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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common disease with high mortality. Kidney involvement in AAV commonly performances as ANCA-associated glomerulonephritis (AAGN). We aimed to identify the risk factors for mortality and end-stage renal disease(ESRD) within 6 months since diagnosis in AAGN patients. A total of 350 AAGN patients were enrolled in our center between 2004 and 2017 retrospectively. We analyzed the demographic, clinical and follow-up data. Factors for mortality and ESRD were investigated with univariate and multivariate Cox regression models. The median follow-up time was 60.8 (IQR 31.2, 84.5) months and 40 (11.4%) patients died within the first 6 months. In the multivariate analysis, age ≥ 65 years (HR = 2.245, 95%CI 1.085-4.645, P = 0.029), high leukocyte counts (HR = 1.089, 95%CI 1.015-1.168, P = 0.018), high Birmingham Vasculitis Activity Score (BVAS) (HR = 1.089, 95%CI 1.017-1.165, P = 0.014), infection (HR = 2.023, 95%CI 1.013-4.042, P = 0.046) and low serum albumin (HR = 0.916, 95%CI 0.845-0.992, P = 0.030) were independent risk factors for all-cause mortality in the first 6 months. A total of 95 patients reached ESRD within the first 6 months. The renal survival rate was 72.9% at 6 months. Multivariate analysis showed that high BVAS (HR = 1.198, 95%CI 1.043-1.376, P = 0.011), high daily urine protein (HR = 1.316, 95%CI 1.046-1.656, P = 0.019) and low eGFR (HR = 0.877, 95%CI 0.804-0.957, P = 0.003) were independent risk factors for ESRD. The mortality and ESRD rates were high in the first 6 months for AAGN patients. High disease activity evaluated by BVAS impacted both on patients' survival and renal survival, while over 65 years of age and infection were risk factors for mortality.

Bee products have been considered as functional foods for a long time in China because of their wide range of biological activity. China has the largest number of bee colonies and the highest production of bee products in the world. Major bee products include honey, royal jelly, propolis and bee pollen. In recent years, consumption of bee products in China has been increasing due to an increased public awareness of their nutritional and health benefits. With the development of the Chinese economy and the improvement of people's living standards, high-end and gift-oriented products have become more popular and bee products are one of the options. However, the production of bee products cannot increase rapidly in short term and this is a driver for substantial economic-motivated adulteration. This is compounded by globalisation of supply chains which has also resulted in a rise in bee products fraud. These illicit products are eroding market prices and consumer trust, causing significant damage to the beekeeping industry. In order to provide information or solutions for regulators and consumers, in this article, we review he characteristics of bee products in China and the current situation regarding adulteration and authenticity of bee products. Moreover, advances in analytical techniques for detection of adulteration and authenticity of bee products including sensory techniques, DNA methods, isotope ratio mass spectrometry, spectroscopic techniques and mass spectrometry are reviewed. Finally, the applications and limitations of analytical methods in authentication are critically assessed. Suggestions are also put forward for the future management of China's bee products industry.

This study evaluated the correlation of anti-β2-glycoprotein I (anti-β2-GPI) antibodies with complement activation in patients with idiopathic membranous nephropathy (IMN). Thirty-two IMN patients with positive anti-β2-GPI antibody were enrolled, and 32 age- and sex-matched IMN patients with negative anti-β2-GPI antibody were randomly enrolled as controls. The frozen serum samples of these 64 patients were collected for detection of anti-phospholipase A2 receptor (PLA2R) antibody and the activity of three complement pathways. Paraffin specimens of the kidney tissues of these 64 patients were collected for immunohistochemical staining of C4d. IMN patients with positive anti-β2-GPI antibody had a significant decline of the residual complement activity of alternative pathway than those with negative anti-β2-GPI antibody (37.4 ± 21.2% vs 65.7 ± 50.5%, P = 0.021). The positive rate of kidney C4d staining in IMN patients with and without anti-β2-GPI was 65.6 and 81.2%, with no significant difference (P = 0.257). Patients with and without anti-β2-GPI had the same positive rate of anti-PLA2R antibody. Anti-β2-GPI antibody was associated with alternative complement activation in patients with IMN.

Background: Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we aimed to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues. Methods: We performed single-cell RNA sequencing analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 control subjects (2 women and 1 man). Cells extracted from aortic tissue were analyzed and categorized with single-cell RNA sequencing data to perform cluster identification. ATAA-related changes were then examined by comparing the proportions of each cell type and the gene expression profiles between ATAA and control tissues. We also examined which genes may be critical for ATAA by performing the integrative analysis of our single-cell RNA sequencing data with publicly available data from genome-wide association studies. Results: We identified 11 major cell types in human ascending aortic tissue; the high-resolution reclustering of these cells further divided them into 40 subtypes. Multiple subtypes were observed for smooth muscle cells, macrophages, and T lymphocytes, suggesting that these cells have multiple functional populations in the aortic wall. In general, ATAA tissues had fewer nonimmune cells and more immune cells, especially T lymphocytes, than control tissues did. Differential gene expression data suggested the presence of extensive mitochondrial dysfunction in ATAA tissues. In addition, integrative analysis of our single-cell RNA sequencing data with public genome-wide association study data and promoter capture Hi-C data suggested that the erythroblast transformation-specific related gene( ERG ) exerts an important role in maintaining normal aortic wall function. Conclusions: Our study provides a comprehensive evaluation of the cellular composition of the ascending aortic wall and reveals how the gene expression landscape is altered in human ATAA tissue. The information from this study makes important contributions to our understanding of ATAA formation and progression.

To establish a risk-scoring system for lymph node metastasis (LNM) of early-stage endometrial carcinoma (EC), and to stratify the preoperative risk of LNM.We retrospectively analyzed the clinical data of 507 patients diagnosed with the early-stage EC (i.e., confined to the uterine corpus). We determined the risk factors for LNM by logistic regression analysis; then constructed a simple logistic scoring system, and an additive scoring system based on the regression coefficient (β), and odds ratio, of each variable, respectively.The overall rate of LNM was 9.1% (46/507). Multivariate analysis showed that preoperative serum cancer antigen 125 (CA125) ≥35 U/mL, histopathology of grade 3 and/or type II, depth of myometrial invasion ≥1/2 and positive immunostaining for Ki-67 ≥50%, were independent risk factors for LNM (P 0.05). The simple logistic and additive scoring systems exhibited good predictive ability (area under the curve [AUC]0.8). Based on the additive scoring system, the risk of LNM in patients with early-stage EC was classified into three groups: a low-risk group (total score:5), an intermediate-risk group (total score: 5-10) and a high-risk group (total score:10). The incidence of LNM differed significantly across these three groups (P 0.05).The risk-scoring system constructed in this study can effectively predict the risk of LNM in patients with early-stage EC, achieve preoperative risk stratification and provide a reference guideline for the use of lymphadenectomy.

Background: We aimed to illustrate gut microbiota and short chain fatty acid (SCFA) levels in diabetic nephropathy (DN) patients, and investigate the mechanism of sodium butyrate in diabetic mellitus (DM) rats. Methods: Gut microbiota and serum SCFA levels were measured by 16S rDNA and GC-MS respectively. After being built by streptozotocin (DM rats), the DM rats were administered 300mg/kg sodium butyrate for 12 weeks (DM+BU rats). Gut microbiota, serum and fecal butyrate level were measured. RT-PCR, WB and transmission electron microscopy were performed to explore LC3mRNA or LC3B protein expression, and autophagosomes in kidney tissues. AMPK/mTOR protein expression in renal tissue were also measured. Results: The gut microbial dysbiosis was found in DM and DN groups, and some SCFAs-producing bacteria were decreased in DN group. The serum butyrate concentrations were lower in SCFA-DN group compared with SCFA-HC group and SCFA-DM group in the other cohort. Serum butyrate level was positively correlated with eGFR. Sodium butyrate increased serum and fecal butyrate levels, and improved the enlargement of glomerular area and fibronectin and collagen Ⅳ expressions in renal tissues in DM+BU rats. The LC3 mRNA, LC3BⅡ/Ⅰ ratio and number of autophagosomes were increased in renal tissue of DM+BU rats. Higher p-AMPK/AMPK ratio and lower p-mTOR/ mTOR ratio were shown in renal tissue of DM+BU rats compared with DM rats. Conclusions: We found the decrease in SCFAs-producing bacteria and low SCFAs concentrations in DN patients. Oral butyrate supplementation may improve kidney injury in DM rats, possibly by increasing autophagy via activating AMPK/mTOR pathway.

ObjectiveTo evaluate the performance of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria in a cohort of patients with biopsy-confirmed lupus nephritis (LN) and their renal prognosis.MethodsPatients with newly diagnosed SLE attending and followed up for >12 months were included. A retrospective review of all patients with renal biopsy fulfilling a consensus expert opinion during 2014 and 2018. Clinical, serological and pathological data were collected and each patient was assigned a high/low criteria scores (HS/LS) group. Survival curves for flare adjusted for multiplicity on renal flares, was applied to the two groups.ResultsApplying EULAR/ACR criteria in our cohort of 126 patients, 6 (4.76%) did not meet the criterion, resulting in a sensitivity of 95.24%. The EULAR/ACR criteria scores was positively correlated with SLE disease activity index scores. Additionally, we noticed that a significant difference in clinical and immunological manifestations between HS and LS group. We observed a higher proportions of class Ⅲ or Ⅳ LN and lower proportions of class Ⅱ or V LN (p=0.034) and pathological higher activity index in HS group (p=0.007). Compared with LS groups, patients involved more severe renal damage and achieved higher rate of complete remission in the HS group. The Kaplan-Meier exploratory analyses, adjusted for LN classification, estimated glomerular filtration rate, activity index and chronicity index and induction and maintenance treatments, showed that patients in the HS group had a tendency of higher renal flare risk than that in the LS group (HR=0.21, p=0.04).ConclusionsThe EULAR/ACR criteria performed high sensitivity in identifying SLE in this cohort of biopsy-confirmed LN. Patients with LN with high criteria scores had more extrarenal manifestations, and worse renal prognosis in the short and long terms.

Background: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. Methods: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting -deficient ( Sting gt/gt ) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. Results: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Sting gt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Sting gt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. Conclusions: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

Background The process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. Materials and methods Wild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP− resident aortic cells. Results Aortic challenge induced recruitment of GFP+ BM cells and activation of GFP− resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non−BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. Conclusions BM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Alternative splicing (AS) is a complex coordinated transcriptional regulatory mechanism. It affects nearly 95% of all protein-coding genes and occurs in nearly all human organs. Aberrant alternative splicing can lead to various neurological diseases and cancers and is responsible for aging, infection, inflammation, immune and metabolic disorders, and so on. Though aberrant alternative splicing events and their regulatory mechanisms are widely recognized, the association between autoimmune disease and alternative splicing has not been extensively examined. Autoimmune diseases are characterized by the loss of tolerance of the immune system towards self-antigens and organ-specific or systemic inflammation and subsequent tissue damage. In the present review, we summarized the most recent reports on splicing events that occur in the immunopathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and attempted to clarify the role that splicing events play in regulating autoimmune disease progression. We also identified the changes that occur in splicing factor expression. The foregoing information might improve our understanding of autoimmune diseases and help develop new diagnostic and therapeutic tools for them.

BackgroundKidney involvement is common in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). It tends to be aggressive, and in some patients, the kidney involvement may reach the criteria of acute kidney injury (AKI). Here, we aim to describe the clinical characteristics of these patients and find risk factors for poor outcomes.MethodsPatients diagnosed with AAV in our hospital from February 2003 to February 2017 were included. Those who reached the KDIGO AKI criteria were reclassified according to the KDIGO AKI stage. The clinical features of these patients were analyzed. Also, according to the variation of serum creatinine 3 months after AKI episode, patients were further divided into two groups: patients whose serum creatinine (Scr) level at the third month decreased by 30% or more from the peak Scr level was classified into G1 and others were classified into G2. Long-term renal and survival outcomes of these patients were analyzed with a Cox model. The renal endpoint was reaching end-stage renal disease (ESRD), and the survival endpoint was death. Nomograms were built based on cox models.ResultsOf 141 AAV patients included, during the median follow-up period of 64.0 (IQR 34.8, 85.4) months, 36 (25.5%) patients reached renal endpoints, and 22 (15.6%) patients died. The median renal survival time was 35.9 (IQR 21.3, 72.6) months and the median survival time was 48.4 (IQR 26.8, 82.8) months. Multivariate analysis showed that poor recovery of Scr level at 90 days (P < 0.001, RR = 9.150, 95%CI 4.163–20.113), BVAS score (P = 0.014, RR = 1.110, 95% CI1.021–1.207), and AKI stage 3 (P = 0.012 RR = 3.116, 95%CI 1.278–7.598) were independent risk factors for renal endpoints; poor recovery of Scr level at 90 days (P = 0.010, RR = 3.264, 95%CI 1.326–8.035), BVAS score (P = 0.010, RR = 1.171, 95%CI 1.038–1.320) and age (P = 0.017, RR = 1.046, 95%CI 1.008–1.086) were independent risk factors for all-cause death. The c-index of nomograms is 0.830 for the renal outcome and 0.763 for the survival outcome.ConclusionKDIGO AKI stage 3 is the risk factor for ESRD in AAV patients with AKI. The BVAS score and level of kidney function recovery at 90 days are the independent risk factors for both ESRD and all-cause death and are of predictive value for the outcome.

BACKGROUND: The novel coronavirus disease (COVID-19) has been declared a global pandemic, with the cumulative number of confirmed cases and deaths exceeding 150 million and 3 million, respectively. Here, we examined the dynamic changes in the immune and clinical features of patients with COVID-19. METHODS: Clinical data of 98 patients with confirmed COVID-19 diagnosis were acquired from electronic medical records and curated. The data were analyzed based on the stage of the admission, deterioration, and convalescence, which included age, sex, severity, disease stages, biochemical indicators, immune cells, inflammatory cytokines, and immunoglobulins. Additionally, temporal changes in the immune response in patients undergoing continuous renal replacement therapy (CRRT) were also examined. RESULTS: Compared to mild stage patients, severe stage patients with COVID-19 exhibited a significant reduction in lymphocyte [23.10 (17.58–33.55) vs. 4.80 (2.95–6.50), P

MYH9-related disease or disorder (MYH9-RD) is an autosomal dominant disease caused by mutations in the MYH9 gene. Mutations in this gene initially affect the hemic system, and other manifestations may evolve with age. Here, we report the case of a 46-year-old Chinese woman with MYH9-RD who was primarily misdiagnosed with idiopathic thrombocytopenia purpura. Exome sequencing of the patient, and the mother and son of the patient revealed a deletion mutation c.5797delC (p. R1933Efs*15) in exon 41 (encoding non-helical tailpiece, NHT) of the MYH9 gene, which consequently led to a frameshift mutation. To the best of our knowledge, this mutation has been reported in Italy once, while the substitution mutation c.5797 C>T is the most frequent mutation. Mutations that affect the NHT region cause thrombocytopenia throughout life; however, our patient presented with a more severe phenotype than previously reported, including thrombocytopenia, inclusion bodies in neutrophils, sensorineural hearing loss, nephropathy, and abnormal liver enzymes. Our goal in the current case is to prevent further progression of renal involvement and to identify other affected members in this family to provide early intervention. This case may raise awareness of MYH9-RD when diagnosing thrombocytopenia and improve our understanding of this condition.

BackgroundIncreasing evidence shows that Angptl4 affects proteinuria in podocytes injured kidney disease, however, whether there is a relationship between Angptl4 and IgA nephropathy (IgAN) has not been studied yet.MethodsPlasma and urine samples were obtained from 71 patients with IgAN and 61 healthy controls. Glomeruli from six renal biopsy specimens (three IgAN patients and three healthy controls) were separated by RNA-Seq. Differentially expressed genes (DEGs) related to podocytes and Angptl4 between IgAN patients and healthy controls were performed using the Limma package. Gene set enrichment analysis was used to determine whether there was a statistically significant difference between the two groups. STRING was used to create a protein-protein interaction network of DEGs. Association analysis between Angptl4 levels and clinical features of IgAN was performed.ResultsThirty-three podocyte-related and twenty-three Angpt4-related DEGs were found between IgAN patients and healthy controls. By overlapping the genes, FOS and G6PC were found to be upregulated in IgAN patients, while MMP9 was downregulated in IgAN patients. Plasma and urine Angptl4 levels were closely related to the degree of podocyte injury and urine protein, but not to the protein-creatine ratio.ConclusionOur findings show that Angptl4 levels in plasma and urine are related to podocyte damage and, therefore, may be a promising tool for assessing the severity of IgAN patients to identify and reverse the progression to ESRD.

Objective: Early detection of aortic degeneration is critical for improving outcomes in patients with aortic aneurysm and dissection. We investigated nanoparticle contrast-enhanced computed tomography for the early detection of aortic injury. Approach and Results: In a mouse model of sporadic aortic aneurysm and dissection, C57BL/6J mice were challenged with a high-fat diet and Ang II (angiotensin II) infusion (n=20). Unchallenged control mice received a standard laboratory diet and saline infusion (n=19). Computed tomography angiography (CTA) was performed to evaluate aortic enlargement, and delayed nanoparticle contrast-enhanced computed tomography (CTD) imaging was performed to detect wall signal enhancement indicative of aortic wall degeneration. Aortic segments that exhibited CTD findings but appeared normal on CTA were termed preclinical aortic disease. Aortic aneurysm and dissection development was determined upon the gross examination of excised aortas. Aortic degeneration and inflammation were examined by performing histological and immunofluorescence analyses. Leakage of Evans blue dye into the aortic wall was used to validate changes in vascular permeability. In challenged mice, gross findings of aortic disease were found in 41% of aortic segments. CTA findings of mild disease (dilatation) and advanced disease (aortic aneurysm and dissection with the presence of false lumen) were seen in 33% of aortic segments. CTD findings of wall signal enhancement were seen in 63% of aortic segments. Of those, 48% appeared normal on CTA. Aortic segments with CTD findings showed aortic wall degeneration and inflammation on histological and immunofluorescence analyses. Immunofluorescence analysis and Evans blue dye uptake suggested passive leakage of nanoparticle contrast agent due to endothelial injury as a potential mechanism underlying the detection of aortic disease on CTD. Conclusions: In mice, CTD imaging exhibits high sensitivity for detecting aortic wall degeneration and inflammation before vessel enlargement becomes evident on CTA.

Background: Studies on the correlation between serum uric acid (SUA) and all-cause mortality in peritoneal dialysis (PD) patients were mainly based on the results of baseline SUA. We aimed to analyze the change of SUA level post PD, and the correlation between follow-up SUA and prognosis in PD patients. Methods: All patients who received PD catheterization and maintaining PD in our center from March 2, 2001 to March 8, 2017 were screened. Kaplan-Meier and Cox proportional-hazards regression models were used to analyze the effect of SUA levels on the risks of death. We graded SUA levels at baseline, 6 months, 12 months, 18 months and 24 months post PD by mean of SUA plus or minus a standard deviation as cut-off values, and compared all-cause and cardiovascular mortality among patients with different SUA grades. Results: A total of 1402 patients were included, 763 males (54.42%) and 639 females (45.58%). Their average age at PD start was 49.50±14.20 years. The SUA levels were 7.97±1.79mg/dl at baseline, 7.12±1.48mg/dl at 6 months, 7.05±1.33mg/dl at 12 months, 7.01±1.30mg/dl at 18 months, and 6.93±1.26mg/dl at 24 months. During median follow-up time of 31 (18, 49) months, 173 (12.34%) all-cause deaths occurred, including 68 (4.85%) cardiovascular deaths. There were no significant differences on all-cause mortality among groups with graded SUA levels at baseline, 12 months, 18 months and 24 months during follow-up or on cardiovascular mortality among groups with graded SUA levels at baseline, 6 months, 12 months, 18 months and 24 months during follow-up. At 6 months post PD，Kaplan Meier analysis showed there was significant difference on all-cause mortality among graded SUA levels (c2=11.315, P=0.010), and the all-cause mortality was lowest in grade of 5.65mg/dl≤SUAConclusion: SUA level decreased during follow up post PD. At 6 months post PD, a grade of 5.65mg/dl≤SUA

Objectives. The causes of ovarian cancer (OC) have been confirmed to be closely related to genetic factors. Identifying sequence variants of hereditary ovarian cancer (HOC) susceptibility genes can increase clinical surveillance, facilitate early detection, and provide personalized treatment for patients. This study is aimed at investigating the variation frequency of HOC susceptibility genes in the Chinese population and providing information for the etiology and genetics of OC. Methods. 118 epithelial OC patients were recruited in this clinical study. Variants of 18-gene panel were detected in blood samples by next-generation sequencing (NGS) technology. Results. Overall, 36.44% (43/118) of patients carried at least one pathogenic variant. Among these, BRCA1 pathogenic variants were detected in 31 (26.27%) patients, and 5 (4.24%) patients carried pathogenic variants of BRCA2. Moreover, 27.12% (32/118) of patients carried variants of unknown significance (VUSs). Importantly, we detected eight variants that were not reported previously. Conclusions. Our study enlarged the spectrum of HOC-associated gene sequence variants in the Chinese population and also proved the necessity of multigene testing in epithelial OC patients. The identification of patients with HOC will allow family members to undergo cascade testing where identification of unaffected carriers can facilitate early detection, risk reduction, or prevention of OC and ultimately improve long-term outcomes.

Background: Thoracic aortic aneurysms associated with Marfan syndrome (MFS) carry a high risk of mortality; however, the molecular and cellular processes leading to aortopathy in this population remain poorly understood. We aimed to use single-cell RNA (scRNA) sequencing to define the non-immune cell populations present within the aortic wall in MFS, hypothesizing that these would differ from those of non-aneurysmal control tissue. Methods: We performed scRNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and of age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). The Seurat package in R was used for analysis. Differentially expressed genes were identified using edgeR. Results: Eighteen non-immune cell clusters were identified, with conserved gene expression of the largest of the clusters consistent with smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (n=3). The SMCs and fibroblasts exhibited graded changes in their expression of contractile and extracellular matrix protein genes, supportive of a phenotypic continuum. Additionally, we identified differences in the proportions of non-immune cells in MFS tissues compared to controls. In control tissues, the most common non-immune cells expressed markers of contractile SMC maturity including CNN1 , MYH11 , and SMTN . In contrast, the largest clusters in MFS tissue were most closely related to SMCs on correlation analysis, but displayed increased expression of cyclin genes as well as immune, endothelial, and fibroblast genes indicative of de-differentiated, proliferative SMCs. Additionally, expression of genes associated with SMC phenotypic maturity, including MYH11 and MYOCD , were significantly downregulated in several of the MFS SMC clusters. Conclusion: Our data demonstrate a phenotypic continuum between fibroblasts and SMCs, with aortas from patients with MFS exhibiting an increased proportion of de-differentiated, proliferative SMCs compared to controls. Additionally, markers of SMC maturity were downregulated in SMCs in MFS compared to controls. This may be due to disruption of signaling pathways that promote differentiation.

Background: The aorta adapts to changes in its biomechanical environment and insufficient adaptation results in aortic failure. However, the molecular and cellular processes underlying this adaptive response are poorly understood. In this study, we performed single-cell transcriptomic and single-cell epigenomic analyses to investigate gene expression and epigenetic regulation responses in aortas subjected to hemodynamic stress. Methods and Results: Angiotensin II infusion in wild-type mice (C57BL/6J) increased ascending aorta wall thickness that was associated with smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. ScRNA-seq revealed an adaptive response in several SMC clusters that was characterized by upregulation of genes in processes such as proliferation, cell junction organization, ECM production and organization, wound healing, as well as DNA repair and anti-oxidation. ScATAC-seq showed increased chromatin accessibility at the locus of these adaptive genes. Motif analysis of the accessible regions showed that several transcription factors and chromatin architecture proteins may be involved in regulating these adaptive response genes. Among these, Yap1 was significantly activated in response to the aortic challenge. YAP1-based ChIP-seq in aortic SMCs indicated that YAP1 and its transcription partners can directly bind to genes involved in the adaptive response to biomechanical stretch. Finally, SMC-specific knockout of Yap1 resulted in a compromised adaptive response and increased expression of genes involved in protein disassembly or degradation, and cell death in all SMC clusters, leading to contractile dysfunction, aortic aneurysm, dissection, and rupture. Conclusion: In mice, hemodynamic stress induces a comprehensive and coordinated adaptive response in SMCs that is critical for maintaining aortic homeostasis. YAP1 in SMCs play an important role in promoting this adaptive response in aortic wall.

Background: Marfan syndrome (MFS) is caused by mutations in the gene for fibrillin-1 ( FBN1 ); however, the mechanisms by which these mutations cause aortic aneurysms are poorly understood. Although it was hypothesized previously that dysregulation of the complex TGF-β signaling pathway leads to aortic aneurysm formation, FBN1 mutations appear to have a paradoxical effect on TGF-β signaling in MFS. In this study, we evaluated cell-specific TGF-β expression in non-immune cells in MFS aortic tissue. Methods: We performed single-cell RNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). Non-immune cells were separated out from the data and analyzed using the Seurat package in R. Differentially expressed genes were identified using edgeR. Results: Conserved gene expression was used to identify populations of smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (ECs; n=3). We found that TGFB1 was significantly upregulated in quiescent fibroblasts (identified by increased expression of DCN , LUM , and complement factors) with log2FC of 1.30 and FDR 8.25x10 -8 , as well as in activated fibroblasts (identified by increased expression of genes involved in blood vessel repair and healing including ACTA2 , NOTCH3 , THBS2 , and PDGFRB ) with log2FC of 1.25 and FDR 6.15x10 -22 . Despite this increase in TGFB1 , expression of TGF-β receptor genes (predominately TGFBR2 ) as well as downstream SMAD genes was downregulated significantly in the SMC, fibroblast, and endothelial cell clusters. Finally, genes involved in the non-canonical TGF-β pathway, including ERK , JNK, and p38, were not differentially expressed in non-immune cells in MFS compared with control tissues. Conclusion: Increased expression of TGFB1 in non-immune cells in MFS was driven by two clusters of fibroblasts. Despite this, our data do not support associated upregulation of other genes in the canonical or non-canonical TGF-β pathways and in fact support downregulation of canonical TGF-β signaling in non-immune cells of aneurysmal tissues from MFS patients with advanced aortic disease.

Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide‐binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3)–caspase‐1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild‐type mice with a high‐fat, high‐cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge‐induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3–caspase‐1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP‐9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase‐1 directly activated MMP‐9 by cleaving its N‐terminal inhibitory domain. Moreover, the genetic knockdown of Nlrp3 or Casp‐1 in mice or treatment of mice with MCC950 diminished the challenge‐induced N‐terminal cleavage of MMP‐9, MMP‐9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3–caspase‐1 inflammasome directly activates MMP‐9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.

Background Insufficient aortic protection and repair may contribute to the development of aortic aneurysms and dissections (AAD). However, mechanisms of aortic protection and repair are poorly understood. We have shown that the multifunctional kinase AKT2 plays an important role in protecting the aortic wall. Here, we examined whether AKT2 protects against AAD by promoting bone marrow cell (BMC)–mediated aortic protection. Methods Irradiated wild-type mice received green fluorescent protein–expressing BMCs from wild-type mice or Akt2 -/- mice, followed by challenge with angiotensin II (1000 ng/kg/min) infusion for 4 weeks. We compared BMC recruitment, aortic destruction, and AAD development between groups. The direct effects of wild-type and Akt2 -/- BMCs on smooth muscle cell survival were examined in coculture experiments. Results After angiotensin II infusion, no (0 of 14) wild-type BMC recipients had AAD; in contrast, 64% (9 of 14) of Akt2 -/- BMC recipients had AAD ( p = 0.002) with severe aortic destruction. Compared with aortas from challenged wild-type BMC recipients, aortas from challenged Akt2 -/- BMC recipients showed significantly less BMC recruitment, NG2 (neuron-glial antigen 2) progenitor activation, and FSP1 (fibroblast-specific protein 1) fibroblast activation. In addition, aortas from challenged Akt2 -/- BMC recipients showed increased apoptosis and inflammation. In coculture experiments, wild-type but not Akt2 -/- BMCs prevented smooth muscle cells from undergoing oxidative stress–induced apoptosis. Conclusions After aortic challenge, BMCs are recruited to the aortic wall and provide protection by activating progenitors and fibroblasts and by promoting aortic cell survival. Our findings indicate that AKT2 is involved in these processes and that defects in this pathway may promote progressive degeneration during AAD development.

Background Henoch-Schönlein purpura nephritis (HSPN) shares many similarities with IgA nephropathy. We aimed to analyze the predictive value of the International Study of Kidney Disease in Children (ISKDC) classification and the updated Oxford classification for IgA nephropathy in HSPN patients. Methods Data of 275 HSPN patients (aged≥14 years) were retrieved, and all of them underwent a renal biopsy. We re-classified the biopsies according to the ISKDC classification and the updated Oxford classification to analyze their correlations with clinical features and renal outcomes. The renal endpoints were defined as ≥30% reduction in baseline estimated glomerular filtration rate (eGFR) in 2 years, doubling of serum creatinine (Scr) or end stage renal disease. Results During follow-up period of 56(30,86) months, 30(10.9%) patients reached renal endpoints. Segmental sclerosis was the only pathological feature independently associated with renal endpoints (HR 4.086, 95%CI 1.111–15.026, P = 0.034). Tubular atrophy/ interstitial fibrosis was associated with eGFR and Scr levels, and its correlation with renal endpoints was found by univariate analysis. Endocapillary hypercellularity was associated with 24 h urine protein and is of prognostic value in univariate analysis. Mesangial hypercellularity was not associated with clinical features or renal endpoints. Crescents were associated with 24 h urine protein, Scr and eGFR levels, but both ISKDC and updated Oxford classifications of crescents were not associated with renal endpoints by multivariate analysis. Conclusions The updated Oxford classification can help in disease management and renal outcome prediction of HSPN. Electronic supplementary material The online version of this article (10.1186/s13000-019-0818-0) contains supplementary material, which is available to authorized users.

Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD.To examine the effect of ciprofloxacin on AAD development in mice.In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells.No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression.Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

Background: Aortic aneurysms and dissections (AAD) are common interrelated cardiovascular diseases that cause more than 10,000 deaths in the United States each year and are a leading cause of death in people 55 years of age or older. Currently, surgery is the only effective treatment; thus, there is a critical need to develop pharmacological agents that can prevent the initiation or progression of AAD. Increasing evidence suggests that the NLRP3 inflammasome plays a critical role in aortic destruction. In this study, we aimed to test the therapeutic potential of MCC950, a potent and specific NLRP3 inhibitor, for preventing AAD. Methods/Results: In a sporadic AAD model induced by a high-fat diet and angiotensin II infusion,, aortic challenge induced significant aortic enlargement and the development of a range of AAD manifestations, including aneurysm without dissection, dissection, and rupture. Importantly, MCC950 treatment significantly inhibited aortic enlargement and the development of AAD, particularly in the ascending and suprarenal aorta. The overall incidence of AAD decreased from 86% in the challenged control group to 40% in the challenged MCC950 treatment group ( P P =0.0001), and the incidence of suprarenal AAD decreased from 60% in the challenged control group to 20% in the challenged MCC950 treatment group ( P 2 O 2 -induced activation of the NLRP3 inflammasome, IL-1β secretion, and MMP-9 activation. Conclusion: The NLRP3 inhibitor MCC950 is effective at preventing inflammasome activation, aortic destruction, inflammation, and the development of AAD in a mouse model of sporadic disease. Further studies are needed to determine whether MCC950 has similar effects in other AAD models.

The aim of this study is to explore the value of transthoracic echocardiography in the diagnosis of eosinophilic myocarditis. The echocardiographic characteristics of nine patients with eosinophilic myocarditis in our hospital between January 2004 and January 2012 were retrospectively reviewed. In our study, four of the nine patients were diagnosed to have small pericardial effusion. The obliteration of the apical cavity was observed in five of the nine patients. There were six patients with both mitral and tricuspid regurgitation, one patient with only mitral regurgitation, and one patient with only tricuspid regurgitation. Transthoracic echocardiography showed that the diameters of the left and right atria were both increased in eight of the nine patients. The diameter of the left ventricle was increased in five patients, and the right ventricular diameter was increased in four patients. The left ventricular ejection fraction was decreased in two of the nine patients. Five of the nine patients had pulmonary hypertension, and one patient had severe pulmonary hypertension. Transthoracic echocardiography is the primary method for the diagnosis of eosinophilic myocarditis and is also useful in follow-up of the disease.

Objective: The treatment of Henoch-Schönlein purpura (HSP) with moderate proteinuria remains controversial. We retrospectively analyzed the efficacy of immune suppressants, with a particular emphasis on mycophenolate mofetil (MMF). Methods: Ninety-five HSP patients with moderate proteinuria (1.0–3.5 g/24 h) after at least three months of therapy with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) were divided into three groups: an MMF group (n=33) that received MMF 1.0–1.5 g/d combined with prednisone (0.4–0.5 mg/(kg·d)), a corticosteroid (CS) group (n=31) that received full-dose prednisone (0.8–1.0 mg/(kg·d)), and a control group (n=31). Patients in the MMF and CS groups continued to take ACEI or ARB at the original dose. The patients in the control group continued to take ACEI or ARB but the dose was increased by (1.73±0.58)-fold. The patients were followed up for 6–78 months (median 28 months). Results: The baseline proteinuria was higher in the MMF group ((2.1±0.9) g/24 h) than in the control group ((1.6±0.8) g/24 h) (P=0.039). The proteinuria decreased significantly in all groups during follow-up, but only in the MMF group did it decrease significantly after the first month. At the end of follow-up, the proteinuria was (0.4±0.7) g/24 h in the MMF group and (0.4±0.4) g/24 h in the CS group, significantly lower than that in the control group ((0.9±1.1) g/24 h). The remission rates in the MMF group, CS group, and control group were respectively 72.7%, 71.0%, and 48.4% at six months and 72.7%, 64.5%, and 45.2% at the end of follow-up. The overall number of reported adverse events was 17 in the MMF group, 30 in the CS group, and 6 in the control group (P

Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency (Adamts-4−/−) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

Objective Transabdominal ultrasound (TAUS)-guided inferior vena cava filter (IVCF) placement currently uses an inferior vena cava (IVC) longitudinal plane with cross-section of the right renal artery or the transverse plane of the right renal vein (RRV)-IVC intersection. The goal of this study was to introduce a new method for TAUS-guided IVCF placement. Methods The study enrolled patients who were at high risk for or had pulmonary embolism from October 22, 2010, to June 30, 2016. The probe was positioned on the right flank to centralize the RRV-IVC junction during imaging and to permit a straight line through the midpoint of the probe on the surface and a parallel line 1.0 cm below the straight line as a marker. The probe was subsequently placed on the abdominal wall with the upper edge at the marker line to show the long axis of the IVC during the process of filter placement. The upper edge of the probe was considered the filter tip position. Results A total of 1029 patients were evaluated, and 98 patients (9.5%) were excluded because of poor IVC visualization (n = 14 [1.4%]), IVC or bilateral iliac vein thrombosis (n = 79 [7.7%]), and unsuitable anatomy (n = 5 [0.5%]). The remaining 931 patients (90.5%) were selected for TAUS-guided IVCF placement, and all filters (100%) were successfully placed. There were no procedure-related complications. Suprarenal IVCF was observed in 4 patients (0.4%) by computed tomography, and the filter tip exceeded the upper edge of L2 in 15 patients (1.6%) by plain film radiography; one of them had two RRVs. Severe filter tilting (20.8 degrees) occurred in one patient. Conclusions This new method of TAUS-guided IVCF placement was simple, safe, and effective. It may be widely applied for the bedside placement of vena cava filters.

Background Early detection of right ventricular (RV) and left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (TOF) is essential because dysfunction is correlated with a poor clinical outcome. The aim of this study was to assess RV and LV function in asymptomatic children with repaired TOF by two-dimensional ultrasound speckle tracking echocardiography (STE). Methods Fifty-six asymptomatic children with a preserved biventricular ejection fraction (EF) after repair of TOF and 35 healthy control subjects were studied. RV and LV strain and strain rate were measured by STE. RVEF and pulmonary regurgitation (PR) were assessed using cardiac magnetic resonance imaging. Results Compared with the control subjects, RV regional longitudinal strain and strain rate and global longitudinal strain (GLS) and strain rate (GLSR) were impaired in children with repaired TOF. Likewise, LV circumferential and radial strain and strain rate were reduced in patients with TOF. In contrast, longitudinal strain and strain rate did not differ between the groups. RV and LV GLSR were correlated with postoperative follow-up period (r1 = −0.44; r2 = −0.48). RV GLS and GLSR were associated with RVEF (r1 = 0.64; r2 = 0.60) and PR (r1 = −0.48; r2 = −0.49). LV circumferential strain rate was related to PR (r = −0.45). Conclusions STE can identify abnormalities that may represent early impairment of RV and LV systolic function in postoperative TOF patients with a preserved EF. PR is associated with decreased biventricular performance in repaired patients. STE-derived strain and strain rate may be useful indices for detecting the early deterioration of biventricular performance in patients with TOF.

As a non-invasive and convenient modality, transthoracic echocardiography (TTE) has been widely recommended for the diagnosis of patent foramen ovale (PFO). In this study our aim was to systematically review the diagnostic accuracy of TTE in detection of PFO. We conducted comprehensive searches in PubMed, Embase and the Cochrane Library to the end of September 1, 2012. Sixteen studies comprising 1831 patients were included in the meta-analysis. The quality of reported studies was modest. The summary sensitivity and specificity of TTE in diagnosis of PFO were 88% (95% confidence interval [CI], 79-94) and 97% (95% CI, 92-99), respectively. The positive likelihood ratio was 27.1 (95% CI, 11.2-65.1), and the negative likelihood ratio was 0.12 (95% CI, 0.07-0.22). The summary diagnostic odds ratio was 221 (95% CI, 95-518). Subgroup analyses suggested that age and initial disease may affect the accuracy of TTE in detection of PFO. The meta-analysis suggested that TTE is a test with high sensitivity and specificity in detection of PFO, but it may not be appropriate for screening for PFO in all patients, especially patients with a small right-left shunt.

Objective To explore the value of transthoracic and right heart contrast echocardiography in the diagnosis of coronary sinus septal defect (CSSD), also known as unroofed coronary sinus. Methods The echocardiographic characteristics of 20 patients with CSSD who underwent surgery in our hospital between October 1999 and June 2012 were reviewed retrospectively, including results of 9 cases studied by contrast echocardiography, and compared with surgical results. Results Of the coronary sinuses in these 20 patients, 40% were totally unroofed, 35% partially unroofed in mid-portion, 20% partially unroofed in terminal portion, and 5% mixed type (mid- and terminal portions). Of these 20 patients, 65% were associated with other types of atrial septal defects, and 65% had a persistent left superior vena cava. The diagnostic accuracy of echocardiography for the CSSD was 65%. In patients whose diagnoses were confirmed by echocardiography, the accuracy for the types of CSSD was 84.6%. All of the first 6 cases studied before 2002 were either undiagnosed or misdiagnosed, and 78.6% of the last 14 cases studied were diagnosed accurately. Of 9 patients who underwent contrast echocardiography, 8 were correctly diagnosed, including 5 type II and 3 Raghib syndromes. 1 case of type IIIa was misdiagnosed as Raghib syndrome. Conclusions The combination of transthoracic and contrast echocardiography can diagnose and classify CSSD accurately in most cases and should be the first choice for diagnosing CSSD.

Background/Aims: In view of the latest findings that matrix metalloproteinase-7 (MMP-7) acted as a vital marker and pathogenic mediator of renal fibrosis in a murine model, we hypothesized that serum MMP-7 level might serve as a noninvasive prognostic biomarker in IgA nephropathy (IgAN) patients. Methods: We conducted a retrospective follow-up study of 244 IgAN patients for a median of 81.9 months. Serum MMP-7 was detected at the time of diagnosis, and renal progression was assessed by Cox proportional hazards method. Results: Compared with healthy populations, the serum levels of MMP-7 were significantly elevated in IgAN patients. Besides, serum MMP-7 levels were well correlated with renal scarring lesions characterized by glomerular sclerosis and interstitial fibrosis. Follow-up analyses revealed that increased serum MMP-7 levels were linked with a greater risk of poor renal outcome with a hazard ratio of 1.898 per doubling MMP-7 concentration. By contrast with the first quartile, the risk of deterioration in renal function elevated such that the hazard ratio for the second quartile was 1.805, 3.383 for the third, and 5.173 for the fourth quartile of the MMP-7 level. Conclusions: This study showed that the higher serum MMP-7 levels were independently associated with renal fibrosis and poor prognosis in IgAN.

Background ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently identified family of extracellular metalloproteinases that has been shown to participate in tissue destruction. We hypothesized that ADAMTS-1 and ADAMTS-4 expression is increased in aortic tissues from patients with thoracic aortic aneurysms and dissections. Methods We examined ADAMTS-1 and ADAMTS-4 expression in human descending thoracic aortic aneurysms (n = 14), chronic descending thoracic aortic dissections (n = 16), and descending thoracic aortas from age-matched control organ donors (n = 12). In these tissues, we also evaluated the degradation of versican, a proteoglycan substrate of ADAMTS-1 and ADAMTS-4. In cultured macrophages, we examined whether ADAMTS-4 functions in macrophage infiltration by using a transwell assay. Results ADAMTS-1 and ADAMTS-4 protein and mRNA expression was significantly higher in thoracic aortic aneurysm and dissection tissues than in control aortic tissues. Double immunofluorescence staining showed the expression of ADAMTS-1 and ADAMTS-4 in smooth muscle cells and macrophages. Consistent with the upregulation of ADAMTS-1 and ADAMTS-4 in thoracic aortic aneurysm and dissection tissues, versican was degraded significantly more in these tissues than in control aortic tissues. In cultured macrophages, transforming growth factor-β increased ADAMTS-4 protein levels and induced macrophage invasion, and the knockdown of ADAMTS-4 reduced cell invasion. Conclusions Increased expression of ADAMTS proteins may promote thoracic aortic aneurysm progression by degrading versican and facilitating macrophage invasion.

Gastric duplication anomaly is an uncommon congenital disease, mostly reported in children. Malignant transformation of the duplication lesion is extremely rare, with only 11 cases reported in the English literature. Here we report three cases of early cancer found in gastric duplications or the adjacent gastric wall. Out of these three cases, one is an early cancer arising from the duplication lesion, one from the gastric wall and another form both. To the best of our knowledge, early cancer arising from both the duplication cyst and the adjacent wall is first reported. Once detected gastric duplication, surgical resection is recommended because of its potential for malignant transformation.

Background Published correlations between histological abnormalities and right ventricular (RV) function, as evaluated by speckle tracking echocardiography (STE), are scarce in patients with tetralogy of Fallot (TOF). The purpose of the study is to assess age-associated differences in the effect of RV myocardial remodeling on ventricular function in patients with TOF. Methods Operatively resected crista supraventricularis muscle from 30 patients (median age 12months) undergoing intracardiac repair of TOF were studied by light microscopy. The patients were divided into younger (age at surgery ≤12months) and older (age at surgery >12months) subgroups. The RV global longitudinal peak systolic strain (GLS), strain rate (GLSRs) and early diastolic strain rate (GLSRe) were measured by two-dimensional STE before and 6months after repair. Results The histopathological data revealed hypertrophy of the cardiomyocytes, a thickened endocardium, and increased interstitial and perivascular collagen in RV, which were associated with older age at the time of repair. The RV global systolic and diastolic functions in patients with repaired TOF were increased compared with the preoperative values. The RV cardiomyocyte diameter and collagen volume fraction (CVF) correlated with the preoperative GLS, GLSRs and GLSRe, respectively, in the younger patients (r 1 =−0.566, P 1 =0.018; r 2 =−0.493, P 2 =0.004; r 3 =−0.504, P 3 =0.039). The RV cardiomyocyte diameter and CVF correlated with preoperative GLS, GLSRs and GLSRe, respectively, in the older patients (r 1 =−737, P 1 =0.004; r 2 =−0.588, P 2 =0.035; r 3 =−0.812, P 3 =0.001). The correlation of the RV cardiomyocyte diameter with the postoperative GLS and GLSRe (r 1 =−665, P 1 =0.036; r 2 =−0.787, P 2 =0.007) and the CVF with the postoperative GLSRs and GLSRe (r 1 =−762, P 1 =0.002; r 2 =−0.713, P 2 =0.004) were identified only in the older patients. Multivariate analysis indicated that the age at repair was an independent predictor of postoperative GLSRs and GLSRe in all of the patients (β=−0.449, P=0.041; β=−0.607, P=0.004). Conclusions The effect of RV myocardial remodeling on preoperative RV function was more pronounced in the older patients with TOF than in the younger ones. Preoperative myocardial remodeling affected the postoperative RV function in the older but not in the younger patients. The age at the time of surgical repair was the independent determinant of the postoperative RV myocardial function.

Background: Henoch-Schönlein purpura (HSP) is a form of systemic vasculitis that can progress to Henoch-Schönlein purpura nephritis (HSPN), and the most effective treatment remains controversial. Our aim was to compare the effects of oral mycophenolate mofetil (MMF) with low-dose prednisone and the full-dose corticosteroids (CS; prednisone) for the induction therapy of HSPN with large proteinuria. Methods: Fifty-three patients with biopsy-proved HSPN with large proteinuria (>2.0 g/24 h) were divided into two groups: the MMF group (n = 27) who received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) combined with low-dose prednisone (0.4–0.5 mg/kg/day), and the CS group (n = 26) who received the full-dose prednisone (0.8–1.0 mg/kg/day). We compared the effects of inducing remission at 6-month follow-up and the overall remission rate at the end of the follow-up between the two groups. Results: At 6 months, the estimated glomerular filtration rate level remained stable, while the urine protein decreased significantly in both groups, and the remission rate was 76.9% in the CS group and 55.5% in the MMF group (p = 0.101). With a median follow-up of 28.8 months in the CS group and 28.2 months in the MMF group, the overall remission rate was 80.8% in the CS group and 77.8% in the MMF group (p = 0.788). The MMF group had less side effects than the CS group (48.1 vs. 76.9%, p = 0.031). The relapse was 4/21 (19.0%) in the CS group and 0/21 in the MMF group (p = 0.115). Conclusion: MMF is useful for inducing remission and maintaining remission in Chinese HSPN, and may be used as a steroid-sparing agent in the treatment of HSPN.

Objectives Patent foramen ovale (PFO) is a failure fusion of the primum and secundum atrial septa after birth and with a prevalence of 27% in the healthy population. It has been associated with cryptogenic stroke most common in patients younger than 55. Transesophageal echocardiography (TEE) has been considered as gold standard to diagnosis patent foramen ovale (PFO). But it is time-consuming and semi-invasive. The transthoracal echocardiography (TTE) is an optional method which is frequently used to screen this disease for it is a non-invasive and easier. But current evidence for its diagnostic accuracy for PFO is still unclear. We aimed to systematic review the diagnostic accuracy of TTE compared to TEE. Methods Comprehensive searching in PubMed, Embase, and Cochrane library was conducted up to the end of October 2011. Two reviewers independently reviewed and extracted the data from each study. Study quality was assessed with the quality assessment for diagnostic accuracy studies (QUADAS). A random effect model was used to summary sensitivity and specificity. Summary receiver operating characteristic (SROC) curves were used to summarise overall test performance. Publication bias was assessed by Egger9s test as well as the funnel plot. Results 15 studies including 1949 subjects were included in the meta-analysis. The quality of reported studies was modest. The summary sensitivity and specificity for TTE for diagnosing PFO was 88% (95% CI 77% to 94%) and 98% (95% CI 93% to 99%), respectively. The positive likelihood ratio is 45.3 (95% CI 12 to 166) and negative likelihood ratio is 0.12 (95% CI 0.07 to 0.24). The summary diagnostic OR was 362 (95% CI 93 to 1329). Although the Egger9s test and funnel plot showed a significant publication bias among studies, but pooled sensitivity and specificity only have a little change after removing the most heterogeneous study. Conclusions The meta-analysis suggested that TTE is a test with high sensitivity and specificity for detecting PFO. It may be a useful and non-invasive modality for initial screening of significant PFO before the further investigation.

Arterial stiffness is related to the increased risk of cardiovascular events. Pulse wave velocity (PWV) is the speed of propagation of arterial pressure waves, which is linked to arterial stiffness and is becoming an essential prognostic indicator for cardiovascular disease. Supersonic Shear Imaging