Annals of medicine最新文献

Background: Voltage-gated sodium channels (VGSCs) are fundamental to electrical signalling in excitable cells, and their dysfunction underlies a wide range of channelopathies. While the existence of nine distinct α-subunit genes contributes to VGSC diversity, alternative splicing serves as a significant post-transcriptional mechanism that profoundly expands their proteomic and functional repertoire. Dysregulation of this splicing process is increasingly linked to disease pathogenesis.

Introduction: This review aims to provide a comprehensive synthesis of the alternative splicing landscape across all nine VGSC α-subunits. It systematically catalogs known splicing variants, details their roles in developmental regulation, tissue-specific expression and fine-tuning of channel biophysics, and examines the regulatory networks controlling these events.

Discussion: We detail conserved splicing switches (e.g. the 5N/5A exon in neuronal channels) and isoform-specific events across the VGSC family (Nav1.1 to Nav1.9), evaluating their functional and clinical impacts. The regulation of these events by key RNA-binding proteins (RBPs), such as Rbfox and Nova2, within cell-type-specific networks is emphasized. Furthermore, we discuss how splicing dysregulation contributes to channelopathies and evaluate the promising potential of novel therapeutic strategies, particularly antisense oligonucleotides (ASOs), to correct pathogenic splicing defects.

Conclusions: By integrating mechanistic insights with clinical implications, this review establishes alternative splicing as a central theme in VGSC biology and pathophysiology. It highlights the critical need for, and the emerging path towards, precision medicine approaches that target splicing defects for the treatment of VGSC-associated disorders, providing a foundational resource to guide future research and therapeutic development.

Background: Cellular senescence plays a critical role in the pathogenesis and progression of osteoarthritis (OA), contributing to articular cartilage degradation, chronic inflammation, and joint function impairment. Mesenchymal stem cells/stromal cells (MSCs) and their derivatives have emerged as potential targets for novel therapeutic strategies against cell senescence in OA, as they exert anti-aging effects in repairing damaged cartilage through multiple mechanisms-including regulating age-related signaling pathways, reducing the secretion of pro-inflammatory cytokines, and improving mitochondrial function.

Discussion: In recent years, a growing body of in-depth studies has focused on various types of MSCsand their derivatives, revealing subtle differences in their anti-cell senescence pathways and therapeutic effects. This review summarizes the latest cutting-edge research, systematically exploring the multi-dimensional roles of these MSCs and their derivatives in ameliorating senescent cell-related pathology in OA, and highlighting their potential clinical application value.

Conclusions: Despite the promising anti-aging effects of MSCs and their derivatives in OA treatment, further molecular-level mechanistic studies and large-scale clinical trials are required to verify the efficacy and safety of therapies based on their anti-cell senescence properties. These efforts are expected to provide new breakthroughs in the clinical management of OA, offering more effective treatment options for patients.

Background: Treatment of brain injuries and neurodegenerative disorders is a critical challenge due to poor regenerative capabilities of the central nervous system. The current therapeutic strategies are primarily focussed on treating the symptoms than addressing the core issue of loss of neurons. Despite advances in stem cell therapies and surgical alternatives, they are not always successful due to challenges like immune rejection and limited efficacy. Direct neuronal reprogramming of endogenous somatic cells is a promising approach to restore lost neurons. This review evaluates traditional reprogramming techniques and their limitations, explores novel in-vivo strategies that address older problems, and analyse clinical trial outcomes to identify key knowledge gaps to guide future research.

Discussion: Traditional neuronal reprogramming is based on in-vitro ectopic expression of lineage-specific transcription factors. To overcome hurdles posed by in-vitro reprogramming, such as insertional mutagenesis, and variable efficiency, in-vivo approaches have emerged. These techniques employ small molecules, nonviral gene delivery, and CRISPR-based activation to reduce protocol complexity and improve cell survival. Combined methodologies integrate transcription factor cocktails with epigenetic modifiers, microRNAs, and neurotrophic factors, and show further enhancements. Despite these advances, translation to clinical applications has been modest. Early-phase trials report limited functional improvements and highlight risks of off-target effects, inconsistent delivery specificity, and unresolved immunogenicity.

Conclusions: Direct neuronal reprogramming offers a viable strategy for replenishing neuronal cell mass in neurodegenerative diseases and brain injuries through autologous therapy. Novel in-vivo and combined approaches show promise in addressing the shortcomings of traditional methods. However, further preclinical validation, comprehensive safety assessments, and uniform frameworks are essential for clinical translation. Future studies should prioritize refining delivery platforms, minimizing off-target reprogramming events, and developing robust biomarkers to monitor conversion efficiency and functional outcomes.

Background: Esophageal cancer is a major health burden, with smoking and alcohol as preventable risk factors. Comprehensive assessments of long-term trends, disparities, and future projections remain insufficient.

Methods: Using data from the Global Burden of Disease Study 2021, this observational study evaluated the burden of esophageal cancer attributable to smoking and alcohol-attributable esophageal cancer burden across 204 countries (1990-2021). Metrics included disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR). Temporal trends were assessed using estimated annual percentage change, decomposition analysis quantified drivers of burden changes, and a Bayesian age-period-cohort model projected burden to 2040.

Results: From 1990 to 2021, global deaths and DALYs increased, while ASMR and ASDR declined. Burden was uneven ; males had higher burden than females and peak burden occurring in the 65-79 age group. Geographically, ASRs declined notably in Central Asia and Latin America but rose sharply in West Africa. Middle SDI regions had the highest absolute burden; low-middle SDI regions showed increasing alcohol-attributable ASRs. Population growth and aging were primary drivers of absolute burden increases. Projections indicate continued declines in age-standardized rates, but male burden will remain higher.

Conclusions: Despite declining age-standardized risks, smoking and alcohol remain major drivers of the global burden of esophageal cancer. Population growth and aging will further increase absolute case numbers. Projections to 2040 show continued declines in age-standardized mortality and DALY rates, yet male burden will remain substantially higher. Prevention should prioritize tobacco/alcohol control and targeted strategies for high-burden regions, males, and the elderly.

Background: Twin pregnancies carry perinatal risks. Gestational weight gain (GWG) is modifiable, but Institute of Medicine (IOM) twin recommendations may not suit Chinese women.

Method: A retrospective cohort study included 3109 twin pregnancies delivered at Northwest Women's and Children's Hospital in Xi'an, China, during 2018-2022. Pre-pregnancy BMI was classified according to WHO criteria, with Chinese criteria used in sensitivity analyses. Optimal BMI-specific GWG ranges were defined as the interquartile range among low-risk pregnancies. GWG adequacy (below/within/above) was evaluated against study-derived and IOM-recommended ranges. Associations were estimated using multivariable generalized estimating equations, with threshold-effect and smooth-curve analyses to assess nonlinearity.

Results: Optimal GWG ranges were: underweight, 15.91-23.68 kg; normal, 14.80-21.46 kg; overweight, 12.95-19.98 kg; obese, 7.03-17.76 kg. GWG below range increased risks of moderate preterm birth (MPTB) (OR 1.62, 95% CI 1.29-2.04), very preterm birth (VPTB) (OR 1.90, 95% CI 1.34-2.70), low birth weight (LBW) (OR 1.87, 95% CI 1.61-2.17), and small for gestational age (SGA) (OR 1.31, 95% CI 1.08, 1.59). Excessive GWG raised large for gestational age (LGA) risk (OR 1.98, 95% CI 1.59, 2.46) but lowered LBW (OR 0.69, 95% CI 0.59-0.81) and SGA (OR 0.75, 95% CI 0.60, 0.95). Nonlinear analyses showed U-shaped risks for MPTB, VPTB, and Apgar ≤ 7; inverted U-shaped for gestational age and birth weight; J-shaped for LGA.

Conclusions: BMI-specific GWG recommendations derived from this large Chinese twin cohort are lower than IOM values. Both inadequate and excessive GWG increase adverse perinatal risks.

Background: Chronic hepatitis B (CHB) is a major cause of hepatocellular carcinoma (HCC). In patients receiving CHB treatment, coexistence of steatotic liver disease (SLD) and cardiometabolic risk factors (CMRFs) markedly influence HCC risk. This study explored hepatic and metabolic profiles, HCC predictors, and the modifying roles of SLD and CMRFs in CHB.

Methods: This study included 1012 patients receiving nucleos(t)ide analogs between 2004 and 2022. They were stratified into SLD (N = 702) or non-SLD (N = 310) groups.

Results: Over a 5.5-year follow-up period, 73 patients developed HCC. At baseline, the SLD group had younger age, higher body mass index values, lower fibrosis indices, and more severe metabolic dysregulation than did the non-SLD group. SLD conferred protection against HCC (adjusted hazard ratio: 0.43; p = 0.001). However, the presence of ≥2 CMRFs significantly increased HCC risk (adjusted hazard ratio: 1.93; p = 0.009). The highest HCC risk was observed in patients without SLD having ≥2 CMRFs (5-year incidence rate: 21.4%). The protective effect of SLD persisted after inverse probability of treatment weighting. It was most pronounced in older, cirrhotic, and high-metabolic-risk subgroups. Hepatitis B virus DNA suppression, hepatitis B surface antigen decline, and fibrosis score improvement during treatment were similar between the two groups.

Conclusions: Among patients with CHB receiving nucleos(t)ide analogs, those without SLD having ≥2 CMRFs had the highest risk of HCC. Thus, steatosis and metabolic burden should be incorporated into precision risk stratification.

Introduction: Programmatic assessment offers a system-level approach to evaluating students' competence by integrating multiple low-stakes assessments, longitudinal evidence and expert judgement. Although widely adopted across several health education disciplines in Australia, radiography education providers have not implemented programmatic assessment at a programme or course level. This paper proposes a radiography-specific programmatic assessment framework. The objective is to translate core programmatic assessment principles into curriculum design strategies that strengthen feedback, improve the defensibility of decisions and enhance national workforce readiness.

Discussion: The paper outlines key purposes of programmatic assessment in undergraduate radiography education including supporting learning, strengthening feedback mechanisms, tracking developmental progress and enabling defensible decisions grounded in longitudinal evidence. Critical design considerations include aligning assessments with a capability framework, generating evidence across diverse clinical contexts, prioritising narrative feedback and using portfolios as central evidence repositories. The analysis highlights the importance of competence committees for high-stakes decisions and the need to support shared assessment practices across varied clinical placement environments. The proposed radiography model integrates six components: capability framework, evidence generation, evidence aggregation, interpretation, decision-making and system learning. This model addresses radiography's multimodality workflow, training variation across sites and accreditation requirements for fairness, transparency and systematic monitoring.

Conclusion: Programmatic assessment offers a coherent approach to strengthening radiography education by supporting clearer insight into learner development and ensuring consistent evidence of capability achievement across clinical environments. When adapted to radiography's multimodality practice and evolving workforce demands, programmatic assessment enhances readiness for independent practice and supports continuous curriculum improvement.

Introduction: The imbalance between osteoblasts and osteoclasts is central to osteoporosis.Insulin like growth factor (IGF) has protective effects on bone. As an IGF-binding protein, the role of IGFBP in bone has also begun to come into the public's view. IGFBP not only serves as an IGF reservoir but also acts independently, interacting with other ligands to regulate cell proliferation and differentiation. Due to the complexity of the molecular network of IGF-IGFBP, the specific mechanism by which IGF-IGFBP affects bone is still unknown. This review introduces the IGF-IGFBP network and its roles in osteogenesis and osteoclast differentiation, and explores its potential as a novel therapeutic target for osteoporosis.

Method: Relevant studies were identified in PubMed and Web of Science using the keywords 'IGFBP', 'Bone', and 'Osteoporosis', followed by a comprehensive review of the literature.

Results: IGF-IGFBP regulates bone metabolism by modulating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteogenic and adipogenic lineages, as well as the differentiation process of osteoclasts. Current studies mainly focuson osteogenic differentiation, while research on adipogenic and osteoclastogenic differentiationis limited. Some IGFBP molecules show inhibitory effects in osteogenesis, but their detailed molecular mechanisms are not fully elucidated.

Conclusion: The IGF-IGFBP family influences bone metabolism through multiple biological pathways. However, the precise molecular mechanisms by which this system regulates bone metabolism remain incompletely understood. Future studies are needed to systematically elucidate its functional networks and pathophysiological significance in bone metabolism.

Background: Walking impairments post-stroke are common but studying their neural basis with fMRI is difficult due to motion constraints. This study used post-task resting-state residual activity (PTRRA) to investigate walking-related neural activity without in-scanner movement.

Methods: Ten patients with subcortical ischemic stroke and ten matched healthy controls underwent two resting-state fMRI sessions: one immediately after overground walking, and another after a 20-minute delay. Clinical assessments included Fugl-Meyer Assessment and Timed Up-and-Go Test (TUGT). Analyses included ALFF, functional connectivity (FC), and graph theory.

Results: Significant group × time interactions showed that stroke patients had increased ALFF in the contralesional primary somatosensory cortex (S1) during the delayed session. This increase inversely correlated with TUGT scores (r = -0.677, p = 0.032). Enhanced FC was found between contralesional S1 and ipsilesional sensorimotor regions. ALFF changes and bilateral S1 FC were significantly associated with mobility outcomes. Graph theory results were atlas-dependent.

Conclusion: Increased contralesional S1 activation and its enhanced connectivity with bilateral motor areas may reflect adaptive changes supporting post-stroke balance. The PTRRA method proved feasible for capturing post-walk neural activity and may be useful for assessing large-scale network dynamics after stroke.