Search Results (6,271)

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with neurotoxicity and increased risk of neurodegenerative diseases. PCB 153, a highly abundant non-coplanar congener, bioaccumulates in human tissues and impairs homeostasis. This study investigated the transcriptomic effects of PCB 153 (2,2′,4,4′,5,5′-Hexachlorobiphenyl) in retinoic acid (RA)-differentiated SH-SY5Y neuronal cells to identify early, sub-cytotoxic molecular alterations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h exposure to increasing PCB 153 concentrations. RNA-Seq was performed on cells treated with 5 μM PCB 153, the highest non-cytotoxic dose. Sequencing reads were quality-filtered, aligned to the human genome, and analyzed with DESeq2. Functional enrichment was conducted using Gene Ontologies and KEGG pathways. Western blot analyses were performed to assess protein level changes in selected targets. RNA-Seq identified 1882 significantly altered genes (q-value < 0.05). Gene Ontology analysis revealed strong enrichment of proteasome-related terms, with most proteasomal subunits displaying coordinated upregulation. KEGG analysis further showed significant enrichment of Alzheimer’s (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disease pathways. These findings indicate that PCB 153 triggers a pronounced proteostatic response in neuron-like cells, suggesting early disruption of protein homeostasis that may contribute to mechanisms associated with neurodegeneration. Full article

Generative artificial intelligence (GenAI), particularly large language models (LLMs) such as ChatGPT and DeepSeek, is transforming healthcare by enhancing clinical decision-making, education, and patient interaction. This exploratory study compares the responses of ChatGPT (GPT-4.1) and DeepSeek-V2 against 90 final-year physiotherapy students in Greece on the quality of the responses to 60 clinical questions across four rehabilitation domains: low back pain, multiple sclerosis, frozen shoulder, and knee osteoarthritis (15 questions per domain). The questions spanned basic knowledge, diagnosis, alternative treatments, and rehabilitation practices. The responses were evaluated for their relevance, accuracy, clarity, completeness, and consistency with clinical practice guidelines (CPGs), emphasizing conceptual understanding. This study provides novel contributions by (i) benchmarking LLMs in physiotherapy-specific domains (low back pain, multiple sclerosis, frozen shoulder, and knee osteoarthritis) underrepresented in prior AI-health evaluations; (ii) directly comparing the LLM written response quality to student performance under exam constraints; and (iii) highlighting the improvement potential for education, complementing ChatGPT’s established role in physician decision support. The results indicate that the LLMs produced higher-quality written responses than students in most domains, particularly in the global response quality and the conceptual depth of written responses, highlighting their potential as educational aids for knowledge-based tasks, although not equivalent to clinical expertise. This suggests AI’s role in physiotherapy as a supportive tool rather than a replacement for hands-on clinical skills and asks whether GenAI could transform physiotherapy practice by augmenting, rather than threatening, human-centered care, for its potential as a knowledge support tool in education, pending validation in clinical contexts. This study explores these findings, compares them with the related work, and discusses whether GenAI will transform or threaten physiotherapy practice. Ethical considerations, limitations, and future directions, including AI voice assistants and AI characters, are addressed. Full article

Purpose: This study aimed to translate the Pain Effects Scale (PES) into Arabic, evaluate its cultural adaptation, and assess its psychometric properties (validity and reliability) among patients with Multiple Sclerosis (MS). Method: The translation and cultural adaptation followed published guidelines. A total of 121 patients with MS completed the PES and several other assessments: the Short-Form McGill Pain Questionnaire (SF-MPQ), the Patient Health Questionnaire-9 (PHQ-9), the Modified Fatigue Impact Scale (MFIS), and the Multiple Sclerosis Impact Scale (MSIS-29), to evaluate construct validity. Reliability was assessed after two weeks using the intraclass correlation coefficient (ICC) and internal consistency (Cronbach’s α). Results: The Arabic version of Pain Effects Scale PES-Ar demonstrated good internal consistency (Cronbach’s α = 0.910) and strong test–retest reliability (ICC (2,1) = 0.88; 95% CI: 0.85–0.92). The corrected item–total correlations for all six items ranged from 0.591 to 0.840. No floor or ceiling effects were observed. Content validity indices were high (I-CVI and S-CVI = 1.00). Construct validity was supported by moderate correlations with PHQ-9 (r = 0.677), MFIS (r = 0.66), and SF-MPQ (r = 0.586), and a weak correlation with the MSIS-29. Conclusions: The PES-Ar showed strong validity and reliability for assessing the impact of pain in Arabic-speaking individuals with MS in Saudi Arabia. Full article

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation). Full article

Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A case–control study involved 215JS patients (194 JLSd, 21 JSSc) and 72 controls. SNPs (MMP1 rs1799750, MMP9 rs3918242, NOS3 rs1799983) were genotyped using real-time PCR followed by minisequencing and mass spectrometric analysis of reaction products. Associations with disease risk, subtypes, and immunological markers were analyzed statistically. The MMP9 (rs3918242) CT genotype was significantly associated with JLSd (OR = 2.23, 95% CI: 1.14–4.37, p = 0.022), showing a trend in linear facial forms. The NOS3 (rs1799983) GG genotype demonstrated a trend toward association with JSSc (OR = 2.61, 95% CI: 0.92–7.37, p = 0.065). No significant associations were found for rs1799750 MMP1 and risk of disease development. The MMP9 risk genotype did not correlate with scleroderma-specific autoantibodies, while the NOS3 GG genotype was associated with lower serum levels of anti-collagen IV antibodies (p = 0.039). Genetic associations differ for JS subtypes: MMP9 with JLSd and NOS3 with JSSc. Children with CT polymorphism MMP9 (rs3918242) and with NOS3 (rs1799983) GG genotype were found to be genetically predisposed for the development of JS. Full article

Background: Multiple sclerosis (MS) involves complex physical, cognitive and behavioral challenges that collectively affect quality of life. Integrating lifestyle components such as sleep optimization, dietary behaviors, stress management, and self-management strategies into rehabilitation may enhance outcomes beyond traditional approaches. This scoping review aimed to map rehabilitation interventions that combine psychomotor, cognitive, lifestyle-focused, or multimodal elements and assess quality of life in adults with MS. Methods: This scoping review was conducted in accordance with the PRISMA-ScR guidelines, which guided the identification, screening, and selection of studies. Screening and data extraction were conducted independently by two reviewers. From 135 records, nine primary studies and four secondary evidence sources were included. Results: Most studies involved adults with mild-to-moderate disability and predominantly relapsing–remitting multiple sclerosis. Physical or motor rehabilitation interventions were examined in five studies, while two studies evaluated multimodal rehabilitation programs, one study focused on cognitive rehabilitation, and one study investigated lifestyle-oriented or self-management-integrated approaches. Quality of life was assessed in all included studies, with improvements reported across multiple domains. Fatigue-related outcomes were reported in four studies, sleep-related outcomes in three studies, and digitally delivered or hybrid rehabilitation interventions were implemented in three studies, indicating an emerging trend toward technology-supported rehabilitation approaches. Conclusions: Contemporary MS rehabilitation is moving toward multidimensional, holistic models that integrate lifestyle components. Standardized outcomes, inclusion of more diverse MS phenotypes, and rigorous evaluation of integrated frameworks are required to strengthen the evidence base and inform clinical practice. Full article

Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—the major protagonists of NDs—while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials. Full article

Gait analysis is a non-invasive, cost-effective method for detecting subtle motor changes in neurodegenerative disorders. This study uses an exploratory approach to identify temporal–kinetic gait feature relationships specific to amyotrophic lateral sclerosis (ALS) and Huntington (HUNT) and Parkinson (PARK) disease versus healthy controls (CONTROL) using recent advances in InterCriteria Analysis (ICrA). The novelty lies in the (i) comprehensive temporal–kinetic feature set, (ii) use of ICrA to characterize inter-feature coordination patterns at population and disease-group levels and (iii) interpretation in a neuromechanical context. Forty-one temporal/kinetic features were extracted from left/right leg ground reaction force and rate-of-force-development signals, considering laterality, gait phase (stance, swing, double support), magnitudes, waveform correlations, and inter-/intra-limb asymmetries. The analysis included 14,580 steps from 64 recordings in the Gait in Neurodegenerative Disease Database: 16 CONTROL (4054 steps), 13 ALS (2465), 20 HUNT (4730), 15 PARK (3331). Sensitivity analysis identified strict consonance thresholds (μ ≥ 0.75, ν ≤ 0.25), selecting <5% strongest inter-feature relations from 820 feature pairs: population level (16 positive, 14 negative), group-level (15–25 positive, 9–14 negative). ICrA identified group-specific consonances—present in one group but absent in others—highlighting disease-related alterations in gait coordination: ALS (15/11 positive/negative, disrupted bilateral stride coordination, prolonged stance/double-support, decoupled stride/cadence, desynchronized force-generation patterns—reflecting compensatory adaptations to muscle weakness and instability), HUNT (11/7, severe temporal–kinetic breakdown consistent with gait instability—loss of bilateral coordination, reduced swing time, slowed force development), PARK (1/2, subtle localized disruptions—prolonged stance and double-support intervals, reduced force during weight transfer, overall coordination remained largely preserved). Benchmarking vs. Pearson correlation showed strong linear agreement (R² = 0.847, p < 0.001), confirming that ICrA captures dominant dependencies while moderating the correlation via uncertainty. These results demonstrate that ICrA provides a quantitative, interpretable framework for characterizing gait coordination patterns and can guide principled feature selection in future predictive modeling. Full article

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease. Full article

Background: Automated AI-based brain volumetry is increasingly used in clinical practice. T1-weighted sequences (e.g., MPRAGE) are considered the current state-of-the art. However, due to faster acquisition and higher in-plane resolution, 2D anisotropic sequences are often preferred in clinical routine. However, these sequences cannot be processed with currently available AI-volumetry software. Thus, we here aimed to evaluate volumetric data from synthetic MPRAGE-like sequences (mprAIge). Methods: We analyzed 412 datasets (206 conventional MPRAGE and 206 T2w/FLAIR) from healthy volunteers (n = 36) and patients with multiple sclerosis (n = 140). Synthetic mprAIge was generated using SynthSR-CNN and assessed via assemblyNET on the volBrain platform. Total brain volume (TBV), gray and white matter volume (GMV/WMV), and key substructures were compared between mprAIge and conventional MPRAGE. Average volume differences (AVDs) and correlations were calculated. Results: Synthetic mprAIge was generated successfully in all 206 cases. Quantitative analysis demonstrated strong correlation and high agreement for key substructures. TBV showed excellent agreement (AVD: 2.75% for controls, 3.90% for MS patients; r = 0.99 and 0.97, respectively). White matter volume exhibited excellent agreement (AVD: −1.92% for controls, 0.28% for MS patients; r = 0.95). Hippocampal volume also demonstrated good to excellent agreement (AVD: 1.13% for controls, −1.92% for MS patients; r = 0.91 and 0.89, respectively). Conclusions: Synthetic mprAIge enables AI-volumetry software application without limitations. Its volumetric assessments align well with conventional MPRAGE, opening new opportunities for volumetric post-processing and mapping of disease progression. Full article

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system with rising prevalence in the Middle East. Real-world comparative data on disease-modifying therapies from this region remain limited. This retrospective study compared the clinical outcomes and tolerability of fingolimod and interferon beta-1a (IFN-β1a) among patients with relapsing–remitting multiple sclerosis treated at a large public referral hospital in Jordan. Materials and Methods: All eligible RRMS patients received fingolimod or IFN-β1a at a single tertiary hospital. The annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and adverse effect frequencies were analyzed using descriptive and inferential statistics. A full-cohort inclusion approach was applied instead of sample-size calculation, as all available cases at Al-Basheer Hospital (Amman, Jordan) were included. Results: Fingolimod-treated patients showed a significantly higher ARR than those on IFN-β1a (0.51 vs. 0.26, p = 0.016), an association likely influenced by treatment sequencing and baseline disease activity. EDSS distributions were similar between treatment groups, with most patients demonstrating mild disability (EDSS ≤ 3.5). IFN-β1a was linked to injection site reactions, while fingolimod was better tolerated. Conclusions: The higher observed relapse rate among fingolimod-treated patients possibly reflects treatment sequencing and underlying disease severity rather than pharmacologic efficacy, as fingolimod was commonly prescribed as an escalation therapy. These findings highlight the importance of individualized treatment selection and underscore the need for prospective studies incorporating standardized baseline disease activity measures to better inform multiple sclerosis care in Jordan and the wider Middle Eastern region. Full article

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections. Full article

Systemic sclerosis (SSc) is a rare multisystemic autoimmune disease associated with progressive fibrosis, vasculopathy, and immune dysregulation. Despite advances in its management, the disease remains associated with substantial morbidity and mortality, with limited therapeutic options. This systematic review aimed to identify phytocompounds and medicinal plants that had demonstrated efficacy in SSc. A comprehensive literature search was performed in PubMed and ScienceDirect, yielding 7797 records, of which 32 studies met the inclusion criteria. A second search was performed using the SwissTargetPrediction tool to identify new putative molecular targets for these phytocompounds, whose relevance for SSc pathogenesis was verified by a third search in PubMed and ScienceDirect databases. Our search found 24 phytocompouds (e.g., halofunginone, crocetin, and tanshinone IIA) and 5 plant extracts (e.g., caper bush and ciplukan) reported to modulate key pathogenic processes in SSc. These phytochemicals were mainly associated with effects on endothelial to mesenchymal transition, oxidative stress, inflammation, and profibrotic signaling pathways, particularly TGF-β/Smad. The SwissTargetPrediction tool indicated 93 new potential molecular targets of the selected phytochemicals, among which only 41 showed relevance to SSc pathogenesis. In conclusion, available evidence is scarce but promising. Further studies, especially human investigations, are required to clarify clinical efficacy, safety, and potential interactions with drugs used in SSc. Full article

Background/Objectives: Insulin resistance (IR) is a relevant metabolic concern in patients with rheumatic diseases; however, data regarding its clinical influence on the systemic sclerosis (SSc) phenotype is lacking. This study aimed to evaluate the characteristics of patients exhibiting IR in a monocentric SSc cohort. Methods: We conducted a cross-sectional study on 178 SSc patients, stratified according to the presence of IR, defined as a HOMA-IR value >1.85 for men and >2.07 for women, based on thresholds previously validated in the Estudio Epidemiológico de la Insuficiencia Renal en España (EPIRCE) cross-sectional study. The rationale for applying the current cut-offs is based on its discriminative potential when using sex- and age-specific thresholds in a nondiabetic population. This approach is particularly applicable to SSc, where the prevalence of diabetes is very low and the median ages of the two cohorts are comparable. Data collected included demographic-, clinical-, laboratory-, pulmonary function-, capillaroscopic-, and treatment-related parameters. A multivariable logistic regression model was used to identify independent predictors of IR. Results: Patients with IR (n = 76) had a significantly higher prevalence of diffuse cutaneous subset (26.3% vs. 11.8%, p = 0.012) and interstitial lung disease (39.5% vs. 17.6%, p = 0.001), along with the positivity for anti-Scl70 antibodies and the current presence of musculoskeletal symptoms (p = 0.021) and digital ulcers (p = 0.037). As expected, body mass index (BMI) was significantly higher in the IR population (24.6 ± 5.2 vs. 22.9 ± 4.1, p = 0.012), along with fasting glucose, insulin, HOMA-IR, and HbA1c levels. IR patients exhibited higher percentages of dyslipidemia and liver steatosis. Medications such as hydroxychloroquine, statins, and Iloprost were more frequently used in the IR group; as for corticosteroids usage (21.1% vs. 5.9%, p = 0.002), however, cumulative glucocorticoid dosage did not differ between the groups. In multivariable analysis, BMI (OR 1.09; p = 0.038) and interstitial lung disease (ILD) (OR 3.03; p = 0.034) were independent predictors of IR. Conclusions: In SSc, IR is associated with ILD, digital ulcers, musculoskeletal involvement, and anti-Scl70 autoantibodies. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article