Huntington’s disease (HD) is an inherited illness. 3-Nitropropionic acid (3-NPA) is a recognized neurotoxin that resembles symptoms similar to HD in laboratory animals and neuroinflammation via the activation of high mobility group box-1 (HMGB1)/Toll-like receptor-4 (TLR-4)/nuclear factor-κB (NF-κB) signaling cascade. Rifampicin (RIF) and probucol (PROB) have been shown to inhibit proposed pathway. The primary aim of this study is to investigate the impact of RIF and PROB on the HMGB1/TLR-4/NF-κB signaling cascade in 3-NPA-induced neurotoxicity. Molecular docking and molecular dynamics simulation (100 ns) were employed to assess target-binding affinity. In vivo investigation employed either sex Wistar rats. 3-NPA (10 mg/kg i.p.) was administered along with PROB (10, 20, and 40 mg/kg p.o.) and RIF (20, 40, and 80 mg/kg i.p.) for 21 days, and assessed in terms of percentage change in body weight, behavioral activities (narrow beam walk, open field test, and rotarod), quantitative real time polymerase chain reaction (qRT-PCR) (caspase-3, Bax, and Bcl-2), neuroinflammatory markers (tumor necrosis factor-alpha, interleukin-1β, and interleukin-6), Western blotting (HMGB1 and NF-κB), and immunohistochemistry (IHC) [pTLR-4]. In silico studies demonstrated that both drugs have good binding affinity and stability with different targets. In vivo investigation revealed that administration of both RIF and PROB significantly rescued 3-NPA-induced behavioral alterations, modulation of HMGB1/TLR-4/NF-κB signaling, apoptotic markers, and neuroinflammation. Both RIF and PROB showed protective effects by inhibiting HMGB1 through TLR-4, thereby further inhibiting HMGB1-mediated downstream signaling axis and apoptosis. Hence, our findings suggest that RIF and PROB may have ability to mitigate 3-NPA-induced neurotoxicity via HMGB1/TLR-4/NF-κB signaling pathway.
Early revascularization and contemporary medical management for myocardial infarction (MI) have significantly improved patients’ survival and performance. However, despite significant advances in MI therapies, several challenges remain in improving cardiac recovery and optimizing long-term clinical outcomes, including persistent cardiomyocyte loss, adverse ventricular remodeling, and subsequent cardiac complications. These have prompted increasing exploration of regenerative approaches for MI, which focus on repairing, regenerating, and/or replacing damaged myocardial tissue to restore cardiac structure and function. This includes stem cell-based therapies, cell-free approaches, gene therapy, tissue engineering, and blood-based regenerative strategies. While significant progress has been made in both preclinical and clinical studies of these regenerative therapies, further research is required to optimize their therapeutic efficacy. This review provides a summary of the recent advances, clinical progress, and translational limitations of some of the commonly investigated regenerative therapies for MI.
Indeterminate thyroid nodules classified as Bethesda III (atypia of undetermined significance) and Bethesda IV (follicular neoplasm) remain a diagnostic challenge because cytomorphology alone cannot reliably distinguish benign from malignant disease. Molecular testing has emerged as an adjunct to cytological, sonographic, and clinical assessment to refine preoperative risk stratification and inform management. This narrative review critically summarizes current evidence for major commercially available molecular platforms, including the Afirma Gene Expression Classifier, Afirma Genomic Sequencing Classifier (GSC), ThyroSeq v3, and ThyGeNEXT ® /ThyraMIR ® , with emphasis on diagnostic performance, clinical utility, limitations, and contemporary practice integration. In pivotal validation studies, Afirma GSC demonstrated a sensitivity of 91%, specificity of 68%, positive predictive value (PPV) of 47%, and negative predictive value (NPV) of 96%, whereas ThyroSeq v3 demonstrated a sensitivity of 94%, specificity of 82%, PPV of 66%, and NPV of 97%. In a blinded multicenter validation study of Bethesda III/IV nodules, ThyGeNEXT/ThyraMIR demonstrated prevalence-adjusted sensitivity of 95%, specificity of 90%, PPV of 75%, and NPV of 97% at a standardized disease prevalence of 30%. These estimates should not be interpreted as direct head-to-head comparisons because studies differ in population characteristics, disease prevalence, reference standards, assay generation, and classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Clinical-utility evidence indicates that molecular testing can influence decisions regarding surveillance and surgery and may reduce potentially avoidable diagnostic operations, although the magnitude of benefit varies across assays and clinical settings. The Bethesda System for Reporting Thyroid Cytopathology supports selective molecular testing when results are expected to meaningfully influence management. Molecular testing should therefore be regarded as an adjunct to integrated risk assessment rather than a stand-alone determinant of management, with results interpreted alongside cytological, sonographic, clinical, patient-specific, and institutional factors.
Gait speed is a key indicator for diagnosing sarcopenia, validated by both the European Working Group on Sarcopenia in Older People in 2018 and the Asian Working Group on Sarcopenia in 2019 for assessing physical performance. While global data link vitamin D to physical performance, regional sex-stratified evidence in East Asian populations remains limited. This study aims to validate and confirm the association between gait speed and vitamin D levels in a middle-aged and older population in Taiwan. This cross-sectional investigation focused on community-dwelling residents. Participants were assigned to vitamin D sufficiency (>= 30 ng/mL), insufficiency (<30 ng/mL and >= 20 ng/mL), and deficiency (<20 ng/mL) defined by the American Endocrine Society and International Osteoporosis Foundation criteria. Analyses included Student's t-tests, analysis of variance (ANOVA), Chi-square test and sex-stratified multiple linear regression. A total of 396 participants (164 men and 232 women) were recruited, with a mean age of 65.18 +/- 8.75 years; mean serum vitamin D concentration of 28.25 +/- 9.45 ng/mL; and mean gait speed of 0.91 +/- 0.23 m/s. A positive association between gait speed and 25(OH)D (p = 0.047), and a negative association between gait speed and age (p < 0.001) and body mass index (BMI) (p = 0.005) were observed in men. Conversely, in women, gait speed was negatively associated with age (p < 0.001), BMI (p = 0.010), hypertension (p = 0.027), and diabetes mellitus (p = 0.009). This study demonstrated a positive association between gait speed and serum 25(OH)D levels in middle-aged and older men.
Falls impose a major public health burden on middle-aged and older adults. Coexisting cardiovascular disease (CVD) and arthritis further increases fall risk, yet targeted prediction models remain scarce, especially in Chinese populations. We analyzed 633 China Health and Retirement Longitudinal Study participants aged >= 45 years with comorbid CVD and arthritis at the 2015 baseline. Seven predictors were selected through univariate analysis, LASSO logistic regression (LR), and clinical review. Eight machine-learning algorithms were compared. Among models with an area under the receiver operating characteristic curve (AUC) >= 0.72, the model with the highest specificity was preferred to reduce false-positive referrals. A geographically defined holdout group (n = 110) from different provincial-code regions, but within the same CHARLS source population, was treated as a geographic split-sample rather than independent external validation. Performance was assessed using AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), F1-score, calibration, decision-curve analysis, precision-recall curves, and SHapley Additive exPlanations (SHAP). During cumulative follow-up, 296 participants (46.8%) reported at least one fall. Random forest (RF) and LR achieved similar internal-validation AUCs (0.730 vs. 0.729); RF was selected because of higher specificity. Internally, RF showed 87.5% specificity, 37.7% sensitivity, 70.3% PPV, 64.2% NPV, and an F1-score of 0.491. Its AUC in the geographic holdout sample was 0.735. Despite similar AUCs, sensitivity and specificity differed substantially between samples, suggesting limited regional stability of the fixed threshold. SHAP identified fall history, ankle pain, activities of daily living impairment, and sleep duration as the most influential predictors. The RF model showed moderate discrimination and a conservative, high-specificity profile. However, its low internal sensitivity means it should not be used alone to rule out falls or as a diagnostic tool. Pending independent validation and regional threshold calibration, it may serve only as adjunctive stratification within a stepped assessment pathway and should not replace routine clinical fall-risk screening.
