ObjectiveTo explore the effect and mechanism of Qigui Didang decoction， formulated based on the principle of Tonifying Deficiency and Unblocking Collaterals， on improving metabolic memory of db/db mice with diabetic nephropathy （DN） through silent information regulator 1 signal regulator 1 （Sirt1）/p53/nuclear factor kappa-B （NF-κB） p65 pathway. MethodsFifteen db/db mice were randomly divided into model group （10 mL·kg^-1·d^-1）， resveratrol group （20 mg·kg^-1·d^-1）， and Qigui Didang decoction group （3.34 g·kg^-1·d^-1） Another five db/m mice were selected as the normal group （10 mL·kg^-1·d^-1）. After the intervention， the kidney weight of each group was measured， and the kidney index （KI） was calculated. Fasting blood glucose （FBG）， creatinine （CRE）， β2-microglobulin （β2-MG）， blood urea nitrogen （BUN）， and cystatin C （CysC） were measured. Renal pathology was observed by hematoxylin-eosin （HE） staining and Masson staining. The mRNA and protein expression levels of Sirt1， NF-κB， tumor suppressor gene p53， interleukin-1β （IL-1β）， and cysteine aspartate protease-3 （Caspase-3） were detected using real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot. ResultsCompared with the normal group， the model group showed disordered renal structure， obvious renal damage， and markedly elevated levels of renal function indexes （CRE， β2-MG， BUN， and CysC） （P<0.01）. The KI and blood glucose were significantly increased （P<0.01）， while Sirt1 expression was markedly decreased （P<0.01）. Expression levels of NF-κB p65， p53， IL-1β， and Caspase-3 were increased significantly （P<0.05）. Compared with those in the model group， DN mice treated with Qigui Didang decoction exhibited significantly decreased FBG， improved renal function， and markedly decreased KI （P<0.01）， along with reduced CRE， β2-MG， BUN， and CysC levels （P<0.05）. Protein expression of Sirt1 was significantly upregulated （P<0.05）， while that of NF-κB p65， p53， IL-1β， and Caspase-3 was markedly decreased （P<0.05）. The mRNA expression levels of NF-κB p65， p53， IL-1β， and Caspase-3 were significantly decreased （P<0.05）. The staining results indicate improved renal fibrosis， significantly decreased fiber deposition （P<0.05）， and less inflammatory infiltration in the Qigui Didang decoction group. ConclusionThe findings suggest that Qigui Didang decoction can alleviate the metabolic memory effect of DN， thereby inhibiting renal cell apoptosis and inflammatory response in mice， and improving renal function. The mechanism of action is closely related to the Sirt1/p53/NF-κB p65 signaling pathway.

ObjectivesTo investigate the molecular epidemiological characteristics of HIV-1 infection among men who had sex with men (MSM) in Taizhou City, Zhejiang Province, and to provide a scientific reference for acquired immune deficiency syndrome prevention and control efforts. MethodsThe research subjects were all newly reported MSM population in Taizhou City from 2020 to 2023. Blood samples without antiviral therapy were collected. The HIV-1 pol gene was amplified and sequenced, and the sequences were submitted to the Stanford University drug resistance database to identify the mutation sites and drug resistance. MEGA 11.0 software was used to analyze the nucleic acid sequences, construct phylogenetic tree, and calculate genetic distance of gene sequences. The molecular transmission network diagram of HIV-1 was constructed using Cytoscape_v3.10.1, and the influencing factors of network entry were analyzed by logistic regression. ResultsA total of 363 newly reported HIV-infected MSM patients were included, with a median age [M (P₂₅, P₇₅)] of 34 (26,47) years old. The majority had an educational level of junior high school or below (55.65%). A total of eight subtypes were found, mainly CRF07_BC and CRF01_AE. The primary drug resistance rate was 10.47% (38/363). The optimal molecular network gene distance was 0.019, with a network access rate of 42.70% (155/363), and a total of 47 molecular clusters were formed. Multivariate logistic analyses showed that compared with the CRF01_AE subtype, the clustering risk of CRF07_BC subtype was higher (OR=1.916, 95%CI: 1.191‒3.109), cases with drug resistance had a higher risk of cluster formation than those without drug resistance (OR=2.011, 95%CI: 1.006‒4.080), and recent infected patients had a lower risk of entering the largest molecular cluster than long-term infected patients (OR=0.376, 95%CI: 0.137‒0.928). ConclusionThe newly diagnosed infections among the MSM population are active in Taizhou City, Zhejiang Province, with a high level of primary drug resistance. Individuals carrying drug-resistant strains are more likely to cluster. Drug resistance monitoring should be strengthened to prevent further spread of drug-resistant strains in the network.

ObjectiveTo establish background data for a 90-day feeding trial of SD rats to ensure the reliability of research data. MethodsBackground data from six independent 90-day feeding trials of SD rats conducted by the National Center for Safety Evaluation of Drugs from 2020 to 2023 were summarized. These studies involved a blank control group of 120 SPF-grade 4-week-old SD rats, with an equal number of males and females, which were only given standard full-nutrient pelleted rat feed. After the quarantine period, the animals were observed for an additional 90 days, followed by intraperitoneal injection of Zoletil (50 mg/mL) for anesthesia, blood sampling, euthanasia, and necropsy. By analyzing the data from the blank control group, a relevant background database for SD rats was established. ResultsBoth male and female rats exhibited steady weight gain, with a more pronounced increase in male rats. Within 90 days, the average body weight of male and female rats increased to over 500 g and 300 g, respectively. Three weeks later, the average daily food intake of male rats stabilized at approximately 25~28 g per rat, while that of female rats remained stable at approximately 16~19 g per rat. The food utilization rate of all animals gradually decreased from the first week of the experiment. In the white blood cell (WBC) differential count results, significant differences were observed in the counts of WBCs, neutrophils (Neut), lymphocytes (Lymph), and monocytes (Mono) between males and females (P<0.001). However, there were no significant differences in the percentages of neutrophil (%Neut), lymphocyte (%Lymph), and monocyte (%Mono) between the sexes (P>0.05). The average red blood cell count (RBC), hemoglobin concentration (HGB), hematocrit (HCT), platelet count (PLT), prothrombin time (PT), and activated partial thromboplastin time (APTT) were higher in male animals than in female animals (P<0.05). The average values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatine phosphokinase (CK), lactate dehydrogenase (LDH), glucose (GLU), and triglyceride (TG) in male rats were higher than those in female rats (P<0.05). The urinary pH range for male animals was 5.0 to 8.5, while for female animals it was 6.5 to 9.0. The majority of male animals had a urinary specific gravity lower than 1.020, and the majority of female animals had a urinary specific gravity lower than 1.015. The weights of various organs (excluding the adrenal glands and reproductive organs) in male animals were heavier than those in female animals (P<0.001), while the organ/body weight ratios (excluding the kidneys and reproductive organs) of female animals were higher than those of male animals (P<0.001). ConclusionThis study summarizes the background reference ranges for body weight, food intake, hematology, and serum biochemistry indicators in SPF-grade SD rats in the untreated control group from six 90-day feeding trials conducted by the National Center for Safety Evaluation of Drugs. It provides important reference data for related research. By summarizing the background and spontaneous histopathological changes in rats, this study aids in the standardization and normalization of subsequent research, as well as in the evaluation and analysis of abnormal results.

OBJECTIVE: To compare the efficacy of the fourth-generation minimally invasive technique-minimally invasive extra-articular metaphyseal distal transverse osteotomy (META) and Chevron osteotomy in treatment of hallux valgus. METHODS: A total of 80 patients with hallux valgus, who underwent single-foot surgery between July 2023 and January 2025 and met the inclusion criteria, were included in the study. Among them, 40 patients were treated with META and 40 with Chevron osteotomy. There was no significant difference in baseline data between the two groups ( P>0.05), including gender, age, height, weight, body mass index, disease duration, lesion site, hallux valgus deformity degree, as well as preoperative scores of each item (pain, function, alignment, total score) in the American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-Interphalangeal Joint Scale (AOFAS-Hallux-MTP-IP), scores of each item (pain, walking/standing, social interaction, total score) in the Manchester-Oxford Foot Questionnaire (MOXFQ), hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), sesamoid position, and the 1st metatarsal head morphology. The postoperative AOFAS-Hallux-MTP-IP scores, MOXFQ scores, as well as HVA, IMA, DMAA, the 1st metatarsal head morphology, and sesamoid position measured based on weight-bearing foot X-ray films were compared between the two groups; the occurrence of postoperative complications was recorded. RESULTS: All patients in both groups were followed up 6-18 months, and there was no significant difference in the follow-up time between the two groups ( P>0.05). At last follow-up, the scores of all items in AOFAS-Hallux-MTP-IP in both groups were higher than those before operation, and the scores of all items in MOXFQ were lower than those before operation, with significant differences ( P<0.05); there was no significant difference in the change values of all items in MOXFQ between the two groups ( P>0.05). The change value in AOFAS function score in the META group was significantly higher than that in the Chevron osteotomy group ( P<0.05), while there was no significant difference in the change value of AOFAS pain score, alignment score, and total score between the two groups ( P>0.05). After operation, 1 case (2.5%) of superficial incision infection and 2 cases (5.0%) of numbness around the incision occurred in the Chevron osteotomy group, while only 2 cases (5.0%) of numbness around the incision occurred in the META group. Imaging reexamination showed that HVA, IMA, and DMAA in both groups were signifncatly smaller than those before operation ( P<0.05), and there was no significant difference in the change values of the above angles between the two groups ( P>0.05). The 1st metatarsal head morphology and sesamoid position in the META group were better than those in the Chevron osteotomy group after operation, with significant differences ( P<0.05). CONCLUSION Both META and Chevron osteotomy can correct hallux valgus deformity, improve foot function, and relieve pain, but META has more advantages in correcting metatarsal rotation and reducing dislocated sesamoids.
Humans ; Hallux Valgus/diagnostic imaging* ; Osteotomy/methods* ; Minimally Invasive Surgical Procedures/methods* ; Male ; Female ; Middle Aged ; Treatment Outcome ; Adult ; Metatarsophalangeal Joint/surgery* ; Aged ; Retrospective Studies

BACKGROUND: The incidence of leptomeningeal metastasis (LM) in patients with advanced non-small cell lung cancer (NSCLC) is increasing gradually. However, it poses therapeutic challenges due to limited effective interventions. Intrathecal Pemetrexed (IP) holds broad application prospects in the therapeutic domain of LM. This study aims to evaluate the efficacy, safety, and optimal combination strategies of IP in NSCLC-LM patients with epidermal growth factor receptor (EGFR) mutation-positive status, with the aim of providing real-world data support for exploring more precise personalized treatment strategies for these patients. METHODS: 104 EGFR-mutated NSCLC-LM patients who received IP treatment at Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School from January 2018 to June 2024 were analyzed retrospectively. Clinical parameters, treatment regimens, and survival outcomes were collected. The overall survival (OS), progression-free survival (PFS), clinical response rate and adverse events (AEs) were evaluated. RESULTS: The cohort demonstrated a median PFS of 9.6 months and OS of 13.0 months with 6-month and 1-year OS rates of 80.8% and 56.5%, respectively. Clinical response was observed in 77.9% of patients. The common AEs were myelosuppression (58.7%) and elevation of hepatic aminotransferases (25.0%). Nine (8.7%) patients experienced grade 4 myelosuppression and recovered to normal after receiving symptomatic treatment. Subgroup analyses revealed prolonged OS in patients with Karnofsky performance status (KPS) ≥60 versus <60 (14.4 vs 9.0 months, P=0.0022) and those receiving Bevacizumab therapy versus not (19.2 vs 10.5 months, P=0.0011). CONCLUSIONS IP exhibits promising efficacy and manageable toxicity in EGFR-mutated NSCLC-LM patients. When combined with Bevacizumab, it exerts synergistic antitumor effects with the potential to further improve clinical outcomes.
Humans ; Pemetrexed/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Male ; Female ; Middle Aged ; Lung Neoplasms/pathology* ; ErbB Receptors/genetics* ; Aged ; Mutation ; Adult ; Retrospective Studies ; Injections, Spinal ; Meningeal Neoplasms/genetics* ; Treatment Outcome ; Aged, 80 and over

BACKGROUND: Heavy metals are significant risk factors for kidney function. Numerous studies have shown that exposure to heavy metals negatively correlates with kidney function through oxidative stress pathways, and serum α-klotho is linked to oxidative stress. However, the role of α-klotho in the relationship between blood lead, mercury, and kidney function remains unclear. METHOD: This study evaluated the mediating role of alpha-klotho in the relationship between lead, mercury and renal function, using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES) in U.S. adults aged 40-79. The sample included 11,032 participants, with blood lead, mercury, α-klotho, and other relevant covariates measured. Inductively coupled plasma mass spectrometry was used to assess blood lead and mercury levels, and enzyme-linked immunosorbent assay (ELISA) was employed to measure serum α-klotho. Kidney function was evaluated using estimated glomerular filtration rate (eGFR) based on creatinine levels. Multivariable linear regression was conducted to analyze the relationships between blood lead, mercury, α-klotho, and eGFR. A mediation analysis model was used to assess whether α-klotho influenced these associations. RESULTS: We observed a significant association between blood lead and eGFR. Mediation analysis revealed that α-klotho accounted for 12.76% of the relationship between serum lead and eGFR in the NHANES population. Subgroup analysis showed that α-klotho mediated 12.43%, 6.87%, 21.50% and 5.44% of the relationship between blood lead and eGFR in women, middle-aged adults (40-59 years old), without cardiovascular disease and hypertension, respectively. However, α-klotho did not mediate the relationship between blood mercury and eGFR in terms of gender or age. This newly identified pathway may provide valuable insights for the prevention and treatment mechanisms related to kidney function impairment. CONCLUSION We found that blood lead was associated with renal function. According to the results of subgroup analysis, for blood lead, serum α-klotho mediated the association in females, middle aged 60-79 years. The relationship between blood mercury and renal function was not clinically significant, and serum α-Klotho mediated the relationship between blood mercury and renal function without significant clinical significance.
Humans ; Middle Aged ; Lead/blood* ; Female ; Klotho Proteins ; Male ; Aged ; Adult ; Mercury/blood* ; Glomerular Filtration Rate ; Nutrition Surveys ; United States ; Kidney/physiology* ; Glucuronidase/blood* ; Environmental Pollutants/blood*

The translocator protein (TSPO) positron emission tomography (PET) can noninvasively detect neuroinflammation associated with epileptogenesis and epilepsy. This study explored the role of the TSPO-targeting radioligand [¹⁸F]F-TFQC, an m-trifluoromethyl ER176 analog, in the PET neuroimaging of epileptic rats. Initially, [¹⁸F]F-TFQC was synthesized with a radiochemical yield of 8%-10% (EOS), a radiochemical purity of over 99%, and a specific activity of 38.21 ± 1.73 MBq/nmol (EOS). After determining that [¹⁸F]F-TFQC exhibited good biochemical properties, [¹⁸F]F-TFQC PET neuroimaging was performed in epileptic rats at multiple time points in various stages of disease progression. PET imaging showed specific [¹⁸F]F-TFQC uptake in the right hippocampus (KA-injected site, i.e., epileptogenic zone), which was most pronounced at 1 week (T/NT 1.63 ± 0.21) and 1 month (T/NT 1.66 ± 0.20). The PET results were further validated using autoradiography and pathological analysis. Thus, [¹⁸F]F-TFQC can reflect the TSPO levels and localize the epileptogenic zone, thereby offering the potential for monitoring neuroinflammation and guiding anti-inflammatory treatment in patients with epilepsy.

Repetitive transcranial magnetic stimulation (rTMS) is a rapid and effective therapy for major depressive disorder; however, there is significant variability in therapeutic outcomes both within and across individuals, with approximately 50% of patients showing no response to rTMS treatment. Many studies have personalized the stimulation parameters of rTMS (e.g., location and intensity of stimulation) according to the anatomical and functional structure of the brain. In addition to these parameters, the internal states of the individual, such as circadian rhythm, behavior/cognition, neural oscillation, and neuroplasticity, also contribute to the variation in rTMS effects. In this review, we summarize the current literature on the interaction between rTMS and internal states. We propose two possible methods, multimodal treatment, and adaptive closed-loop treatment, to integrate patients' internal states to achieve better rTMS treatment for depression.
Humans ; Transcranial Magnetic Stimulation/methods* ; Depressive Disorder, Major/physiopathology* ; Neuronal Plasticity/physiology* ; Brain/physiopathology*

The NOD-like receptor protein 3 (NLRP3) inflammasome is essential in innate immune-mediated inflammation, with its overactivation implicated in various autoinflammatory, metabolic, and neurodegenerative diseases. Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions, although no medications targeting the NLRP3 inflammasome are currently available. This study demonstrates that clioquinol (CQ), a clinical drug with chelating properties, effectively inhibits NLRP3 activation, resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages, with a half maximal inhibitory concentration (IC₅₀) of 0.478 μM. Additionally, CQ mitigates experimental acute peritonitis, gouty arthritis, sepsis, and colitis by lowering serum levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Mechanistically, CQ covalently binds to Arginine 335 (R335) in the NACHT domain, inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein. Collectively, this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.

Objective:To investigate the clinicopathological, molecular pathological features, and family genetic pedigree of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).Methods:A total of 16 cases of SCCOHT diagnosed in Obstetrics and Gynecology Hospital of Fudan University from January 2013 to January 2023 were collected. The clinicopathologic features, SMARCA4/2/B1 protein expression, outcomes and SMARCA4 gene detection were reported. A follow-up study was also carried out.Results:The average age at diagnosis was 28.7 years (range 17-38 years). The preoperative calcium level was evaluated in 3 of 6 patients. The tumor was unilateral in all 16 cases, ranged from 8 to 26 cm (average 15.8 cm) in the greatest dimension. Extraovarian spread was present in 7 cases. In 10 cases, the tumors were initially misinterpreted as other ovarian neoplasms. BRG1 and BRM expression by immunohistochemistry were all lost in detected cases, while INI1 exhibited retained nuclear expression. All BRM-negative SCCOHTs also lacked BRG1 protein,but retained INI1 expression. SCCOHTs were only focally positive for EMA, CKpan, Calretinin, SALL4, and diffusely positive for WT1. Two of nine cases exhibited mutation-type p53 immunoreactivity. Ki-67 index was 58% on an average. ER, PR, FOXL2, α-inhibin, chromogranin A and LCA were negative in all the cases. SMARCA4 sequencing was available in 8 cases of SCCOHT, which revealed a germline SMARCA4 mutation in one patient, and others carried somatic mutation. Furthermore, two daughters, mother and an aunt of a patient with germline mutation were reported to be SMARCA4 mutation carriers. Follow-up was available for 15 patients, and the 6-month, 1-year and 2-year survival rate was 65.8%, 45.1%, and 22.6%, respectively. For patients in FIGO stages Ⅱ+Ⅲ, 6-month, 1-year survival rate was 53.6% and 35.7% respectively, compared to 80% (6-month) and 60% (1-year) in patients of staged I ( P=0.358). Conclusions:With dismal prognosis of SCCOHT, accurate diagnosis is necessary. The typical age distribution, a panel of various staining results, especially concomitant loss of BRG1 and BRM may be of diagnostic aid and can be used to distinguish SCCOHT from its histological mimics. After the diagnosis of SCCOHT, genetic testing and genetic counseling are recommended.