Search Results (881)

In equine veterinary medicine, there is a lack of correlation between the structural severity of orthopaedic disease and the perceived severity of presenting signs, resulting in a variable influence on performance, pain and disability. Across equine industries, there is selective pressure through breeding for specific traits, such as the “speed” gene (MSTN) in racing thoroughbreds and the “gait keeper” gene (DMTR3) in pacing breeds, potentially resulting in genetic predispositions that lead to an increased risk of musculoskeletal disorders. With advancements in molecular sequencing techniques, researchers have been able to identify various genes (e.g., ECA, RUNX, and ADAME1) as well as biomarkers influencing performance and the development of orthopaedic disease. In combination, these techniques could be applied clinically in the future to improve welfare and disease management through advanced characterization and treatments to delay the onset of orthopaedic disease. Full article

Testicular germ cell tumor (TGCT) is a common tumor type in young men. Family history of TGCT and its presence in twins support the involvement of inherited genetic factors. Germline exome sequencing was performed on monozygotic twins with TGCT and their parents. The twins presented compound heterozygous variants in PDE11A (rs776984134 and rs17400325) inherited from each parent. The rs776984134 variant disrupts the canonical splice acceptor site, leading to aberrant splicing and a frameshift predicted to affect protein structure. The rs17400325 missense variant, located in the catalytic domain, reduces hydrogen bonding capacity and may impair protein stability. Both variants map to a genomic region overlapping the antisense lncRNA PDE11A-AS1. In silico transcript-level analysis predicted multiple energetically favorable RNA–RNA interactions between PDE11A and PDE11A-AS1 transcripts, with rs17400325 located within predicted hybridization regions of several isoforms. These results suggest a potential impact on PDE11A–PDE11A-AS1 pairing and post-transcriptional regulation. Additional variants in MSH6 and CTU2 were also identified and may act as potential modifiers of disease susceptibility, consistent with a multigenic contribution to TGCT risk. These findings support a contributory role for the PDE11A locus in TGCT predisposition and underscore the biological relevance of overlapping sense–antisense genomic regions in hereditary cancer studies. Full article

Coronary artery calcification (CAC) represents a clear sign of advanced atherosclerosis and a strong indicator of coronary artery disease burden and cardiovascular risk. Beyond its established prognostic value, CAC significantly influences plaque biology, lesion morphology, and the technical complexity of percutaneous coronary intervention (PCI). This review summarizes current knowledge on the mechanisms of vascular calcification, its clinical determinants, diagnostic assessment, and therapeutic implications. Vascular calcification is now understood as an active, regulated process involving osteogenic transdifferentiation of vascular smooth muscle cells, inflammatory signaling pathways, extracellular vesicle release, and disturbances in mineral metabolism. Distinct calcification phenotypes exert different effects on plaque stability: micro- and spotty calcifications are frequently linked to plaque vulnerability, whereas dense, sheet-like calcification is more typical of stable fibrocalcific lesions. The prevalence of CAC increases with age and differs between sexes, while cardiometabolic risk factors, chronic kidney disease, systemic inflammation, and genetic predisposition further contribute to its development. Noninvasive computed tomography remains the cornerstone for CAC detection and quantification, enabling reliable cardiovascular risk stratification. Intravascular imaging techniques, particularly intravascular ultrasound and optical coherence tomography, provide detailed characterization of calcified plaque morphology and support optimal procedural planning. In patients with heavily calcified lesions, intravascular imaging-guided lesion preparation and stent optimization represent the most effective strategy for improving PCI outcomes. Full article

Background/Objectives: In individuals with a genetic predisposition, acute rheumatic fever (ARF) can manifest as arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. It occurs after a latent period of 1–3 weeks of untreated upper respiratory tract infections caused by group A beta-hemolytic streptococci. The presence and severity of carditis determine the prognosis for ARF. Carditis manifests as pancarditis, and although all patients have pericarditis, not all experience a pericardial effusion. Patients with severe carditis exhibit pericardial effusion more frequently. The physiopathology of ARF remains unclear, specifically which patients will experience carditis, arthritis, or chorea. However, the Turkish population has fully clarified the physiopathology and clinical features of Familial Mediterranean fever (FMF), a common rheumatic disease. In the Turkish population, the heterozygous positivity rate for the FMF gene mutation is 15–35%. For these reasons, we examined the presence of FMF gene mutations in our patients to determine whether there is a correlation between the clinical course of ARF and the FMF gene mutation. Methods: The study included 60 patients with arthritis (n = 11), carditis (n = 26), or both (n = 23), as well as 60 healthy controls. These pediatric patients underwent screening for mutations in exons 2 and 10 of the MEFV gene. Results: There was no statistically significant difference between the patient and control groups in terms of the incidence of MEFV gene mutations in exon 10. However, in patients with ARF, the exon 2 E148Q variant was significantly more common than in the control group. Conclusions: This study suggests a relationship between certain clinical manifestations of ARF and MEFV gene mutations in children. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder driven by genetic predisposition, epigenetic programming, metabolic rewiring, and immune dysregulation. Although population genetics and single-cell transcriptomics have advanced our understanding, the multi-omic causal architecture of MASLD at cellular resolution remains poorly defined. This study aimed to establish an integrative framework linking genetic causality to cell-type-specific tissue dysfunction. Methods: Multi-layered Mendelian randomization (MR) and summary-data-based MR (SMR) across large-scale eQTL and pQTL datasets were applied to prioritize causal genes. Single-cell eQTL-based MR across 14 immune lineages generated cell-type-specific causal hypotheses, which were validated using human hepatic single-cell RNA-sequencing data (GSE136103). Two-step mediation MR quantified upstream epigenetic and downstream metabolic mechanisms. A high-fat diet (HFD)-induced murine model provided organismal validation. Results: Multi-layered MR nominated PLXND1 as a robust causal driver of MASLD. Single-cell eQTL-based MR revealed a functional dichotomy: PLXND1 upregulation in CD8⁺ effector memory T-cells decreased MASLD risk (OR = 0.486, 95% CI: 0.290–0.813, p = 0.006), whereas upregulation in natural killer cells (OR = 1.567, 95% CI: 1.337–1.837, p < 0.001), non-classical monocytes, and dendritic cells increased risk. Human hepatic single-cell transcriptomics confirmed that PLXND1 marks an anti-fibrotic, IFNG-high CD8⁺ T subset and a pro-inflammatory lipid-associated macrophage (LAM) population. Mediation MR identified DNA methylation at cg26767922 and cg08471739 as protective mediators acting predominantly via PLXND1 downregulation (92.39% and 64.50% mediation, respectively), and linked PLXND1 to six circulating metabolites. HFD mice showed significant hepatic PLXND1 upregulation. Conclusions:PLXND1 functions as a lineage-dependent molecular switch in MASLD, validated across genetic, epigenetic, metabolic, and single-cell dimensions. These findings caution against systemic PLXND1 blockade and support precision therapeutic strategies targeting hepatic innate immune cells. Full article

Background/Objectives: Keratoconus is a corneal disorder that causes thinning and bulging of the cornea, resulting in astigmatism and other refractive errors. Mechanical effects and environmental factors are known to exacerbate the disease, and genetic predisposition plays a significant role in its development. Methods: This study investigated the presence of genetic variants in 32 keratoconus patients. We used a next-generation sequencing-based method, and variant interpretation was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Variants were prioritized based on multiple criteria, including population frequency data from the Genome Aggregation Database (gnomAD) (minor allele frequency < 1%), variant type and predicted functional effect, gene–disease association, inheritance pattern, phenotypic relevance, and in silico prediction tools. Results: Thirteen variants were identified in 11 patients (34.3%). Two patients carried variants in two different genes, raising the possibility of oligogenic contributions. Ten variants (76.9%) were novel. The variants were detected in 12 genes, namely ADAMTS18, BEST1, CHST6, COL17A1, CYP1B1, KRT3, PAX6, SLC4A11, TACSTD2, UBIAD1, VSX1, and ZNF469. No association was observed between detected variants and patient age. Conclusions: Our findings demonstrate a substantial proportion of novel variants and support the genetic heterogeneity of keratoconus, while also raising the possibility of oligogenic contributions in a subset of patients. Full article

Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression. Full article

Periodontitis (PD) and rheumatoid arthritis (RA) are chronic inflammatory disorders that impose substantial individual and societal burdens worldwide. PD is characterized by progressive destruction of the periodontal ligament and alveolar bone, leading to tooth loss, impaired oral function, and sustained systemic inflammatory burden. RA, affecting approximately 0.5–1% of the population, is a chronic autoimmune disease marked by persistent synovial inflammation, progressive joint destruction, disability, and reduced quality of life. Increasing evidence indicates that these conditions are biologically and clinically interconnected. Both diseases share key pathogenic pathways, including microbial dysbiosis, immune dysregulation, chronic inflammation, genetic susceptibility, and aberrant autoantibody responses. Particular attention has focused on keystone periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, which may promote protein citrullination and the formation of anti-citrullinated protein antibodies (ACPA), thereby providing a plausible mechanistic bridge between periodontal infection and systemic autoimmunity. Shared genetic risk factors, including HLA-DRB1 susceptibility alleles, further support a common host predisposition. Clinical, epidemiological, and translational studies increasingly support a bidirectional association. Individuals with PD appear to have a higher risk of RA development, whereas patients with RA demonstrate greater prevalence, severity, and progression of periodontal disease. Interventional studies suggest that nonsurgical periodontal therapy may reduce local periodontal inflammation, circulating inflammatory biomarkers, and RA disease activity indices, while effective pharmacological control of RA may also improve periodontal outcomes. This narrative review critically evaluates the PD–RA relationship across four interconnected domains: (i) epidemiological and clinical associations between PD and RA, (ii) key mechanisms underlying RA pathogenesis, (iii) shared biological pathways linking both diseases, and (iv) the extent to which treatment of one condition influences the other. Particular emphasis is placed on major sources of heterogeneity and confounding—including smoking, metabolic comorbidities, disease stage, therapeutic exposure, and variable diagnostic definitions—that may explain inconsistencies across the literature. By integrating current mechanistic and clinical evidence, this review provides a structured synthesis that extends beyond a descriptive overview of association studies. A clearer understanding of the periodontal–rheumatologic axis may facilitate risk stratification, identify novel therapeutic targets, and support integrated multidisciplinary care. Targeting both oral and systemic inflammation may improve outcomes in patients with coexisting PD and RA and may potentially reduce the risk or severity of one condition in individuals already affected by the other. Full article

Inflammatory bowel disease (IBD) is a chronic inflammatory condition resulting from complex interactions between the immune system, genetic predisposition, and the gut microbiota. In this context, Escherichia coli (E. coli) plays a dual role in the human gut, ranging from harmless commensal strains to pathobionts capable of promoting intestinal inflammation. A growing body of evidence suggests that specific E. coli pathotypes, such as adherent-invasive E. coli (AIEC) and diffusely adherent E. coli (DAEC), contribute to the development and progression of IBD. This narrative review critically examines the microbiological, immunological, and clinical evidence supporting the role of E. coli in IBD, with particular emphasis on mechanisms of mucosal colonization, host–microbe interactions, and persistence within the inflamed intestinal environment. Furthermore, the lack of a standardized operational definition and the limited reproducibility of the AIEC phenotype are addressed, as well as uncertainty about the role played by E. coli as a primary initiator of the disease or as an opportunistic amplifier of intestinal inflammation, and the varying strength of evidence supporting associations with Crohn’s disease versus ulcerative colitis. Diagnostic implications, antimicrobial resistance, and therapeutic aspects are addressed as downstream and context-dependent consequences of E. coli–host interactions, with relevance for disease management and therapeutic response in patients with established IBD. By integrating data from experimental models, clinical studies, and translational research, the review identifies areas of consensus, ongoing controversy, and major knowledge gaps in IBD pathophysiology and clinical practice. Full article

Background: Hypermobile Ehlers–Danlos syndrome (hEDS), the most common EDS subtype, is characterized by chronic pain and joint laxity, yet no definitive causative genes or imaging-based diagnostic criteria have been established. This study investigated the genetic basis of hEDS using whole-exome sequencing (WES) and objectively evaluated ankle instability. Methods: We conducted an observational cohort study with a case–control comparison, including 22 patients and a three-generation Korean family (six individuals, four affected) diagnosed with hEDS by the 2017 criteria. WES was performed; ankle laxity was assessed by the anterior drawer test (ADT), stress ultrasonography, and stress radiography. Healthy young adults (n = 24, Beighton score < 5) from our previous study served as controls. Results: The hEDS cohort had a mean Beighton score of 8.5, with all participants reporting a family history of hypermobility and musculoskeletal complications. Family-based WES identified variants in CD44 (c.1516 + 1G > A), ITIH2 (c.783C > G), and ADAM21 (c.397C > T) in all affected individuals. In 22 unrelated patients, 114 variants in 103 candidate genes were identified; 17 patients harbored variants in genes from the same pathways as the family-derived causative genes. Compared with controls, the hEDS group showed significantly greater manual ADT grade, anterior talofibular ligament (ATFL) length at rest and under stress, dynamic ATFL change, anterior talar translation, and talar tilt. Conclusions: These findings provide molecular evidence that hEDS is a multifactorial disorder involving interconnected biological pathways, and confirm ankle instability as a clinically meaningful diagnostic feature. These complementary approaches may improve diagnostic accuracy and provide insights into the prognosis and therapeutic strategies for hEDS. Full article

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the blood and bone marrow characterized by the uncontrolled proliferation of precursor cells of B- or T-lymphocyte lineage. Usually, the disease arises because of spontaneous mutations in bone marrow cells. Risk factors include genetic predisposition, exposure to ionizing radiation, prior chemotherapy or radiotherapy, and certain environmental factors. Clinical manifestations may include recurrent infections, anemia, and an increased tendency toward bleeding and stroke. A 12-year-old boy presented to the emergency department with a sudden decrease in visual acuity in the right eye. Best-corrected visual acuity (BCVA) in the right eye was 0.02, and intraocular pressure (IOP) was 16 mmHg. Ophthalmologic examination revealed a macular hemorrhage in the right eye. Blood samples were obtained for laboratory analysis. Complete blood count demonstrated leukocytosis with a white blood cell (WBC) count of 362.58 × 10³/µL, thrombocytopenia with a platelet (PLT) count of 87 × 10³/µL, hemoglobin (Hgb) level of 8.7 g/dL, and a red blood cell (RBC) count of 3.46 × 10⁶/µL. The patient was subsequently referred to the Department of Pediatric Hematology, where the diagnosis of acute lymphoblastic leukemia of B-cell precursor origin was confirmed. Appropriate systemic therapy targeting the underlying disease was initiated. Full article

Ménière’s disease is a complex disorder of the inner ear, characterized by recurrent episodes of vertigo, progressive hearing loss, tinnitus, and aural fullness. The pathophysiology of this condition is dominated by endolymphatic hydrops, reflecting imbalances in fluid regulation and pressure within the membranous labyrinth, which impair cellular function and the transmission of vestibular and auditory signals. Although genetic predisposition provides a susceptible background, recent studies emphasize that non-genetic factors act as critical triggers of clinical events, determining both the onset of symptoms and the modulation of their severity. These factors directly influence pathophysiology by disrupting endolymphatic homeostasis and altering the intracellular and tissue dynamics of the membranous labyrinth, thereby contributing to the phenotypic variability observed among patients. The key to this process lies in the synergistic interaction between genetic predisposition and external or contextual influences, which determines the threshold at which the compensatory mechanisms of the inner ear fail, triggering the characteristic episodes. Understanding this interdependence, as well as the underlying disease mechanisms, provides essential insights for the identification of preventive and therapeutic strategies aimed not only at symptom control but also at modulating the factors that influence susceptibility to endolymphatic imbalance. Full article

The relationship between stress and Parkinson’s disease is regarded as complex and multifaceted, although a direct causal link has not yet been conclusively proven. One prevailing hypothesis is based on the activation of the hypothalamic–pituitary–adrenal (HPA) axis and the consequent elevation of glucocorticoid levels. Prolonged exposure to these hormones may exacerbate oxidative stress, thereby rendering the dopaminergic neurons within the brain’s subcortical structures more susceptible to degeneration. Furthermore, stress may intensify neuroinflammation through the activation of microglia—a mechanism that could constitute a significant factor in the pathogenesis of Parkinson’s disease. Another important concept concerns the direct interaction of stressors with the dopaminergic system. Physiological and psychological stress can alter dopaminergic transmission by affecting both the synthesis and release of dopamine, as well as the sensitivity of dopamine receptors. Severe or chronic stress may contribute to the disruption of dopaminergic mechanisms and accelerate the onset of clinical symptoms in predisposed individuals. Furthermore, many researchers draw attention to the role of stress-induced aggregation of α-synuclein—a key protein implicated in the pathogenesis of Parkinson’s disease. Clinical data suggest a highly probable link between post-traumatic stress disorder and an increased risk of developing Parkinson’s disease, although these findings remain inconclusive. It is possible that stress acts not as a primary cause, but rather as a modifying factor that interacts with genetic predisposition, accelerating or triggering neurodegenerative processes. The aim of our narrative review was to examine these concepts and discuss possible directions for future research into the interaction between stress and Parkinson’s disease. Full article

Preeclampsia (PE) is a multifactorial hypertensive disorder of pregnancy that significantly increases both short- and long-term cardiovascular risk for affected women. PE and cardiovascular disease (CVD) share common risk factors, including endothelial dysfunction, obesity, insulin resistance, and dyslipidemia. Women with a history of PE face a markedly elevated risk of chronic hypertension, heart failure, and adverse cardiac remodeling, with evidence suggestive of persistent vascular and myocardial changes after pregnancy. The complex pathophysiology of PE is multifactorial and is thought to involve a combination of abnormal placentation, immune dysregulation, and anti-angiogenic factors, which may induce permanent cardiovascular alterations. Genetic predispositions may further link PE with cardiomyopathies and peripartum cardiomyopathy. However, despite these well-established risks, standardized long-term surveillance and management strategies for women with prior PE remain lacking. Early identification and targeted intervention in women with a history of PE represent critical opportunities to mitigate future cardiovascular morbidity and mortality. This review highlights the urgent need for comprehensive, evidence-based strategies that incorporate personalized follow-up and risk stratification to improve cardiovascular outcomes in this high-risk population. Full article

As in other mammalian species, the complex and specific interactions between internal biological processes and external factors regulate and impact the male dog reproductive system functions. This comprehensive review integrates physiological and molecular mechanisms underlying the reproductive system maintenance throughout the anatomical and histological structure of reproductive organs and their functions from development to aging. Simultaneously, the presentation of fundamental hormonal regulations and functions of the reproductive system is comprised. Special attention is put on e.g., genetic, developmental, age- and environmental-related disorders. The structural and hormonal status of the reproductive organs in response to single or mixed influences: genetic predispositions (e.g., cryptorchidism, sex chromosome aneuploidy syndrome), developmental courses (e.g., cryptorchidism, uterus masculinus, hypospadias), age-related diseases (e.g., tumors), and environmental stressors: e.g., endocrine-disrupting chemicals, toxins, heat stress (possibly leading to e.g., hypogonadism, cryptorchidism, infertility, tumors, precocious aging) is provided. Such multidirectional and comprehensive associations of grouped, selected, clinically significant pathological processes and diseases are broadly considered and linked here for the first time. Based on both epidemiological and experimental findings, the etiologies, current diagnostic approaches, treatment options, and prognostic assessments of these common male dog disorders are presented. This compendium seems useful for young veterinarians, researchers, breeders, and dog owners, enabling them to integrate knowledge on biological principles and processes with clinical practices and research in recent and future canine andrology. Full article