AIM:To optimize the clinical dosage and administration regimen of a novel long-acting injectable aripiprazole microsphere(LZMT05)using plasma concentration data from two clinical trials.METHODS:Plasma concentrations were collected from 196 schizophrenia patients administered LZMT05,and a population pharmacokinetic(Pop-PK)model was developed.The therapeutic window was defined as the steady-state trough-to-peak concentration range(94.0-534 ng/mL)of oral ar-ipiprazole.Multiple clinical scenarios were simulat-ed to identify the optimal regimen.RESULTS:A one-compartment model with dual first-order ab-sorption and first-order elimination characterized LZMT05 pharmacokinetics.Covariates like sex and CYP2D6 genotype were integrated into the final model.Simulations demonstrated that switching from 10 mg oral aripiprazole to 350 mg LZMT05 ev-ery 4 weeks sustained concentrations within the therapeutic window with minimal peak-to-trough fluctuations.CONCLUSION:The PopPK-guided opti-mized LZMT05 regimen maintained drug exposure within the therapeutic window,suggesting favor-able efficacy and safety.

Objective To investigate the effect and mechanisms of celecoxib on right heart function in mice with acute high-altitude hypoxia exposure.Methods Male C57BL/6J mice(7 weeks old)were housed in a hypobaric chamber simulating an altitude of 5 800 m for 2 d to establish an animal model of acute hypobaric hypoxia.①Eighteen mice were randomly assigned to plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S),and high-altitude hypoxia exposure+celecoxib(H+Cel).Body weight and routine blood indicators were measured,and cardiac ultrasound examination were performed for heart rate(HR),pulmonary artery acceleration time to ejection time ratio(AT/ET),tricuspid annular plane systolic excursion(TAPSE),tricuspid annular systolic velocity(S'),and left ventricular ejection fraction(LVEF)and fractional shortening(FS).Targeted metabolomic profiling was applied to detect the cardiac arachidonic acid(AA)metabolite levels.The contents of 12,13-dihydroxy-9Z-octadecenoic acid(12,13-diHOME)in the heart,liver,brown adipose tissue,and plasma were quantified by ELISA.② Eighteen mice were randomly assigned into plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S)and high-altitude hypoxia exposure+12,13-diHOME(H+di)groups.Body weight,routine blood tests,and echocardiography were performed as above.③ Thirty-two mice were randomly divided into high-altitude hypoxia exposure+saline(H+S),high-altitude hypoxia exposure+celecoxib(H+Cel),high-altitude hypoxia exposure+soluble epoxide hydrolase inhibitor(sEHI)(H+sEHI),and high-altitude hypoxia exposure+sEHI+celecoxib(H+sEHI+Cel)groups.Body weight,routine blood tests,and echocardiography were performed as above.Cardiac and plasma contents of 12,13-diHOME and epoxyeicosatrienoic acids(EETs)were measured by ELISA.Results ① Compared to the P+S group,the H+S group exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.001),increased counts of white blood cells(WBC)and neutrophils(P<0.01)and decreased TAPSE,S'and AT/ET both at resting state and under stress(P<0.01,P<0.001).Compared to the H+S group,the H+Cel group exhibited significantly increase of cardiac 12,13-diHOME level(P<0.05),reduced WBC and lymphocyte counts(P<0.01,P<0.05)and improved TAPSE and S'levels at resting state and under stress(P<0.01,P<0.001).② Compared to the H+S group,the H+di group demonstrated significantly improvement of TAPSE at basal and under stress(P<0.001)and a trend towards improved TAPSE at resting state(P=0.0532),but no obvious differences was observed in WBC and neutrophil counts between the H+di group and the H+S group.③ Compared to the H+Cel group,both the H+sEHI and H+sEHI+Cel groups exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.01,P<0.05)though no statistical changes in cardiac function indicators.Compared to the H+S group,WBC counts and lymphocyte were decreased,and serum EETs level was incrased in the H+Cel group,H+sEHI group and H+sEHI+Cel group(P<0.01,P<0.001).Conclusion Celecoxib can elevate cardiac level of 12,13-diHOME and improves right heart function in mice after acute high-altitude hypoxia exposure through the CYP450-sEH metabolic pathway.

Objective To explore the impact of Shexiang Baoxin Pill(SXBXP,a traditional Chinese patent medicine,broadly applied for the treatment of cardiovascular diseases)on coronary microvascular disease(CMD)and investigate the role and underlying mechanisms of muscone,a key bioactive component of the pills,in the treatment.Methods A total of 16 ob/ob mice(8 weeks old)were randomly and equally divided into an ob/ob-SXBXP group and a ob/ob-Control group,receiving 10 mg/kg·d SXBXP or PBS via oral gavage,and another 8 wild-type mice with the same genetic background(WT group)were subjected as a negative control group.Cell model of CMD was established based on mouse coronary microvascular endothelial cells(MCMEC)under ischemia and hypoxic(HI)condition,and the cells were further treated with 20 μg/mL SXBXP(HI+SX)and 30 μmol/L muscone(HI+Muscone),respectively.Echocardiography was carried out for coronary flow reserve(CFR)and left ventricular function,and laser speckle imaging was applied to evaluate myocardial blood flow(MBF).Microvascular density in the heart was evaluated with CD31 immunofluorescence staining.The expression levels of vascular endothelial growth factor(VEGF)in cardiac microvascular endothelial cells of both mouse and cell models were detected by immunofluorescence staining and Western blot analysis.The proliferation and angiogenesis of MCMEC were observed by 5-ethynyl-2'-deoxyuridine staining and angiogenesis experiments.Results In the ob/ob-Control group of mice,the levels of CFR,MBF,and cardiac microvascular density were significantly lower than those in the WT group(P<0.05),and these indicators were significantly improved in the ob/ob-SXBXP group when compared with the ob/ob-Control group(P<0.05),which indicates that SXBXP improves the CMD phenotype.The expression level of VEGF in cardiac microvascular endothelial cells was significantly lower in the ob/ob-Control mice than the WT mice(P<0.05),while the level in the ob/ob-SXBXP group was significantly higher than that in the ob/ob-Control group(P<0.05),illustrating that SXBXP may ameliorate CMD through VEGF-mediated microvascular angiogenesis.In vitro experiments further revealed that the VEGF expression level and the proliferation and angiogenesis abilities in MCMEC were significantly lower in the HI group than the cells under the normoxia control condition(P<0.05).Both SXBXP and muscone treatment resulted in enhanced expression of VEGF and improved proliferative and angiogenesis abilities of MCMEC(P<0.05).These results suggest that muscone could improve CMD by VEGF-mediated microvascular angiogenesis.Conclusion SXBXP can improve CMD.Muscone,as a key component of SXBXP,promotes microvascular angiogenesis by inducing the expression of VEGF,then enhances myocardial perfusion,and consequently alleviates CMD.

Under the background of breaking the " five only" evaluation criteria, continuously optimizing the scientific research performance evaluation system of hospitals to mobilize the enthusiasm and creativity of scientific researchers and guide the direction of scientific research development plays an important role in enhancing the overall scientific research capability of hospitals. Through literature analysis and expert consultation, a certain hospital has constructed a personal scientific research performance evaluation index system for medical staff in tertiary public hospitals, oriented towards innovation quality and member contributions, and began to implement it throughout the hospital in 2021. This index system included four categories of scientific research performance: vertical scientific research projects, academic influence, science and technology awards, and transformation of achievements, with a total of 20 indicators. The annual scientific research performance score of an individual would serve as the basis for the distribution of year-end scientific research performance and an important reference for applying for key and major projects within the hospital. After the application of this evaluation index system, the enthusiasm of medical staff for scientific research has been effectively stimulated. The average individual scientific research performance score increased from 0.974 in 2020 to 1.220 in 2023. All scientific research indicators involved in the evaluation system have shown growth, with a significant increase in high-quality results. This evaluation system can provide a reference for the scientific research performance evaluation of public hospitals under the background of breaking the " five only" evaluation criteria.

Aim To explore the predictive value of serum free triiodothyronine(FT3)on the long-term prognosis of patients with coronary heart disease after percutaneous coronary intervention(PCI).Methods All the subjects were from a prospective cohort study(PRACTICE study).In this study,15 250 patients with coronary heart disease after PCI in the First Affiliated Hospital of Xinjiang Medical University were selected,and the clinical data,FT3 and creatinine were collected.All the subjects were followed up regularly,and the primary follow-up endpoints were all-cause mortality and cardiogenic mortality,the secondary endpoints were major adverse cardiovascular events(MACE)and major adverse cardiovascular and cerebrovascular events(MACCE).According to the admission criteria,3 109 patients were finally in-cluded in this study.According to the baseline value of FT3,patients were divided into normal FT3 group(FT3:3.65～6.8 pmol/L,1 446 cases)and low FT3 group(FT3＜3.65 pmol/L,1 663 cases).Kaplan-Meier analysis was used for survival analysis,and Log-rank test was used for survival comparison.Multivariate Cox regression analysis was used to e-valuate the risk factors of the follow-up results of the two groups.Results Compared with the normal FT3 group,all-cause mortality and cardiogenic mortality in the low FT3 group increased significantly(P＜0.05).Kaplan-Meier analysis showed that the cumulative risk of all-cause mortality and cardiogenic mortality increased in the low FT3 group(P＜0.05).Multivariate Cox regression analysis indicated that the risk of all-cause mortality increased by 1.639 folds in the low FT3 group(HR=2.639,95％CI:1.385～5.348,P=0.007),while no statistical difference was found in cardiogenic mortality after adjusting for multiple factors(P=0.125).Conclusion The decrease in serum FT3 levels has important predictive value for all-cause mortality after PCI in patients with coronary heart disease.

Aim To investigate the role and mechanism of KLHL21 gene in myocardial infarction(MI)of mice.Methods KLHL21 gene knockout(KO)mice were generated using CRISPR/Cas9 technology,and C57BL/6 wild-type mice were used as controls.Sixty KLHL21 KO mice and 60 wild-type mice were randomly divided into four groups:WT+Sham group(n=30),WT+MI group(n=30),KO+Sham group(n=30)and KO+MI group(n=30).Postoperative is-chemic and infarct areas were assessed using TTC and Evans Blue staining,myocardial injury markers were measured by ELISA,cardiac function was evaluated by ultrasound,and histological changes were examined using HE and Masson stai-ning.Western blot was used to detect proteins related to the nuclear factor-κB(NF-κB)signaling pathway.Results KLHL21 protein expression in the myocardial tissue of KO mice was significantly lower than that in WT mice.The infarct area in KO+MI mice was significantly larger than that in WT+MI group.KO+MI mice showed reduced cardiac function compared with WT+MI mice.HE staining revealed myocardial cell loss,liquefactive necrosis,nuclear fragmentation,and significant neutrophil infiltration,while Masson staining showed aggravated fibrosis in KO+MI group.Serum tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),creatine kinase-MB(CK-MB),and cardiac troponin Ⅰ(cTnⅠ)lev-els were significantly increased in KO+MI mice compared with WT+MI mice.Western blot analysis showed increased lev-els of phosphorylated inhibitor of nuclear factor-κB alpha(p-IKBα),P65,and P50,and decreased nuclear factor-κB al-pha(IKBα)in KO+MI mice.Conclusion KLHL21 gene plays a preventive role in myocardial infarction in mice,possibly through inhibition of NF-κB signaling pathway activation.

Objective:To explore the effect, postoperative mucosal pathological changes and molecular biological changes of reboot operation for type 2 inflammation chronic rhinosinusitis with nasal polyps（CRSwNP） patients, and to provide theoretical basis for the clinical application of this kind of operation. Methods:We collected 29 patients who were diagnosed with CRSwNP with type 2 inflammatino response and underwent Reboot surgery from June 2022 to August 2023, and 27 patients who were diagnosed with deviated septum and underwent simple submucosal resection of the septum as the control group. We conducted nasal symptom scoring, endoscopic sinusitis scoring, and CT scanning of the sinuses before and after surgery, as well as HE staining, immunohistochemical staining, and detection of inflammatory factors using Elisa kits at the time of surgery, 1, 3, and 6 months postoperatively. We also observed the ultrastructural changes using transmission electron microscopy and scanning electron microscopy, and performed proteomic analysis of the mucosa in the ethmoid sinus area of the sinusitis patients at the time of surgery and 6 months postoperatively. Results:After 6 months of postoperative follow-up, CT scores of the nasal cavity and sinuses had gradually decreased compared with the preoperative period. The VAS score of main symptoms, SNOT-22 score and Lund-Kennedy endoscopic score were decreased after 12 months follow-up. The histological morphology of the mucosa in the area of the screen was significantly improved compared with the preoperative period, with a reduction in the number of eosinophils. The levels of inflammatory factors such as IL-4 and IL-5 et al. in the mucosa of the area of the screen were gradually reduced compared with the preoperative period. The histological morphology, ultrastructure, and cilia structure of the mucosa in the area of the screen were gradually improved compared with the preoperative period, though not recovered completely. The number of CD4⁺T and CD8⁺T cells not changed significantly before and after the surgery yet. By conducting proteomic analysis of the ethmoidal sinus mucosa before and after surgery, differential proteins were selected, and bioinformatics analysis was conducted on the differentially expressed proteins. By using cytoHubba to identify hub genes and intersecting them with the genes related to chronic sinusitis, we found that MMP9 expression increased in non-type 2 CRS and type 2 CRS in sequence, while ACTC1 expression decreased in non-tpye 2 CRS and type 2 CRS in sequence. Conclusion:Reboot surgery can improve the postoperative symptoms and signs of patients, improve the pathological morphology of the mucosa, and influence the expression of protein after surgery. However, the surgery may not have a significant impact on the distribution of T cell subpopulations and inflammation signal pathway in the nasal mucosa.
Humans ; Sinusitis/metabolism* ; Nasal Polyps/metabolism* ; Nasal Mucosa/ultrastructure* ; Chronic Disease ; Rhinitis/complications* ; Inflammation ; Male ; Female ; Postoperative Period ; Adult ; Interleukin-5/metabolism* ; Interleukin-4/metabolism* ; Middle Aged ; Proteomics ; Rhinosinusitis

Lacking therapeutic targets highlights the crucial roles of chemotherapy and radiotherapy in the clinical management of triple-negative breast cancer (TNBC). To relieve the side effects of the chemoradiotherapy combination regimen, we design and develop a self-assembled micelle nanosystem consisting of perfluorocarbon chain-modified cisplatin prodrug. By incorporating perfluorodecalin, this nanosystem can effectively carry ozone and promote irradiation-derived reactive oxygen species (ROS) production. By leveraging the perfluorocarbon sidechain, the nanosystem exhibits efficient internalization by TNBC cells and effectively escapes from lysosomal entrapment. Under X-ray irradiation, ozone-generated ROS disrupts the intracellular redox balance, thereby facilitating the release of cisplatin in a reduction-responsive manner mediated by reduced glutathione. Moreover, oxygen derived from ozone decomposition enhances the efficacy of radiotherapy by alleviating tumor hypoxia. Notably, the combination of irradiation with ozone-loaded cisplatin prodrug nano system synergistically prompts antitumor efficacy and reduces cellular/systemic toxicity in vitro and in vivo. Furthermore, the combo regimen remodels the tumor microenvironment into an immune-favored state by triggering immunogenic cell death and relieving hypoxia, which provides a promising foundation for a combination regimen of immunotherapy. In conclusion, our nanosystem presents a novel strategy for integrating chemotherapy and radiotherapy to optimize the efficacy and safety of TNBC clinical treatment.

OBJECTIVE: To observe the effects of Xingnao Kaiqiao acupuncture technique (for regaining consciousness and opening orifice) on methylation of N6-methyladenosine (m6A), and key methyltransferases and demethylases, so as to clarify the mechanism of acupuncture on cerebral ischemia-reperfusion injury (CIRI). METHODS: Of 68 male Sprague-Dawley rats of SPF grade, 15 rats were randomly selected as a sham-operation group, and the remaining rats were subjected to the model of middle cerebral artery occlusion using the suture ligation. CIRI was induced by ischemia for 2 h followed by reperfusion. Rats that failed to modeling or died were excluded. The rest 45 rats were randomly divided into three groups, i.e. model group, acupuncture group, and non-point acupuncture group, with 15 rats in each group. The rats in the acupuncture group were treated with acupuncture at bilateral "Neiguan" (PC6) and "Shuigou" (GV26). In the non-point acupuncture group, acupuncture was delivered at three non-points, located 3 mm below the bilateral midaxillary line and 3 mm lateral to the tip of the coccyx. One intervention was operated in these two acupuncture groups and the needles were retained for 30 min. Before modeling start and 2 h after ischemia, a laser speckle flowmeter was used to monitor the cerebral blood perfusion. In 2 h of ischemia and 24 h of reperfusion, the neurological behavioral score was evaluated. The volume of rat cerebral infarction was determined by triphenyltetrazolium chloride (TTC) staining, and the level of m6A methylation in ischemic cortical area was detected by Dot blot, and the protein and mRNA expression of the demethylase i.e. fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and key methyltransferases, i.e. methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), and Wilms' tumor 1-associated protein (WTAP) in ischemic cortical area were detected by Western blot and real-time PCR. RESULTS: Cerebral blood perfusion decreased by>70% after 2 h ischemia. Compared with the sham-operation group, the neurobehavioral score and the percentage of cerebral infarction volume increased in the model group (P<0.01); the level of m6A methylation in the ischemic cortical area increased (P<0.01), the protein and mRNA expression of FTO decreased (P<0.01), and that of ALKBH5, METTL3, and METTL14 increased (P<0.01, P<0.05) in the model group. When compared with the model group and the non-point acupuncture group, the acupuncture group showed a decrease in the neurobehavioral score and the percentage of cerebral infarction volume (P<0.01), the level of m6A methylation in the ischemic cortical area was reduced (P<0.01, P<0.05), and the protein and mRNA expression of FTO was elevated (P<0.01). CONCLUSION Xingnao Kaiqiao acupuncture technique presents its protective effect on the brain in the rats with CIRI, which is related to up-regulating the expression of FTO and modulating m6A methylation.
Animals ; Rats, Sprague-Dawley ; Male ; Acupuncture Therapy ; Reperfusion Injury/genetics* ; Rats ; Brain Ischemia/genetics* ; Humans ; Adenosine/metabolism* ; Methylation ; Acupuncture Points ; Cerebral Cortex/metabolism*

Congenital lower urinary tract obstruction (CLUTO) is a spectrum of fetal malformations caused by anatomical abnormalities of the urethra, characterized by high rates of perinatal complications and mortality. The 2024 joint guideline from the European Association of Urology (EAU) and the European Society for Paediatric Urology (ESPU) introduced systematic revisions to the comprehensive management of CLUTO. Key updates encompass advancements in prenatal and postnatal screening and precise diagnosis, refined fetal prognosis assessment, clearer indications and modality selection for prenatal intervention, optimization of postnatal treatment strategies, and the establishment of a lifelong follow-up framework within an integrated care pathway. This article elucidates these key updates by comparing the 2024 EAU/ESPU guideline with the 2022 European Rare Kidney Disease Reference Network (ERKNet) consensus. It also discusses ongoing controversies and future research directions. The aim is to provide clinicians with the latest evidence-based insights to inform practice, ultimately improving outcomes and quality of life for children with CLUTO.
Humans ; Urology ; Female ; Urethral Obstruction/therapy* ; Pregnancy ; Child ; Europe ; Prenatal Diagnosis ; Infant, Newborn ; Urethra/abnormalities*