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.

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 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 Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated 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 therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

BACKGROUND: Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels may not fully translate into patient-reported health status in patients with heart failure (HF). We aimed to evaluate the correlation between NT-proBNP levels and patient-reported health status changes at one month after discharge of patients, and their associations with risk of death and rehospitalization in patients with acute HF. METHODS: We used data from the China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study (PEACE 5p-HF Study). Patient-reported health status was measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Patients who were hospitalized for HF and completed the KCCQ-12 and NT-proBNP tests before and one month after discharge were eligible in our study. We stratified patients into different groups based on NT-proBNP levels (i.e., improved, stable, and deteriorated) and KCCQ-12 scores (i.e., not deteriorated and deteriorated). We also examined the associations of the joint NT-proBNP and KCCQ-12 change with the risk of one-year and four-year clinical outcomes. RESULTS: A total of 2461 patients were included in the analysis. The mean age was 64.06 ± 13.51 years, and 36.37% (895/2461) of the study population were female. Among patients with improved NT-proBNP levels, 115 (10.95%) patients had deteriorated KCCQ-12 scores. The correlation between the change in the KCCQ-12 score and NT-proBNP level was weak ( r2 = 0.002, P = 0.013). Stratification by changes in the KCCQ-12 score revealed subgroups with distinctive risks, such that patients with deteriorated KCCQ-12 scores in any of the NT-proBNP change groups exhibited an increased risk of one-year all-cause death than participants with not deteriorated KCCQ-12 scores in any of the NT-proBNP change groups. Patients with improved NT-proBNP levels and deteriorated KCCQ-12 scores presented greater risks of one-year all-cause death (hazard ratio [HR]: 2.45, 95% confidence interval [CI]: 1.34-4.48) than patients with stable NT-proBNP levels and not deteriorated KCCQ-12 scores (HR [95% CI], 1.77 [1.25-2.53]). CONCLUSIONS: A discrepancy between changes in NT-proBNP levels and KCCQ-12 scores was common. The change in NT-proBNP levels was not sufficient to characterize critical aspects related to HF during one month after discharge of patients. Changes in the KCCQ-12 score exhibit complementary information to NT-proBNP levels for the prediction of clinical outcomes in patients with acute HF. REGISTRATION www.clinicaltrials.gov (No. NCT02878811).
Aged ; Female ; Humans ; Male ; Middle Aged ; Health Status ; Heart Failure/metabolism* ; Natriuretic Peptide, Brain/metabolism* ; Peptide Fragments/metabolism* ; Prospective Studies

With societal development and accelerated population aging in China, the demand for high-quality nursing services continues to grow, placing the nursing sector in a dual scenario of challenges and opportunities that necessitate parallel advancements in development and reform. Clinical practice guidelines (CPGs), as critical tools for enhancing nursing quality and standardizing evidence-based care, face multifaceted challengesincluding complexities in evidence integration, methodological and reporting irregularities, barriers to multidisciplinary collaboration, and suboptimal clinical adherence. However, emerging opportunities—such as optimized methodological frameworks, the application of implementation science, and the integration of digital and intelligent technologies—are creating new pathways for advancing high-quality nursing practice. This article elaborates on the necessity of developing rigorous nursing CPGs and analyzes the current opportunities and challenges in their formulation, dissemination, and implementation, aiming to provide theoretical insights for strengthening guideline-driven nursing care.

Objective To investigate the influencing factors of opioid analgesics need within 48 hours after arthroscopic rotator cuff repair.Methods Clinical data of 90 consecutive arthroscopic rotator cuff repairs by the same operator from March 2017 to July 2022 were retrospectively analyzed.The patients were divided into opioid group(62 patients)and control group(28 patients)according to whether they used opioid analgesics within 48 hours after surgery.The control group consisted of patients who did not use analgesics or who had good analgesic effects with conventional analgesic regimens(non-steroidal anti-inflammatory drugs or non-opioid central analgesics)after surgery,and the opioid group consisted of patients who required opioid analgesics as assessed by the surgeon or who need opioid analgesics because of inefficacy of conventional analgesic regimens.The following factors were selected as independent variables:gender,age(whether≥65 years old),duration of disease(whether≥4 weeks),body mass index(BMI)(whether≥25),occupation(whether employed),with or without a history of smoking and alcohol consumption,hypertension,diabetes,heart disease,and trauma,duration of surgery(whether≤180 min),number of torn tendons(whether≥2),number of screws(whether≥2),large nodular osteophyte,and whether there was moderate-to-severe impingement.Single factor analysis was used to screen the factors influencing the need for opioid analgesics within 48 hours after arthroscopic rotator cuff repair.Results The results of univariate analysis showed that among the above independent variables,only the number of torn tendons≥2 was the factor affecting the need for opioid analgesics within 48 hours after arthroscopic rotator cuff repair(OR = 5.263,P = 0.007).Conclusions Patients with rotator cuff tears with≥2 tendons had more severe pain within 48 hours after rotator cuff repair,requiring opioid analgesics.Focus should be placed on postoperative pain in such patients,and a diverse analgesic regimen should be used early.

ObjectiveTo investigate the effect of intermittent theta burst stimulation (iTBS) of the multi-target cerebral cortex after stroke on functional recovery of the upper limb of the hemiplegic side. MethodsFrom November, 2019 to August, 2020, 40 stroke patients in Gansu Provine Hospital Rehabilitation Center were included and randomly divided into single-target stimulation group (n = 20) and multiple-target stimulation group (n = 20). Both groups underwent basic neurorehabilitation drug therapy and conventional rehabilitation exercises. The single-target stimulation group received repetitive transcranial magnetic stimulation (rTMS) (iTBS mode) only in the primary motor cortex (M1) of the affected side. The multi-target stimulation group received rTMS (iTBS mode) in the cerebellar cortex of the healthy brain and M1 of the affected side, once a day, six days a week, for four weeks. Before and after treatment, the scores of Fugl-Meyer Assessment-Upper Extremities (FMA-UE), Action Research Arm Test (ARAT) and modified Barthel Index (MBI), and the latency and amplitude of somatosensory-evoked potentials N20 were compared. ResultsNo serious adverse reaction occurred during treatment. After treatment, the scores of FMA-UE, MBI and ARAT, and the amplitude and latency of N20 improved in both groups (|t| > 3.478, |Z| > 2.243, P < 0.05); and the scores of FMA-UE and ARAT, and the amplitude of N20 were better in the multiple-target stimulation group than in the single-target stimulation group (t > 2.939, Z = -2.697, P < 0.01). ConclusionMulti-target stimulation is superior to single-target stimulation for improving upper limb motor function and N20 amplitude in the hemiplegics after stroke.

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH

OBJECTIVE: To study the effect of aquaporin 4(AQP4) in regulating the permeability of blood-brain barrier(BBB) induced by subacute 1,2-dichloroethane(1,2-DCE) inhalation. METHODS: Specific pathogen free healthy CD-1 male Aqp4 genetically engineered mice(Aqp4~(+/+)and Aqp4~(-/-)) were randomly divided into control and low-, medium-and high-dose groups. The mice were exposed to 1,2-DCE at the dosages of 0.00, 100.00, 350.00 and 700.00 mg/m~3 for 6 hours per day for consecutive 28 days by systemic dynamic inhalation. After the end of 1,2-DCE exposure, the BBB permeability was evaluated by Evans blue staining. Real-time fluorescence quantitative polymerase chain reaction method was used to detect the mRNA expression of genes related to BBB tight junction protein(Tjp)1, Tjp2, Tjp3, claudin(Cldn)3, Cldn5, Cldn11, occludin(Ocln), matrix metalloproteinase(Mmp)2, Mmp9 and Na-K-Cl cotransporter-1(Nkcc1). RESULTS: The BBB permeability in mice showed significant change with 1,2-DCE dose and Aqp4 genotype(P<0.01). The BBB permeability of Aqp4~(+/+) genotype mice was higher in low-, medium-and high-dose groups than that of control group(all P values were <0.05). The permeability of BBB was lower in Aqp4~(+/+) genotype mice in the control group than that of Aqp4~(-/-) genotype mice in the same group(P<0.05), but BBB permeability was higher in Aqp4~(+/+) genotype mice in the three dose groups than that of Aqp4~(-/-) genotype mice in the same group(all P values were <0.05). The Cldn3 and Olcn mRNA relative expression in the brain cortex had statistical difference in mice with different genotype(all P values were <0.01). The mRNA relative expressions of Cldn3 and Olcn in the brain cortex were higher in Aqp4~(-/-) genotype mice than that of Aqp4~(+/+) genotype mice(all P values were <0.01). The relative mRNA expression levels of Tjp1, Tjp2, Tjp3, Cldn5, Cldn11, Mmp2, Mmp9 and Nkcc1 in the cerebral cortex of mice were not statistically significant in aspect of 1,2-DCE exposure dose and genotype(all P values were >0.05). CONCLUSION: Exposure to 1,2-DCE can increase BBB permeability in mice, and the mechanism may be associated with 1,2-DCE-induced down-regulation of Aqp4 and up-regulation of mRNA expression of the cerebral cortex TJP-related molecules Cldn3 and Ocln.

OBJECTIVE: To investigate the effect of 1,2-dichloroethane(1,2-DCE) acute inhalation exposure on the differential gene expression of phase Ⅰ metabolic enzymes. METHODS: The specific pathogen free SD rats were randomly divided into control group(16 rats), low-and high-dose groups(24 rats in each group, half males and half females). Low-and high-dose group were given daily 600, 1 800 mg/m~(3 ) of 1,2-DCE, and the control group given the fresh air by dynamic inhalation for 8 hours per day for consecutive 7 days. After the end of exposure, the relative mRNA expression of cytochrome P450 2 E1(CYP2 E1), alcohol dehydrogenase(ADH1) and acetaldehyde dehydrogenase 3 alpha 1(ALDH3α1) in the liver tissue was detected by real-time fluorescence quantitative polymerase chain reaction. RESULTS: The relative expression of CYP2 E1 in male high-dose group was higher than that in male low-dose group and female high-dose group(P<0.05). The relative expression of ADH1 in male low-and high-dose groups was higher than that in male control group(P<0.05). The relative expression of ADH1 in male high-dose group was higher than that in male low-dose group and female high-dose group(P<0.05). The relative expression of ALDH3α1 in high-dose group was higher than that in control group and low-dose group(P<0.05). CONCLUSION: High dose 1,2-DCE could increase the gene expression of phase Ⅰ metabolic enzymes in rat liver. The 1,2-DCE has more obvious effect in male rats than in female rats.

OBJECTIVE: To investigate the effect and mechanism of lead exposure on hypothalamic inflammatory factors in mice fed with high-fat diet. METHODS: Specific pathogen free healthy male Kunming mice were randomly divided into control group, high-fat diet group, lead exposure group, and combined exposure group, with 8 rats in each group. The control group and the lead exposure group were given regular diet, while high-fat diet group and combined exposure group were given high-fat diet. The lead exposure group and combined exposure group were given water with 250 mg/L lead acetate. The control group and high-fat diet group were given double distilled water. Continuous lead exposure was given for 9 weeks, 7 days per week. Body weights of the mice were measured every other week. After 9 weeks of exposure, the behavioral changes of mice were detected by open field test. The levels of triglyceride(TG), low density lipoprotein(LDL) and high density lipoprotein(HDL) in serum were detected by microplate reader. Western blotting was used to detect the relative protein expression of interleukin(IL)-1β, IL-6, IL-17 A, IL-22, tumor necrosis factor-α(TNF-α) and transforming growth factor-β(TGF-β) in the hypothalamus of mice. The relative expression of mRNA of IL-1β, IL-6, IL-17 A and TNF-α mRNA was detected by real-time fluorescence quantitative polymerase chain reaction. RESULTS: Beginning from the first week, the body weights of mice in the high-fat diet group and the combined exposure group were higher than that in the control group and the lead exposure group(P<0.05). The numbers of standing in the lead exposure group and the combined exposure group were lower than that in the control group and the high-fat diet group(P<0.05). The distances of central area activity in the high-fat diet group, the lead exposure group and the combined exposure group were lower than that in the control group(P<0.05). The total distances in the high-fat diet group and the combined exposure group were lower than that in the control group(P<0.05). The serum levels of TG and LDL in the combined exposure group increased(P<0.05), and the HDL level decreased(P<0.05), when compared with the control group and the lead exposure group. The relative protein expression of IL-1β, IL-6, IL-17 A and IL-22 in the hypothalamus of the high-fat diet group and lead exposure group was higher than those of the control group(P<0.05). The relative protein expression of TNF-α and TGF-β in the hypothalamus of the lead exposure group was higher than that in the control group(P<0.05). The relative protein expression of IL-1β, IL-6, IL-17 A, TGF-β in the hypothalamus of the combined exposure group was higher than the other 3 groups(P<0.05). The relative protein expression of IL-22 in the hypothalamus of the combined exposure group was higher than that of the control group(P<0.05), while the relative protein expression of TNF-α was higher than that of the control group and the high-fat diet group(P<0.05). The relative expression of IL-1β, IL-6, IL-17 A, and TNF-α mRNA in the hypothalamus of the high-fat diet group, the lead exposure group and the combined exposure group was higher than that in the control group(P<0.05). The above indicators of mice in the lead exposure group were higher than that in the high-fat diet group(P<0.05). The above indicators of mice in the combined exposure group were higher than those in the high-fat diet group and the lead exposure group(P<0.05). CONCLUSION: Lead exposure can promote neurobehavioral changes and hypothalamic inflammatory damage in high-fat diet mice. IL-1β, IL-6, IL-17 A, TGF-β and TNF-α might involve in the process of synergistic effect of lead and high-fat diet exposure on inflammatory hypothalamic injury.