Search Results (3,894)

Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions that may present with developmental delay, intellectual disability, language impairment, epilepsy, autism-like features, motor abnormalities, or syndromic manifestations. Ubiquitination is an essential post-translational mechanism that regulates protein stability, localization, trafficking, and signaling. Because E3 ubiquitin ligases determine substrate specificity in this process, abnormalities in E3 ligases or E3-associated complexes can selectively affect proteins required for brain development and neuronal function. This review summarizes genetic and functional evidence linking E3 ubiquitin ligases, E3-complex components, substrate-recognition factors, and related ubiquitination regulators to NDDs. Gene Ontology enrichment analysis and mechanistic studies suggest that these genes converge on several major biological themes, including early neurodevelopment, neuronal migration, synaptic and circuit maturation, proteostasis, metabolism, and intracellular trafficking. However, the strength and translational relevance of the available evidence vary across genes. UBE3A-related Angelman syndrome currently provides the clearest example of mechanism-guided therapeutic development through UBE3A restoration and paternal allele reactivation. In contrast, many non-UBE3A mechanisms remain at the stage of pathway analysis, preclinical modulation, or candidate substrate validation. Future studies should clarify variant-specific functional effects, define direct disease-relevant substrates, and establish reproducible readouts that can support mechanism-based therapeutic development. Full article

Fragility fracture and osteoporotic bone loss represent an increasing global burden in ageing populations: the Global Burden of Disease Study 2021 estimated 172.79 million new fractures, 453.31 million prevalent cases, and 25.18 million years lived with disability in 2021, yet the resulting defects are still managed with grafts and scaffolds validated in healthy bone. Osteoporotic bone is not merely rarefied normal bone but a distinct regenerative microenvironment, in which we propose that oxidative stress, cellular senescence, and loss of osteogenesis-coupled type-H vasculature act as a mutually reinforcing triad, superimposed on an adipogenically biassed progenitor pool, blunted osteocyte mechanotransduction and immunosenescence. Additive manufacturing and biofabrication permit patient-specific geometry and spatial and temporal programming of mechanical and biological cues. This review appraises four interdependent design axes—mechanical adaptation through functionally graded, trabecular-mimetic architectures; redox regulation; senescence modulation; and osteoimmunomodulation coupled to vascularisation—distinguishing study type, disease specificity and author-proposed hypotheses. The most direct clinical signal is mechanical: in a retrospective cohort of 163 lumbar interbody fusion levels, printed porous titanium was associated with subsidence in 5.5% of levels versus 24.4% for solid titanium. By contrast, almost all redox, senescence and immunomodulatory scaffold evidence remains preclinical: osteoporosis-specific evidence relies heavily on ovariectomised rodents, and much of the rest comes from non-osteoporotic models. Within the searches described, we identified no completed clinical evaluation with reported results of a multifunctional scaffold in an osteoporosis-defined cohort. As the authors’ proposed conceptual framework rather than an established result, we suggest that these axes be engaged sequentially rather than additively, and that timing, dose and spatial distribution may matter more than the number of bioactivities. Full article

Animal models are critical for elucidating disease mechanisms and pathological outcomes, and for evaluating therapeutic interventions. Osteoarthritis (OA) is a leading cause of chronic pain and disability globally. Clinically, individuals with OA experience both sensory and ongoing pain. However, ongoing pain, as assessed by the Mouse Grimace Scale (MGS), has not yet been evaluated in animal models of OA. This study aims to address this significant knowledge gap. We induced OA by intra-articular injection of monosodium iodoacetate (MIA), while control mice received saline injections. We assessed pain behaviors using the MGS on days 1, 3, 7, and 14 after MIA administration. MIA-treated mice exhibited significantly higher MGS scores than saline-treated controls throughout the study period, indicating ongoing pain-related behavior in the MIA OA model. Furthermore, longitudinal studies showed that this pain is chronic, as seen in people with OA. These findings support the usefulness of the MGS test in the MIA model for studying ongoing pain. Full article

The gut microbiota plays a key role in immune regulation in multiple sclerosis (MS), yet longitudinal data on microbiome dynamics and their relationships with disability and biomarkers remain limited. This study aimed to identify longitudinal gut microbiome changes in patients with relapsing-remitting multiple sclerosis (RRMS) and their association with disability and specific serum biomarkers, including predicted metabolic pathways. In this prospective longitudinal study, 29 treatment-naïve RRMS patients were evaluated at baseline and after one year of disease-modifying therapy. Clinical assessments included the Expanded Disability Status Scale (EDSS) and disability tests. Serum glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and S100B protein concentrations were measured at both visits. Gut microbiota composition was characterized by shotgun metagenomic sequencing, including taxonomic composition, diversity measures, functional pathways, gut metabolic modules, and gut–brain modules. In the 29 patients, overall gut microbiota composition and diversity remained stable during follow-up. Although EDSS progression was associated with a trend toward greater microbiome instability, this association did not reach statistical significance. Several bacterial taxa and predicted metabolic pathways showed nominal associations with disability, but were not significant after correction. GFAP levels increased significantly over time, whereas NfL levels decreased and S100B levels remained unchanged. Early RRMS is characterized by a stable gut microbiome during the first year of treatment. Exploratory taxonomic and functional associations did not remain significant after correction for multiple testing, highlighting the need for larger longitudinal cohorts. Full article

Background: Chronic refractory angina is a disabling syndrome of persistent ischemic symptoms despite guideline-directed medical therapy and, in many patients, prior coronary revascularization. Enhanced external counterpulsation [EECP] is a noninvasive therapy that augments diastolic coronary perfusion, reduces systolic afterload, improves endothelial function, and may promote collateral recruitment. Although developed for obstructive coronary artery disease, its vascular and microvascular effects may also be relevant to contemporary ischemic syndromes, including ischemia with non-obstructive coronary arteries [INOCA] and myocardial infarction with non-obstructive coronary arteries [MINOCA]. A contemporary quantitative synthesis of EECP across angina burden, functional capacity, quality of life, and safety is therefore warranted. Methods: We performed a systematic review and meta-analysis of randomized trials and prospective studies of adults with chronic refractory angina treated with EECP versus standard medical therapy, usual care, or sham EECP. Outcomes were Canadian Cardiovascular Society [CCS] angina class, nitroglycerin use, the 6 min walk test [6MWT], treadmill exercise testing, quality-of-life measures, adverse events, and treatment withdrawal. Because the eligible evidence combined sham-controlled randomized trials with single-arm and registry cohorts, pooled estimates were derived using random-effects models and are interpreted in that context. Results: Twenty-six studies were included. EECP was associated with improvement across every prespecified domain: CCS angina class [standardized mean difference [SMD] −1.56; 95% confidence interval [CI], −2.54 to −0.58; p = 0.002], nitroglycerin use [SMD −2.41; 95% CI, −3.34 to −1.49; p < 0.00001], 6MWT [SMD 1.59; 95% CI, 0.64 to 2.54; p = 0.001], treadmill exercise testing [SMD 1.03; 95% CI, 0.15 to 1.91; p = 0.02], and quality of life [SMD 1.12; 95% CI, 0.71 to 1.53; p < 0.00001]. Heterogeneity was high for all pooled outcomes [I² ≥ 79%], and the largest effect sizes were driven substantially by uncontrolled before–after data. Conclusions: EECP is associated with statistically significant and clinically meaningful reductions in angina burden and nitrate use, with parallel improvements in objective exercise capacity and patient-reported quality of life among patients with chronic refractory angina. These findings support EECP as a reasonable adjunctive option for appropriately selected patients who remain symptomatic despite conventional treatment, while the magnitude of heterogeneity and the contribution of non-randomized data temper the certainty of the pooled estimates and underscore the need for standardized protocols, contemporary sham-controlled trials, and dedicated investigation in INOCA and MINOCA populations. Full article

Background and Objectives: Persistent pain in rheumatoid arthritis (RA) may reflect mechanisms not fully captured by systemic inflammatory markers. This study estimated the frequency of elevated Central Sensitization Inventory (CSI) scores in women with RA and examined associations with pain, fatigue, depressive symptoms, function, inflammatory markers, and disease activity. Materials and Methods: This prospective single-center observational cohort included 97 female inpatients who completed a standardized three-week rehabilitation program. The CSI was used as a symptom-based screening instrument. Pain, function, fatigue, and depressive symptoms were assessed with the Visual Analog Scale (VAS), Health Assessment Questionnaire (HAQ), FACIT-Fatigue scale, and Beck Depression Inventory-II (BDI-II), respectively. Results: Fifty-seven participants (58.8%) had CSI scores ≥ 40. Higher CSI scores were associated with greater pain, more depressive symptoms, more fatigue, and higher DAS28-CRP scores, but not with ESR, CRP, IL-6, or disease duration. In adjusted baseline models, the association with VAS pain was statistically significant but modest (unstandardized beta = 0.024 per CSI point; standardized beta = 0.273). Across the three-week follow-up, VAS pain decreased by 2.53 points; mean FACIT-Fatigue and HAQ changes were smaller than commonly cited clinically important thresholds, and CSI changed only modestly. In adjusted multivariable models, higher CSI scores remained independently associated with VAS pain, FACIT-Fatigue, and BDI-II scores, whereas no significant association was found with HAQ. CSI was not associated with CRP, IL-6, or disease duration. Conclusions: In this cohort of women with RA, elevated CSI scores identified a greater self-reported symptom burden and were independently associated with pain, fatigue, and depressive symptoms after adjustment, though the pain association remained modest in magnitude. No meaningful association was found with functional disability. The uncontrolled, single-arm design and restricted inflammatory-marker range preclude causal conclusions or proof that symptoms were independent of inflammation. Full article

Background/Objectives: We assessed changes in nonfatal disease burden and risk attribution in Romania between 1990 and 2023. Methods: We analysed Global Burden of Disease (GBD) 2023 estimates of years lived with disability (YLDs), related nonfatal measures and risk attribution for 199 causes and 61 risks, with seventeen comparator locations. Results: The age-standardised YLD rate changed by −4.1% (95% uncertainty interval [UI] −10.1 to 1.3), and total YLDs by −3.9% (95% UI −9.2 to 0.7). Both intervals included zero. The crude rate rose by 17.0%. The population size and age structure components of the decomposition were approximately −552,000 and +545,000 YLDs; their uncertainty was not estimated. Healthy life expectancy increased by 5.2 years. Its difference from life expectancy rose from 9.2 to 10.2 years, without an uncertainty interval for this derived change. Low-back pain remained the leading level 3 cause. Anxiety disorders increased by 41.7% (95% UI 4.5 to 101.8) and ranked second by point estimate; rank uncertainty was not estimated. The joint risk-attributable fraction fell from 31.2% to 28.3%. Conclusions: Romania had more disability per inhabitant and a larger share at older ages in 2023. Musculoskeletal disorders remained the main source of nonfatal burden, while anxiety disorders and diabetes increased. Full article

Diabetes mellitus (DM) is a rapidly expanding global health burden and a leading cause of chronic complications. Among these, diabetic peripheral neuropathy (DN) is one of the most prevalent and disabling, affecting up to half of individuals with long-standing diabetes and involving both somatic and autonomic nerve fibers. DN is characterized by an insidious onset: axonal and glial damage begins during subclinical phases and is frequently detected only when irreversible injury has occurred, as conventional neurological examinations and nerve conduction studies lack sensitivity for detecting early-stage disease. DN pathogenesis is multifactorial and primarily driven by chronic hyperglycemia, which triggers a network of converging pathogenic mechanisms. This narrative review aims to explore the evolving landscape of DN, with a particular focus on the study of neuronal injury biomarkers in the early detection of diabetic nerve damage. In addition, it highlights the relevance of in vitro neuronal and glial models as complementary experimental platforms to investigate the molecular and cellular mechanisms underlying DN and to support the identification and validation of candidate biomarkers. Moreover, these in vitro systems provide a strategic tool for examining the impact of circulating factors on axonal and glial integrity, thereby facilitating the discovery and preliminary assessment of potential blood-based biomarkers. Full article

Background/Objectives: Telerehabilitation may extend neurorehabilitation beyond conventional settings, but comparative effects across neurological diagnoses and motor domains remain uncertain. This systematic review and meta-analysis synthesized motor outcomes while distinguishing International Classification of Functioning, Disability and Health activity domains, delivery models, and comparator questions. Methods: Five databases were searched from inception to 8 June 2026 using two database-specific Boolean search strategies. Comparative studies of adults with neurological disorders receiving active remote, digital, virtual, wearable, or hybrid rehabilitation were eligible. Random-effects models used restricted maximum likelihood estimation; Hartung–Knapp confidence intervals were primary when at least three studies were available, and DerSimonian–Laird models were sensitivity analyses. Results: Eighty-seven studies included stroke, Parkinson’s disease, multiple sclerosis, spinal cord injury, acquired brain injury, or ataxia. For walking and mobility activities versus usual care, no additional therapy, or waitlist, the point estimate favoured telerehabilitation but was imprecise and compatible with no difference (standardized mean difference 1.06, 95% confidence interval −0.23 to 2.35; three studies; 121 participants; I² = 57.6%). Global motor-functional and activities-of-daily-living outcomes showed similar uncertainty (0.83, −0.35 to 2.00; three studies; 304 participants; I² = 73.6%). Both findings had very-low-certainty evidence. No pooled comparison included enough studies to assess publication bias. Two-study datasets for balance-related activity/postural control and upper-limb impairment were highly heterogeneous and interpreted descriptively. Conclusions: Comparative evidence for telerehabilitation across neurological diagnoses and motor domains remains uncertain. Programme characteristics are plausible implementation considerations, not established efficacy modifiers. Small evidence sets, wide intervals, clinical heterogeneity, risk of bias, and inconsistent adverse-event ascertainment preclude conclusions about clinical importance or established safety. Full article

Background/Objectives: Reduced hand function significantly contributes to disability in patients with systemic sclerosis (SSc). We aimed to evaluate the effects on hand function and quality of life of a multicomponent hand rehabilitation program in patients with longstanding SSc. Methods: This prospective, controlled, interventional pilot study enrolled adults with SSc, disease duration >5 years and ≥1 upper limb joint contracture. The intervention consisted of 10 sessions over 5 weeks, including paraffin wax therapy and individualized hand rehabilitation. The allocation to the intervention or control group was based on the patients’ availability to participate in the program. Hand mobility/function and health-related quality of life were assessed through validated outcome measures at baseline and after 5 weeks. Results: Sixteen patients were included (intervention N = 10; control N = 6), with a median disease duration of 19.5 (15.3–24.3) years. Within the intervention group, significant improvements were observed in right-hand Hand Mobility in Scleroderma (HAMIS) score (p = 0.033) and in the Short Form (SF)-36 domains of “Energy/fatigue” (p = 0.008), “Emotional well-being” (p = 0.009), “Pain” (p = 0.020), and “General health” (p = 0.050). Compared with controls, significant benefit was observed in the SF-36 “Energy/fatigue” (p = 0.002; d = 1.97) and “General health” (p = 0.011; d = 1.50) domains. Between-group differences in hand function measures did not reach statistical significance, although moderate-to-large effect sizes favored rehabilitation across several outcomes. Conclusions: In this pilot study, a multicomponent hand rehabilitation program was associated with improvements in quality of life in patients with longstanding SSc, despite limited effects on hand mobility. These preliminary findings suggest a potential benefit of hand rehabilitation even in advanced disease. Full article

Depression and Alzheimer’s disease are among the most prevalent and disabling disorders worldwide, imposing a substantial social, economic, and healthcare burden. Increasing evidence suggests that these conditions share several pathophysiological mechanisms, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered neurotransmission, and gut microbiota dysbiosis. In recent years, the microbiota–gut–brain axis has emerged as a key regulatory system linking gastrointestinal, immune, metabolic, and neural functions. Within this complex network, the tryptophan–kynurenine pathway has gained considerable attention as a critical mediator connecting gut microbial activity, immune responses, and central nervous system function. This review examines the role of the microbiota–gut–brain axis and the tryptophan–kynurenine pathway in the development and progression of depression and Alzheimer’s disease. Particular emphasis is placed on the regulation of tryptophan metabolism by gut microbiota, the inflammatory activation of indoleamine 2,3-dioxygenase, and the generation of neuroactive kynurenine metabolites. Dysregulation of these processes may reduce serotonin synthesis while promoting the accumulation of neurotoxic compounds such as quinolinic acid and 3-hydroxykynurenine, thereby contributing to neuroinflammation, excitotoxicity, cognitive decline, and depressive symptoms. Current evidence also highlights the therapeutic potential of interventions targeting gut microbiota composition and kynurenine pathway activity. A better understanding of these interconnected mechanisms may facilitate the identification of novel biomarkers and the development of personalized strategies for the prevention and treatment of both psychiatric and neurodegenerative disorders. Full article

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disability-adjusted life years (DALYs) and all-cause mortality worldwide, imposing an increasing global health burden. Atherosclerosis (AS) is a complex multifactorial disease, and the concept of organ crosstalk has provided a new perspective for understanding its pathogenesis. Although circulating chemerin levels are closely associated with the development and adverse prognosis of ASCVD, the functional heterogeneity and regulatory characteristics of chemerin derived from different tissues have not been systematically investigated. This review elucidates the tissue-specific roles of chemerin in AS from both endocrine and paracrine perspectives, with a focus on chemerin derived from the liver, white adipose tissue, perivascular adipose tissue, and epicardial adipose tissue. Endocrine chemerin primarily contributes to systemic metabolic dysfunction and endothelial injury, whereas locally produced chemerin regulates vascular smooth muscle cell remodeling and vascular inflammation through paracrine signaling. Collectively, endocrine and paracrine chemerin constitute a dual regulatory network that links metabolic abnormalities with vascular remodeling during AS progression. Full article

Background/Objectives: Eating-related difficulties in people with multiple sclerosis (MS) may reflect different behavioural and psychological processes, including emotional responses to illness-related stress, habitual overeating, attempts to control food intake, and broader self-management routines. Variable-centred analyses may obscure this heterogeneity by examining eating-related tendencies separately. This study aimed to examine whether habitual overeating, emotional overeating, and dietary restraint in adults with MS are better represented as one general continuum of eating-related difficulty or as distinct person-centred profiles that differ in coping styles, health locus of control, and MS self-management. Methods: This cross-sectional secondary analysis included 382 adults with definite MS. Latent class analysis used 30 binary My Eating Habits Questionnaire items. One-step latent class regression models examined coping and health locus of control. Linear regression compared self-management scores. The models were adjusted for sex, age, disease duration, and Expanded Disability Status Scale score. Results: A five-class solution was retained (BIC = 11,067.60; entropy = 0.920), comprising low difficulties, moderate mixed tendencies, two emotional eating/restraint profiles, and dysregulated overeating. Emotional eating with moderate restraint was associated with lower task-oriented coping and internal health control, and with higher emotion-oriented and avoidance-oriented coping and external health-control beliefs. Dysregulated overeating was associated with lower task-oriented coping, higher avoidance-oriented coping, and stronger powerful-others health beliefs. Self-management was higher for emotional eating with moderate restraint (B = 5.3, 95% CI 1.8 to 8.9; p = 0.003) and high emotional eating and restraint (B = 6.0, 95% CI 1.8 to 10.3; p = 0.005), versus low difficulties. Sensitivity analyses gave similar findings. Conclusions: Eating-related tendencies in MS formed distinct profiles rather than a single continuum. These profiles differed in coping and health-control patterns, suggesting that similar eating-related difficulties may occur in different psychological and self-management contexts. The higher self-management scores observed in restraint-related profiles should be interpreted cautiously and should not be taken to indicate that restrictive eating is adaptive. This study does not establish clinical classification or treatment recommendations. Instead, it provides a descriptive empirical basis for future studies testing whether these profiles are stable and whether they predict dietary, nutritional, psychological, and clinical outcomes. Full article

Aging is a gradual process of structural and functional decline, marked by erosion of physiological integrity, adaptive capacity, and resilience, and by a concomitant increase in vulnerability to disease, disability, and death. The hallmarks of aging framework provides a widely used and experimentally tractable taxonomy of molecular and cellular processes associated with aging. In 2023, López-Otín and colleagues expanded the framework from nine to twelve hallmarks by adding disabled macroautophagy, chronic inflammation, and dysbiosis. Here, we evaluate the mechanistic and translational evidence for all twelve hallmarks. We also examine RNA-processing defects and extracellular matrix remodeling as candidate processes without classifying either as an additional hallmark. Experimental studies in model organisms support causal roles for several hallmarks. However, their causal priority, necessity, sufficiency, tissue specificity, and relevance to human aging remain unresolved. Clinical translation is limited by pleiotropy, compensatory responses, heterogeneous trajectories, uncertain biomarkers, and the long period required to detect meaningful outcomes. Future geroscience studies should treat hallmarks as provisional causal modules within interacting physiological networks, select mechanism-linked and function-centered endpoints, and test interventions against prospectively defined claims. Full article

Background and Objectives: Visual evoked potentials (VEPs) are established tools for detecting optic pathway involvement in multiple sclerosis (MS); however, the distinct clinical significance of longitudinal changes in latency and amplitude remains unclear. This exploratory study aimed to evaluate the clinical utility of serial VEP assessments in patients with relapsing–remitting MS (RRMS) by examining the associations between temporal changes in latency and amplitude and concurrent markers of disease activity and disability. Materials and Methods: We retrospectively analyzed 83 patients with RRMS from three centers who underwent at least two pattern-reversal VEP assessments ≥ 1 year apart. Patients with recent optic neuritis were excluded. Longitudinal changes in VEP latency and amplitude were evaluated in relation to relapse activity during the same inter-assessment interval, baseline MRI and CSF findings, and disability assessed by the Expanded Disability Status Scale (EDSS). Sensitivity analyses were stratified and adjusted for disease-modifying therapy (DMT) efficacy tier, and progression independent of relapse activity (PIRA) was examined using a formal definition. Results: Over a median follow-up of 2 years, 43.4% of patients developed P100 latency prolongation, which was independently associated with a higher annualized relapse rate during the same interval (odds ratio [OR] 2.91, p = 0.005; area under the curve (AUC) 0.72 for concurrent on-study relapse activity), an association that persisted after adjustment for DMT efficacy tier, but not with disability worsening. In contrast, 56.6% of patients exhibited amplitude reduction, which was associated with greater disability accumulation at the group level, with higher EDSS scores at follow-up despite similar baseline values (p < 0.05); the corresponding inverse correlation between amplitude decline and EDSS change was only nominally significant (ρ = −0.231, p = 0.036), did not survive correction for multiple comparisons, and was attenuated after adjustment for baseline EDSS. Formally defined PIRA events were rare (n = 3), precluding inference. Baseline magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings differed in the latency group, with fewer MRI lesions and a lower immunoglobulin G (IgG) index, whereas no corresponding differences were observed in the amplitude group. Conclusions: In this exploratory cohort, longitudinal prolongation of VEP latency was associated with concurrent relapse activity, whereas amplitude decline showed a weaker, group-level association with disability. These findings are consistent with, but do not demonstrate, distinct inflammatory and neurodegenerative substrates, and warrant prospective validation before serial VEP monitoring can inform individualized management in MS. Full article