BACKGROUND: Epoxyeicosatrienoic acids (EETs), which are metabolites of arachidonic acid catalyzed by cytochrome P450 epoxygenase, are degraded into inactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Many studies have revealed that sEH gene deletion exerts protective effects against diabetes. Vascular calcification is a common complication of diabetes, but the potential effects of sEH on diabetic vascular calcification are still unknown. METHODS: The level of aortic calcification in wild-type and Ephx2-/- C57BL/6 diabetic mice induced with streptozotocin was evaluated by measuring the aortic calcium content through alizarin red staining, immunohistochemistry staining, and immunofluorescence staining. Mouse vascular smooth muscle cell lines (MOVAS cells) treated with β-glycerol phosphate (0.01 mol/L) plus advanced glycation end products (50 mg/L) were used to investigate the effects of sEH inhibitors or sEH knockdown and EETs on the calcification of vascular smooth muscle cells, which was detected by Western blotting, alizarin red staining, and Von Kossa staining. RESULTS: sEH gene deletion significantly inhibited diabetic vascular calcification by increasing levels of EETs in the aortas of mice. EETs (especially 11,12-EET and 14,15-EET) efficiently prevented the osteogenic transdifferentiation of MOVAS cells by decreasing nidogen-2 (NID2) expression. Interestingly, suppressing sEH activity by small interfering ribonucleic acid or specific inhibitors did not block osteogenic transdifferentiation of MOVAS cells induced by β-glycerol phosphate and advanced glycation end products. NID2 overexpression significantly abolished the inhibitory effect of sEH gene deletion on diabetic vascular calcification. Moreover, NID2 overexpression mediated by adeno-associated virus 9 vectors markedly increased insulin-like growth factor 2 (IGF2) and phospho-ERK1/2 expression in MOVAS cells. Overall, sEH gene knockout inhibited diabetic vascular calcification by decreasing aortic NID2 expression and, then, inactivating the downstream IGF2-ERK1/2 signaling pathway. CONCLUSIONS sEH gene deletion markedly inhibited diabetic vascular calcification through repressed osteogenic transdifferentiation of vascular smooth muscle cells mediated by increased aortic EET levels, which was associated with decreased NID2 expression and inactivation of the downstream IGF2-ERK1/2 signaling pathway.
Animals ; Mice ; Vascular Calcification/metabolism* ; Mice, Inbred C57BL ; Epoxide Hydrolases/metabolism* ; Diabetes Mellitus, Experimental/genetics* ; Male ; Gene Deletion ; MAP Kinase Signaling System/genetics* ; Cell Line ; Immunohistochemistry ; Muscle, Smooth, Vascular/metabolism* ; Signal Transduction/genetics* ; Mice, Knockout

OBJECTIVES: To analyze sex and age distribution of global disease burden of calcific aortic valve disease (CAVD) from 1990 to 2021. METHODS: CAVD data during 1990-2021 were obtained from the IHME website for Global Burden of Disease (GBD). The prevalence, mortality, years lived with disability (YLDs), and disability-adjusted life years (DALYs) were analyzed by gender and age groups. Joinpoint regression was used to calculate annual percentage change (APC) and average annual percentage change (AAPC). RESULTS: In 2021, there were 13.32 million CAVD patients and 142 000 deaths caused by CAVD globally. Age-standardized prevalence was higher in males (193.2/10⁵) than that in females (128.9/10⁵). Patients in 65-<85 age group accounted for 64.0% of total cases, while those ≥85 years old accounted for 16.1%. From 1990 to 2021, prevalence increased in both sexes with an AAPC of 0.72% for males and 0.57% for females, respectively. Prevalence grew fastest from 2000 to 2010, slowed thereafter, and declined from 2015 to 2021. In <65 years old, the mortality of males was 2.4 times higher than that of females, while in ≥85 years old, mortality of females (117.3/10⁵) exceeded that of males (99.1/10⁵). YLD rates increased with age, and were higher in males for all age groups. DALY rates decreased overall but increased in ≥85 years old, with a greater increase in females. CONCLUSIONS There are significant gender and age disparities in global disease burden of CAVD, with the elderly, especially super-elderly females deserving particular attention. It is recommended to develop personalized intervention strategies for these populations.
Humans ; Male ; Female ; Aged ; Calcinosis/mortality* ; Prevalence ; Global Burden of Disease ; Aged, 80 and over ; Middle Aged ; Aortic Valve/pathology* ; Aortic Valve Stenosis/epidemiology* ; Age Distribution ; Adult ; Disability-Adjusted Life Years ; Sex Distribution ; Global Health ; Aortic Valve Disease/epidemiology* ; Sex Factors

Transcatheter aortic valve replacement (TAVR) has emerged as the standard treatment for severe aortic stenosis, demonstrating comparable efficacy to traditional surgery in low and intermediate-risk patients. However, the bioprosthetic valves utilized in TAVR have a limited lifespan, and bioprosthetic valve failure, including calcification, rupture or infection may develop, leading to poor clinical outcomes. Elevated blood pressure has been identified as a key factor in aortic valve calcification, and its role in bioprosthetic valve failure is gaining increasing attention. Hypertension may accelerate the calcification process and exacerbate valve failure due to increased mechanical stress on the valve, activation of the renin-angiotensin system, and enhanced thrombus formation. Furthermore, elevated blood pressure interacts with prosthesis mismatch and paravalvular leak, jointly affecting valve durability. This review explores the impact of elevated blood pressure on bioprosthetic valve calcification and failure after TAVR, and emphasizes the importance of blood pressure control, optimized preoperative assessment, and appropriate valve selection in reducing valve failures.
Humans ; Transcatheter Aortic Valve Replacement/adverse effects* ; Calcinosis/etiology* ; Bioprosthesis ; Heart Valve Prosthesis/adverse effects* ; Prosthesis Failure ; Aortic Valve Stenosis/surgery* ; Aortic Valve/surgery* ; Hypertension/physiopathology*

Lung cancer is still one of the most common malignant tumors in the world. With the increase of its incidence and the development of medical technology, the overall survival of lung cancer patients has significantly extended compared to before. The incidence of brain and meningeal metastases from lung cancer has also been rising year by year, but patients with brain and meningeal metastases from lung cancer have a poor prognosis and a very high mortality rate, and the diagnosis is mainly based on computed tomography (CT), magnetic resonance imaging (MRI) and other imaging examinations. However, the imaging features are diverse and the specificity is low, which makes it easy to be misdiagnosed and missed. Therefore, accurately identifying brain and meningeal metastases and timely targeted treatment is crucial for improving patient prognosis. This paper analyzed the diagnosis and treatment of a case of lung cancer with no obvious recurrence and metastasis in nearly 7-year long-term follow-up after radical lung cancer surgery, but the patient with abnormal behavior, impaired consciousness and epilepsy in the past 5 months, and multiple punctate calcifications in the brain found by head CT and MRI. This paper consider that the patient's mental and behavioral symptoms were caused by brain and meningeal metastasis of lung cancer after excluding infectious disease and ineffective treatment of autoimmune encephalitis, and further pathological biopsy and genetic detection confirmed the diagnosis of metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) L858R gene mutation, and the patient's symptoms were significantly improved after targeted therapy by Osimertinib. This paper also searched the relevant literatures of brain calcifications in databases such as China National Knowledge Infrastructure (CNKI), Wanfang, UpToDate, PubMed, etc., and found that intracerebral calcifications exist in a variety of diseases, including infectious, genetic and neurodegenerative diseases, vascular diseases, metabolic diseases and tumors. However, brain calcification in brain and meningeal metastases are often underestimated, and the consequent risk is misdiagnosis and delayed treatment. Therefore, brain and meningeal metastases manifested as brain calcification should not be ignored in patients with a history of previous tumors.
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Humans ; Lung Neoplasms/pathology* ; Brain Neoplasms/diagnostic imaging* ; Meningeal Neoplasms/diagnostic imaging* ; Calcinosis/diagnostic imaging* ; Male ; Middle Aged ; Tomography, X-Ray Computed ; Magnetic Resonance Imaging

OBJECTIVE: To investigate the clinical characteristics and genetic etiology of a primary familial brain calcification (PFBC) family, and analyze the pathogenic mechanism of MYORG gene variants. METHODS: A 17-year-old female who presented to the Second Affiliated Hospital of Zhejiang University School of Medicine on 13 May 2024 with "paroxysmal limb twitching for 1 day" was enrolled. The patient and her parents underwent clinical evaluation and neuroimaging. Peripheral blood samples were collected for whole exome sequencing (WES). Candidate variants were confirmed by Sanger sequencing and interpreted using the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants (hereinafter referred to as the ACMG Guidelines). This study was approved by Medical Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (Ethics No. 2020-674). RESULTS: The patient experienced epileptic seizures. Cranial CT revealed multiple calcifications in the bilateral basal ganglia and cerebellum, with a total calcification score of 23. WES identified compound heterozygous variants in MYORG: c.337_348dup (p.Leu113_Arg116dup), a known pathogenic variant, and c.1268T>G (p.Val423Gly). Segregation analysis showed that the father carried the c.337_348dup heterozygous variant, whereas the mother carried the c.1268T>G heterozygous variant. According to ACMG guidelines, the c.1268T>G variant was classified as "likely pathogenic" (PM2_Supporting + PM3_Supporting + PP1_Supporting + PP3_Moderate + PP4_Supporting). CONCLUSION The novel compound heterozygous MYORG variants c.337_348dup and c.1268T>G have broadened the mutational spectrum of the MYORG gene and further supported compound heterozygosity as an important genetic mechanism in MYORG-related PFBC.
Adolescent ; Female ; Humans ; Brain Diseases/genetics* ; Calcinosis/genetics* ; Exome Sequencing ; GPI-Linked Proteins/genetics* ; Mutation ; Pedigree ; Glycoside Hydrolases

OBJECTIVE: To explore the clinical characteristics and genetic cause of a child with gastrointestinal hemorrhage and Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) and to review the literature. METHODS: Clinical data of a child with gastrointestinal hemorrhage with CRMCC admitted to the Hepatology Department of Hunan Children's Hospital in September 2019 were collected, and peripheral blood DNA of the child and his parents were analyzed by whole exome sequencing. Candidate variants were validated by Sanger sequencing, followed by bioinformatics analysis, American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants pathogenicity classification, and protein structure prediction. A literature search with "Coats Plus syndrome" or "Cerebroretinal microangiopathy with calcifications and cysts" as keywords was conducted at PubMed, China National Knowledge Infrastructure and Wanfang databases to include recently published studies (up to December 2023). This study has been approved by the Ethics Committee of Hunan Children's Hospital (Ethics No. KY2020-07). Informed consent for clinical research was obtained from the guardian of the child. RESULTS: The proband was a 10-year-10-month-old boy. The clinical manifestations were intrauterine and postnatal growth retardation, gastrointestinal hemorrhage, liver fibrosis, panhemopenia, bilateral exudative retinopathy, intracranial lesions and facial pigmentation. WES and Sanger sequencing revealed two novel heterozygous variants in the CTC1 gene: c.787G>A (p.Val263Met) in exon 5 and c.2930C>G (p.Ser977Cys) in exon 17, which were inherited from his mother and father, respectively. According to ACMG pathogenicity classification, both missense variants were classified as variants of uncertain significance (VUS). Protein structure prediction showed the absence of LIG_SH3_3 motif and LIG_SH3_3 motif, and the p.Ser977Cys mutation may affect the binding between CST (CTC1-STN1-TEN) complex and DNA strand. The child had continued to experience recurrent gastrointestinal bleeding episodes despite propranolol treatment, but the condition was controlled after liver transplantation. According to the predefined literature search strategy of this study, a total of 10 relevant articles on pediatric CRMCC patients were retrieved, involving 11 children with gastrointestinal bleeding. Pharmacological and endoscopic therapies play a certain role in the management of CRMCC children complicated with gastrointestinal bleeding. CONCLUSION The CTC1 gene c.787G>A and c.2930C>G variants probably underlay CRMCC in this child. This study has broadened the variation spectrum of CTC1-related diseases and provided a basis for genetic counseling. Liver transplantation may be an important treatment for gastrointestinal hemorrhage in children who do not respond well to medication and endoscopic therapy.
Humans ; Male ; Gastrointestinal Hemorrhage/genetics* ; Child ; Calcinosis/genetics* ; Cysts/genetics* ; Central Nervous System Cysts/genetics* ; Mutation ; Exome Sequencing ; Leukoencephalopathies ; Retinal Diseases ; Seizures ; Muscle Spasticity ; Brain Neoplasms ; Ataxia

Vascular calcification significantly increases the incidence of cardiovascular disease and all-cause mortality patients with chronic kidney disease(CKD), severely affecting their health and lifespan. However, the mechanisms underlying vascular calcification in CKD remain incompletely understood, and the available therapeutic agents are limited. Research has found that the transformation of vascular smooth muscle cells(VSMCs) from a contractile phenotype to an osteoblast-like phenotype is a key step in CKD-related vascular calcification. As research on the pathogenesis of calcification progresses, it has been demonstrated that bone morphogenetic protein(BMP) and silent information regulator(SIRT) signaling pathways can participate in the process of vascular calcification by regulating the osteogenic transdifferentiation of VSMCs. Traditional Chinese medicine(TCM) has accumulated a wealth of valuable experience in the prevention and treatment of kidney diseases over centuries. Modern research indicates that TCM, with its multi-pathway, multi-target, and low-toxicity properties, has shown certain advantages in the prevention and treatment of CKD-related vascular calcification and in improving patients' quality of life. Therefore, in this study, we will introduce the latest research progress of TCM in preventing and treating CKD-related vascular calcification, particularly focusing on the BMP and SIRT signaling pathways, with the aim of providing ideas for the clinical diagnosis and treatment of CKD-related vascular calcification with TCM and related basic research.
Humans ; Vascular Calcification/genetics* ; Renal Insufficiency, Chronic/genetics* ; Signal Transduction/drug effects* ; Bone Morphogenetic Proteins/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Sirtuins/genetics* ; Medicine, Chinese Traditional

Objective To observe the effect of calcified lymph nodes on video-assisted thoracoscopic surgery (VATS) lobectomy in the chronic obstructive pulmonary disease (COPD) patients with lung cancer. Methods A retrospective analysis was conducted on the COPD patients with lung cancer who underwent VATS lobectomy in the Department of Thoracic Surgery in the First Affiliated Hospital of Hebei North University from May 2014 to May 2018.The patients were assigned into a calcified lymph node group and a control group according to the presence or absence of calcified lymph nodes in CT,and the size,morphology,and calcification degree of the lymph nodes were recorded.The operation duration,intraoperative blood loss,chest tube retention time,hospitalization days,and overall complication rate were compared between the two groups. Results The 30 patients in the calcified lymph node group included 17 patients with one calcified lymph node and 13 patients with two or more calcified lymph nodes,and a total of 65 calcified lymph nodes were recorded.The calcified lymph nodes with the size ≤5 mm were the most common (53.8%),and complete calcification was the most common form (55.4%) in lymph node calcification.The mean operation duration had no significant difference between the calcified lymph node group and the control group (t=-1.357,P=0.180).The intraoperative blood loss (t=-2.646,P=0.010),chest tube retention time (t=-2.302,P=0.025),and hospitalization days (t=-2.274,P=0.027) in the calcified lymph node group were higher than those in the control group. Conclusion Calcified lymph nodes increase the difficulty and risk of VATS lobectomy in the COPD patients with lung cancer.The findings of this study are conducive to predicting the perioperative process of VATS lobectomy.
Humans ; Blood Loss, Surgical ; Retrospective Studies ; Lung Neoplasms/surgery* ; Pulmonary Disease, Chronic Obstructive ; Calcinosis ; Lymph Nodes

Humans ; Temporomandibular Joint/diagnostic imaging* ; Temporomandibular Joint Disorders/complications* ; Calcinosis/diagnostic imaging*

BACKGROUND: Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23. METHODS: We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined. RESULTS: DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown. CONCLUSIONS Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP / OPN pathway.
Humans ; Osteopontin/genetics* ; Alkaline Phosphatase/metabolism* ; Receptor, Fibroblast Growth Factor, Type 3/metabolism* ; Scoliosis/genetics* ; Osteoblasts/metabolism* ; Calcinosis ; RNA, Messenger/metabolism* ; Bone Diseases, Metabolic/metabolism* ; Fibroblast Growth Factors/genetics*