This study aimed to convene experts engaged in the diagnosis and treatment of laryngeal contact granuloma (LCG) and form a consensus group to guide primary care and specialist physicians in managing the condition. Twenty-three Chinese experts were invited to participate in the modified Delphi process to revise 16 statements regarding the definition, epidemiology, etiology, clinical manifestations, diagnosis, and treatment of LCG. Experts independently rated the statements on four dimensions: importance, scientific acceptability, availability, and feasibility. After three rounds of voting, a statement was considered to have reached consensus if at least 80% of experts gave it a score of ≥8 in each of the four evaluation categories (using a 9-point Likert scale). After three rounds of voting, 87.5% of the statements were approved (N = 14/16). At present, laryngopharyngeal reflux and mechanical injuries such as excessive voice use are considered the main causes. LCG can be diagnosed by laryngoscopy, and biopsy is generally not required. Lifestyle modification is the foundation of treatment, and voice therapy helps patients recover and reduces recurrence. For those with poor conservative treatment outcomes, steroid injections into the lesion or botulinum toxin injections into the same side vocal cord can be considered. The recurrence rate of surgical treatment is high, and it is usually not the first-line treatment option. Using a well-tested methodology, optimal practice statements regarding LCG have been established. This information can serve to guide primary care and specialist physicians in managing this condition.
Platelet-Rich Plasma (PRP) has emerged as a promising biological agent in reproductive medicine, with validated efficacy in managing endometrial disorders and improving pregnancy outcomes in recurrent implantation failure (RIF). Specifically, PRP modulates uterine Natural Killer (uNK) cell cytotoxicity, drives macrophage polarization toward the anti-inflammatory M2 phenotype through the AMPK signaling pathway, and fine-tunes T cell subset balance and function. These coordinated immunomodulatory actions, coupled with its endometrial repair capacity, collectively foster a maternal-fetal immune tolerance state critical for successful embryo implantation and pregnancy maintenance, thus providing a novel integrated strategy for reproductive disorders. However, the clinical translation of PRP is currently hindered by the lack of standardized preparation protocols and an incomplete elucidation of its precise molecular mechanisms underlying the crosstalk between endometrial repair and maternal-fetal immune regulation. We conclude that future research should focus on establishing disease-specific standardized PRP workflows and leveraging multi-omics technologies to decipher the core regulatory pathways of this bridging effect. This will pave the way for developing targeted therapies and optimizing the clinical application of PRP in reproductive medicine.
Aspiration pneumonia (AP) is a prevalent and life-threatening pulmonary disease resulting from repeated aspiration of exogenous materials such as food or gastric contents. However, most existing animal models simulate only acute injury and fail to reproduce the chronic pathological features observed in patients. This study aimed to establish a stable and clinically relevant chronic AP mouse model. First, four inhalation techniques including unilateral vagotomy (UV), intranasal inoculation (IN), intratracheal instillation (IT), and oropharyngeal aspiration (OA) were evaluated for model establishment in mice. The optimal method OA was applied to administer normal saline (NS), food suspension (FS), or gastric contents (GC) once weekly. Disease progression was evaluated at 2, 4, and 8 weeks. Lung injury was evaluated by tracer distribution, histopathology, cytokine profiling, transcriptomic analysis, and micro-computed tomography (micro-CT). OA achieved stable pulmonary delivery. Both FS and GC induced lung injury. However, 8-week FS exposure resulted in more severe and persistent damage, characterized by increased alveolar-capillary barrier permeability and elevated cytokine and chemokine levels. Histology showed FS-specific obstructive bronchiolitis with retained food particles, closely mimicking human aspiration pneumonia. Micro-CT revealed gravity-dependent pulmonary consolidation, most evident in the FS group. Transcriptomic analysis indicated activation of neutrophil extracellular traps (NETs) formation during chronic AP progression. This OA-based FS model reproduced the key pathological and imaging features of human chronic AP and implicated NETs in the disease progression. It provides a robust platform for mechanistic investigation and therapeutic development.
Post-endoscopic submucosal dissection (ESD) electrocoagulation syndrome (PEECS) is a known complication in colorectal laterally spreading tumors (LSTs), but its risk factors in elderly patients remain unclear. This study aimed to develop and validate a risk-stratification scoring system for PEECS in elderly ESD patients. A multicenter retrospective study (2020-2025) enrolled 506 elderly patients with colorectal LSTs undergoing ESD, randomly allocated to training (TC, n = 354) and validation (VC, n = 152) cohorts (7:3). Synthetic minority over-sampling technique (SMOTE) was used in the TC to identify risk factors and construct a predictive model, which was validated in the VC. The incidence of post-ESD PEECS was 8.1% (41 cases). After applying the SMOTE, multivariate analysis identified sex, lesion with fibrosis, and intraoperative bleeding as independent risk factors. The scoring system assigned: 1 point for female sex, 3 points for lesion with fibrosis, and 2 points for intraoperative bleeding. In the VC, the model demonstrated an area under the curve (AUC) of 0.921, with a specificity of 0.949 and an accuracy of 0.908. Following risk stratification, the low-risk group (0-4 points) showed a PEECS incidence of 10.1% in the TC and 5.1% in the VC, while the high-risk group (5-6 points) exhibited 94.5% in the TC and 53.3% in the VC. In elderly patients with colorectal LSTs undergoing ESD, female sex, fibrotic lesions, and intraoperative bleeding were identified as independent predictors of PEECS. The proposed scoring system demonstrated good discriminatory ability in both cohorts and may be useful for risk stratification in this population.
This study aimed to refine risk stratification of advanced extranodal extension (ENE) in retropharyngeal lymph nodes (RLNs) and evaluate its prognostic significance. A total of 1,373 non-metastatic NPC patients at three centers between 2011 and 2021 were retrospectively enrolled. For advanced RLN ENE, we documented all involved structures, maximum axial diameter (MAD), presence of lymph node necrosis (LNN), and bilaterality. High-risk structures were identified using adjusted hazard ratios and LASSO-Cox models. Multivariable Cox models and Kaplan-Meier analyses were used to evaluate associations with survival outcomes. Of the 1,373 patients, 1061 had RLN metastasis, including 168 with advanced RLN ENE. Involvement of interval structures, the lower cranial nerves region, internal jugular vein, and longus capitis muscle was classified as high-risk, whereas isolated internal carotid artery involvement was low-risk. Advanced RLN ENE with high-risk structure involvement or LNN was defined as high-risk RLN ENE. High-risk RLN ENE was an independent adverse prognostic factor for NPC. N1/N2 patients with high-risk RLN ENE showed survival comparable to N3 disease. High-risk RLN ENE is an independent adverse prognostic factor in NPC. N1/N2 patients with high-risk RLN ENE exhibit N3-like survival, supporting its potential incorporation into future refinements of N staging.
To characterise the immune cellular landscape and paired B-cell and T-cell receptor repertoires of hypertrophic adenoids in children with obstructive sleep apnoea. We performed 10x Genomics 5' single-cell RNA sequencing with paired V(D)J profiling on adenoid tissues from children (AH, n = 4; control, n = 4) and analysed 72 076 high-quality cells. Compared with controls, AH adenoids exhibited an expanded B-cell compartment (62.26% vs 51.94%, P = 0.029) and a modest increase in plasmacytoid dendritic cells (0.37% vs 0.15%, P = 0.029), accompanied by reduced T-cell representation (34.19% vs 44.54%, P = 0.029). Within the B-cell compartment, GC B cell populations were expanded in AH, particularly Cycling B cells (15.07% vs 2.86%, P = 0.029), whereas memory B cells were reduced (21.48% vs 32.18%, P = 0.029). B-cell receptor analysis demonstrated reduced somatic hypermutation frequencies across multiple mature B-cell subsets in AH, accompanied by an isotype distribution skewed towards IgM with reduced class-switched fractions. Although CD8+ tissue-resident memory T-cell (TRM) frequencies were similar between groups, CD8+ TRM in AH adenoids displayed interferon-polarised and antigen-processing signatures, and T-cell clonal expansion occurred predominantly within this subset. These findings suggest that AH is not merely an anatomic cause of upper airway obstruction but also an immunologically active mucosal state associated with ongoing immune remodelling and antiviral defence.
Serum cholesterol level plays a vital role in cancer development. Several studies have suggested a potential relationship between non-high-density lipoprotein cholesterol (non-HDL-c) levels and cancer risk. However, little is known about the association between non-HDL-c levels and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs). This study aimed to explore the relationship between non-HDL-c levels and high-risk IPMNs. This retrospective study included 185 patients with IPMNs. Participants were divided into high and low non-HDL-c groups according to the third quartile of non-HDL-c levels. The associations between total cholesterol, non-HDL-c, and malignant IPMN were evaluated with univariate and multivariate logistic regression. In addition, the relationship between non-HDL-c levels and invasive carcinoma was examined. Finally, we explored the associations of the non-HDL-C/total cholesterol and non-HDL-c/HDL-c ratios with high-risk IPMNs. In addition to HDL-c levels, the average levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and carcinoembryonic antigen (CEA) in patients with high non-HDL-c levels were higher than those in the low non-HDL-c group (P < 0.05). In multivariate logistic regression analysis, non-HDL-c levels were significantly associated with the high-risk IPMNs (P = 0.043), but such an association was not observed between non-HDL-c levels and invasive carcinoma. No such relationship was observed between the non-HDL-c/TC ratio, non-HDL-c/HDL ratio, and high-risk IPMNs (P = 0.43; P = 0.16). High non-HDL-c levels are associated with high-risk IPMNs. Serum non-HDL-c levels may be a potential associated factor for high-risk IPMNs.
Titanium clips are commonly used to close mucosal defects after gastric lesion endoscopic submucosal dissection (ESD). However, prolonged titanium clip retention beyond the healing period may have potential negative effects on postoperative outcomes. This study developed and validated a scoring model to predict titanium clip retention at six months post-gastric ESD. A multicenter retrospective study was conducted on 1,055 patients who underwent gastric ESD with titanium clips closure for wound management. Patients were grouped into a training cohort (TC, n = 509), an internal validation cohort (IVC, n = 218), and an external validation cohort (EVC, n = 328). Univariate and multivariate logistic regression were applied to identify risk factors for titanium clip retention at the 6-month follow-up. A scoring system was then built by assigning weighted scores based on the regression coefficients of independent predictors. The model's performance was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and predictive values. Among the patients, 132 (12.5%) experienced prolonged titanium clip retention. Multivariate analysis revealed three independent predictors: tumor in the upper third of the stomach (2 points), diabetes (1 point), and the use of ≥ 8 clips (1 point). The scoring model exhibited strong predictive ability, with AUCs of 0.809 in the IVC and 0.855 in the EVC, along with high negative predictive values (0.946 and 0.984, respectively). Risk stratification classified patients into low-risk (0-1 points), intermediate-risk (2-3 points), and high-risk (4 points) groups. The observed retention rates were 3.5%, 14.8%, and 58.8% in the IVC, and 1.6%, 20.8%, and 76.5% in the EVC, respectively. The proposed predictive score, which combines tumor location, diabetic status, and clip number, effectively stratifies the risk of long-term titanium clip retention after ESD. This tool may assist in risk stratification for personalized postoperative surveillance, pending prospective validation.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by a highly immunosuppressive tumor microenvironment (TME) that facilitates immune evasion and tumor progression. Integrated analysis of TCGA and GEO datasets was performed to evaluate CALB2 expression and its prognostic significance in CRC. Functional experiments including proliferation, migration, colony formation, and apoptosis assays were conducted following CALB2 knockdown. Co-culture assays and multiplex immunohistochemistry (mIHC) were used to assess TME remodeling. Elevated CALB2 expression correlated significantly with poor prognosis in CRC patients. CALB2 knockdown suppressed CRC cell proliferation, migration, and colony formation, while promoting apoptosis. CALB2 silencing also reprogrammed TME by inducing macrophage M1 polarization, enhancing CD8+T cell cytotoxicity, and reducing immunosuppressive cell infiltration. Mechanistically, CALB2 activated the STAT3 signaling pathway to promote CCL5 secretion, facilitating M2 polarization of macrophages and activation of fibroblasts. Our findings identify CALB2 as a critical regulator of tumor progression and immune escape in CRC, acting through dual oncogenic and immunomodulatory mechanisms. CALB2 represents a promising therapeutic target for enhancing immunotherapy efficacy in CRC.
Researchers have postulated a link between higher levels of brain-derived neurotrophic factor (BDNF) and more favorable outcomes in patients with normal pressure hydrocephalus (NPH). However, there is no clear evidence regarding the causal association between neurotrophins and NPH. To delve deeper into this potential connection, scientists employed a rigorous method known as bidirectional Mendelian randomization (MR). This technique was utilized to explore the causal impact of various neurotrophins-such as BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), NT-4, ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF)-on the development or progression of NPH. To investigate the causal relationship between five neurotrophin subtypes and NPH, we designed a two-sample Mendelian randomization (MR) study using comprehensive genome-wide association study (GWAS) data. Our primary approach involved the inverse-variance weighted (IVW) method. We also conducted reverse causality analysis to ensure robustness. Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were employed to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. MR analysis of genetic prediction showed no statistical association of neurotrophins on NPH. However, a reverse analysis indicated a causal association between NPH and two neurotrophins: CNTF and GDNF. Specifically, individuals with NPH had a lower risk of CNTF (odds ratio: 0.7963, with a 95% confidence interval of 0.6537 to 0.9701, p = 0.0237) and a slightly reduced risk of GDNF (odds ratio: 0.9576, with a 95% confidence interval of 0.9226 to 0.9940, p = 0.0230). MR-Egger regression showed that pleiotropy did not affect the analysis. In addition, MR-PRESSO detected no outliers, and a leave-one-out analysis verified the robustness of the results. NPH was negatively and causally associated with CNTF and GDNF. Additional research is crucial to uncover the underlying mechanisms and devise strategies, including nutritional guidelines, to prevent NPH.
Circadian disruption and metabolic stress are implicated in Parkinson's disease (PD), but the epigenetic mechanisms linking nutrient fluctuations to circadian regulation remain poorly understood. Here, we combined genome-wide 5-hydroxymethylcytosine (5hmC) profiling, CRISPR-based genetic perturbations, and circadian models to investigate how glucose availability shapes epigenetic dynamics and circadian transcription. We found that low glucose activates AMP-activated protein kinase (AMPK), upregulating TET2 transcription and increasing global 5hmC remodeling. These effects are reversible upon glucose restoration and are abolished by AMPK deficiency, establishing AMPK as a key mediator of metabolic control over TET2. Notably, Tet2 exhibits intrinsic circadian rhythmicity and is temporally coupled with clock-associated gene expression. Disruption of TET2 impairs glucose-responsive 5hmC dynamics and alters circadian transcriptional outputs. Together, our findings define a glucose-responsive AMPK-TET2-5hmC axis that links metabolic state to epigenetic and circadian regulation. This work provides a mechanistic framework for understanding how metabolic dysfunction may contribute to circadian abnormalities in Parkinson's disease.
Although various submucosal injection solutions are used in endoscopic submucosal dissection (ESD), whether they should routinely contain a staining agent remains debated. This study aimed to compare the efficacy and safety of dye-free submucosal injection solutions (DFSIs) versus dye-containing submucosal injection solution (DCSIs) for colorectal laterally spreading tumors (LSTs). This retrospective study included 526 patients with colorectal LSTs who underwent ESD between January 2021 and December 2025. Patients were divided into two groups based on the injection solution used: DFSIs (n = 138) and DCSIs (n = 388). The primary safety endpoint was severe intraoperative bleeding. Primary efficacy endpoints included total procedure time, mucosal dissection time, and submucosal dissection speed. Subgroup analyses were performed according to tumor characteristics and technical factors. Baseline characteristics were comparable between groups. While R0 resection, perforation, and postoperative complication rates were similar (all P > 0.05), the DFSIs group was associated with a significantly lower rate of severe intraoperative bleeding (0.0 vs. 3.9%, P = 0.015). Sensitivity analysis using Firth's penalized logistic regression confirmed a reduced odds of severe bleeding associated with DFSIs (odds ratio 0.096, 95% CI 0.002-0.960, P = 0.026). Subgroup analyses revealed that DFSIs were associated with a statistically significant reduction in total procedure time for lesions ≥ 3.5 cm (P = 0.005), left colon lesions (P = 0.007), fibrotic lesions (P = 0.040), and when traction (P = 0.009) or pocket-creation methods (P = 0.024) were used. Mucosal dissection time was also shorter for lesions ≥ 3.5 cm (P = 0.001), left colon lesions (P = 0.008), fibrotic lesions (P = 0.027), and with traction method (P = 0.036). DFSIs are safe and effective for colorectal LST ESD. Despite comparable overall outcomes, exploratory subgroup analyses suggested potential advantages of DFSIs in complex cases, including shorter procedure times for larger or fibrotic lesions.
Plant polysaccharides have demonstrated significant potential for the management of metabolic diseases. This study investigated the protective effects of polysaccharide from North Hawthorn (NHP) against high-fat diet (HFD)-induced metabolic disorders in mice. Oral NHP administration (200-800 mg/kg/day) for 12 weeks dose-dependently alleviated HFD-induced weight gain, dyslipidemia, hepatic steatosis, and inflammation. Furthermore, NHP ameliorated oxidative stress by reducing MDA levels and enhancing SOD activity, which was mechanistically linked to the activation of the Nrf2/Keap1/HO-1 pathway. 16S rRNA sequencing revealed that NHP administration restored gut microbial diversity and increased the abundance of beneficial bacteria, including Lactobacillus, Bifidobacterium, and Akkermansia muciniphila. Integrated correlation analysis indicated strong associations between these microbiota changes and improved metabolic and inflammatory parameters. These findings demonstrate that NHP alleviates HFD-induced metabolic dysfunction through simultaneous regulation of the gut-liver axis and activation of the Nrf2/Keap1/HO-1 pathway, highlighting its potential as a novel prebiotic agent for managing obesity-related metabolic disorders. The online version contains supplementary material available at 10.1007/s10068-026-02133-9.
Anemia is associated with cognitive decline, but the influence of its temporal patterns on cognitive trajectories remains unknown. This study investigated the longitudinal association between dynamic anemia patterns (persistent, intermittent, never) and cognitive function in middle-aged and older Chinese adults. We analyzed data from 6,364 participants aged ≥ 45 years in the China Health and Retirement Longitudinal Study (2011-2020). Based on 2011 and 2015 hemoglobin measurements, participants were categorized as never, intermittent, or persistent anemia. Linear mixed-effects models assessed associations with cognitive function. Sensitivity analyses included multiple imputation, varying anemia thresholds, and inverse probability weighting. Based on hemoglobin levels in 2011 and 2015, 4,769 (74.9%) participants had never anemia, 1,201 (18.9%) had intermittent anemia, and 394 (6.2%) had persistent anemia. In linear mixed-effects models adjusted for age and sex, both intermittent anemia (β = -0.31, 95% CI: -0.56 to -0.06, P = 0.016) and persistent anemia (β = -0.47, 95% CI: -0.88 to -0.06, P = 0.025) were associated with lower baseline cognitive scores compared to the never anemia group. However, only persistent anemia was associated with a faster rate of cognitive decline over time (time × persistent anemia: β = -0.057, 95% CI: -0.100 to -0.014, P = 0.009), whereas the interaction for intermittent anemia was not significant (time × intermittent anemia: β = 2.18e-5, 95% CI: -0.025 to 0.025, P = 0.999). Sensitivity analyses, including multiple imputation and inverse probability weighting, and analyses using different diagnostic thresholds produced directionally consistent results, with more lenient thresholds attenuating the effects; the WHO threshold demonstrated the strongest discriminatory power. Transition pattern analysis revealed that, compared to the persistently normal group, the persistent anemia and incident anemia groups maintained lower cognitive levels throughout follow-up, whereas anemia remission was associated with significant, though incomplete, cognitive improvement. Persistent anemia is associated with the most rapid cognitive decline, while intermittent anemia is associated with lower baseline cognition. Improvement in anemia status may confer cognitive benefits, highlighting the importance of dynamic anemia monitoring and timely intervention in cognitive health management.
Selegiline, rasagiline, safinamide, and zonisamide are commonly used with levodopa to manage motor fluctuations in Parkinson's disease (PD). This study compared the efficacy and safety of these agents as adjuncts to levodopa in Asian PD patients with motor fluctuations. A Bayesian network meta-analysis (NMA) was conducted. Randomized controlled trials (RCTs) published from database inception to August 31, 2025 were identified through PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, Wanfang, and ClinicalTrials.gov. Eligible studies enrolled PD patients treated with levodopa plus any of the four agents. Primary outcomes included changes in daily OFF-time and Unified Parkinson's Disease Rating Scale (UPDRS) Part III score. This study is registered in PROSPERO (CRD42024627701). Eleven RCTs involving 2824 patients were included, no eligible RCTs evaluating selegiline in Asian PD patients were identified for inclusion in the analysis. All combination therapies, except for zonisamide 25 mg, were more effective than levodopa plus placebo. NMA indicated that safinamide 100 mg was significantly superior to both rasagiline 1 mg and zonisamide 25 mg in reducing OFF-time (safinamide 100 mg vs. rasagiline 1 mg: MD = - 0·52, 95% CI - 0·97 to - 0·07; safinamide 100 mg vs. zonisamide 25 mg: MD = - 0·84, 95% CI - 1·46 to - 0·22) and improving UPDRS III score (safinamide 100 mg vs. rasagiline 1 mg: MD = - 2·00, 95% CI - 3·30 to - 0·67; safinamide 100 mg vs. zonisamide 25 mg: MD = - 2·50, 95% CI - 4·10 to - 0·94). Compared with zonisamide 50 mg, safinamide 100 mg showed a trend toward a reduction in OFF-time (MD = - 0·56, 95% CI - 1·18 to 0·08) and UPDRS III score (MD = - 1·40, 95% CI - 2·90 to 0·08). Safinamide 100 mg ranked first in SUCRA ranking for reducing OFF-time and UPDRS III score. These findings were robust in sensitivity analyses. The findings suggest that levodopa in combination with safinamide 100 mg is more efficacious than combinations with rasagiline 1 mg or zonisamide 25 mg for alleviating motor fluctuations and improving motor symptoms in Asian PD patients, and shows a more favourable (though not statistically significant) trend compared with zonisamide 50 mg.
Piecemeal resection (PR) during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) is associated with an increased risk of tumor recurrence and incomplete resection. Identifying risk factors and developing a predictive model for PR may aid in preoperative planning and patient counseling. This multi-center retrospective study analyzed 809 patients who underwent ER for gGISTs. Patients were divided into a training cohort (TC, n = 387), an internal validation cohort (IVC, n = 166), and an external validation cohort (EVC, n = 256). Baseline characteristics were compared between the en bloc resection and PR groups in the TC. Independent risk factors for PR were identified using multivariate logistic regression analysis, based on which a scoring system was developed. The model underwent internal and external validation, and its performance was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. In the TC, tumor size ≥ 2.5 cm (OR = 2.61, 95% CI 1.28-5.45, P = 0.009), irregular shape (OR = 5.03, 95% CI 2.28-11.08, P < 0.001), severe intraoperative bleeding (OR = 5.53, 95% CI 2.23-13.55, P < 0.001), and operator experience < 50 cases (OR = 4.23, 95% CI 2.10-8.73, P < 0.001) were independently associated with piecemeal resection. A scoring system based on these factors showed good predictive performance, with AUCs of 0.799 in the TC, 0.847 in the IVC, and 0.842 in an EVC. Sensitivity and specificity ranged from 0.652 to 0.818 and 0.736 to 0.833, respectively. We developed and validated a simple scoring system incorporating tumor size, shape, intraoperative bleeding, and operator experience to predict the risk of piecemeal resection during endoscopic resection of gGISTs. This tool may assist in preoperative risk stratification and optimize treatment strategies.
The prevalence of drug-induced acute liver injury, represented by acetaminophen (APAP), has seriously threatened human lives. Macrophages play an important role in acute liver injury; however, the treatment options remain limited. Therefore, exploring the pathogenesis of the disease and developing new treatment strategies targeted macrophages are particularly important. This study innovatively evaluates the hepatoprotective effects of magnesium isoglycyrrhizinate (MgIG) and elucidates its underlying mechanisms modulating Kupffer cell (KC) inflammation using an APAP-overdose mouse model. Hyperglycaemia was induced in C57BL/6J mice by streptozotocin treatment, and the mice were randomly divided into Saline, APAP, APAP + NAC, and APAP + MgIG groups. The data demonstrated that APAP administration elicited pronounced histopathological injury and markedly upregulated serum transaminases (ALT and AST). Treatment with MgIG ameliorated these histological lesions and suppressed transaminase elevations, paralleling the effect of N-acetylcysteine (NAC). APAP induced oxidative stress in KCs, as evidenced by increased malondialdehyde (MDA) levels, decreased superoxide dismutase (SOD) activity, and a reduction in glutathione (GSH) content. Moreover, APAP exposure significantly impaired autophagy in KCs. MgIG mitigated oxidative damage and restored autophagic activity through the AMPK/AKT signalling cascade. Notably, combined treatment with MgIG and NAC produced even greater protection against APAP-induced hepatic injury. This study demonstrates that MgIG provides both protective and therapeutic effects in APAP-challenged mice with hyperglycaemia by modulating autophagy and oxidative stress in liver-resident macrophages.
Trigeminal neuralgia (TN) typically presents with paroxysmal, shock-like, or stabbing pain in the unilateral facial region corresponding to the trigeminal nerve distribution. However, cases manifesting solely as isolated tongue pain are exceedingly rare. A 63-year-old female presented with a two-year history of left-sided tongue pain. She was initially suspected of having glossopharyngeal neuralgia (GPN) and treated with oxcarbazepine at the local hospital, which provided suboptimal relief. Over the past two months, her pain intensified significantly. Upon referral to our department, a comprehensive evaluation was conducted-including a detailed history, neurological examination and high-resolution magnetic resonance imaging (MRI). However, we ruled out the diagnosis of glossopharyngeal neuralgia and strongly believe the patient suffered from trigeminal neuralgia. First, MRI imaging revealed vascular compression of the trigeminal nerve. Then, glossopharyngeal nerve block helped rule out glossopharyngeal neuralgia. Most importantly, intraoperative exploration confirmed definite vascular compression of the trigeminal nerve, while vessels were observed adjacent to the glossopharyngeal nerve without significant compression. The patient subsequently underwent left microvascular decompression (MVD) of the trigeminal nerve. Postoperatively, her pain resolved completely. Trigeminal neuralgia and glossopharyngeal neuralgia share overlapping clinical features, pathogenesis, imaging findings and triggering factors. These two diseases are typically distinguished by their characteristic pain locations. This case illustrates a diagnostically challenging presentation of TN, with pain confined exclusively to the tongue, which is highly prone to being misdiagnosed as glossopharyngeal neuralgia. The definitive identification of neurovascular compression on imaging, coupled with the complete resolution of pain following MVD, conclusively confirmed the diagnosis of TN. This report emphasizes that clinicians should meticulously analyze pain distribution and correlate it with imaging evidence of vascular compression to accurately differentiate between these two entities, thereby avoiding misdiagnosis and mitigating the risk of unnecessary interventions or secondary injury.
Itaconate is a Krebs cycle-derived metabolite whose production is catalyzed by immune response gene 1 (IRG1). As an anti-inflammatory metabolite, itaconate primarily exerts its effects through alkylation of target proteins. Previous studies have identified the JAK-STAT pathway as a key therapeutic target in sepsis. Interestingly, we report that itaconate, a metabolite significantly upregulated during metabolic reprogramming, suppresses type I interferon (IFN-I) signaling. Exogenous supplementation with the itaconate derivative 4-octyl itaconate (4OI) inhibits the JAK-STAT pathway. Mechanistically, 4OI inhibits the binding of tyrosine kinase 2 (TYK2) to IFNAR1 and JAK1 to IFNAR2 by alkylating cysteine 192 in TYK2 and cysteine 189 in JAK1. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid (TCA) cycle in restricting JAK-STAT signal transduction, thereby linking metabolism and innate immunity, and provides a theoretical basis for the therapeutic application of 4OI in sepsis.
Myocardial ischemia remains one of the principal causes of mortality and morbidity worldwide, necessitating novel approaches to facilitate early diagnosis and subsequent risk evaluation following reperfusion. Although advancements in wearables capable of ECG (electrocardiogram) monitoring have been initiated, these devices have encountered barriers due to limited capacities to encapsulate the temporally complex nature of ischemic events, notably in risk stratifying reperfusion injury. In this paper, we describe a framework that leverages bionic, wearable ECG sensor technologies along with multimodal large language models using a coherent temporal modeling effort to address the intertwining of fine-grained temporal dependencies, heterogeneous biomedical modalities, and interpretable risk stratification. Our temporally hierarchical fusion transformer utilizes a cross-granularity attention mechanism to model intrabeat, interbeat, and long-term dependencies all simultaneously. The validation of our system was carried out using 4 datasets across n = 108,778 patients, 17,173 of whom were ischemia-positive cases (4,627 from PTB-XL, 5,243 from MIMIC-IV, 6,891 from CODE-15%, and 412 in the wearable cohort). The area under receiver operating characteristic curve (AUROC) for the model for ischemia was 0.947, and the C-index for post-reperfusion risk stratification was 0.923, with a relative AUROC improvement of 4.8% to 9.5% over the best baseline in each dataset. Importantly, we achieved an average lead time of 18.4 min prior to the ischemic event to allow the clinician to enact interventions. Ultimately, this research demonstrates a prototype of an intelligent cardiovascular care monitoring system that couples advanced sensing with clinical decision support.