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Scrotoliths, or "scrotal pearls," are calcified fibrous loose bodies found within the tunica vaginalis, often seen during radiological evaluation or autopsies. Chronic inflammation due to trauma, parasitic infestations, and torsion and subsequent detachment of the appendices of the testis or epididymis are postulated mechanisms suggested for their formation. They are benign but can mimic a tumor. Scrotoliths can be diagnosed with high-resolution ultrasonography. Here, we report a case in which, during routine dissection, two scrotoliths were found within the tunica vaginalis of the left testis in an elderly male cadaver. Histologically, the central portion of the scrotoliths exhibited concentric collagen lamellae that enclosed calcified remains of tissue debris. There were no arterioles, venules, or microfilarial larvae seen within them. Awareness about the histological findings can help understand the mechanism that led to their formation.
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Cadáver , Testículo , Humanos , Masculino , Testículo/patología , Testículo/diagnóstico por imagen , Enfermedades Testiculares/patología , Enfermedades Testiculares/diagnóstico por imagen , Anciano de 80 o más Años , Escroto/diagnóstico por imagen , Escroto/patología , Anciano , Calcinosis/patología , Calcinosis/diagnóstico por imagenRESUMEN
Calcific aortic valve disease (CAVD) primarily involves osteogenic differentiation in human aortic valve interstitial cells (hVICs). Schisandrol B (SolB), a natural bioactive constituent, has known therapeutic effects on inflammatory and fibrotic disorders. However, its impact on valve calcification has not been reported. We investigated the effect of SolB on osteogenic differentiation of hVICs. Transcriptome sequencing was used to analyze potential molecular pathways affected by SolB treatment. The study also included an in vivo murine model using aortic valve wire injury surgery to observe SolB's effect on valve calcification. SolB inhibited the osteogenic differentiation of hVICs, reversing the increase in calcified nodule formation and osteogenic proteins. In the murine model, SolB significantly decreased the peak velocity of the aortic valve post-injury and reduced valve fibrosis and calcification. Transcriptome sequencing identified the p53 signaling pathway as a key molecular target of SolB, demonstrating its role as a molecular glue in the mouse double minute 2 (MDM2)-p53 interaction, thereby promoting p53 ubiquitination and degradation, which further inhibited p53-related inflammatory and senescence response. These results highlighted therapeutic potential of SolB for CAVD via inhibiting p53 signaling pathway and revealed a new molecular mechanism of SolB which provided a new insight of theraputic mechanism for CAVD.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Ciclooctanos , Lignanos , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , Válvula Aórtica/patología , Válvula Aórtica/efectos de los fármacos , Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/patología , Calcinosis/tratamiento farmacológico , Calcinosis/patología , Calcinosis/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Ciclooctanos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Lignanos/farmacología , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Lipid metabolism disorders are associated with degeneration of multiple tissues and organs, but the mechanism of crosstalk between lipid metabolism disorder and intervertebral disc degeneration (IDD) has not been fully elucidated. In this study we aim to investigate the regulatory mechanism of abnormal signal of lipid metabolism disorder on intervertebral disc endplate chondrocyte (EPC) senescence and calcification. METHODS: Human intervertebral disc cartilage endplate tissue, cell model and rat hyperlipemia model were performed in this study. Histology and immunohistochemistry were used to human EPC tissue detection. TMT-labelled quantitative proteomics was used to detect differential proteins, and MRI, micro-CT, safranin green staining and immunofluorescence were performed to observe the morphology and degeneration of rat tail intervertebral discs. Flow cytometry, senescence-associated ß-galactosidase staining, alizarin red staining, alkaline phosphatase staining, DCFH-DA fluorescent probe, and western blot were performed to detect the expression of EPC cell senescence, senescence-associated secretory phenotype, calcification-related proteins and the activation of cell senescence-related signaling pathways. RESULTS: Our study found that the highly expressed oxidized low-density lipoprotein (ox-LDL) and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) in human degenerative EPC was associated with hyperlipidemia (HLP). TMT-labelled quantitative proteomics revealed enriched pathways such as cell cycle regulation, endochondral bone morphogenesis and inflammation. The rat model revealed that HLP could induce ox-LDL, LOX-1, senescence and calcification markers high expression in EPC. Moreover, we demonstrated that ox-LDL-induced EPCs senescence and calcification were dependent on the LOX-1 receptor, and the ROS/P38-MAPK/NF-κB signaling pathway was implicated in the regulation of senescence induced by ox-LDL/LOX-1 in cell model. CONCLUSIONS: So our study revealed that ox-LDL/LOX-1-induced EPCs senescence and calcification through ROS/P38-MAPK/NF-κB signaling pathway, providing information on understanding the link between lipid metabolism disorders and IDD.
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Senescencia Celular , Condrocitos , Degeneración del Disco Intervertebral , Metabolismo de los Lípidos , Lipoproteínas LDL , Receptores Depuradores de Clase E , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Lipoproteínas LDL/metabolismo , Animales , Humanos , Receptores Depuradores de Clase E/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Ratas , Masculino , Calcinosis/metabolismo , Calcinosis/patología , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Modelos Animales de Enfermedad , Femenino , Persona de Mediana Edad , Transducción de Señal , Adulto , Proteómica/métodos , Ratas Sprague-DawleyRESUMEN
Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.
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Calcinosis , Fibroblastos , Glicoproteínas , Humanos , Calcinosis/patología , Calcinosis/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Glicoproteínas/metabolismo , Glicoproteínas/genética , Calcio/metabolismo , Riñón/patología , Riñón/metabolismo , Fosfatasa Alcalina/metabolismo , Cálculos Renales/metabolismo , Cálculos Renales/patología , Cálculos Renales/etiología , Cálculos Renales/genética , Células CultivadasRESUMEN
Numerous small biomolecules exist in the human body and play roles in various biological and pathological processes. Small molecules are believed not to induce intrafibrillar mineralization alone. They are required to work in synergy with noncollagenous proteins (NCPs) and their analogs, e.g. polyelectrolytes, for inducing intrafibrillar mineralization, as the polymer-induced liquid-like precursor (PILP) process has been well-documented. In this study, we demonstrate that small charged molecules alone, such as sodium tripolyphosphate, sodium citrate, and (3-aminopropyl) triethoxysilane, could directly mediate fibrillar mineralization. We propose that small charged molecules might be immobilized in collagen fibrils to form the polyelectrolyte-like collagen complex (PLCC) via hydrogen bonds. The PLCC could attract CaP precursors along with calcium and phosphate ions for inducing mineralization without any polyelectrolyte additives. The small charged molecule-mediated mineralization process was evidenced by Cryo-TEM, AFM, SEM, FTIR, ICP-OES, etc., as the PLCC exhibited both characteristic features of collagen fibrils and polyelectrolyte with increased charges, hydrophilicity, and density. This might hint at one mechanism of pathological biomineralization, especially for understanding the ectopic calcification process.
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Citrato de Sodio , Citrato de Sodio/química , Citrato de Sodio/metabolismo , Animales , Humanos , Citratos/química , Colágeno/química , Colágeno/metabolismo , Calcinosis/metabolismo , Calcinosis/patología , Propilaminas/químicaAsunto(s)
Calcinosis , Tumor de Células de Sertoli , Neoplasias Testiculares , Humanos , Masculino , Tumor de Células de Sertoli/patología , Tumor de Células de Sertoli/diagnóstico , Tumor de Células de Sertoli/cirugía , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcinosis/diagnóstico , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Neoplasias Testiculares/diagnósticoRESUMEN
BACKGROUND: The foramen transversarium is a vital anatomical structure found in the cervical vertebrae of the spine. Typically, it serves as a passageway for important neurovascular structures, including the vertebral artery and vein, as well as the vertebral nerve. However, abnormal calcification or ossification of soft tissues in and around this area can lead to various clinical implications. Understanding the presence and implications of abnormal ossified structures in and around the foramen transversarium is crucial for clinicians involved in the diagnosis and management of cervical spine disorders. AIMS: Accordingly, this present study was designed to evaluate the abnormal ossified structures anatomically and radiologically within and around the foramen transversarium. MATERIALS AND METHODS: This study was conducted on 182 (26 sets of cervical vertebrae) dried human cervical vertebrae obtained from the respective departments of anatomy and on 190 (95 males and 95 females) adult patients who visited the radiology department for neck-related problems such as stiff neck, neck/shoulder pain, dizziness, vertigo, imbalance, visual disturbances, and cognitive impairment. RESULTS: Among 182 examined cervical vertebrae, unilateral complete accessory foramen transversarium was found in 23 vertebrae (12.63%), bilateral complete in 19 (10.44%), bilateral incomplete in 6 (3.29%), unilateral complete double in 4 (2.19%), and unilateral complete absence of foramen transversarium in 3 (1.64%). Stenosis due to aberrant osteophytes was noted in 9 vertebrae (4.9%). Out of 190 patients, three males presented with cervical kyphosis, severe spinal canal stenosis, and spinal cord compression due to ossification of the posterior longitudinal ligament and osteophyte complexes at C3-C6, with the most significant compression at C5-C6. CONCLUSION: A thorough understanding of abnormal ossifications in and around the foramen transversarium is crucial for the management of cervical spine disorders; imaging modalities such as X-ray, computed tomography, and magnetic resonance imaging are crucial for recognizing and intervening in these cases, which is essential to prevent adverse neurological outcomes associated with vertebral artery involvement.
Résumé Contexte:Le foramen transversarium est une structure anatomique vitale trouvée dans les vertèbres cervicales de la colonne vertébrale. Généralement, il sert de passage pour d'importantes structures neurovasculaires, notamment l'artère et la veine vertébrale, ainsi que le nerf vertébral. Cependant, anormal la calcification ou l'ossification des tissus mous dans et autour de cette zone peut entraîner diverses implications cliniques. Comprendre la présence et Les implications des structures ossifiées anormales dans et autour du foramen transversarium sont cruciales pour les cliniciens impliqués dans le diagnostic et prise en charge des troubles de la colonne cervicale.Objectifs:En conséquence, cette présente étude a été conçue pour évaluer les structures ossifiées anormales anatomiquement et radiologiquement à l'intérieur et autour du foramen transversarium.Matériels et méthodes:Cette étude a été menée sur 182 (26 ensembles de vertèbres cervicales) vertèbres cervicales humaines séchées obtenues auprès des départements d'anatomie respectifs et sur 190 (95 hommes et 95 femmes) patients adultes qui ont consulté le service de radiologie pour des problèmes liés au cou tels qu'une raideur de la nuque, des douleurs au cou/à l'épaule, des étourdissements, vertiges, déséquilibre, troubles visuels et troubles cognitifs.Résultats:Parmi 182 vertèbres cervicales examinées, unilatérales completes un foramen transversarium accessoire a été trouvé dans 23 vertèbres (12,63%), bilatéral complet dans 19 (10,44%), bilatéral incomplet dans 6 (3,29%), double complet unilatéral chez 4 (2,19 %) et absence complète unilatérale de foramen transversarium chez 3 (1,64 %). Sténose due à une aberration des ostéophytes ont été notés dans 9 vertèbres (4,9 %). Sur 190 patients, trois hommes présentaient une cyphose cervicale, une sténose sévère du canal rachidien, et compression de la moelle épinière due à l'ossification du ligament longitudinal postérieur et des complexes ostéophytes en C3C6, le plus compression importante en C5C6.Conclusion:Une compréhension approfondie des ossifications anormales dans et autour du foramen transversarium est crucial pour la gestion des troubles de la colonne cervicale; modalités d'imagerie telles que les rayons X, la tomodensitométrie et la résonance magnétique l'imagerie est cruciale pour reconnaître et intervenir dans ces cas, ce qui est essentiel pour prévenir les conséquences neurologiques indésirables associées avec atteinte de l'artère vertébrale.
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Vértebras Cervicales , Humanos , Masculino , Femenino , Vértebras Cervicales/diagnóstico por imagen , Adulto , Persona de Mediana Edad , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Anciano , Dolor de Cuello/diagnóstico por imagen , Dolor de Cuello/etiología , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/patología , RadiografíaRESUMEN
BACKGROUND: Calcification is common in advanced atheromatous plaque, but its clinical significance remains unclear. This study aimed to assess the prevalence of plaque calcification in the moderate-to-severe internal carotid artery stenosis and investigate its relationship with ipsilateral ischemia. METHODS: The retrospective study included 178 patients detected with proximal internal carotid artery (pICA) stenosis of ≥ 50% on multidetector computed tomography at Zhejiang Hospital from January 2019 to March 2023. Association between plaque calcification characteristics (calcification thickness, position, type, circumferential extent, calcium volume and calcium score) and ipsilateral cerebrovascular events was analyzed. RESULTS: The 178 patients (mean age 71.24 ± 10.02 years, 79.78% males) had 224 stenosed pICAs overall. Plaque calcification was noted in 200/224 (89.29%) arteries. Calcification rates were higher in older age-groups. Calcification volume (r = 0.219, p < 0.001) and calcification score (r = 0.230, p < 0.001) were correlated with age. Ipsilateral ischemic events were significantly more common in the noncalcification group than in the calcification group (χ2 = 4.160, p = 0.041). The most common calcification type was positive rim sign calcification (87/200, 43.50%), followed by bulky calcification (66/200, 33.00%); both were significantly associated with ischemic events (χ2 = 10.448, p = 0.001 and χ2 = 4.552, p = 0.033, respectively). Calcification position, thickness, and circumferential extent, and calcification volume and score, were not associated with ischemic events. In multivariate analysis, positive rim signs (OR = 2.795, 95%CI 1.182-6.608, p = 0.019) was an independent predictor of ischemic events. CONCLUSIONS: Plaque calcification in proximal internal carotid artery is common, and prevalence increases with age. Calcification characteristics could be predictive of ipsilateral ischemic events. The positive rim sign within plaque is a high-risk factor for a future ischemic event.
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Arteria Carótida Interna , Estenosis Carotídea , Humanos , Estenosis Carotídea/epidemiología , Estenosis Carotídea/diagnóstico por imagen , Estudios Retrospectivos , Masculino , Femenino , Anciano , Prevalencia , Persona de Mediana Edad , Anciano de 80 o más Años , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Calcificación Vascular/epidemiología , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/patología , Placa Aterosclerótica/epidemiología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Calcinosis/epidemiología , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Tomografía Computarizada Multidetector/métodosRESUMEN
Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.
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Astrocitos , Encefalopatías , Calcinosis , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Astrocitos/patología , Astrocitos/metabolismo , Autopsia , Encéfalo/patología , Encefalopatías/genética , Encefalopatías/patología , Calcinosis/genética , Calcinosis/patología , Glicósido Hidrolasas , LinajeRESUMEN
Background Quantifying the fibrotic and calcific composition of the aortic valve at CT angiography (CTA) can be useful for assessing disease severity and outcomes of patients with aortic stenosis (AS); however, it has not yet been validated against quantitative histologic findings. Purpose To compare quantification of aortic valve fibrotic and calcific tissue composition at CTA versus histologic examination. Materials and Methods This prospective study included patients who underwent CTA before either surgical aortic valve replacement for AS or orthotopic heart transplant (controls) at two centers between January 2022 and April 2023. At CTA, fibrotic and calcific tissue composition were quantified using automated Gaussian mixture modeling applied to the density of aortic valve tissue components, calculated as [(volume/total tissue volume) × 100]. For histologic evaluation, explanted valve cusps were stained with Movat pentachrome as well as hematoxylin and eosin. For each cusp, three 5-µm slices were obtained. Fibrotic and calcific tissue composition were quantified using a validated artificial intelligence tool and averaged across the aortic valve. Correlations were assessed using the Spearman rank correlation coefficient. Intermodality and interobserver variability were measured using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Results Twenty-nine participants (mean age, 63 years ± 10 [SD]; 23 male) were evaluated: 19 with severe AS, five with moderate AS, and five controls. Fibrocalcific tissue composition strongly correlated with histologic findings (r = 0.92; P < .001). The agreement between CTA and histologic findings for fibrocalcific tissue quantification was excellent (ICC, 0.94; P = .001), with underestimation of fibrotic composition at CTA (bias, -4.9%; 95% limits of agreement [LoA]: -18.5%, 8.7%). Finally, there was excellent interobserver repeatability for fibrotic (ICC, 0.99) and calcific (ICC, 0.99) aortic valve tissue volume measurements, with no evidence of a difference in measurements between readers (bias, -0.04 cm3 [95% LoA: -0.27 cm3, 0.19 cm3] and 0.02 cm3 [95% LoA: -0.14 cm3, 0.19 cm3], respectively). Conclusion In a direct comparison, standardized quantitative aortic valve tissue characterization at CTA showed excellent concordance with histologic findings and demonstrated interobserver reproducibility. Clinical trial registration no. NCT06136689 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Almeida in this issue.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Angiografía por Tomografía Computarizada , Fibrosis , Humanos , Masculino , Estudios Prospectivos , Femenino , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Persona de Mediana Edad , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Fibrosis/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , AncianoRESUMEN
In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease and cause for valve replacement. The prevalence of the disease increases with age, reaching over 5 % in adults over 75 years of age. The cases of CAS are classified as either of a previously normal (tricuspid) aortic valve (senile, syn. age - related, "sclerotic" type), or based on a congenitally malformed, usually bicuspid aortic valve. This paper is a brief summary of our 5 previous publications from the years 2007 - 2021, devoted to histopathology of CAS, namely to vascularization, inflammatory infiltrate and metaplastic ossification of the valve, and also to topography of these lesions in individual valve cusps. We conclude that calcification of the aortic valve is not a passive degenerative lesion, but an active multifactorial inflammatory process driven by cells native to the aortic valve. Pathogenesis of CAS is similar to that of atherosclerosis.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Humanos , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/etiología , Calcinosis/patología , Válvula Aórtica/patología , Válvula Aórtica/anomalías , Inflamación/patologíaRESUMEN
Calcified cysticerci are often associated with hippocampal atrophy (HA). While most studies suggest that repetitive seizures cause HA in these patients, others have demonstrated that HA may also occur in persons without epilepsy. Little is known about mechanisms triggering HA in seizure-free individuals with calcified cysticerci. Here, we aimed to assess whether the size of the calcification is associated with HA. Using a population-based design, we selected apparently seizure-free individuals with a single calcified cysticercus in whom interictal paroxysmal activity and other causes of HA have been discarded. A total of 55 individuals (mean age, 58.3 ± 13 years, 62% women) fulfilled inclusion criteria. Unadjusted and multivariate models were fitted to assess the association between the size of the calcification dichotomized into <3 mm and ≥3 mm (exposure) and the presence of HA (outcome). Sixteen participants (29%) had HA, which was asymmetric in eight (50%) cases. Hippocampal atrophy was noted in 11/20 (55%) participants with large calcifications and in 5/35 (14%) with small calcifications (P = 0.001). A multivariate logistic regression model showed a significant association between the presence of large calcifications and HA, after adjustment for relevant confounders (odds ratio: 7.78; 95% CI: 1.72-35.1). Participants with calcifications ≥3 mm in diameter were 7.8 times more likely to have HA than those with smaller ones. Study results open avenues of research for the use of agents to prevent HA progression.
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Atrofia , Calcinosis , Hipocampo , Humanos , Femenino , Hipocampo/patología , Masculino , Persona de Mediana Edad , Atrofia/patología , Calcinosis/patología , Anciano , Neurocisticercosis/complicaciones , Neurocisticercosis/patología , Neurocisticercosis/diagnóstico por imagen , Adulto , Convulsiones/patología , Encéfalo/patología , Encéfalo/diagnóstico por imagenRESUMEN
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (eg, total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of mineralization activity (eg, mean standardized uptake values-SUVs). Microcalcification scores were calculated for the vasculature of 6 patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the abdominal aorta, carotid, and coronaries in 50%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride PET/CT scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. Eighty-two percent of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active vs stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.
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Calcinosis , Factor-23 de Crecimiento de Fibroblastos , Hiperfosfatemia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Calcificación Vascular , Humanos , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcinosis/genética , Femenino , Masculino , Hiperfosfatemia/diagnóstico por imagen , Hiperfosfatemia/patología , Hiperfosfatemia/complicaciones , Hiperfosfatemia/genética , Adulto , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/patología , Calcificación Vascular/metabolismo , Persona de Mediana Edad , Adolescente , Niño , Imagen Molecular/métodos , Hiperostosis Cortical Congénita/diagnóstico por imagen , Hiperostosis Cortical Congénita/genética , Hiperostosis Cortical Congénita/patología , Hiperostosis Cortical Congénita/complicaciones , Hiperostosis Cortical Congénita/metabolismo , Fluoruro de Sodio , Adulto JovenRESUMEN
BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Biomarcadores , Progresión de la Enfermedad , Oxidorreductasas Intramoleculares , Factores Inhibidores de la Migración de Macrófagos , Tromboinflamación , Humanos , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Masculino , Femenino , Anciano , Estudios Prospectivos , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Válvula Aórtica/diagnóstico por imagen , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Oxidorreductasas Intramoleculares/sangre , Biomarcadores/sangre , Tromboinflamación/genética , Tromboinflamación/patología , Tromboinflamación/metabolismo , Plaquetas/metabolismo , Plaquetas/patología , Anciano de 80 o más Años , Monocitos/metabolismo , Persona de Mediana Edad , Implantación de Prótesis de Válvulas Cardíacas , Factores de Tiempo , Índice de Severidad de la Enfermedad , Calcinosis/patología , Calcinosis/genética , Calcinosis/sangre , Calcinosis/metabolismoRESUMEN
BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Colesterol , Dispositivos Laboratorio en un Chip , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Calcinosis/patología , Calcinosis/metabolismo , Animales , Colesterol/metabolismo , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/metabolismo , Ciclo Celular , Humanos , Porcinos , Homeostasis , Progresión de la Enfermedad , Hidrogeles/química , Técnicas de Cocultivo , Matriz Extracelular/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Sistemas MicrofisiológicosAsunto(s)
Calcinosis , Ombligo , Humanos , Calcinosis/diagnóstico , Calcinosis/patología , Ombligo/patología , Femenino , Enfermedades de la PielRESUMEN
PURPOSE: To investigate whether qualitative and quantitative imaging phenotypes can predict the grade of oligodendroglioma. METHODS: Retrospective chart and imaging reviews were conducted on 180 adults with oligodendroglioma (IDH-mutant and 1p/19q codeleted) between 2005 and 2021. Qualitative imaging characteristics including tumor location, calcification, gliomatosis cerebri, cystic change, necrosis, and infiltrative pattern were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate total, contrast-enhancing (CE), non-enhancing (NE), and necrotic tumor volumes. Logistic analyses were conducted to determine predictors of oligodendroglioma grade. RESULTS: This study included 180 patients (84 [46.7%] with grade 2 and 96 [53.3%] with grade 3 oligodendrogliomas), with a median age of 42 years (range 23-76 years), comprising 91 females and 89 males. On univariable analysis, calcification (odds ratio [OR] = 6.00, P < 0.001), necrosis (OR = 21.84, P = 0.003), presence of CE tumor (OR = 7.86, P < 0.001), larger total (OR = 1.01, P < 0.001), larger CE (OR = 2.22, P = 0.010), and larger NE (OR = 1.01, P < 0.001) tumor volumes were predictors of grade 3 oligodendroglioma. On multivariable analysis, calcification (OR = 3.79, P < 0.001) and larger CE tumor volume (OR = 2.70, P = 0.043) remained as independent predictors of grade 3 oligodendroglioma. The multivariable model exhibited an AUC, accuracy, sensitivity, specificity of 0.78 (95% confidence interval 0.72-0.84), 72.8%, 79.2%, 69.1%, respectively. CONCLUSION: Presence of calcification and larger CE tumor volume may serve as useful imaging biomarkers for prediction of oligodendroglioma grade. CLINICAL RELEVANCE STATEMENT: Assessment of intratumoral calcification and CE tumor volume may facilitate accurate preoperative estimation of oligodendroglioma grade. Presence of intratumoral calcification and larger contrast-enhancing tumor volume were the significant predictors of higher grade oligodendroglioma based on the 2021 WHO classification.
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Neoplasias Encefálicas , Calcinosis , Medios de Contraste , Imagen por Resonancia Magnética , Clasificación del Tumor , Oligodendroglioma , Carga Tumoral , Humanos , Oligodendroglioma/diagnóstico por imagen , Oligodendroglioma/patología , Oligodendroglioma/genética , Femenino , Masculino , Adulto , Persona de Mediana Edad , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Anciano , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Organización Mundial de la Salud , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored. METHODS: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications. RESULTS: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications. CONCLUSION: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement.
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Quinasa de Linfoma Anaplásico , Calcinosis , Neoplasias Pulmonares , Ganglios Linfáticos , Humanos , Masculino , Femenino , Quinasa de Linfoma Anaplásico/genética , Estudios Transversales , Persona de Mediana Edad , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcinosis/genética , Calcinosis/epidemiología , Prevalencia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/diagnóstico por imagen , Anciano , Ganglios Linfáticos/patología , Ganglios Linfáticos/diagnóstico por imagen , Endosonografía , Adulto , Reordenamiento GénicoRESUMEN
Calcific aortic valve disease (CAVD) is prevalent in developed nations and has emerged as a pressing global public health concern due to population aging. The precise etiology of this disease remains uncertain, and recent research has primarily focused on examining the role of valvular interstitial cells (VICs) in the development of CAVD. The predominant treatment options currently available involve open surgery and minimally invasive interventional surgery, with no efficacious pharmacological treatment. This article seeks to provide a comprehensive understanding of valvular endothelial cells (VECs) from the aspects of valvular endothelium-derived nitric oxide (NO), valvular endothelial mechanotransduction, valvular endothelial injury, valvular endothelial-mesenchymal transition (EndMT), and valvular neovascularization, which have received less attention, and aims to establish their role and interaction with VICs in CAVD. The ultimate goal is to provide new perspectives for the investigation of non-invasive treatment options for this disease.