstrated the best specificity (100%, 21/21), positive predictive value (100%, 58/58), and AUC (0.860, 95% CI: 0.777-0.920). The mpMRI AI analysis provided rapid diagnostic results and the sensitivity and accuracy were improved by combining with PET (sensitivities of PET, mpMRI and the combination of the two were 70.73%(58/82), 86.59%(71/82), and 92.68%(76/82), respectively; the accuracies were 76.70%(79/103), 81.55%(84/103) and 86.41%(89/103), respectively). Among 44 patients with negative PET, 30 patients received an accurate diagnosis when the results of mpMRI AI analysis were added. Conclusions:68Ga-PSMA PET demonstrates good specificity for prostate cancer and mpMRI AI analysis is time-saving. The combined application improves the diagnostic sensitivity and accuracy, which provides a valuable tool for 68Ga-PSMA PET/MR image analysis.

OBJECTIVE: To evaluate and summarize the relevant evidence of anticoagulation and bleeding risk management in patients with extracorporeal membrane oxygenation (ECMO), and provide the evidence-based basis for the management of anticoagulation and bleeding during ECMO treatment. METHODS: According to the evidence "6S" pyramid model, all evidence on ECMO anticoagulation management and bleeding risk was searched in relevant databases, organizations and guideline websites at home and abroad. Evidence types included guidelines, expert consensus, systematic evaluation, Meta-analysis and original study. The search time limit was from May 31, 2012 to May 31, 2022. Two researchers with evidence-based research background conducted independent literature quality evaluation of the retrieved evidence, and the evidence that met the quality standards was extracted and summarized based on the opinions of industry experts. RESULTS: A total of 315 articles were retrieved, and 13 articles were included, including 3 guidelines, 6 expert consensus, and 4 Meta-analysis. A total of 27 best evidences were summarized from 7 aspects, including the selection of ECMO anticoagulation, anticoagulation in priming, anticoagulation in operation, anticoagulation monitoring, bleeding and treatment, thrombosis and treatment, and prevention and management of terminal limb ischemia. CONCLUSIONS This study provides evidence-based basis for bleeding prevention and anticoagulant management in ECMO patients. It is recommended to selectively apply the best evidence after evaluating the clinical environmental conditions of medical institutions, so as to improve the prognosis of ECMO patients.
Humans ; Extracorporeal Membrane Oxygenation/adverse effects* ; Blood Coagulation ; Hemorrhage/etiology* ; Anticoagulants/adverse effects* ; Thrombosis/prevention & control* ; Retrospective Studies

[Abstract] Objective To explore the effect of serine protease inhibitor Kazal-type 1(SPINK1) on the proliferation of hepatocellular carcinoma cells RH-35 and its underling molecular mechanism. Methods Spink1 gene expression in liver cancer and rat liver cancer models were analyzed by Gene Expression Omnibus (GEO) data, RH-35 cells were treated with rrSPINK1 protein, the effect of rrSPINK1 on the proliferation and apoptosis of RH-35 cells was explored by MTT, 2’-deoxy-5-ethynyluridine(EdU) and flow cytometry, the molecular mechanism of SPINK1 regulating liver cancer were detected by Real-time PCR and Western blotting. Results The results showed that Spink1 gene was over-expressed significantly in liver cancer and rat liver cancer models, rrSPINK1-treated RH-35 cells showed increased viability, EdUpositive cell rate, and the proportion of cells in S phase and G

Objective : To analyze the expression and clinical significance of circ⁃RACGAP1 in bladder cancer tissues , and to explore the influence and mechanism of circ⁃RACGAP1 on the malignant biological behavior of bladder cancer cells. Methods : The expression of circ⁃RACGAP1 in bladder cancer tissues was explored through the TCGA database , and the relationship between the expression of circ⁃RACGAP1 and the clinicopathological features of bladder cancer patients was analyzed. The expression of circ⁃RACGAP1 in cell lines 5637 , T24 , J82 , RT⁃4 and UM⁃UC⁃3 was analyzed by quantitative real⁃time PCR (qPCR) . The circ⁃RACGAP1 knockdown plasmid was transfected into T24 cells by lipofection technology. Colony formation assay , scratch assay and Transwell assay were used to analyze the effects of knocking down circ⁃RACGAP1 on the proliferation , migration and invasion of T24 cells , respectively. The targeted binding between circ⁃RACGAP1 and miR⁃4324 was verified using deepBase , Circbank , CircInteractome , circRNABase databases and a fluorescent reporter system. The effect of knocking down circ⁃RACGAP1 on the expression of miR⁃4324 in T24 cells was detected by qPCR. Western blot was used to detect the effect of knocking down circ⁃RACGAP1 on the expression of recombinant rac⁃GTPase activating protein 1 (RACGAP1) protein and phosphatidylinositol⁃3 ⁃kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in T24 cells. Results circ⁃RACGAP1 was highly expressed in bladder cancer tissues (P < 0. 01) , and its expression increased with the clinical stage of the patients ( P < 0. 01) . The expression of circ⁃RACGAP1 in bladder cancer cell lines was significantly higher than that in normal human bladder epithelial cells ( all P < 0. 01) . Compared with the control group , the proliferation , migration and invasion abilities of T24 cells in the sh⁃circ⁃RAC⁃GAP1 group significantly decreased (all P < 0. 01) . circ⁃RACGAP1 could target and inhibit the expression of miR⁃4324 (P < 0. 01) . Compared with the control group , the expression level of RACGAP1 protein in T24 cells in the sh⁃circ⁃RACGAP1 group decreased (P < 0. 01) , and the expression levels of PI3K/AKT signaling pathway proteins phosphatidylinositol⁃3 ⁃kinase (p⁃PI3K) , phosphorylated protein kinase B (p⁃AKT) , nuclear factor kappa B (NF-κB) decreased (all P < 0. 01) . Conclusion circ⁃RACGAP1 is highly expressed in bladder cancer tissues and cell GAP1 plays a role by inhibiting the expression of miR⁃4324 and activating the PI3K/AKT signaling pathway.

A cross-sectional study was conducted to estimate the age-stratified normal levels and age-related changes in the risk predictors of benign prostatic hyperplasia (BPH) progression. A total of 4706 male participants aged 40 years or older in Zhengzhou (China) were enrolled. The values of the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), prostate volume (PV), and postvoid residual urine volume (PVR) significantly increased with age. Nonlinear relationships between age and IPSS scores ≥8 (P for nonlinearity = 0.046), PSA level ≥1.6 ng ml^-1, PV ≥31 ml, or PVR ≥39 ml (all P for nonlinearity <0.001) were observed. After the age of 61 years, the risk indicators related to BPH progression were positively correlated with age (odds ratio [OR] >1), regardless of the predictors of the IPSS score, PSA level, PV, or PVR; and the OR values increased gradually. Therefore, after the age of 61 years, the risk predictors related to BPH progression were positively correlated with age.
Humans ; Male ; Prostatic Hyperplasia/diagnosis* ; Prostate-Specific Antigen ; Cross-Sectional Studies ; East Asian People ; Risk Factors