Search Results (26,149)

Over the past two decades, advances in molecular genetics, immunology, neuroimaging, fluid biomarkers, and artificial intelligence have substantially transformed the diagnosis, classification, and treatment of neuromuscular disorders. However, increasing biological precision has also highlighted an important distinction between identifying disease mechanisms and characterizing their functional expression. Clinical neurophysiology occupies a specific position within this evolving diagnostic landscape by directly assessing nervous system function and providing objective information on impulse conduction, neuromuscular transmission, motor unit integrity, physiological reserve, and disease activity. Consequently, neurophysiological assessment contributes not only to diagnosis but also to differential diagnosis, longitudinal monitoring, prognostic assessment, and therapeutic evaluation. In this critical review, I examine the factors that have progressively shifted clinical neurophysiology from an interpretative clinical discipline toward a more procedural role. Using representative examples from myasthenia gravis, immune-mediated neuropathies, myopathies, and amyotrophic lateral sclerosis, I discuss how physiological information complements molecular, serological, imaging, and other biological biomarkers. I further examine the emerging role of artificial intelligence, including its potential for automated signal analysis and quantitative assessment, as well as current limitations related to generalizability, validation, and overreliance on pattern recognition. I propose a complementary conceptual framework in which biological and molecular approaches characterize disease mechanisms, while clinical neurophysiology defines their functional expression and clinical relevance in the individual patient. Within this framework, clinical neurophysiology should not be considered an alternative to precision medicine, but an integrated physiological dimension of it, connecting biological characterization with clinically actionable functional information. Full article

While typically associated with benign infectious mononucleosis, Epstein–Barr virus (EBV) is now recognized as a pivotal driver of complex immunopathological disorders. By shuttling between lytic replication and strategic latency programs, EBV reprograms B-cell biology to evade immune surveillance and disrupt homeostasis. Central to this pathogenesis is the viral protein EBNA1, which triggers autoimmunity through molecular mimicry with host antigens, including GlialCAM in multiple sclerosis (MS), keratin in rheumatoid arthritis, and nuclear proteins in systemic lupus erythematosus. These autoimmune responses are further exacerbated by bystander activation and epitope spreading, fueling chronic inflammation in Crohn’s disease, type 1 diabetes, and IgA nephropathy. EBV can also promote the development of lymphoproliferative disorders, whether in immunocompetent hosts or in the context of immunosuppression; however, the emergence of EBV-positive forms within diseases that are usually EBV-negative is closely linked to an underlying state of immunosuppression. Distinct from these chronic states, EBV-associated hemophagocytic lymphohistiocytosis (HLH) represents a critical hyperinflammatory emergency in which defective cytotoxicity leads to an uncontrolled T-cell- or NK-cell-driven cytokine storm; together with chronic active EBV disease (CAEBV), HLH disproportionately affects children, and both receive particular attention in this review. More recently, emerging but not yet consolidated evidence has also suggested a possible association between EBV reactivation and long COVID. Elucidating these diverse molecular interactions is essential for developing the next generation of targeted therapies and vaccine strategies aimed at mitigating the systemic impact of this virus. Full article

Centenarians, semi-supercentenarians and supercentenarians (i.e., oldest centenarians) display complex and heterogeneous immune remodelling. In this setting, immune attrition, memory, cytotoxic defence, inflammatory regulation and tissue surveillance remain sufficiently balanced to support survival with relatively preserved health. This review examines these processes within an integrated framework encompassing sex and gender differences, genetic background, the exposome and immunobiography. We consider how haematopoietic stem cell ageing, age-related myeloid bias, thymic involution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. Findings from conventional phenotyping and single-cell transcriptomic studies in centenarians, semi-supercentenarians and supercentenarians indicate selective immune remodelling rather than preservation of a youthful immune system. These changes include NK-cell expansion, differentiated B-cell states, enrichment of effector-memory CD8⁺ T cells, marked expansion of clonally selected cytotoxic CD4⁺ T cells and increased GZMK⁺GZMB⁻ CD8⁺ T cell populations. Exceptional longevity also appears to depend on limiting the detrimental consequences of chronic inflammation through delayed or better-controlled inflammaging, restrained NLRP3 inflammasome activation and preserved capacity to buffer oxidative stress. Thus, extreme survival appears to reflect successful accommodation of age-related immune change through sustained cytotoxic surveillance, immune memory, inflammatory control and favourable lifelong adaptation to antigenic exposures. Full article

Periodontitis is a chronic immune-mediated inflammatory disease of the oral cavity, frequently linked to systemic conditions through complex immunological pathways. Regulatory T lymphocytes (Tregs) are pivotal in maintaining immune homeostasis by producing anti-inflammatory mediators and enforcing self-tolerance. Recent research has highlighted their role in inflammatory, immune-mediated, and neoplastic diseases. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, exploring the role of Tregs in periodontitis, including patients with comorbidities such as type 2 diabetes mellitus, rheumatoid arthritis, atherosclerosis, and cancer, with a focus on cytokine profile alterations and therapeutic implications of Treg modulation. A systematic search of PubMed, Scopus, Web of Science, and Cochrane from January 2015 to August 2025 using “periodontitis” and “Tregs” or “regulatory T cells” yielded 20 studies. Available evidence suggests alterations in the balance between immunomodulatory Tregs and pro-inflammatory Th17 lymphocytes, together with changes in related cytokine profiles compared with healthy controls. Changes in Treg-related immune markers have also been reported following periodontal interventions; however, these findings do not establish a causal role for Treg modulation or support Treg-targeted therapies in current clinical practice. Well-designed prospective studies and, where appropriate, randomized controlled trials are required to strengthen causal and therapeutic inference. Full article

Sporothrix globosa is the predominant cause of sporotrichosis in China, highlighting the need for effective vaccine strategies. Cyclophilins from pathogenic microorganisms have emerged as potential vaccine antigens. We previously generated a high-yield, high-purity recombinant truncated S. globosa cyclophilin B protein (SgtrCypB) retaining its functional domain. Here, BALB/c mice were immunized subcutaneously with SgtrCypB alone or formulated with Freund’s adjuvant to evaluate immunogenicity. Only the adjuvant-formulated vaccine induced a high antibody titer (1:51,200). Then, the infection-challenge experiments compared the SgtrCypB formulated with Freund’s adjuvant and PBS formulated with Freund’s adjuvant groups. Following challenge, SgtrCypB plus adjuvant reduced cutaneous lesion size (0.6 vs. 1.0 cm at week 1) without significantly affecting ulcer incidence. In systemic S. globosa infection, vaccination increased survival to 90% versus 40% in controls and reduced organ fungal burdens. Partial cross-protection was observed against S. schenckii, with 60% versus 20% survival and lower fungal burdens in the kidneys and lungs. Protection against C. albicans was minimal. These findings identify SgtrCypB as a promising protective antigen against S. globosa and S. schenckii and support further evaluation with clinically applicable adjuvants. Full article

Transcriptomic technologies have revolutionized our understanding of skeletal biology by shifting research from descriptive cellular characterization to a systems-level analysis of bone homeostasis and pathology. The rapid evolution of bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and integrative multi-omics approaches has enabled unprecedented resolution of the molecular and cellular complexity of the skeletal microenvironment. Bone remodeling is a tightly regulated process driven by coordinated interactions among bone marrow-derived mesenchymal stem/stromal cells (BMSCs), osteoblasts, osteoclasts, osteocytes, immune cells, and other bone microenvironment components. This narrative review summarizes recent advances in bulk RNA-seq, scRNA-seq, spatial transcriptomics, and emerging multi-omics approaches that have transformed the study of bone development, remodeling, and disease. We discuss how transcriptomic analyses have revealed the heterogeneity of BMSCs and osteoblasts, elucidated the molecular mechanisms regulating osteoclast differentiation, and identified transcriptional changes associated with osteoclast dysregulation in metabolic, inflammatory, and age-related bone disorders. We further evaluate the limitations of bulk and scRNA-seq, including technical biases, loss of spatial information, and computational challenges. Finally, we highlight how spatial transcriptomics and integrative multi-omics approaches are overcoming these limitations by combining transcriptional, spatial, epigenetic, proteomic, and metabolomic data to provide a comprehensive understanding of skeletal biology, accelerate biomarker discovery, identify novel therapeutic targets, and advance precision medicine for bone diseases. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction, immune dysregulation, and increased oxidative stress. The current treatment strategies include topical corticosteroids, calcineurin inhibitors, and systemic immunomodulators. However, long-term use of steroids and other immunomodulators has unwanted side effects, and therefore recent interest has shifted towards complementary natural therapeutic approaches. Several studies indicate that natural plant-based antioxidants may help prevent AD. Specifically, a few studies demonstrated the significance of fat-soluble vitamins (A, D, E, and K) in controlling AD, owing to their strong roles in antioxidant defense, immune regulation, and maintenance of epidermal barrier integrity. In this review, we discussed recent evidence demonstrating the significant biological and therapeutic roles of fat-soluble vitamins in AD. We also discussed how vitamins A, D, E, and K may influence multiple mechanisms involved in AD pathogenesis and their potential as adjuvant therapy. Based on limited preclinical and clinical data, additional well-designed mechanistic and clinical trials are needed to establish their therapeutic efficacy in treating AD. Full article

Background: Melanoma disproportionately affects older adults, who account for a growing share of cases as populations age. Its incidence rises with age, and the number of ultra-octogenarians (≥85 years) is expected to triple by 2050, particularly in high-incidence regions such as Australia, North America and Europe. Moreover, older adults frequently present with substantial comorbidities, making management complex and complicating treatment decisions. Methods: This comprehensive review summarizes evidence concerning the clinicopathological characteristics, treatment patterns, systemic therapy outcomes, and geriatric considerations relevant to patients aged 75 years or older with melanoma. PubMed/MEDLINE was searched from January 2000 to March 2026. Reference lists of eligible articles and relevant reviews were examined to identify additional studies. Priority was given to studies reporting age-stratified outcomes for patients aged at least 75 years. Because relatively few studies reported outcomes specifically for patients aged ≥75 years, evidence using thresholds of ≥65, ≥70, or ≥80 years was included when directly relevant. Age thresholds are reported for each study and should not be considered interchangeable. Results: Most evidence specific to patients aged ≥75 years derives from retrospective cohorts and registries. Compared with younger patients, elderly patients more often present with melanomas of the head, neck, hands and feet, a higher prevalence of the nodular subtype, greater Breslow thickness, higher mitotic rates and lower tumor-infiltrating lymphocyte density. Diagnosis is frequently delayed due to difficulties with self-examination, visual impairment, benign age-related skin changes and social factors. Despite presenting such a high-risk disease, older patients are less likely than their younger counterparts to receive immunotherapy or BRAF/MEK-targeted agents. This treatment gap may reflect comorbidities, altered pharmacokinetics, concerns about toxicity, under-representation in pivotal trials, and limited caregiver support. Available real-world data suggest that the efficacy of immune checkpoint inhibitors and targeted therapies is comparable to that in younger adults, although treatment selection, discontinuation, hospitalization, and dose modification differ across studies. Conclusions: Melanoma in older adults has distinct clinical and pathological patterns, but treatment evidence for patients aged ≥75 years remains limited and subjected to selection bias. Tailored, geriatric-informed treatment strategies integrating tumor biology, comorbidity, functional status and patient preferences are needed to optimize outcomes for patients aged 75 years and older. Full article

An optical vector analysis (OVA) based on serrodyne modulation is proposed and numerically verified by simulations. In the proposed OVA, serrodyne modulation is implemented using a dual-parallel dual-drive Mach–Zehnder modulator to generate asymmetric optical double-sideband (ODSB) signals including a frequency-shifted optical carrier. The generated signals subsequently propagate through the optical device under test (ODUT). Owing to the asymmetric ODSB structure, the proposed OVA is inherently immune to errors induced by the nonlinearity of the electro-optic modulator (EOM). Consequently, the responses of the ODUT can be accurately obtained by processing the frequency-shifted photocurrent, which is converted from the frequency-shifted carrier and the two desired sidebands. Furthermore, the proposed approach overcomes the limitation of conventional optical single-sideband-based OVA in characterizing bandpass responses. Through numerical simulations, the frequency responses of a uniform fiber Bragg grating, a Fabry–Perot cavity, and a bandpass filter are obtained within a bandwidth of 20 GHz. The proposed OVA provides an approach for characterization of optical devices and integrated microwave photonics systems. Full article

Tumors of the spine and spinal cord, including primary and metastatic vertebral tumors, intramedullary gliomas, and refractory intradural lesions, are challenging to treat because curative local therapy is limited by the eloquent, nonregenerating neural tissue surrounding them. Oncolytic virotherapy may offer a rational alternative by combining tumor-selective oncolysis with the induction of systemic antitumor immunity, while sparing normal neural cells. This review summarizes the current field of oncolytic viruses, including adenovirus, herpes simplex virus, reovirus, and others, in the context of spinal and spinal cord tumors. Clinical data in the spine remain scarce; however, the rationale is based on histological evidence from sarcomas and other tumors, extensive glioma experience, including diffuse intrinsic pontine glioma, and preclinical activity in nerve sheath and meningioma models. We discuss the telomerase-specific oncolytic adenovirus OBP-301 and its derivatives, whose hTERT-driven replication provides histology-agnostic tumor selectivity, while sparing the telomerase-silent spinal cord. This telomerase dependence, however, limits activity against tumors that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, such as many osteosarcomas and some spinal cord astrocytomas. We also discuss delivery and safety within the confined spinal canal, combination strategies, and future directions, such as extracellular vesicle-mediated delivery and biomarker-guided patient selection. Although clinical translation to the spine will require dedicated preclinical and early-phase studies, virotherapy represents a promising, mechanistically grounded modality for these therapeutically challenging tumors. Full article

Ocular diseases remain a major global health challenge with substantial unmet therapeutic needs. Small nucleic acid therapeutics offer a precise strategy to regulate disease-related mRNAs or noncoding RNAs through base pairing, thereby modulating protein expression at the RNA level. Major modalities include antisense oligonucleotides, small interfering RNAs, microRNA-based therapeutics, small activating RNAs, and nucleic acid aptamers, which act through RNA degradation, RNA interference, splicing modulation, microRNA regulation, transcriptional activation, or structure-dependent target binding. These properties make them attractive for ocular diseases involving genetic defects, pathological angiogenesis, inflammation, fibrosis, or neurodegeneration. However, their clinical translation in ophthalmology remains limited by poor molecular stability, insufficient tissue retention, immune activation, off-target effects, and inefficient delivery to target ocular tissues. Rational oligonucleotide design, appropriate local administration routes, and optimized delivery platforms are therefore essential for improving stability, tissue penetration, cellular uptake, and therapeutic durability. This review summarizes the major classes, mechanisms, chemical modification strategies, ocular delivery systems, and therapeutic applications of small nucleic acid drugs in ophthalmology. We also discuss lessons from clinical successes and failures and propose future directions for safe, durable, and individualized ocular therapy. Full article

Background/Objectives: Vitamin D is an important regulator of immune and inflammatory processes, while its deficiency is frequently observed in Hashimoto’s thyroiditis (HT). The relationship between Vitamin D and systemic inflammation in HT remains insufficiently understood, particularly across different disease stages. Methods: We used the Olink Target 96 Inflammation panel to investigate this association. Inflammatory proteins and serum 25(OH)D levels were measured in 257 HT patients and 173 controls from the CROHT biobank. Participants were categorized as Vitamin D deficient (<20 ng/mL) or non-deficient (≥20 ng/mL), with HT patients further stratified as euthyroid, hypothyroid, or levothyroxine-treated. Associations between 25(OH)D and 92 inflammatory proteins were assessed using multivariable linear regression adjusted for age, sex, BMI, smoking, and season of blood sampling, followed by interaction testing and meta-analysis. Results: Vitamin D deficiency was prevalent in both HT patients and controls. Among Vitamin D-deficient HT patients, higher 25(OH)D levels showed nominal inverse associations with the previously reported HT-associated inflammatory proteins IL-17C, CCL20, and CCL11, as well as with GDNF. Among non-deficient HT patients, a nominal positive association with CD6 was observed. None of these associations or interaction terms remained statistically significant after false discovery rate correction. Conclusions: These findings should therefore be considered exploratory and hypothesis-generating. Nevertheless, the observed Vitamin D status-specific patterns suggest that the relationship with inflammatory profiles in HT may differ according to Vitamin D status and warrant validation in prospective and mechanistic studies. Full article

Adipose tissue expandability refers to the capacity of white adipose tissue to store excess energy safely while preserving metabolic homeostasis. This adaptive response takes place via both an increase in adipocyte number (hyperplasia) and size (hypertrophy). Healthy expansion requires coordinated angiogenesis, extracellular matrix remodeling, and functional adipose stem and progenitor cells. Within this conceptual framework, when expandability is limited—due to genetic factors, aging, or chronic overnutrition—adipocyte hypertrophy predominates, which is hypothesized to trigger hypoxia, endoplasmic reticulum stress, chronic low-grade inflammation, and fibrosis. These changes are proposed to form a physical and metabolic barrier that compromises further safe lipid storage, potentially driving the spillover of surplus lipids to ectopic sites: the liver (promoting steatosis and hepatic insulin resistance), skeletal muscle (intramyocellular lipid accumulation and impaired glucose uptake), and pancreas (β-cell dysfunction and reduced insulin secretion). Lipotoxic intermediates such as diacylglycerols and ceramides activate protein kinase C isoforms and may impair insulin receptor signaling, thereby contributing to systemic insulin resistance. The clinical correlate is a spectrum of metabolic disorders including type 2 diabetes, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Understanding the determinants of adipose tissue expandability—from adipose stem cell function and angiogenesis to fibrosis and immune cell infiltration—provides a framework for identifying individuals at risk despite normal body weight and for developing targeted therapies that restore healthy adipose tissue expansion. The aim of this narrative review is to analyze how nutritional factors shape adipose tissue expandability and how limitations in expandability drive obesity-related metabolic disease. To this end, we leverage bariatric surgery as a physiological model illustrating how weight loss reduces lipid overflow while intrinsic adipose tissue expandability may remain incompletely restored. Full article

Background/Objectives: Systemic administration of recombinant cytokines for immunomodulation in cancer and chronic infection is limited by toxicity and poor spatial control. Messenger RNA (mRNA)-encoded cytokines offer a programmable alternative, but the immunological consequences of interferon-β (IFN-β) mRNA delivery in primary human immune cells, and its compatibility with co-delivered antigen-encoding mRNA, remain incompletely defined. This study evaluated whether nucleoside-modified, mRNA-encoded human IFN-β can function as a multifunctional immunomodulator with pro-apoptotic activity and timing-dependent immunostimulatory properties. Methods: N1-methylpseudouridine-modified IFN-β mRNA was transfected into HEK293T and HepG2 cell lines and into primary human monocyte-derived dendritic cells (MDDCs) and M2-polarized macrophages (MDMs) using Lipofectamine MessengerMAX, with OVA mRNA as a non-adjuvant control. Apoptosis, interferon-stimulated CXCL10 secretion, activation marker expression, and cytokine profiles were assessed by flow cytometry, ELISA, Western blot, and cytometric bead array. Adjuvant activity was evaluated in MDDCs co-transfected with IFN-β and antigen (EGFP or OVA) mRNA under four temporal delivery regimens. Results: IFN-β mRNA induced time-dependent apoptosis, most pronounced in HepG2 cells, and CXCL10 secretion in both cell lines. In primary immune cells, IFN-β mRNA activated MDDCs, increased pro-inflammatory cytokine secretion, and repolarized M2-like macrophages toward a pro-inflammatory phenotype. In co-transfection experiments, IFN-β mRNA enhanced MDDC activation across regimens, but antigen expression was preserved only when antigen mRNA was delivered before IFN-β mRNA. Conclusions: mRNA-encoded IFN-β combines direct pro-apoptotic activity with programmable, timing-dependent immunostimulatory effects, supporting its development as a component of next-generation mRNA-based immunotherapies and vaccines. Full article

Background/Objectives: Acute kidney injury (AKI) is a frequent complication following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The association between preoperative inflammatory and immune-nutritional indices and postoperative AKI after CRS-HIPEC remains unclear. We aimed to investigate whether these prespecified candidate preoperative markers are associated with postoperative AKI in patients undergoing CRS-HIPEC. Methods: This retrospective single-center study included 87 patients who underwent CRS-HIPEC between October 2022 and April 2025. All received intraoperative cisplatin and mitomycin C. AKI was defined according to Kidney Disease: Improving Global Outcomes serum creatinine criteria. Preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, pan-immune-inflammation value, systemic inflammation response index, and C-reactive protein–albumin–lymphocyte (CALLY) index were calculated from routine laboratory parameters. Each candidate marker was evaluated in a separate model adjusted for age and sex, and then in a second model additionally adjusted for baseline estimated glomerular filtration rate. Discriminatory performance was assessed using receiver operating characteristic analysis. The CALLY index was calculated using albumin in g/dL, lymphocyte count in ×10⁹/L, and C-reactive protein in mg/L. Results: AKI developed in 24 patients (27.6%). In-hospital mortality was higher in patients with AKI than in those without AKI (25.0% vs. 1.6%; p = 0.002). A higher log10-transformed CALLY index remained associated with lower odds of AKI after adjustment for age and sex (adjusted OR, 0.276; 95% CI, 0.113–0.673; p = 0.005). The CALLY index had the numerically highest AUC among the evaluated indices, with moderate discriminatory performance (AUC, 0.708; 95% CI, 0.579–0.836). A data-derived exploratory cutoff of ≤1.640 yielded 79.2% sensitivity and 63.5% specificity. Conclusions: In this selected retrospective cohort of patients without established chronic kidney disease, a lower preoperative CALLY index was associated with postoperative AKI and showed moderate discrimination as an individual marker. The data-derived threshold should be considered exploratory and requires independent validation before clinical application. Full article