Search Results (596)

Background: Tracheobronchopathia osteochondroplastica (TO) is a rare benign disorder characterized by submucosal cartilaginous and osseous nodules of the tracheobronchial tree, typically sparing the posterior membranous wall. Involvement of the vocal cords is exceedingly rare and may result in critical airway obstruction. The underlying genetic and molecular mechanisms of TO remain largely unexplored. Case presentation: We report a rare case of TO extending from the vocal cords to the bronchi in a 76-year-old man who initially presented with pneumonia and later developed acute respiratory failure due to severe airway narrowing, necessitating emergency tracheostomy. Bronchoscopy and computed tomography revealed diffuse calcified nodules involving the anterior and lateral airway walls, including the subglottic region. Histopathology demonstrated chronic inflammatory cell infiltration with squamous metaplasia. To explore the molecular basis of this condition, whole-genome sequencing (WGS) was performed using peripheral blood samples—the first such application in TO. WGS identified 766 germline mutations (including 27 high-impact variants) and 66 structural variations. Candidate genes were implicated in coagulation and inflammation (KNG1), arachidonic acid metabolism and extracellular matrix remodeling (PLA2G4D), ciliary dysfunction and mineralization (TMEM67), vascular calcification (CDKN2B-AS1), smooth muscle function (MYLK4), abnormal calcification (TRPV2, SPRY2, BAZ1B), fibrotic signaling (AHNAK2), and mucosal barrier integrity (MUC12/MUC19). Notably, despite systemic germline mutations, calcification was restricted to the airway. Conclusions: This case highlights that TO with vocal cord involvement can progress beyond a benign course to cause life-threatening airway obstruction. Integrating clinical, histological, and genomic findings, we propose a novel pathophysiological model in which systemic genetic susceptibility interacts with local immune cell infiltration and fibroblast-driven extracellular matrix remodeling, resulting in airway-restricted dystrophic calcification. This first genomic characterization of TO provides new insights into its pathogenesis and suggests that multi-omics approaches may enable future precision medicine strategies for this rare airway disease. Full article

Calcium deposition within soft tissues is a significant pathological process, bearing significant implications for animal and human health. It is classified into four categories, including dystrophic, metastatic, idiopathic, and iatrogenic. It involves multiple molecular mechanisms. Vascular calcification includes medial artery mineralization, siderocalcinosis in equine cerebral arteries, and vitamin D-induced arterial mineralization in multiple species. Renal and urinary mineralization occurs with kidney disease, uremic gastropathy, and ethylene glycol toxicity. Calcinosis cutis is associated with renal insufficiency and systemic fungal infections and is commonly observed in dogs with hyperadrenocorticism, while calcinosis circumscripta occurs at pressure points secondarily to trauma. Multiple pathogens are responsible for soft tissue calcification; they can be zoonotic and include Mycobacterium spp., Brucella spp., Toxoplasma gondii, and Echinococcus granulosus, underscoring the translational role of veterinary medicine surveillance from a public health standpoint. In addition, the placental chorioallantois is frequently affected by idiopathic or infection-induced calcification, highlighting the convergence of metabolic dysregulation and infectious mechanisms. Tissue calcifications provide valuable insights into disease mechanisms and diagnostic challenges, with comparative pathology serving as a powerful tool to enhance our understanding of these processes from a One Health standpoint. Full article

Background/Objectives: This study aimed to evaluate the relationship between preoperative clinical, ultrasonographic, and cytologic findings and postoperative histopathology in patients with thyroid nodules, and to determine diagnostic factors associated with malignancy. Materials and Methods: A retrospective analysis was conducted on 100 patients who underwent thyroid surgery between September 2012 and April 2014. Preoperative data—including clinical examination, thyroid function tests, and high-resolution ultrasonography—were compared with fine-needle aspiration biopsy (FNAB) results and final histopathology. Ultrasonographic features (echogenicity, calcification, vascularity, and margin) were analyzed for their association with malignancy. Statistical tests included chi-square, t-test, and correlation analysis (p < 0.05 considered significant). Results: Among 100 patients (79 females, 21 males; mean age 47.5 ± 13.9 years), 29 (29%) had benign and 71 (71%) malignant histopathology. Malignancy was significantly associated with older age (p = 0.025), smaller nodule size (p = 0.019), hypoechogenicity (p = 0.001), microcalcifications (p = 0.014), and irregular margins (p = 0.017). FNAB showed a strong correlation with final histopathology (r = 0.65, p = 0.001). The overall sensitivity and specificity of FNAB were 25.4% and 82.8%, respectively. Conclusions: Hypoechogenicity, microcalcifications, and irregular margins were the most reliable ultrasonographic predictors of malignancy. FNAB remains a highly specific but variably sensitive diagnostic tool, and its accuracy increases when interpreted in conjunction with ultrasonographic findings. Integrating cytology with structured imaging systems such as ACR TI-RADS and Bethesda classification enhances diagnostic precision in thyroid nodule evaluation. Full article

Chronic kidney disease (CKD), which affects over 850 million individuals globally, is increasingly regarded as a systemic condition in which the gut microbiota represents a key pathogenic node. This review provides an integrated overview of mechanistic, translational and clinical data implicating the gut–kidney axis in CKD. The CKD-associated microbiota displays a characteristic dysbiosis, marked by depletion of short-chain fatty acid–producing commensals, overgrowth of proteolytic and urease-expressing taxa and disruption of epithelial barrier integrity. These disturbances favor the generation and systemic accumulation of gut-derived uremic toxins, most notably indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid and trimethylamine-N-oxide, which promote endothelial dysfunction, vascular calcification, fibrosis and chronic inflammation, thereby hastening renal function loss and heightening cardiovascular risk. Microbiome-directed interventions, including dietary modification, prebiotics, probiotics, synbiotics, intestinal dialysis, fecal microbiota transplantation, gut-acting sorbents and nephroprotective phytochemicals, are summarized with emphasis on their effects on uremic toxin burden and clinical surrogates. System-level implications of the gut–kidney axis for cardiovascular disease, immunosenescence and sarcopenia are discussed, together with future priorities for integrating multi-omics profiling and precision microbiome-based strategies into nephrology practice. Full article

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

Vitamin D, traditionally regarded as a nutrient, is increasingly recognized as a pharmacologically active secosteroid with pleiotropic effects extending beyond calcium homeostasis and bone integrity. Together with vitamin K2, it participates in the fine-tuning of mineral metabolism and vascular health, potentially modulating cardiometabolic risk through intertwined endocrine and paracrine pathways. Despite widespread fortification and supplementation, vitamin D deficiency remains a major global health concern, driven by limited sun exposure, obesity, and metabolic dysfunction. Observational and mechanistic studies consistently link low serum 25(OH)D concentrations with hypertension, insulin resistance, heart failure, and increased cardiovascular mortality. At the molecular level, vitamin D exerts pharmacological actions—modulating the renin–angiotensin–aldosterone system, exerting anti-inflammatory and antifibrotic effects, and influencing endothelial and cardiomyocyte signaling. While experimental and epidemiological evidence suggests potential cardiovascular benefits, large randomized controlled trials (RCTs) provide conflicting results, particularly regarding hypertension and heart failure. However, these often-neutral results do not preclude a targeted action. On the contrary, clinical efficacy is strongly dependent on baseline deficiency status and the presence of metabolic cofactors. In this context, high-dose supplementation of Vitamin D, in combination with Vitamin K2 to prevent vascular calcification, elevates the supplement to a genuine pharmacological agent, with a distinct therapeutic potential for modulating cardiometabolic risk in selected patient subgroups. Emerging evidence supports the concept that vitamin D, when appropriately dosed and combined with K2, may act more as a low-potency pharmacological modulator than a simple nutritional supplement. This review synthesizes current mechanistic, observational, and interventional evidence, aiming to clarify whether vitamin D should be reclassified—from a micronutrient to a pharmacologically relevant agent—in cardiometabolic prevention and therapy, proposing a paradigm shift toward personalized and targeted dosing strategies, characteristic of precision pharmacology. Full article

Background and Objectives: Access-site complications (ASCs) remain clinically relevant after peripheral endovascular procedures, particularly with large femoral sheaths and complex anatomy. While randomized coronary trials show non-inferiority of vascular closure devices (VCDs) versus manual compression (MC), real-world data in peripheral interventions performed under systematic ultrasound-guided access are limited. Materials and Methods: This retrospective single-center cohort included consecutive peripheral arterial revascularizations (2010–2023) performed via common femoral access under real-time ultrasound guidance. Hemostasis was achieved using MC or VCDs, categorized as collagen plug-based, suture-mediated, or clip-based systems. The primary endpoint was 30-day ASCs, defined as hematoma requiring management, pseudoaneurysm, bleeding requiring transfusion, access-site thrombosis/occlusion, arteriovenous fistula, or infection. The secondary endpoint was VCD failure, defined as unsuccessful hemostasis requiring adjunctive measures. Multivariable logistic regression adjusted for prespecified anatomical and procedural covariates, including sheath size > 6 Fr and puncture-site calcification. Results: Among 231 procedures, VCDs were used in 139 (60.2%) and MC in 92 (39.8%). ASC occurred in 28 cases (12.1%), with higher rates in the MC group compared with VCDs (18.5% vs. 9–14% across device types; p = 0.044). In adjusted analyses, MC (vs any VCD) (odds ratio [OR] 2.41, 95% confidence interval [CI] 1.06–5.47; p = 0.035), sheath size > 6 Fr, and puncture-site calcification were independently associated with ASCs. VCD failure occurred in 5 cases (3.6%) and was not observed with collagen plug-based devices. Conclusions: In this ultrasound-guided real-world peripheral cohort, VCD use was associated with lower 30-day ASC rates and low device failure rates compared with MC. Given the retrospective and non-randomized design, these findings should be considered hypothesis-generating and support individualized, imaging-guided strategies for femoral closure in peripheral interventions. Full article

West Nile virus (WNV) is an arthropod-borne flavivirus first identified in 1937. Over time, WNV has spread globally and is now endemic in Italy. Although most human WNV infections are asymptomatic (80%), less than 1% progress to a neuroinvasive disease with high mortality rates. This case involves a 45-year-old woman with post-surgical hypoparathyroidism and Sjögren’s syndrome who developed severe encephalomyelitis linked to WNV, leading to ventilator-associated pneumonia and death. Neuropathological findings revealed a bilaterally cribriform thalamus and reddish punctate lesions near the dentate nucleus of the cerebellum. The trachea and bronchial hilum branches contained whitish foamy liquid. The left lung showed multiple brownish-violet areas, with whitish regions at dissection. The heart appeared unremarkable. A detailed neuropathological examination focused on areas involved in motor control pathways. Tissue samples were stained with hematoxylin and eosin and trichrome techniques, and immunohistochemistry was performed using CD68, CD3, and CD20. A significant damage was observed in the lenticular nucleus and motor thalamus, with prominent concentric vascular calcifications. The cerebellar cortex showed near-total depletion of Purkinje cells. In the spinal cord, CD68 and CD3 positivity was noted in the lateral funiculi, anterior horns, and Clarke’s column. Lung findings showed pulmonary edema, chronic emphysema, and bronchopneumonia. The observed CD3 and CD68 positivity confirms that WNV spreads trans-synaptically along motor control pathways. We speculate on the potential molecular mechanisms by which hypoparathyroidism and Sjögren’s syndrome may have played a role in the neuroinvasive progression of the disease. Full article

Chronic kidney disease (CKD) is associated with gut microbiota alterations that contribute to increased inflammation and the generation of uremic toxins and may worsen the disease progression. While probiotics may improve the pro-inflammatory cytokine profile, their effects on mineral metabolism, vascular calcification (VC), and CKD progression remain unclear. We aimed to evaluate the impact of a commercial probiotic (Probimel) supplementation on kidney function, mineral metabolism, inflammation and VC in both an experimental rat model and patients with advanced CKD and VC. The experimental model of VC was performed through 5/6 nephrectomy (Nx), a high-phosphate diet, and calcitriol. Animals were divided into three groups: Sham, Nephrectomy, and Nephrectomy + Probiotic. In the exploratory clinical study, 23 patients with advanced stage 5 CKD and VC were randomized and either received or did not receive daily probiotics for 6 months. Kidney function, mineral metabolism, uremic toxins, inflammation, VC, and fecal microbiota were evaluated. Probiotic supplementation decreased interleukin-6 (IL-6) and interpheron-γ (IFN-γ) and levels of the uremic toxin, indoxyl sulfate (IS), in the experimental model. However, no clear evidence of improvement in kidney function or vascular calcification was observed in either rats or patients with this probiotic. Under our experimental and clinical conditions, the selected probiotic did not modify key parameters related to CKD progression or VC. Full article

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) is associated with vascular calcification and diabetes-related complications. However, the effect of exosomal MALAT1 derived from macrophages induced by hyperglycemia on vascular calcification (VC) remains unclear. In this study, we investigated the effect of VC and its regulatory mechanisms in cultured vascular smooth muscle cells (VSMCs) and diabetic rats by exosomal MALAT1 derived from macrophages treated with high levels of glucose. Macrophages and VSMCs were cultured in 25 mM glucose. Macrophages exposed to high glucose exhibited increased expression of exosomal MALAT1. When transferred to VSMCs, exosomal MALAT1 significantly suppressed the expression of miR-143-3p while upregulating Matrix Gla protein (MGP, an inhibitor of VC) mRNA and protein levels. Interventions using MALAT1 siRNA or miR-143-3p mimics effectively reversed this effect. Both MALAT1 siRNA and overexpression of miR-143-3p significantly increased the calcium content in cultured VSMCs and in the carotid artery of diabetic rats following balloon injury. Balloon injury to the carotid artery in diabetic rats treated with macrophage-derived exosomes significantly increased the expression of MALAT1 and MGP while reducing the expression of miR-143-3p in the carotid artery. These findings demonstrate that macrophage-derived exosomal MALAT1 modulates VC via the MALAT1/miR-143-3p/MGP axis under hyperglycemic conditions. The results suggest that targeting exosomal MALAT1 may offer a novel and effective therapeutic approach for mitigating VC in metabolic disorders such as diabetes. Full article

In recent years, lactate has transitioned from being considered a mere metabolic end-product to being regarded as a critical signaling molecule that links cellular metabolism with gene regulation. Protein lactylation, a post-translational modification (PTM) mediated by lactate, is central to this functional transformation. In vascular diseases, the lactate–lactylation process demonstrates a marked double-edged sword characteristic, with its regulatory effects highly dependent on cell type, disease stage, and the pathological microenvironment. On one hand, lactylation can exert protective roles by promoting reparative gene expression, driving anti-inflammatory cell polarization, and maintaining myocardial structural integrity; on the other hand, aberrant lactylation can exacerbate inflammatory responses, promote fibrosis, and induce cell death and vascular calcification, thereby driving the development and progression of atherosclerosis, heart failure, and stroke. This review systematically delineates the paradoxical yet unified dual roles of lactylation across various vascular diseases and explores the molecular bases that underlie these functional differences. We propose that deciphering and precisely modulating the ‘double-edged sword’ of lactylation—selectively enhancing its protective functions while suppressing its pathological actions—represents a central challenge and a critical opportunity for translating basic research into clinical applications. Such advances could provide a novel theoretical framework for the development of diagnostic biomarkers and cell-specific precision therapeutic strategies. Full article

Background: Vascular calcification is a frequent consequence of ageing and is associated with an increased risk of cardiovascular disease. This study aimed to compare two rapid scoring systems for quantifying calcification of the distal abdominal aorta and iliac arteries and to investigate correlations with increasing age. Methods: Patients aged ≥65 years who sustained pelvic trauma between 2003 and 2023 and underwent computed tomography (CT) were included in this retrospective study. Patients were categorised into three age groups (65–74, 75–84, ≥85). The abdominal aorta calcification score (AACS) and the common, external, and total iliac artery calcification scores (CIACS, EIACS, TIACS) were assessed on cross-sectional images and classified into three severity grades (mild, moderate, severe). Results: A total of 224 patients (mean age 78.8 ± 8.5 years; 62% female) were included. Significant differences between age groups were identified for hypertension (p < 0.001), osteoporosis (p < 0.001), atrial fibrillation (p = 0.015), chronic heart failure (p = 0.004), chronic kidney disease (p < 0.001), neurocognitive disorders (p < 0.001), and anticoagulant therapy (p = 0.002). Calcification severity increased with age across all vascular territories (EIACS p = 0.006; others p < 0.001). In multivariable linear regression, age remained the strongest adjusted predictor of calcification across all vascular regions (β = 0.323–0.376, all p < 0.001). Significant positive correlations were found between aortic and iliac calcifications (all p < 0.001), strongest between AACS and CIACS (ρ = 0.78, CI 0.719–0.835) and TIACS (ρ = 0.745, CI 0.676–0.807). Corresponding categorical associations were most pronounced between AACS and CIACS. Conclusions: The evaluated calcification scores were strongly correlated and demonstrated clear age-dependent trends. Given their simplicity and applicability to routine CT imaging, these methods may provide practical tools for assessing vascular ageing. Full article

Background and Objectives: Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those on hemodialysis. Once considered a passive process, VC is now recognized as an active, cell-mediated pathology influenced by mineral dysregulation, chronic inflammation, and oxidative stress. This review aims to synthesize current evidence on the underlying mechanisms of VC in CKD and hemodialysis, with particular focus on emerging biomarkers and therapeutic implications. Materials and Methods: A structured narrative review was conducted by searching PubMed, Web of Science, ScienceDirect, and Google Scholar. The final search was completed on 29 August 2025. A total of 1326 articles were initially retrieved, of which 65 met the inclusion criteria and were analyzed. Studies addressing VC mechanisms, the bone–vascular axis, mineral metabolism, vitamin K–dependent proteins, and biomarkers such as matrix Gla protein (MGP), osteocalcin (OC), and intact parathyroid hormone (iPTH) were included. Results: VC in CKD arises from phenotypic transformation of vascular smooth muscle cells, vesicle-mediated calcification, oxidative stress, and impaired activity of endogenous calcification inhibitors. Disruption of the fibroblast growth factor 23 (FGF23)–Klotho axis and secondary hyperparathyroidism further exacerbate vascular pathology. Among emerging biomarkers, dp-ucMGP reflects vitamin K deficiency and correlates with calcification burden, while OC and iPTH provide insight into bone–vascular crosstalk and mineral turnover. However, biomarker interpretation is limited by assay variability, renal clearance, and clinical heterogeneity. Conclusions: VC in CKD represents a complex process driven by systemic and cellular dysregulation. While biomarkers such as dp-ucMGP, OC, and iPTH offer mechanistic insights and prognostic potential, further validation is required for clinical application. A multimarker approach, combined with individualized management of mineral metabolism, may improve risk stratification and therapeutic targeting in this high-risk population. Full article

Objective: This study systematically evaluates the association between breast arterial calcifications (BACs) on mammography and systemic vascular calcifications detected by computed tomography (CT) in female lung transplant recipients, representing the first investigation of this relationship in this population. Methods: This retrospective single-center study included 78 female LTX recipients who underwent both digital mammography and thoracoabdominal CT. BACs were graded on a four-point scale. Calcifications in seven arterial territories were visually assessed on CT with a binary scale (“present”, “not present”) and graded on a severity scale of systemic calcifications ranging from no involvement (0) and minor vascular calcification (1–4 vessels) to major vascular calcification (5–10 vessels). Associations between BACs and systemic vascular calcifications were analyzed using correlation, logistic regression, and ROC analysis. Results: BACs were present in 31 of 78 patients (40%). Vascular calcifications were frequent, most often affecting the thoracic aorta (82%), abdominal aorta (76%), and iliac arteries (72–73%). Coronary calcifications were more common in BAC-positive than BAC-negative patients (77% vs. 40%, p = 0.002). BAC grade correlated with the cumulative vascular calcification (ρ = 0.35, p = 0.0017). In ROC analysis, BACs discriminated patients with vascular calcification with fair accuracy (AUC 0.73, 95% CI 0.67–0.79). In multivariable logistic regression adjusted for age, diabetes, chronic kidney disease, and hypertension, BACs remained independently associated with systemic calcification, with an adjusted odds ratio of approximately 2.0 for ≥1 affected vascular territory. Interreader agreement for the 4-level BAC score was excellent with a quadratic-weighted κ of 0.91 and a linear-weighted κ of 0.88. Conclusions: BACs are common in female LTX recipients and independently predict systemic vascular calcifications. Their detection in routine mammography may provide a simple, opportunistic marker to support cardiovascular risk stratification in this high-risk population. Full article

Menaquinone-7 (MK-7) is an important bioactive form of vitamin K₂ that inhibits vascular calcification, maintains systemic calcium homeostasis, demonstrates high bioavailability, and possesses an extended plasma half-life. Bacillus subtilis naturally possesses the complete biosynthetic pathway for MK-7, benefits from a well-characterized genetic background and advanced genome-editing tools, and is regarded as a safe and efficient microbial chassis for industrial MK-7 fermentation. This review summarizes recent advances in the metabolic engineering of Bacillus subtilis for high-level MK-7 production, highlights pathway analyses, and discusses engineering strategies targeting four key modules: substrate utilization, secretion, spore/biofilm formation, and oxidative-stress defense. Full article