Search Results (590)

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by immune dysregulation, microvascular damage, and progressive fibrosis affecting multiple organs. While cardiopulmonary, renal, and gastrointestinal manifestations have been extensively investigated, involvement of the vestibular system remains insufficiently explored and is likely underrecognized in clinical practice. Vestibular symptoms such as dizziness, vertigo, imbalance, and postural instability may significantly affect quality of life and functional independence in patients with SSc. The pathophysiology of vestibular involvement in SSc is presumed to be multifactorial, involving microangiopathy of the inner ear, immune-mediated damage to vestibular end organs, fibrotic changes affecting inner ear homeostasis, and, in some cases, central nervous system involvement. This narrative review provides a comprehensive and critical synthesis of the current literature on vestibular alterations in systemic sclerosis. We discuss underlying mechanisms, clinical manifestations, diagnostic strategies, associations with common vestibular disorders, and the role of vestibular rehabilitation. By consolidating existing evidence and identifying knowledge gaps, this review aims to promote a more systematic and multidisciplinary approach to the evaluation and management of vestibular dysfunction in SSc. Full article

Background: Vascular compression syndromes are increasingly recognized as underdiagnosed contributors to morbidity in patients exhibiting dysautonomia. Underlying vascular compression syndromes affecting the head and neck, abdomen, pelvis, and lower extremities may influence venous return, neurohormonal signaling, and autonomic regulation. There is considerable clinical overlap among these syndromes, as well as between hypermobility spectrum disorders (HSD) and dysautonomia, indicating possible shared or interacting pathophysiological mechanisms. Purpose/Aims: This hypothesis-generating narrative review synthesizes current evidence linking vascular compression syndromes with dysautonomia, highlights potential mechanistic pathways, identifies patterns of syndromic overlap, and emphasizes the importance of systematic evaluation in affected patient populations. Key Findings: Evidence from retrospective studies, case series, and clinical observations indicates that vascular compression syndromes may be prevalent among patients with dysautonomia, particularly postural orthostatic tachycardia syndrome (POTS) and HSD, yet are often unrecognized. Proposed mechanisms based on limited data include impaired venous capacitance and preload reserve, increased intracranial pressure, altered renin–aldosterone and cortisol signaling, underlying autoimmune and systemic diseases, and sympathetic ganglion irritation. Several compression syndromes show symptom overlap and frequent co-occurrence, especially in patients with connective tissue disorders. Emerging data suggest that targeted interventions, such as surgical decompression or venous stenting, may improve orthostatic intolerance and quality-of-life measures in selected patients, though high-quality prospective data remain limited. Conclusions: Vascular compression syndromes may be an important yet underappreciated contributor to dysautonomia. Increased clinical awareness and systematic screening may reduce diagnostic delays and morbidity in this underserved population. Prospective studies are needed to clarify prevalence, establish causal relationships, and determine the impact of targeted treatments on autonomic outcomes. Full article

Objectives: Oral leukoplakia (OL) is the most prevalent oral potentially malignant disorder and requires accurate diagnosis, safe excision, and reliable margin evaluation to minimize recurrence and malignant transformation. Diode laser excision is increasingly adopted due to its precision and favorable clinical outcomes; however, laser-induced thermal effects at surgical margins raise concerns regarding tissue integrity and histopathological reliability. This study aimed to evaluate optical coherence tomography (OCT) as a real-time, high-resolution, non-invasive imaging modality for assessing peri-incisional thermal effects during diode laser excision of non-dysplastic OL. The primary objective was to validate OCT for ultrastructural and morphometric tissue analysis while ensuring preservation of diagnostic readability. Methods: A single-center observational case series was conducted at the University of Turin. Thirty patients with clinically and histopathologically confirmed oral leukoplakia without epithelial dysplasia were enrolled and allocated to two groups: 15 lesions excised using a 980 nm diode laser in continuous-wave contact mode (laser group) and 15 lesions removed by conventional scalpel biopsy (control group). Laser excisions were performed with standardized parameters and a circumferential safety margin of 5 mm. Immediately after excision, specimens underwent ex vivo spectral-domain OCT (SD-OCT) imaging to evaluate the epithelial and connective tissue microarchitecture at surgical margins and central lesion areas. OCT acquisition sites were precisely correlated with histological sections. Quantitative OCT measurements of epithelial thickness, lamina propria thickness, and laser-induced thermal alterations were compared with corresponding histological findings. Results: OCT consistently provided high-resolution visualization of oral mucosal microarchitecture in both groups, allowing clear identification of epithelial stratification, basement membrane continuity, and lamina propria organization. In the laser group, OCT detected superficial optical alterations at the surgical margins consistent with laser-induced thermal effects, while deeper tissue layers remained structurally readable. Histological analysis revealed mean epithelial and connective tissue thermal alterations of 288.9 μm and 430.3 μm, respectively. OCT-derived measurements showed high concordance with histology, with an overall agreement of 88.5% and no statistically significant differences between OCT and histological assessments. Importantly, laser-induced thermal effects did not impair definitive histopathological diagnosis in any specimen. Comparison with the control group confirmed preserved tissue architecture in scalpel-excised samples and highlighted OCT sensitivity in detecting laser-related structural remodeling. Conclusions: OCT proved to be a reliable, non-invasive imaging technique for real-time assessment of diode laser-induced thermal effects during OL excision. The technique accurately delineated tissue microstructure and surgical margins without compromising histopathological interpretation. Integration of OCT into the laser-assisted management of oral potentially malignant disorders may enhance surgical precision, optimize margin control, reduce diagnostic uncertainty, and support individualized follow-up strategies. Full article

Three-dimensional (3D) ex vivo imaging of cleared tissue from intact brains from animal models, human brain surgical specimens, and large postmortem human and non-human primate brain specimens is essential for understanding physiological neural connectivity and pathological alterations underlying neurological and neuropsychiatric disorders. Contemporary light-sheet microscopy enables rapid, high-resolution imaging of large, cleared samples but is limited by the orthogonal arrangement of illumination and detection optics, which constrains specimen size. Light-sheet theta microscopy (LSTM) overcomes this limitation by employing two oblique illumination paths while maintaining a perpendicular detection geometry. Here, we report the development of a next-generation, fully integrated and user-friendly LSTM system that enables uniform subcellular-resolution imaging (with subcellular resolution determined by the lateral performance of the system) throughout large specimens without constraining lateral (XY) dimensions. The system provides a seamless workflow encompassing image acquisition, data storage, pre- and post-processing, enhancement and quantitative analysis. Performance is demonstrated by high-resolution 3D imaging of intact mouse brains and human brain samples, including complete downstream analyses such as digital neuron tracing, vascular reconstruction and design-based stereological analysis. This enhanced and accessible LSTM implementation enables rapid quantitative mapping of molecular and cellular features in very large biological specimens. Full article

Background: Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease which presents with clinical features that overlap with at least two connective tissue disorders, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM), and rheumatoid arthritis (RA). It is characterized by the presence of anti-ribonucleoprotein (anti-U1RNP) antibodies. The mechanism of the vasculopathy associated with MCTD remains largely unknown. Optical coherence tomography angiography (OCTA) is a non-invasive imaging method of the microvasculature of the retina and choroid, providing the assessment of retinal perfusion. Objectives: The aim of the study was to evaluate the optical coherence tomography angiography (OCTA) parameters in patients with mixed connective tissue disease compared to healthy individuals. Methods: In this study, we compared the following parameters between patients with MCTD and healthy subjects: foveal avascular zone (FAZ), FAZ perimeter (PERIM), flow density (FD), choriocapillaris flow area (CCFA), outer retina flow area (ORFA), and foveal and parafoveal mean superficial and deep vessel density. Results: Parafoveal mean superficial vessel density and parafoveal mean deep vessel density were significantly lower in the MCTD group than in controls. The FAZ, FAZ PERIM, and FD values in the patients with MCTD were lower than in the control group and statistically significant for all parameters. Conclusions: The present study’s findings suggest the presence of ocular vascular abnormalities in patients suffering from MCTD. These abnormalities are characterized by decreased retinal vessel density and lower choriocapillaris flow. The results of the study demonstrate the significant role of OCTA in the diagnosis and monitoring of microvascular changes in patients with MCTD. Full article

Objective: To evaluate the diagnostic yield and clinical impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with unexplained inflammation, fever, or suspected malignancy, and to assess its role across different rheumatologic subgroups. Methods: We retrospectively analyzed 280 patients who underwent PET/CT between 2010 and 2020 in a tertiary rheumatology center. Demographic, clinical, and laboratory data including erythrocyte sedimentation rate, C-reactive protein, and PET/CT indications were collected. PET/CT findings were categorized as inflammatory, neoplastic, or normal based on visual assessment and SUVmax. Final diagnoses were confirmed using clinical, histopathological, or follow-up data. Statistical analysis compared PET/CT results, inflammatory markers, and diagnostic outcomes among disease subgroups. Results: Of 280 patients (mean age 58 ± 15 years, 63.9% female), 72% had an established rheumatologic diagnosis prior to PET/CT. A new diagnosis, confirmed by predefined clinical, histopathological, or follow-up criteria, was established in 29.6% of patients, predominantly among those undergoing diagnostic evaluation for unexplained inflammation, including 40 rheumatologic and 43 non-rheumatologic conditions (22 malignancies). PET/CT led to therapeutic modification in 27.1% of all cases, based on multidisciplinary clinical decision-making. PET/CT demonstrated the highest diagnostic contribution in vasculitis, IgG4-related disease, and sarcoidosis. Median SUVmax was higher in malignancies than in inflammatory diseases [8.0 vs. 4.6, p < 0.05]. Lymphadenopathy was more frequent in non-rheumatologic and malignant conditions (p = 0.002). PET/CT findings showed variable but clinically relevant concordance with other imaging modalities. Conclusions: PET/CT provides supportive diagnostic and management insights in complex or atypical rheumatologic presentations. It demonstrated high yield in systemic inflammatory disorders and providing supportive information for malignancy exclusion in connective tissue diseases when interpreted alongside clinical and laboratory follow-up. Integration of PET/CT with clinical and laboratory data enhances diagnostic accuracy and supports patient-centered management in rheumatology. Full article

Stickler syndrome is a monogenic connective tissue disorder primarily caused by pathogenic variants in collagen-related genes, most commonly COL2A1. Prenatal diagnosis remains challenging, particularly in healthcare systems with limited access to molecular genetic testing. We report a prenatal case of suspected craniofacial anomaly detected on second-trimester ultrasound. Fetal DNA obtained by amniocentesis underwent next-generation sequencing. Parental testing was performed to assess inheritance. It was confirmed that autosomal dominant Stickler syndrome type I (ORPHA:90653) was caused by a heterozygous pathogenic frameshift variant in COL2A1 (c.3137del) that was inherited from the mother and identified in the fetus. Micrognathia was identified during prenatal ultrasound, and postnatal evaluation revealed characteristics that were consistent with Pierre Robin sequence and connective tissue involvement. The molecular discoveries elucidated the observed phenotype and facilitated multidisciplinary perinatal management. This case underscores the indispensable function of molecular diagnostics in the prenatal identification of monogenic disorders, including Stickler syndrome, in cases where conventional karyotyping is inadequate. Targeted clinical surveillance and family counseling are facilitated by early genetic confirmation. The report also emphasizes the necessity of incorporating molecular diagnostics into routine prenatal care for rare genetic diseases and the systemic limitations in access to genomic testing. Although the identified variant has been previously reported, this case highlights the clinical and diagnostic value of prenatal molecular confirmation in a resource-limited healthcare setting. Full article

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications. Full article

Background: Developing an evidence base for physiotherapy programs for patients with Cerebral Palsy (CP) requires an understanding of the microscopic and metabolic processes in striated muscle. The gracilis muscle represents a logical object of study due to the significant morphological changes in individuals with cerebral palsy. This research aims to study morphological and biochemical alterations in the gracilis muscle depending on the severity of motor impairments in CP patients. Methods: The cross-sectional study included 24 patients stratified by the severity of motor impairment. Intraoperative gracilis muscle samples were obtained during tenomyotomies. Nutritional status of patients, morphometric, and biochemical parameters were evaluated. Results: Initial body mass and Quetelet index (p = 0.02) were lower in GMFCS V patients (p = 0.01) compared to GMFCS IV and GMFCS II-III. Muscle tissue predominated in histological samples of GMFCS II-III and GMFCS V patients (p = 0.79), while connective tissue content was higher in the GMFCS IV group (p = 0.03). Strong, fast-twitch, anaerobic fibers (p = 0.761) with reduced creatine phosphokinase activity (p = 0.012) were more frequently observed in the intraoperative samples of GMFCS V patients. Low creatine phosphokinase activity was revealed in children in the GMFCS V group (p = 0.012). Conclusions: The structural and metabolic abnormalities observed in gracilis muscle of patients with spastic cerebral palsy indicates profound functional muscular dysfunction, representing one of the factors limiting children’s motor ability. The morphological and biochemical alterations in the striated muscle of CP children correlate with severity of motor dysfunction conditioned by the primary upper motor neuron disorders. Less significant changes in muscles in ambulatory children reflect favorable basis for physical therapy. Full article

Background: Autoimmune diseases (AIDs) are characterized by chronic inflammation and tissue damage resulting from abnormal immune responses. While genetic and environmental factors play significant roles in disease development, essential micronutrient deficiencies (MNDs) represent a critical and often overlooked contributor. Methods: This review examines the interactions between micronutrients and immune cells, focusing on vitamin D, vitamin B12, folate (FA), and iron, and their roles in AIDs, such as rheumatoid arthritis, autoimmune thyroid disorders, multiple sclerosis, systemic lupus erythematosus, and other connective tissue diseases. We explore the immunomodulatory effects of these micronutrients, their impact on immune tolerance, and the mechanisms by which MNDs contribute to disease progression. Results: MNDs are commonly observed in patients with AIDs and are associated with worsening immune dysregulation, increased inflammation, and disease severity. Vitamin D plays a pivotal role in modulating immune responses and attenuating inflammation, while iron and FA are essential for immune cell proliferation and function. Vitamin B12 supports methylation processes and genomic stability. Conclusions: MNDs significantly influence the pathogenesis and progression of AIDs. Routine micronutrient screening and targeted supplementation should be considered as part of clinical management, offering potential adjunctive benefits alongside conventional therapies. Further research is needed to define optimal dosing strategies and to identify patient subgroups most likely to benefit from nutrition-based interventions. Full article

Introduction: Urinary incontinence (UI) is one of the most common pelvic floor disorders after childbirth and depends on hormonal changes, anatomical damage that occurs after childbirth, muscle and connective tissue weakness, fascia and nerves. UI is distinguished into three subtypes, including stress urinary incontinence (SUI), urgent urinary incontinence (UUI) and mixed urinary incontinence (MUI). Aim: The purpose of this review is to collect and summarize the results of studies related to the risk factors of urinary incontinence, to disseminate this information to scientists so that this major issue can be prevented, identified and managed. Methodology: This review followed the methodology of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PECO eligibility criteria were used. We included studies published up to 2025 and not before 2019. The review was limited to studies published within the last six years in order to reflect contemporary diagnostic criteria, assessment tools and current postpartum care practices related to urinary incontinence. We searched PubMed, Google Scholar and Scopus for studies concerning the relationship between risk factors and postpartum UI. Results: A total of 1321 citations were identified. Following our exclusion criteria, 36 papers were selected to identify the risk factors for UI. All the research focused on the associated factors of any type of urinary incontinence. Vaginal and instrumental delivery, obesity, maternal age and the neonate’s birth weight were the main risk factors. The multiparity and incontinence symptoms before and during pregnancy were also strong risk factors. Heterogeneity across studies in assessment tools, in outcome measures and timing of postpartum assessment are some of the limitations of the study. Restriction to English-language publications and the absence of protocol registration were some of the additional limitations of the study. Conclusions: This problem affects the inclusion of women in society, the family, limits social activities and even their ability to work. Detection of the type of urinary incontinence by healthcare professionals, lifestyle modifications, monitoring women’s body weight and encouraging them to follow a program of pelvic floor muscle exercises should be a priority for professionals. The strategy of developing prognostic models in the coming years will be the only way to ensure the early identification and follow-up of women at high risk for urinary disorders. Full article

Tuberculosis and coronavirus disease 2019, also known as COVID-19, remain major global health challenges that disproportionately affect individuals with metabolic disorders, chronic inflammation, and limited access to healthcare. Although these diseases are caused by different pathogens, they share important host-related determinants of severity, including immune dysfunction, oxidative stress, endothelial injury, and maladaptive inflammatory responses. Glutathione, the primary intracellular antioxidant and a key regulator of redox balance, has emerged as an important host factor connecting these processes across infectious diseases. This review integrates experimental, translational, and clinical evidence supporting the role of glutathione in regulating immune function, oxidative stress, and tissue damage in tuberculosis and COVID-19. In tuberculosis, glutathione deficiency compromises macrophage antimicrobial activity, disrupts granuloma structure, and alters T helper cell responses, leading to impaired immune containment and disease progression. In COVID-19, reduced glutathione levels are associated with redox imbalance, excessive cytokine signaling, endothelial dysfunction, and thromboinflammatory complications, especially in high-risk populations. In both diseases, glutathione depletion reduces host resilience and increases vulnerability to severe outcomes through shared immune and vascular pathways. By unifying disease-specific findings within a host-directed framework, this review highlights glutathione and redox signaling as common vulnerability pathways that help explain overlapping risk profiles for severe tuberculosis and COVID-19. It also places glutathione biology within the broader context of host-directed immunotherapy, emphasizing its potential role in prevention-focused and resilience-based strategies that complement pathogen-targeted treatments. Although current evidence does not support simple claims of disease prevention, it provides strong mechanistic justification for further investigation of glutathione as a modifiable host factor in high-risk populations. Full article

Objectives: Connective tissue dysplasia (CTD) is associated with disorders of collagen synthesis and is widely spread among the healthy population and people with disabilities. In the heart, primarily in the left ventricle (LV), CTD manifests itself as the formation of false tendons (LVFTs) to maintain close-to-normal LV pump function. This exploratory work is devoted to the search for general patterns of cardiac response to physical activity in athletes with disabilities, CTD, and LVFTs. The extent to which “the type of sports or the type of disability” determines the involvement of the heart’s functional reserve is the main testable question of the proposed research. Methods: The group under this study included 610 individuals with disabilities aged from 6 to 60 years with at least two transverse and/or oblique FTs per LV. Participants represented different sports disciplines (n = 10) and various forms of disabilities (n = 4). Cardiovascular indicators were obtained by means of standard TTE, impedance cardiography for hemodynamic monitoring in active orthotest, resting, and stress 12-lead ECG. Exercise testing of the athletes was performed with the use of appropriate methods of physical loading. In total, 141 parameters of cardiorespiratory function and exercise performance per participant were recorded. Statistical analysis of the dataset obtained across sports types or disability types was performed using one-way ANOVA or the Kruskal-Wallis test, depending on the assumptions of normality and homogeneity of variance. Results: Most importantly, it was found that only maximum relative oxygen consumption (VO₂max, mL·kg⁻¹·min⁻¹) as a reliable indicator of the heart’s functional reserve and the corrected QT (QTc, ms) interval as an integral measure of the heart’s electrical activity demonstrated statistically significant differences across the sports specialization or the disability type. In particular, significance values (P) for VO₂max across athletic disciplines and nosology categories were equal to 0.00063 and 0.01028 (one-way ANOVA), while for QTc they were 0.00001 and 0.02185 (Kruskal-Wallis), respectively. Furthermore, the type of disability had a lower impact on VO₂max and QTc than the type of athletic activity. Conclusions: In athletes with disabilities and CTD, sport specialization may involve the heart’s functional reserve to a greater extent than the type of disability. To prescribe training loads for people with disabilities and CTD, individual cardiology screening with an emphasis on VO₂max and QTc is necessary. Full article

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10⁻⁶) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10⁻⁶), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10⁻⁴). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article

Background: Superficial venous thrombosis (SVT) is an inflammatory and thrombotic disorder affecting superficial veins. While varicose veins (VVs) are the primary risk factor, SVT occurring in non-varicose veins (NVVs) is a critical clinical finding, often acting as a sentinel marker for severe systemic pathologies. Aims: This review aims at examining incidence, mechanisms, underlying causes, and clinical outcomes of SVT within the NVV population. Materials and Methods: We conducted a comprehensive narrative review of the existing medical literature. Results: SVT in NVVs is frequently associated with systemic conditions, including inherited or acquired thrombophilia, visceral or hematologic malignancies (notably Trousseau’s syndrome), vasculitis (e.g., Behçet’s syndrome), and connective tissue disorders. Specific manifestations like migratory SVT or Mondor’s disease provide crucial diagnostic clues. Notably, NVV-SVT carries a significantly higher risk of recurrence and venous thromboembolic events compared to VV-associated cases. Conclusions: A thorough diagnostic work-up is essential for patients with NVV-SVT to ensure early detection of underlying systemic diseases. Although current management does not differentiate between VV and NVV cases, the increased thromboembolic risk in the latter suggests a need for tailored therapeutic approaches. Further prospective studies are required to evaluate differentiated anticoagulant strategies regarding dosage and duration for this high-risk population. Full article