ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

OBJECTIVES: To investigate the molecular epidemiology of children with phenylketonuria (PKU) in Gansu, China, providing foundational data for intervention strategies. METHODS: A retrospective analysis was conducted on 1 159 PKU families who attended Gansu Provincial Maternity and Child Care Hospital from January 2012 to December 2024. Sanger sequencing, multiplex ligation-dependent probe amplification, whole exome sequencing, and deep intronic variant analysis were used to analyze the PAH gene. RESULTS: For the 1 159 children with PKU, 2 295 variants were identified in 2 318 alleles, resulting in a detection rate of 99.01%. The detection rates were 100% (914/914) in 457 classic PKU families, 99.45% (907/912) in 456 mild PKU families, and 96.34% (474/492) in 246 mild hyperphenylalaninemia families. The 2 295 variants detected comprised 208 distinct mutation types, among which c.728G>A (14.95%, 343/2 295) had the highest frequency, followed by c.611A>G (4.88%, 112/2 295) and c.721C>T (4.79%, 110/2 295). The cumulative frequency of the top 23 hotspot variants reached 70.28% (1 613/2 295), and most variant alleles were detected in exon 7 (29.19%, 670/2 295). CONCLUSIONS Deep intronic variant analysis of the PAH gene can improve the genetic diagnostic rate of PKU. The development of targeted detection kits for PAH hotspot variants may enable precision screening programs and enhance preventive strategies for PKU.
Humans ; Phenylketonurias/epidemiology* ; Female ; Male ; Retrospective Studies ; Phenylalanine Hydroxylase/genetics* ; Mutation ; Child, Preschool ; China/epidemiology* ; Child ; Infant

Objective:To investigate effect of hospital-family chain rehabilitation management mode on self-man-agement and quality of life in elderly patients with coronary heart disease(CHD).Methods:This randomized con-trolled study enrolled 220 elderly CHD patients admitted in Hai'an Hospital of Traditional Chinese Medicine between December 2020 and August 2022.They were divided into control group(n=110,routine nursing)and intervention group(n=110,hospital-family chain rehabilitation management mode nursing).After 6-month intervention,scores of Coronary Self-Management Scale(CSMS),China Questionnaire of Quality of life in patients with Cardio-vascular diseases(CQQC)and Perceived Social Support Scale(PSSS)were compared between two groups as well as incidence of adverse cardiovascular events.Pearson method was employed to analyze the association among total scores of CSMS,CQQC and PSSS.Results:After 6-month nursing,compared with patients in control group,those in intervention group had significant higher CSMS total score[(116.03±5.41)points vs.(89.97±4.21)points],CQQC total score[(107.30±6.99)points vs.(80.86±6.38)points],PSSS total score[(69.05±7.42)points vs.(57.05±5.19)points]and each dimensional score(P＜0.001 all).Pearson correlation analysis indica-ted that total scores of CSMS,CQQC and PSSS were positively correlated with each other(r=0.437～0.562,P＜0.001 all).Incidence of adverse cardiovascular events in intervention group was significantly lower comparing to that of control group(2.73％vs.13.64％,P=0.003).Conclusion:Hospital-family chain rehabilitation manage-ment mode could improve the self-management ability and quality of life,increase the patient's social support,and reduce incidence of adverse cardiovascular events in elderly patients with coronary heart disease.

Objective:To investigate effect of hospital-family chain rehabilitation management mode on self-man-agement and quality of life in elderly patients with coronary heart disease(CHD).Methods:This randomized con-trolled study enrolled 220 elderly CHD patients admitted in Hai'an Hospital of Traditional Chinese Medicine between December 2020 and August 2022.They were divided into control group(n=110,routine nursing)and intervention group(n=110,hospital-family chain rehabilitation management mode nursing).After 6-month intervention,scores of Coronary Self-Management Scale(CSMS),China Questionnaire of Quality of life in patients with Cardio-vascular diseases(CQQC)and Perceived Social Support Scale(PSSS)were compared between two groups as well as incidence of adverse cardiovascular events.Pearson method was employed to analyze the association among total scores of CSMS,CQQC and PSSS.Results:After 6-month nursing,compared with patients in control group,those in intervention group had significant higher CSMS total score[(116.03±5.41)points vs.(89.97±4.21)points],CQQC total score[(107.30±6.99)points vs.(80.86±6.38)points],PSSS total score[(69.05±7.42)points vs.(57.05±5.19)points]and each dimensional score(P＜0.001 all).Pearson correlation analysis indica-ted that total scores of CSMS,CQQC and PSSS were positively correlated with each other(r=0.437～0.562,P＜0.001 all).Incidence of adverse cardiovascular events in intervention group was significantly lower comparing to that of control group(2.73％vs.13.64％,P=0.003).Conclusion:Hospital-family chain rehabilitation manage-ment mode could improve the self-management ability and quality of life,increase the patient's social support,and reduce incidence of adverse cardiovascular events in elderly patients with coronary heart disease.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates gene expression in a range of cells, including immune and epithelial cells. AhR signaling plays important roles in the immune system in both health and disease states. Tapinarof is a first-in-class small-molecule topical therapeutic AhR modulating agent launched for the treatment of psoriasis. To improve the activity and chemical stability of Tapinarof, a series of 2-phenylchromen-4-one derivatives were designed, synthesized and evaluated as novel AhR agonists. Compounds 5a, 5c, 5e and 5f potently activated AhR with an EC₅₀ value of 7, 9, 6 and 6 nmol·L^-1, respectively, which are 10-14 fold more potent than Tapinarof. Compounds 5a and 5e exhibit comparable inhibitory effects on IFN-γ production as Tapinarof. Furthermore, compounds 5a-5f exhibited favorable photochemical stability compared to Tapinarof. The compounds may eventually serve as lead compounds for the development of new AhR agonists.

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.
Humans ; Esophageal Squamous Cell Carcinoma/pathology* ; Cardia/surgery* ; Esophageal Neoplasms/pathology* ; Lymphatic Metastasis/pathology* ; Lymph Nodes/pathology* ; Lymph Node Excision ; Tomography, X-Ray Computed/methods* ; Esophagectomy/methods* ; Retrospective Studies

The 3-succinate-30-stearyl glycyrrhetinic acid(18-GA-Suc) was inserted into glycyrrhetinic acid(GA)-tanshinone Ⅱ_A(TSN)-salvianolic acid B(Sal B) liposome(GTS-lip) to prepare liver targeting compound liposome(Suc-GTS-lip) mediated by GA receptors. Next, pharmacokinetics and tissue distribution of Suc-GTS-lip and GTS-lip were compared by UPLC, and in vivo imaging tracking of Suc-GTS-lip was conducted. The authors investigated the effect of Suc-GTS-lip on the proliferation inhibition of hepatic stellate cells(HSC) and explored their molecular mechanism of improving liver fibrosis. Pharmacokinetic results showed that the AUC_(Sal B) decreased from(636.06±27.73) μg·h·mL~(-1) to(550.39±12.34) μg·h·mL~(-1), and the AUC_(TSN) decreased from(1.08±0.72) μg·h·mL~(-1) to(0.65±0.04) μg·h·mL~(-1), but the AUC_(GA) increased from(43.64±3.10) μg·h·mL~(-1) to(96.21±3.75) μg·h·mL~(-1). The results of tissue distribution showed that the AUC_(Sal B) and C_(max) of Sal B in the liver of the Suc-GTS-lip group were 10.21 and 4.44 times those of the GTS-lip group, respectively. The liver targeting efficiency of Sal B, TSN, and GA in the Suc-GTS-lip group was 40.66%, 3.06%, and 22.08%, respectively. In vivo imaging studies showed that the modified liposomes tended to accumulate in the liver. MTT results showed that Suc-GTS-lip could significantly inhibit the proliferation of HSC, and RT-PCR results showed that the expression of MMP-1 was significantly increased in all groups, but that of TIMP-1 and TIMP-2 was significantly decreased. The mRNA expressions of collagen-I and collagen-Ⅲ were significantly decreased in all groups. The experimental results showed that Suc-GTS-lip had liver targeting, and it could inhibit the proliferation of HSC and induce their apoptosis, which provided the experimental basis for the targeted treatment of liver fibrosis by Suc-GTS-lip.
Humans ; Liposomes ; Hepatic Stellate Cells ; Glycyrrhetinic Acid/pharmacology* ; Liver ; Liver Cirrhosis/genetics* ; Collagen/pharmacology*

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.
Humans ; Esophageal Squamous Cell Carcinoma/pathology* ; Cardia/surgery* ; Esophageal Neoplasms/pathology* ; Lymphatic Metastasis/pathology* ; Lymph Nodes/pathology* ; Lymph Node Excision ; Tomography, X-Ray Computed/methods* ; Esophagectomy/methods* ; Retrospective Studies

Intestinal flora is the largest microbial community in human body， which consists of more than 1 000 species. Its structure and metabolites change dynamically with the age， diet and intestinal environment of the host. Study shows that the intestinal microbes play a pivotal role in regulating human physiological and pathological processes， and intestinal flora imbalance may be the key factors affecting the occurrence and development of bone and joint diseases， including osteoporosis， osteoarthritis， rheumatoid arthritis and gouty arthritis. At present， calcitonin， estrogen， nonsteroidal anti-inflammatory drugs， immunosuppressants， xanthine oxidase inhibitors and other western drugs are mostly used to treat the above diseases. However， long-term use of western drugs leads to poor compliance and obvious gastrointestinal adverse reactions among patients. Traditional Chinese medicine （TCM） predominates in the treatment of bone and joint diseases due to its low price， high efficacy and slight side effects， with the advantages of multi-targets， multi-mechanism and multi-levels. In recent years， many scholars have carried out experiments and clinical studies on the treatment of bone and joint diseases by TCMs on the basis of the liver and kidney theory such as "tonifying liver and kidney and strengthening muscles and bones". Gratifying results have been achieved. However， the mechanism of action has not been fully clarified. Intestinal flora becomes a hot spot in medical research， and a close relationship between intestinal flora and bone and joint diseases has been unveiled. Relevant literature in China and abroad showed that TCM has a significant effect on the treatment of bone and joint diseases by regulating intestinal flora. In this paper， the relationship between intestinal flora and bone and joint diseases was summarized and the intervention of TCM active ingredients and compounds on intestinal flora was reviewed to facilitate the prevention and treatment of bone and joint diseases by TCM.

ObjectiveTo explore the material basis and mechanism of Nardostachyos Radix et Rhizoma （NRER）-Agrimoniae Herba （AH）， the herbal pair effective in regulating the liver， invigorating Qi， and calming palpitations， in the treatment of premature ventricular contractions （PVCs） by network pharmacology and molecular docking. MethodThe chemical components and targets of NRER and AH were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） combined with relevant literature. GeneCards，Online Mendelian Inheritance in Man（OMIM），and DrugBank were used to predict the potential targets against PVCs. STRING platform was used for protein-protein interaction （PPI） analysis. Metascape platform was used for Gene Ontology（GO） and Kyoto Encyclopedia of Genes and Genomes（KEGG） enrichment analysis. Cytoscape 3.8.0 was used to construct the NRER-AH component-potential target-signaling pathway network. The main target proteins underwent molecular docking to the active components of NRER-AH by AutoDock 4.2.6. ResultThe targets of nine active components in NRER-AH （such as quercetin，kaempferol，and acacetin） against PVCs mainly involved tumor necrosis factor （TNF），mitogen-activated protein kinase 1（MAPK1），and protein kinase B1（Akt1）. The potential targets were mainly enriched in 26 signaling pathways，such as pathways in cancer and the advanced glycosylation end product （AGE）-receptor of advanced glycosylation end product（RAGE） signaling pathway. The results of molecular docking showed that the majority of the active components （92.59%） of NRER-AH had good binding activities with the main target proteins TNF，MAPK1，and Akt1. ConclusionThe active components of NRER-AH can regulate cardiac ion channels，resist inflammation， and combat oxidative stress to treat PVCs through multi-target and multi-pathway interventions. They can also improve symptoms related to depression and anxiety by inhibiting monoamine oxidase activity and protecting nerves from damage. This study is expected to provide research ideas and the theoretical basis for further exploring the material basis and mechanism of NRER-AH in the treatment of PVCs.