This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Nav1.7,Nay1.8,and Nay1.9 and Kv7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Nav1.7,Nav1.8,and Nav1.9 channels with a particularly low half maximal inhibitory concentration(ICs0)for Nay1.9 by promoting sodium channel inactivation,and also effectively increased Kv7.2/73,Kv7.2,and Kv7.5 channels,excluding Kv7.1 by promoting potassium channel acti-vation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alle-viated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe thera-peutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.

Objective:To investigate the relationship among iron content, volume and drainage venous oxygen saturation (SvO 2) in deep gray matter nuclei of healthy people using quantitative susceptibility mapping (QSM). Methods:The study was a cross-sectional study. A total of 126 healthy volunteers were prospectively enrolled in the community in Tianjin from June 2019 to December 2023, and 57 males and 69 females, aged 48±15 years. All healthy volunteers underwent MRI examinations to get STrategically Acquired Gradient Echo images, then it was post-processed to obtain T 1 weighted enhanced images, QSM maps and the maximum intensity projection images. In QSM maps, caudate nucleus (CN), putamen (PUT), globus pallidus (GP), thalamus (THU), subthalamic nucleus (STN), substantia nigra (SN) and red nucleus (RN) were semi-automatically segmented to calculate the iron content and volume using SPIN software. Four bilateral deep cerebral veins regions of interest, including septum pellucidum veins, thalamostriate veins, internal cerebral veins and basilar veins, were manually delineated on the maximum intensity projection images of QSM to obtain venous magnetic sensitivity. The venous magnetic sensitivity was calculated as SvO 2. To observe the age-related trend of SvO 2, iron content and volume, the partial correlation analysis was conducted. The relationships between iron content, volume and SvO 2 were explored using the partial correlation analysis. To explore the potential effects of SvO 2 between iron content and volume in deep gray matter, the mediation analysis was utilized. Results:The relationships between the SvO 2 of thalamostriate veins ( r=0.23, P=0.018), basilar veins ( r=0.27, P=0.004) and age were positive. The relationships between the SvO 2 of internal cerebral veins and the iron contents of CN ( r=?0.25, P=0.042) and PUT ( r=?0.33, P<0.001) were negative. The relationships between the SvO 2 of basilar veins and the iron contents of STN ( r=?0.25, P=0.042) and SN ( r=?0.24, P=0.045) were negative. The relationships between iron content and volume including CN ( r=0.46, P<0.001), PUT ( r=0.20, P=0.027), GP ( r=0.76, P<0.001), STN ( r=0.87, P<0.001), SN ( r=0.90, P<0.001), RN ( r=0.79, P<0.001) were positive. The mediation analysis showed that the SvO 2 of internal cerebral veins indirectly mediated the relationship between iron content and volume of CN, PUT, GP and THU. Conclusions:The process of iron deposition required the participation of oxygen in deep gray matter nuclei. Volume shows positive correlation with iron content in deep gray matter nuclei, with individual variations. The SvO 2 of internal cerebral veins mediate the relationship between iron content and volume of deep gray matter nuclei.

Objective:To observe the effects of sorafenib on the lesions and vascular growth factors in the mouse model of hepatic alveolar echinococcosis.Methods:One hundred healthy female Kunming mice weighing (20±4) g were used to establish a model of alveolar echinococcosis infection by intraperitoneal injection of alveolar echinococcosis protoscoleces. After 6 weeks of feeding, the rats were divided into 5 groups, 15 rats in each group, which were given warm saline, albendazole (100 mg/kg), and sorafenib at high-dose (100 mg/kg), middle-dose (50 mg/kg) and low-dose (30 mg/kg) by gavage for 6 weeks, respectively. Eyeball blood and hepatic alveolar echinococcosis tissue were collected from the mice after the last administration, and the body weight of the mice and the lesion weight were weighed. The concentrations and expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor-A (VEGF-A) and vascular endothelial growth factor receptor-2 (VEGFR-2) in serum and lesion tissues were detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting.Results:There was no statistically significant difference in the body weight of mice among the saline group, albendazole group and low-dose, medium-dose and high-dose sorafenib groups ( F=0.43, P=0.784). The ratios of lesion weight to body weight in the above groups were (0.057±0.009), (0.031±0.005), (0.033±0.005), (0.031±0.005), and (0.031±0.005), respectively. The saline group had a higher ratio than the other four groups, and the differences were statistically significant (all P<0.05). The relative expression levels of HIF-1α, VEGF-A, VEGFR-2, CD31 and CD34 detected by Western blotting in the saline group were all higher than those in the albendazole group and the high-dose, medium-dose and low-dose sorafenib groups, and the differences were statistically significant (all P<0.05). The relative expression levels of the above proteins in the medium-dose and high-dose sorafenib groups were lower than those in the albendazole group, and the relative expression levels of the above proteins in the high-dose sorafenib group were also lower than those in the medium-dose sorafenib group, and the differences were statistically significant (all P<0.05). The concentration levels of HIF-1α, VEGF-A and VEGFR-2 in serum of mice in each group detected by ELISA were consistent with those detected by Western blotting. Conclusion:Sorafenib inhibits the proliferation of alveolar echinococcosis in mice by suppressing the expression of angiogenic factors in alveolar echinococcosis lesions.

Objective:To explore the role and mechanism of Ras homolog gene family member E (RhoE) gene in myocardial fibrosis in diabetic cardiomyopathy.Methods:Wild-type SD rats were intraperitoneally injected with streptozotocin solution (STZ, 70 mg/kg) and an equal volume of sodium citrate solution to establish the type 1 diabetes mellitus (T1DM) group ( n=15) and the T1DM control group ( n=15), respectively. db/db spontaneous type 2 diabetes mellitus (T2DM) mice and wild-type C57BL/6J mice were conventionally housed for 8 weeks to establish the T2DM group ( n=5) and the T2DM control group ( n=5), respectively. Heterozygote SD rats with systemic knockout of the RhoE gene were intraperitoneally injected with STZ solution (70 mg/kg) and an equal volume of sodium citrate solution to establish the RhoE knockout T1DM group ( n=5) and the RhoE knockout control group ( n=5), respectively. Wild-type SD rats were injected with RhoE-overexpressing adeno-associated virus 9 through tail vein and intraperitoneally injected with STZ solution (70 mg/kg) to establish the RhoE overexpression T1DM group ( n=5), while wild-type SD rats injected with negative control virus through tail vein and intraperitoneally injected with an equal volume of sodium citrate solution served as the RhoE overexpression control group ( n=5). After successful modeling, all animals in each group were conventionally housed for an additional 6 or 8 weeks, which marked the experimental endpoint. At the experimental endpoint, echocardiography was performed to assess cardiac function of animals in each group, and left ventricular ejection fraction (LVEF) and the ratio of early to late diastolic transmitral flow velocity (E/A ratio) were analysed. Masson staining was used to detect collagen fiber deposition in myocardial tissue of animals in each group. Western blot analysis was conducted to detect the expression levels of RhoE gene, type Ⅰ collagen, type Ⅲ collagen, Smad2/3, and phosphorylated Smad2/3 protein in myocardial tissue of rats. Enzyme-linked immunosorbent assay was used to measure the levels of transforming growth factor-β1 (TGF-β1) in serum of rats. Results:Compared with their respective control groups, the expression of RhoE in the heart tissues of mice in the T2DM group and rats in the T1DM group was significantly downregulated, and the deposition of collagen fibers was more significant ( P<0.05), and LVEF and E/A ratio were lower (all P<0.05). Compared with the T1DM group, the phosphorylation level of Smad2/3、the levels of type Ⅰ collagen and type Ⅲ collagen in myocardial tissue and the level of TGF-β1 in serum were higher in the RhoE knockout T1DM group (all P<0.05). Additionally, rats in the RhoE overexpression T1DM group had higher LVEF and E/A ratios (both P<0.05) and less collagen fiber deposition ( P<0.05) compared with the T1DM group. Conclusions:Myocardial fibrosis induced by diabetes mellitus activates TGF-β1/Smads signaling pathway by inhibiting RhoE gene expression. Myocardial targeting overexpression of the RhoE mediated by adeno-associated virus 9 can alleviate myocardial fibrosis and improve cardiac function in rats with diabetic cardiomyopathy.

Objective:To investigate the effects of baicalein on the protein kinase B(AKT)/glycogen synthase kinase 3β(GSK3β)pathway and the expression of tumor necrosis factor-α(TNF-α)and interleukin-1 β(IL-1 β)in lipopolysaccharide(LPS)-activated BV2 microglial cells.Methods:BV2 microglial cells were cultured and divided into control group,LPS-induced group,and LPS+Baicalein group.Molecular docking was conducted to verify the bind-ing affinity of baicalein to AKT.Western blot and immunofluorescence staining were used to assess the expression and phosphorylation levels of AKT,GSK3β,TNF-α,and IL-1β in activated BV2 cells.Results:Baicalein exhibited a strong binding affinity for AKT.Western blot results showed that LPS stimulation led to increased TNF-α and IL-1 βexpression and decreased phosphorylation of AKT and GSK3β in BV2 cells(P＜0.05).After Baicalein treatment,TNF-α and IL-1 β expression significantly decreased,while AKT and GSK3β phosphorylation levels increased compared to the LPS group(P＜0.05).Immunofluorescence staining results were consistent with those of Western blot.Conclusion:Baicalein inhibits the expression of TNF-α and IL-1 β in activated microglia,potentially through activation of the AKT/GSK3β pathway.

Objective To explore the long-term efficacy of percutaneous pulmonary valve implantation(PPVI)and the durability of the domestic self-expanding Venus P valve.Methods A total of 8 patients with post-surgical right ventricular outflow tract(RVOT)dysfunction,who were admitted to hospital from October 2014 to July 2016 and deemed anatomically suitable for PPVI with self-expanding valve,were included prospectively.Clinical,imaging,procedural and follow-up data were analyzed.The survival rates,perioperative and long-term complication rates,long-term efficacy of PPVI,and long-term function of Venus P in 8 patients were evaluated.The immediate procedural results were evaluated by clinical implant success rate,which is defined as successful valve implantation with echocardiography-assessed pulmonary regurgitation＜moderate and peak trans-pulmonary pressure gradient＜40 mmHg.Results A total of 8 patients were included,with 7 females,aged 14 to 36 years.The initial diagnosis included post-surgical Tetralogy of Fallot(5 cases),post-surgical Trilogy of Fallot(1 case),post-surgical Quadricuspid pulmonary valve stenosis(1 case)and post-surgical Double-Outlet Right Ventricle(1 case).The indications of PPVI included RVOT-pulmonary obstruction and regurgitation(1 case)and isolated regurgitation(7 cases).Clinical implant success was achieved in all of the 8 patients with firmly fixed valve,and there were no such complications as valve detachment,displacement or stent fracture.All patients experienced significant symptom relief after the procedure.The right ventricular end-diastolic volume index(RVEDVi)measured by CMR 6 months after PPVI showed a significant decrease compared to preprocedural values[(89.99±13.85)ml/m2 vs.(144.93±11.28)ml/m2,P=0.001].Postoperative pulmonary regurgitation were significantly improved or disappeared in all patients,and there was no statistically significant difference in the average peak pressure gradient measured by echocardiogram between preoperative and the latest follow-up[(23.25±8.39)mmHg vs.(18.75±6.28)mmHg,P=0.210].Over an average follow-up period of(9.25±0.71)years,1 case of infective endocarditis occurred 5 years after PPVI.During the follow-up,no death,deterioration of heart failure,malignant arrhythmia or other serious complications were observed.All patients completed 8-year follow-up,and 3 completed 10-year follow-up.All patients were graded as NYHA functional class one at the latest follow-up.Conclusions PPVI using the domestically produced self-expanding Venus P is safe and feasible for the treatment of patients with post-surgical RVOT dysfunction and suitable anatomy.Our study confirms the long-term efficacy and durability of Venus P from multiple perspectives,and no severe stent fracture occurred without pre-stent implantation in the native RVOT.

Helicobacter pylori(Hp)is a major pathogen that causes peptic ulcer,mucosa-associated tissue lymphoma and gastric cancer.Adhesion colonization is a prerequisite for the pathogenesis of Hp.After infec-tion,Hp first uses urease to neutralize gastric acid,and then it adapts to the environment through motility and chemotactic swimming of flagella.Finally,Hp adheres to gastric epithelial cells through outer membrane pro-teins.Some outer membrane proteins have the biological effect of transporting virulence factors,mediating in-flammation and assisting Hp to produce pathological changes on human body.This paper reviews the mecha-nism of main colonization factors of Hp.

Objective:To investigate clinical efficacy and safety of dupilumab in the treatment of moderate to severe atopic dermatitis (AD) complicated with asthma.Methods:A self-controlled study before and after treatment was conducted to retrospectively analyze 45 patients with moderate to severe atopic dermatitis combined with asthma who received dupilumab in the respiratory allergy clinic of North Theater Command General Hospital from January 2021 to May 2024, which age ≥12 years, including 27 males, 18 females. The treatment period was 4 to 12 months. All patients were treated with dupilumab combined with inhaled glucocorticoids and long-acting beta2-receptor agonists, as well as symptomatic drugs for atopic dermatitis. Analyze the clinical data of the patients before and after treatment, including lung function, asthma and AD-related assessment scales. Generalized estimation equation was used to analyze the simple effect of time on the repeated measurement data following non-normal distribution, and Wilcoxon signed rank test was used to compare the differences of each observation index before and after treatment.Results:Among 45 patients with moderate to severe atopic dermatitis complicated with asthma, after treatment with dupilumab, the FEV 1 increased from 2.39 (1.87, 2.83) L at baseline to 2.50 (1.84, 2.97) L 3 months after treatment ( Z=2.417, P=0.016), 2.60 (1.95, 3.14) L 6 months after treatment ( Z=2.896, P=0.004); the FEV 1pred% increased from 74.10% (67.70%, 78.75%) at baseline to 77.09% (68.40%, 80.24%) at 3 months after treatment ( Z=2.574, P=0.010), and 77.20% (71.10%, 80.72%) at 6 months after treatment ( Z=2.861, P=0.004). Meanwhile, there were statistically significant differences in the ACT and Mini-AQLQ scales at 3, 6, and 12 months after treatment compared with those before treatment (ACT score Z=3.170, 4.216, 5.723; Mini-AQLQ score Z=3.231, 4.133, 5.826; all P<0.05). The EASI scale decreased from baseline 25.90 (18.95, 33.45) to 6.20 (1.15, 8.35) at 4 months after treatment ( Z=5.842, P<0.05) and 4.90 (2.75, 8.35) at 6 months after treatment ( Z=5.841, P<0.05), 4.00 (3.15, 5.05) at 12 months after treatment ( Z=5.841, P<0.05); The scores of each scale of IGA, NRS and DLQI decreased significantly compared with the baseline after 4 months, 6 months and 12 months of treatment, and this trend became more obvious with the extension of treatment time. The differences were statistically significant (IGA score Z=6.247, 6.070, 5.946; NRS score Z=5.960, 5.893, 5.879; DLQI score Z=5.880, 5.850, 5.848; all P<0.05). During treatment, 1 patient had local adverse reactions at the injection site and 1 patient had conjunctivitis. Conclusion:Dupilumab may have a positive effect on improving the clinical efficacy of patients with moderate to severe atopic dermatitis complicated with asthma. During the 12-month observation period, this biological agent generally demonstrated good safety characteristics.

Objective:To understand the composition of infectious pathogens and the changes in the epidemic characteristics of inpatients with acute respiratory tract infections in Pudong New Area of Shanghai, from 2018 to 2023.Methods:Specimens of inpatients with acute respiratory infection cases were collected from 14 healthcare institutions in Pudong New Area, Shanghai, from 2018-2023 and tested for eight respiratory pathogens: influenza virus, adenovirus, rhinovirus, parainfluenza virus, respiratory syncytial virus, common coronavirus, metapneumovirus, and bocavirus. The groups were divided into three periods,2018-2019, 2020-2022 and 2023, and the chi-square or Kruskal-Wallis rank sum test was used to compare the group differences. The SPSS 22.0 software was used for statistical analysis.Results:Among the 3 023 inpatients with acute respiratory infection, the positive rate of any virus was 24.25% (733/3 023). The positive rates of any virus in 2018-2019, 2020-2022, and 2023 were 33.40% (336/1 006), 12.01% (116/966), and 26.74% (281/1 051), respectively, and the differences were statistically significant ( χ2=128.20, P<0.001). Among the age groups, in 2018-2019 and 2020-2022, the positive rate of any virus was the highest in the <5 years age group (46.20% and 14.64%), while in 2023, the 15-59 years age group had the highest positive rate (32.97%). The positive rate of any virus in winter was the highest in 2018-2019 (53.21%) and 2020-2022 (17.58%), and the highest in autumn was in 2023 (31.53%). The peak positive rate of respiratory syncytial virus was in winter of 2018-2019 and 2020-2022, as well as the summer of 2023.The positive rates of influenza virus in 2018-2019, 2020-2022 and 2023 were 9.84%, 1.55% and 9.71%, respectively. Conclusions:The pathogen epidemic characteristics of inpatients with acute respiratory infection in Pudong New Area from 2018 to 2023 have shown certain changes. It is necessary to strengthen monitoring. Targeted prevention and control strategies should be developed and implemented in a timely manner.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.