Search Results (1,289)

Localized scleroderma (LSc), or morphea, is an autoimmune connective tissue disease causing inflammation and fibrosis of the skin and underlying tissues. While distinct from systemic sclerosis, its clinical presentation is highly diverse. This review summarizes recent advances in the understanding and management of LSc. Pathophysiological insights have evolved significantly; the somatic mosaicism hypothesis is now supported by the observation of all six of Happle’s classic lesion patterns in LSc. Furthermore, recent single-cell RNA sequencing has elucidated key cellular mechanisms, revealing an IFN-γ-driven pro-fibrotic crosstalk between T cells, dendritic cells, and specific inflammatory fibroblast subpopulations. The discovery of a rare monogenic form of LSc caused by a STAT4 gain-of-function mutation provides a powerful human model, solidifying the critical role of the JAK-STAT pathway. Clinically, LSc is classified into subtypes such as circumscribed, linear, and generalized morphea. Extracutaneous manifestations are common, particularly in juvenile LSc, and are associated with higher disease activity and reduced quality of life, necessitating a multidisciplinary approach. Management is becoming standardized, with methotrexate as the first-line systemic therapy for severe disease. For refractory cases, targeted treatments including abatacept, tocilizumab, and JAK inhibitors are emerging as promising options. In addition, reconstructive therapies like autologous fat grafting are crucial for managing atrophic sequelae. These recent advances are paving the way for more effective, targeted therapies to improve outcomes for patients with this complex disease. Full article

We carried out a comprehensive literature search for publications on the range of vascular events that have been linked to adenomyosis. This covered vascular diseases, blood coagulation disorders, thrombosis, hypercoagulation, stroke (embolic, ischemic, thrombotic, hemorrhagic), cerebrovascular episodes, cerebral infarction, cerebral hemorrhage) and renal disease. This review covers 63 articles. Nineteen articles reported clinical manifestations of intravascular thrombosis in women with adenomyosis. Eleven publications were identified that reported on cerebral involvement and adenomyosis, including cases of ischemic stroke or infarction. Dysregulation primarily seems to occur via local factors leading to altered angiogenesis. Five case reports were identified that reported on various vascular complications attributed to the presence of adenomyosis. The search also identified reports of cerebral complications in women with adenomyosis. Through a secondary search, we identified publications dealing with a possible connection between cardiac complications and renal pathology, which the authors attributed to adenomyosis. Vascular involvement in adenomyosis is documented in rare cases by the presence of endometrial tissue in myometrial vessels both in menstrual and non-menstrual uteri. Women with adenomyosis have a higher platelet count, a shorter thrombin and prothrombin time and an activated partial thromboplastin time. These findings has been applied to attempts to identify therapies for adenomyosis based on targeting the vasculature, but the existence of a link between the two conditions is under question for several reasons: only case reports (or very small series) have been published; all published cases come from one region of the world (the Far East); the published literature does not contain objective proof of a causal relationship between the two pathologies, except for the elevation of some markers. In summary, it is not possible to conclude that the presence of adenomyosis has a pathogenetic role in causing vascular events, first and foremost because available evidence consists mostly of case reports. Full article

Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1^−/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities. Full article

Background: Interstitial lung diseases (ILDs) often progress quickly and are associated with a poor prognosis. New noninvasive biomarkers to assist in the classification and prognostication of ILD are needed. Exhaled nitric oxide (FeNO), Cavity nitric oxide (CaNO), and carbon monoxide (eCO) are biomarkers of airway inflammation, widely used in respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, their value in ILD remains unclear. Objective: To evaluate the potential diagnostic and prognostic value of FeNO, CaNO, and eCO in ILD, and explore their integration into clinical practice. Methods: A total of 237 patients were recruited for the study, including 14 with idiopathic pulmonary fibrosis (IPF), 46 with interstitial pneumonia with autoimmune features (IPAF), 19 with mixed connective tissue disease–associated ILD (MCTD-ILD), 65 with polymyositis/dermatomyositis-associated ILD (PM/DM-ILD), 17 with rheumatoid arthritis-associated ILD (RA-ILD), 7 with systemic lupus erythematosus-associated ILD (SLE-ILD), 19 with Sjögren’s syndrome-associated ILD (SS-ILD), and 50 with systemic sclerosis-associated ILD (SSc-ILD). Multiple-flow FeNO and eCO analyses were performed in this population. The associations of these biomarkers with pulmonary function, acute exacerbations, and radiologic fibrosis classification were evaluated. Results: Patients with IPF exhibited significantly higher levels of FeNO at 50 mL/s (FeNO50) compared to those with connective tissue disease-associated ILD (CTD-ILD) and IPAF. Both CaNO and eCO were negatively correlated with pulmonary function parameters, particularly forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO). Receiver operating characteristic (ROC) curve analysis indicated that CaNO is a reliable biomarker for acute exacerbation, with an area under the ROC curve (AUC) of 0.8887, and a cutoff value of 6.35. Additionally, CaNO > 6.35 was associated with a relative risk (RR) of 12.87 for acute exacerbation (AE) compared to CaNO ≤ 6.35. Moreover, both CaNO and eCO levels were significantly higher in the fibrotic ILD group compared to the non-fibrotic group, with ROC analysis indicating AUCs of 0.7173 for CaNO and 0.6875 for eCO. Conclusions: FeNO, CaNO, and eCO can provide strong support for the early diagnosis and monitoring of ILD, especially with CaNO playing a crucial role in predicting acute exacerbations. Integrating these biomarkers into clinical practice can help doctors more accurately assess the progression of ILD and develop personalized treatment plans, ultimately improving the prognosis of ILD patients. Future research is needed to validate the effectiveness of these biomarkers in clinical management, facilitating their integration as standard tools for clinical monitoring. Full article

Post-translational modifications (PTMs) provide an integrated regulatory layer that couples nutrient and hormonal signals to whole-body energy homeostasis across metabolic organs. PTMs modulate protein activity, localization, stability, and metabolic networks in a tissue- and state-specific manner. Through network remodeling, PTMs integrate receptor signaling with chromatin and organelle function and align transcriptional control with mitochondrial function, proteostasis, and membrane trafficking. PTM crosstalk connects kinase cascades, nutrient-sensing pathways, and ubiquitin-family modifiers to orchestrate gluconeogenesis, lipolysis, glucose uptake, thermogenesis, and insulin secretion in response to nutrient cues. The metabolic state regulates PTM enzymes through changes in cofactors, redox tone, and compartmentalization, and PTM-dependent changes in transcription and signaling feedback to metabolic tone. In obesity and diabetes, dysregulated post translational modification networks disrupt insulin receptor signaling, disturb organelle quality control, and impair beta cell function, which promotes insulin resistance and beta cell failure. Consequently, PTMs organize metabolic information flow and modulate tissue responses to overnutrition and metabolic stress. A systems-level understanding of PTMs clarifies mechanisms of whole-body energy homeostasis and supports the discovery of new therapeutic targets in metabolic disease. Full article

Background: Primary Sjogren Disease (pSD) is a chronic autoimmune disease characterized by a classic triad of keratoconjunctivitis sicca, xerostomia, and polyarthritis. The primary pathological feature of pSD is lymphoplasmacytic infiltration in glandular epithelial tissue, often affecting the salivary and lacrimal glands, leading to classic sicca symptoms (ocular and oral dryness). Sjogren Disease (SD) can be categorized as “primary” when occurring independently or “secondary” when accompanying another autoimmune connective tissue disorder such as rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis. Additionally, systemic disease is common in pSD and can manifest with kidney dysfunction resulting in nephrolithiasis and distal renal tubular acidosis (dRTA). Methods: This report details a case series drawing patients from the literature as well as patients from our institution which serves to demonstrate key points in clinical hallmarks. We utilize a literature search with key words Sjogren Disease, nephrolithiasis, renal tubular acidosis, and nephrocalcinosis in addition to pSD patients with concomitant nephrolithiasis at our institution to characterize clinical and serologic findings as well as treatment modalities. Results: We find well demonstrated clinical hallmarks such as female predominance and presence of dRTA amongst the cohort of pSD patients. We also find that further research on pSD serologies could prove beneficial in risk stratifying those most likely to develop renal disease and nephrolithiasis. Furthermore, we review signs, symptoms, pathophysiology, and management of SD with added emphasis on associated renal disease including nephrolithiasis and dRTA. Conclusion: Overall, pSD associated renal disease remains an area of ongoing research and further study on patient serologies may aid clinicians in better serving and surveilling patients at risk of systemic involvement. Full article

Microplastics and nanoplastics (MNPs) are pervasive contaminants infiltrating water, food, and human tissues. The sharp rise in plastic production—with over half manufactured between 2003 and 2022—has heightened concerns about their health impacts. Methods included: (1) a literature review of clinical studies on MNPs focusing on human health and (2) analysis of Standardized Mortality Rates (SMRs) for 44 groups of diseases in Italy (2003–2022, Italian National Institute of Statistics, ISTAT data). The outcomes suggest that MNPs have been connected to pathological alterations in a number of organ systems, such as the gastrointestinal tract (intestine, liver, and pancreas), breathing system, eyes, brain, and vascular structures. SMRs increased significantly in only eight of the 46 illness categories examined between 2003 and 2022. The analysis of clinical and epidemiological data allows us to identify a possible clinical assessment consisting of a 30-variable diagnostic questionnaire (Chicago Cluster Evaluation System, CCES), encompassing laboratory markers, clinical signs, and ultrasound findings. A binomial distribution model suggests that more than 8 positive responses may indicate a presumptive diagnosis of Microplastic Syndrome (MP-Sy). This framework reflects observed clinical/epidemiological patterns and provides a foundation for hypothesis-driven research. Prospective longitudinal studies are warranted to validate the proposed definition and its diagnostic utility. The aim of the present study is to propose a preliminary clinical framework for a potential MP-Sy integrating toxicological evidence with epidemiological data, define diagnostic criteria and assess their consistency with observed disease trends. Full article

Lipid metabolism and lipid-derived signaling together ensure cellular and systemic homeostasis. Their dysregulation causes obesity, type 2 diabetes, cardiovascular disease, NAFLD/MASH, and neurodegeneration throughout life. This review integrates central pathways, such as ACC–FASN-mediated de novo lipogenesis, lipid-droplet lipolysis, and mitochondrial and peroxisomal β-oxidation, and their regulation by insulin–PI3K–Akt, glucagon–cAMP–PKA, SREBPs, PPARs, and AMPK. We emphasize the mechanisms by which bioactive lipids like diacylglycerols, ceramides, eicosanoids, and endocannabinoids serve as second messengers linking nutrient state to insulin signaling, inflammation, and stress response; pathologic accumulation of these species enhances insulin resistance and lipotoxicity. Aging disrupts these axes via diminished catecholamine-stimulated lipolysis, defective fatty-acid oxidation, mitochondrial failure, and adipose depot redistribution, facilitating ectopic fat and postprandial dyslipidemia. We suggest a pathway-to-phenotype paradigm that connects lipid species and tissue environment to clinical phenotypes, allowing for mechanism-to-intervention alignment. Therapeutic avenues range from lipid lowering for atherogenic risk to novel agents targeting ACLY, ACC, FASN, CPT1, and nuclear receptors, with precision lifestyle intervention in diet and exercise. Translation is still heterogeneous because of isoform-dependent effects, safety trade-offs, and inconsistent adherence. We prioritize harmonization of lipidomics with multi-omics for stratifying patients, enriching responders, and bridging gaps between mechanistic understanding and clinical outcome, with focus on age-sensitive prevention and treatment for lipid-mediated metabolic disease. Full article

The extracellular matrix (ECM) constitutes a dynamic scaffold composed of both cellular and non-cellular elements that not only ensure tissue integrity but also regulate signaling events crucial for development and homeostasis. While its dysregulation has long been investigated in cancer, fibrosis, and autoimmunity, increasing evidence implicates ECM remodeling in neurodegenerative diseases, including motor neuron diseases (MNDs). Amyotrophic lateral sclerosis and spinal muscular atrophy, the most studied MNDs, both exhibit profound ECM alterations that influence synaptic connectivity, glial reactivity, and neuroinflammation. This review outlines recent data on ECM dynamics in MNDs, highlighting shared and disease-specific mechanisms, their potential as biomarkers, and therapeutic opportunities targeting the ECM environment to preserve neuronal function and slow disease progression. Full article

Pulmonary fibrosis is a progressive lung disease characterized by interstitial tissue fibrosis, with idiopathic pulmonary fibrosis being the most common subtype. The disease leads to persistent scarring and fibrotic remodeling of lung tissue following injury, and under current medical conditions, it remains incurable and irreversible. Chest X-ray imaging is widely used in clinical diagnosis; however, traditional interpretation methods face challenges in accurately detecting fibrotic lesions and quantifying disease severity. To address these limitations, we propose the Attention Feature Transformation Network (AFTNet) for automated identification and precise quantification of pulmonary fibrosis regions. AFTNet integrates two key modules—Spatial-Based Multi-Head Self-Attention (SB-MSA) and Channel-Based Multi-Head Self-Attention (CB-MSA)—which enhance the model’s ability to capture subtle features in chest X-ray images. In addition, a specially designed skip connection mechanism preserves multi-level details and improves boundary delineation accuracy. Experimental results demonstrate that AFTNet outperforms comparative models, achieving superior performance with IoU (80.34%), Dice (81.76%), and Hausdorff Distance (21.54%). Furthermore, by incorporating data augmentation strategies, the model shows robust adaptability to chest X-ray images under different clinical conditions, enabling accurate boundary detection of fibrotic regions and quantifying fibrosis extent. The proposed AFTNet provides an efficient, accurate, and clinically valuable solution for the quantitative analysis of pulmonary fibrosis, contributing to improved diagnostic efficiency and treatment monitoring in pulmonary diseases. Full article

Pectus excavatum (PE) is the most frequent chest wall deformity, representing 65–95% of all cases, with an estimated prevalence of up to 1 in 300 births. Despite its frequency, it remains underrecognized in sports cardiology. PE results from sternal depression and narrowing of the anterior chest, which may lead to cardiac compression, impaired diastolic filling, and reduced stroke volume during exercise. Consequently, athletes with PE often present with cardiovascular symptoms such as exercise-induced dyspnoea, chest pain, palpitations, presyncope, or reduced physical fitness. Electrocardiographic changes, including right bundle branch block, axis deviation, atrial enlargement, T-wave inversion, QS complexes or Brugada phenocopies, are frequent and may mimic serious cardiovascular conditions, complicating pre-participation screening. Furthermore, PE is associated with potentially high-risk conditions including mitral valve prolapse, ventricular arrhythmias, and connective tissue disorders such as Marfan syndrome, which carry implications for sports eligibility and safety. Assessment of athletes with PE requires multimodal imaging (echocardiography, computed tomography, magnetic resonance), cardiopulmonary exercise testing, and exclusion of concomitant cardiovascular disease. Treatment strategies range from conservative approaches (physiotherapy, vacuum bell therapy) to surgical correction, most commonly with the Nuss procedure, which can improve cardiac function, exercise capacity, and quality of life. Management should involve shared decision making between clinicians, athletes, and families, weighing potential risks against athletic aspirations. Awareness of PE in sports cardiology is crucial, as it not only influences differential diagnosis and screening outcomes but also impacts career decisions and the psychological well-being of athletes. Full article

Background: Advances in diagnosis and treatment have led to a growing population of adults with congenital heart disease (ACHD). Despite increasing life expectancy, their clinical needs—especially in older age—remain poorly defined. Cardiac and non-cardiac comorbidities are prevalent, and emerging evidence suggests accelerated biological aging compared to the general population. However, data on older patients and geriatric patients with CHD are limited. Objectives: This study aimed to characterize patients with CHD aged ≥50 years, focusing on functional status, comorbidities, sex-specific differences, and therapeutic patterns. Methods: The PATHFINDER-CHD Registry is a prospective, observational, multicenter registry enrolling patients with CHD with manifest heart failure (HF), HF history, or high HF risk. Data include anatomy, prior treatments, comorbidities, and medication use. Results: Among 1935 patients, 297 were ≥50 years old. Most had acyanotic CHD (62%); Tetralogy of Fallot (21%) was the most frequent diagnosis. A morphologic right systemic ventricle was present in 12%, and 5% had univentricular hearts. HF was manifest in 21%; 44% were classified as ACC/AHA stage B, 51% as stage C, yet 77% were in Perloff class I/II. Common cardiovascular comorbidities included aortopathy (55%), hypertension (37%), and arrhythmia (33%). Non-cardiac comorbidities included thyroid dysfunction (25%), renal impairment (18%), and neurological disease (13%). Sex-specific differences were observed. Despite HF burden, SGLT2 inhibitors and ARNIs were used in only 17% and 8.4%, respectively. Conclusions: Older patients with CHD represent a clinically complex cohort with high comorbidity burden. The findings support the concept of accelerated aging and emphasize the need for tailored interdisciplinary care strategies. Full article

Background/Objectives: Periodontitis is a chronic inflammatory disease initiated by dysbiotic biofilms and driven by host immune dysregulation, leading to connective tissue destruction and alveolar bone loss. Its early diagnosis is closely linked to the progression and outcome of the disease. Active-matrix metalloproteinase-8 (aMMP-8) is one of the key biomarkers for estimating irreversible collagenolytic degradation. aMMP-8 is among the key biomarkers for estimating irreversible collagenolytic degradation. To evaluate the role of oral fluid/salivary/mouthrinse aMMP-8 tests for early detection and treatment monitoring of periodontitis. Methods: A search was conducted in the Medline, Embase, Scopus, and Cochrane databases, restricted to articles published between January 2020 and December 2024 to capture the most recent literature. Pilot, cohort, case–control, and cross-sectional studies were included, while studies not aligning with the objectives of this review, as well as narrative reviews, editorials, and opinions were excluded. Results: A total of 276 articles were retrieved. After removing duplicates, 226 studies remained, of which 216 were retained following title, abstract, and keyword screening. From these, 26 studies were finally included in this review. aMMP-8 point-of-care tests appear to be promising tools for early diagnosis, disease severity assessment, and treatment monitoring in periodontitis, though findings remain conflicting across studies. Elevated aMMP-8 levels are associated with active periodontal pathology and tissue destruction, reflecting ongoing collagenolytic degeneration. Conclusions: aMMP-8 mouthrinse, saliva, or oral fluid tests can be used for predictive and early diagnosis as well as for treatment monitoring in patients with periodontal disease, and they function effectively as biomarkers for periodontitis. Full article

Background/Objectives: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a safe and established therapy for management of refractory motor fluctuations and dyskinesia in Parkinson’s disease (PD). However, the relationship between stimulation site connectivity and improvement of axial gait symptoms remains poorly understood, particularly when stimulating in the GPi. This study investigated functional and structural connectivity patterns specifically associated with axial symptom outcomes following bilateral GPi-DBS, and, as a secondary exploratory analysis, examined whether Volumes of tissue activated (VTAs)-based connectivity related to overall UPDRS-III change. Methods: We retrospectively analyzed 19 PD patients who underwent bilateral GPi-DBS at the University of Florida (2002–2017). Unified Parkinson’s Disease Rating Scale (UPDRS-III) axial gait subscores were assessed at baseline and 36-month follow-up. VTAs were reconstructed using Lead-DBS and coregistered to Montreal Neurological Institute (MNI) space. Structural connectivity was evaluated with diffusion tractography, and functional connectivity was estimated using normative resting-state fMRI datasets. Correlations between VTA connectivity and clinical improvement were examined using Spearman correlation and voxelwise analyses. Results: Patients with axial improvement in motor scales demonstrated specific VTA connectivity to sensorimotor and supplementary motor networks, particularly lobule V and lobules I–IV of the cerebellum. These associations were specific to axial gait subscores. In contrast, worsening axial gait symptoms correlated with connectivity to cerebellar Crus II, cerebellum VIII, calcarine cortex, and thalamus (p < 0.05). Total UPDRS-III scores did not show a significant positive correlation with supplementary motor area or primary motor cortex connectivity; a non-significant trend was observed for VTA–M1 connectivity (R = 0.41, p = 0.078). Worsening total motor scores were associated with cerebellar Crus II and frontal–parietal networks. These findings suggest that distinct connectivity patterns underlie differential trajectories in axial and global motor outcomes following GPi-DBS. Conclusions: Distinct connectivity profiles might underlie axial gait symptom outcomes following GPi-DBS. Connectivity to motor and sensorimotor pathways supports improvement, whereas involvement of Crus II and occipital networks predicts worsening. Additional studies to confirm and expand on these findings are needed, but our results highlight the value of connectomic mapping for refining patient-specific targeting and developing future programming strategies. Full article

In recent decades, the novel role of Galectin-3 (Gal-3) in both physiological and pathological conditions has emerged. Gal-3 is a key protein involved in immunity, inflammation, cell adhesion, proliferation, differentiation, and apoptosis. Its physiological role is crucial for the regulation of these cellular functions. In pathological settings, elevated levels of Gal-3 are associated with diseases such as cancer, heart failure, and fibrotic diseases, making it an important diagnostic and prognostic biomarker in these conditions. It seems that Gal-3 acts as a bridge between different diseases. Because of its pro-inflammatory and pro-tumorigenic properties, it connects atherosclerosis and cancer, regulating inflammation, cell proliferation, immune evasion, angiogenesis and survival in both diseases. Specifically, in atherosclerosis, Gal-3 promotes plaque formation by driving inflammation, oxidative stress, lipid deposition, and vascular cell migration. In cancer, Gal-3 influences tumor growth and metastasis by modulating an immunosuppressive tumor microenvironment, increasing cell survival, and enhancing cell–matrix and cell–cell interactions. Moreover, by stimulating fibroblasts, Gal-3 favors matrix deposition and tissue fibrosis that together with the inflammatory properties contributes to adverse ventricular remodeling leading to heart failure. Finally, taking into account its role in pathogen recognition and immune cells (B and T cells) modulation, Gal-3 might be a critical factor in host defense, disease progression, and the development of autoimmune conditions. Thus, targeting Gal-3 might be a promising therapeutic strategy to pursue for management of different pathological scenarios. Full article