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Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.

Nephrotic syndrome (NS) is one of the most common causes of chronic kidney disease in the pediatric population. Hyperlipidemia is one of the main features of NS. The present study investigated the role of CXC motif chemokine ligand 16 (CXCL16) and ADAM metallopeptidase domain 10 (ADAM10) in oxidized low‑density lipoprotein (oxLDL)‑stimualted podocytes and the underlying mechanisms. CXCL16 and ADAM10 expression levels in oxLDL‑treated podocytes were measured via reverse transcription‑quantitative PCR and western blotting. Cell migration assays were conducted to assess the migration of oxLDL‑treated podocytes. CXCL16 or ADAM10 overexpression and knockdown assays were conducted. The results indicated that oxLDL stimulation increased ADAM10 and CXCL16 expression levels, and enhanced podocyte migration compared with the control group. Moreover, CXCL16 and ADAM10 overexpression significantly increased podocyte migration and the expression of actinin‑α4 (ACTN4) compared with the control groups. By contrast, CXCL16 and ADAM10 knockdown significantly reduced podocyte migration and the expression of ACTN4 compared with the control groups. The results suggested that oxLDL promoted podocyte migration by regulating CXCL16 and ADAM10 expression, as well as by modulating the actin cytoskeleton. Therefore, CXCL16 and ADAM10 may serve as novel therapeutic targets for primary nephrotic syndrome in children.

Parthenolide (PTL) is a natural product from the shoots of Tanacetum parthenium, which has immunomodulatory effects in multiply type of diseases. This study aimed to explore the effect and the underlying mechanism of PTL on the anti-apoptotic and anti- inflammatory ability of tweak-induced podocytes. Conditionally immortalized mouse podocytes were incubated with Tumor necrosis factor-like weak inducer of apoptosis (Tweak, 100 ng/ml), PTL(10 µM) or Tweak + PTL for 12 h, 24 and 48 h, respectively. Podocytes viability was detected by CCK-8 assay. Tweak and Cxcl16 expression were evaluated by western blot and immunofluorescence assay. Dil-oxLDL stain was detected by immunofluorescence analysis. Intracellular Total Cholesterol (TC) content was measured through TC detection Kit. These results demonstrated that the podocytes cells viability was gradually decreased after treatment with different concentrations of Tweak (0, 50, 100, 150). Tweak and Cxcl16 protein expression in mouse podocytes treated with tweak were remarkably elevated and were found to have higher intracellular lipid accumulation compared with the control group, whereas co-administration with PTL, tweak and Cxcl16 expression as well as the intracellular lipid accumulation were notablely decreased in tweak-induced podocytes. Therefore, our conclusion was that tweak and Cxcl16 were involved in the regulation of tweak-induced podocytes injury. Meanwhile, the anti-apoptotic and anti-inflammatory effect of PTL may be correlated with the tweak and Cxcl16 expression decreased.

In mainland China, dialysis for children with end-stage renal disease (ESRD) was not introduced until the 1980s. To describe the development of pediatric dialysis in different regions of China, a national pediatric dialysis network, namely, International Pediatric Dialysis Network-China (IPDN-China) ( www.pedpd.org.cn ), was launched in 2012. Original and updated information from the renal centers registered with the IPDN-China was collected between 2012 and 2016 from two sources, namely, the registry and the survey, and demographic features were analyzed. Due to promotion by the IPDN-China, the number of registered renal centers increased from 12 to 39 between 2012 and 2016, with a significant increase in the coverage of the Chinese administrative divisions (from 26.5 to 67.6%) (p < 0.01); and the coverage of the pediatric (0~14 years old) population increased to nearly 90% in 2016. The distribution of renal centers indicated that East China had the highest average number of registered centers per million population (pmp) 0~14-year-old age group. Seventeen relatively large dialysis centers were distributed across 14 divisions. Various modalities of renal replacement therapy (RRT) were available in most centers. The IPDN-China has promoted collaborations between dieticians, psychologists, and social workers on dialysis teams to provide better service to children with ESRD and their families. The proportion of centers with all three types of paramedic support (i.e., dieticians, psychologists, and social workers) as well as the proportion of centers with a partial paramedic team significantly increased between 2012 (25.0%) and 2016 (69.2%) (p < 0.05). In terms of the point prevalent cases of patients (aged < 18 years), data from the survey of 39 registered centers revealed that the number of children with ESRD who were on RRT was 578 (49% received a kidney transplant) at the end of 2016, which was more than that reported in previous surveys. Data from the registry showed that 349 dialysis patients had been enrolled as of the end of 2016. The median age at RRT start was 9.5 years, and the leading cause of ESRD was congenital abnormalities of the kidney and urinary tract (CAKUT). The IPDN-China has helped to promote the development of pediatric dialysis for ESRD in China by improving the organization of care for dialysis patients and increasing the availability and the quality of RRT for patients who need it. To improve knowledge about the epidemiology and outcomes of pediatric RRT around the country, a sustained effort needs to be made by the IPDN-China to increase the enrollment of dialysis patients and increase the number of registered centers in the future.

Background Synovitis is characterized by the infiltration of inflammatory cells and often accompanies the pathological progression of the clinical symptoms affecting the temporomandibular joint (TMJ), such as pain, snapping, and limited mouth opening. It has been suggested that the signal transduction pathway and resultant proinflammatory mediators play important roles in the pathogenesis of synovitis. Therefore, in this present research, we aimed to investigate the changes in the expressions of stromal cell‐derived factor 1 (SDF‐1) and interleukin (IL)‐1β in rats with occlusal interference. Materials and Methods We divided 36 male Wistar rats into the following groups: Group A (control group), Group B (occlusal interference group), and Group C (AMD3100 group). Synovial inflammation was induced in the rats in Groups B and C to establish the occlusal interference model. The inflammatory changes were detected, and the expressions of SDF‐1 and IL‐1β in the synovium were assayed via immunostaining and a real‐time quantitative polymerase chain reaction (PCR). Results In Group B, obvious inflammatory changes were observed in the synovial membranes; additionally, the SDF‐1 and IL‐1β expression levels were significantly higher at the protein and mRNA levels. However, in Group C, these experimental results were inhibited by an injection with AMD3100. Conclusion These results may indicate that SDF‐1 regulates the expression level of inflammatory factors, such as IL‐1β, in the synovial membranes of rats with occlusal interference. Our findings suggest that the SDF‐1 axis may contribute to the onset of synovitis during the development of TMJ joint disease.

Behavioral barriers to gene flow often evolve faster than intrinsic incompatibilities and can eliminate the opportunity for hybridization between interfertile species. While acoustic signal divergence is a common driver of premating isolation in birds and insects, its contribution to speciation in mammals is less studied. Here we characterize the incidence of, and potential barriers to, hybridization among three closely related species of grasshopper mice (genus Onychomys). All three species use long‐distance acoustic signals to attract and localize mates; Onychomys arenicola and Onychomys torridus are acoustically similar and morphologically cryptic whereas Onychomys leucogaster is larger and acoustically distinct. We used genotyping‐by‐sequencing (GBS) to test for evidence of introgression in 227 mice from allopatric and sympatric localities in the western United States and northern Mexico. We conducted laboratory mating trials for all species pairs to assess reproductive compatibility, and recorded vocalizations from O. arenicola and O. torridus in sympatry and allopatry to test for evidence of acoustic character displacement. Hybridization was rare in nature and, contrary to prior evidence for O. torridus/O. arenicola hybrids, only involved O. leucogaster and O. arenicola. In contrast, laboratory crosses between O. torridus and O. arenicola produced litters whereas O. leucogaster and O. arenicola crosses did not. Call fundamental frequency in O. torridus and O. arenicola was indistinguishable in allopatry but significantly differentiated in sympatry, a pattern consistent with reproductive character displacement. These results suggest that assortative mating based on a long‐distance signal is an important isolating mechanism between O. torridus and O. arenicola and highlight the importance of behavioral barriers in determining the permeability of species boundaries., Divergence in behavioral traits is fundamental to the evolution of reproductive isolation and maintenance of species barriers. We characterized the incidence of, and potential barriers to, hybridization among three closely related species of grasshopper mice (genus Onychomys). We found little evidence for hybridization and a signature of reproductive character displacement in the mate attractions calls of the species pair with highest ecological and morphological overlap, highlighting the importance of behavioral barriers in determining the permeability of species boundaries.

Renal cell carcinoma (RCC) accounts for 2-3% of adult malignant tumors, and the incidence of RCC worldwide has increased by about 2% over the past two decades. The homeobox protein Six2 has been shown to promote the stemness of breast cancer cells and play a role in kidney development, but its involvement in RCC progression has not previously been investigated. Here, we found that six2 expression was significantly increased in RCC tissues and negatively correlated with the overall survival of patients with RCC. In addition, six2 expression exhibited a remarkably higher level relative to that in normal renal cells. Functional experiments showed that six2 knockdown attenuated the stemness of RCC cells, which was evident by decreased spheroid formation ability and stemness marker (sox2 and nanog) expression. Mechanistic studies indicated that Six2 directly bound to the enhancer of sox2, promoting sox2 expression and downstream effector expression of nanog. Furthermore, overexpression of sox2 rescued the inhibitory effects of six2 on the stemness of RCC cells. Notably, six2 expression is positively correlated with sox2 and nanog expression in RCC tissues. Collectively, our results point toward a six2/sox2 axis responsible for RCC cell stemness.

Evidence to date suggests that β-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of β-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5 U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h. In β-arrestin 2 KO mouse hearts, deletion of β-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10−9–10−6 M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-κB signaling and ERK1/2 phosphorylation, whereas knockdown of β-arrestin 2 blocked AVP-induced IL-6 increase, NF-κB activation and ERK1/2 phosphorylation. Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-κB activation and IL-6 production. The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-κB phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2 mg/kg, iv) abolished AVP-induced NF-κB activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V1A receptor-mediated β-arrestin2/ERK1/2/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/β-arrestin 2/ERK1/2/NF-κB signaling pathway.

The purpose of our research is to elucidate whether oxLDL activates P2X7R in cultured human podocytes and if the activation of P2X7R leads to podocyte apoptosis. Additionally, we explore the underlying mechanism involved in podocyte apoptosis. Immortalized human podocytes were incubated with oxLDL (80 µg/ml), P2X7R antagonist A438079 (10 µM), or the compound of A438079 and oxLDL for 48 h, respectively. Cellular apoptosis and ROS were evaluated using flow cytometer. P2X7R, Bax, and Caspase-3 protein expression were detected by western blot and immunofluorescence analysis.The expression of P2X7R, ROS, Bax, and Caspase-3 in human podocytes incubated with oxLDL was significantly up-regulated and was found to have higher intracellular lipid accumulation and podocyte apoptosis compared with the NC group. However, co-administration with A438079, ROS, Bax, and Caspase-3 expression both significantly down-regulate as well as lower lipid accumulation and cellular apoptosis in the oxLDL-induced podocyte group. We revealed that P2X7R is involved in the regulation of oxLDL-treated podocytes. Additionally, we found that the anti-apoptotic effect of A438079 is correlated with ROS, Bax, and Caspase-3 expression down-regulated.

Bcl-2-associated athanogene3(BAG3) protects the heart and cardiomyocytes from ischaemia/reperfusion (I/R) injury. Although the anti-apoptosis effect of BAG3 has been demonstrated in multiple cell types, the structural domain of BAG3, which is responsible for its anti-apoptosis effect, is not well understood. BAG3 protein consists of various characteristic amino acid motifs/regions that permit the interaction of BAG3 with numerous proteins involved in many cellular key pathways. The purpose of this study is to determine whether the proline-rich (PXXP) domain of BAG3 is necessary for its cellular protection against hypoxia-reoxygenation (H/R) stress by binding to its chaperone, heat shock cognate 71 kDa protein (HSC70). Cell apoptosis induced by H/R was evaluated using propidium iodide (PI) staining, caspase 3/7 activation and TUNEL staining in cultured H9C2 cells. The expression levels of BAG3 and HSC70 were manipulated, where BAG3 or its mutant, which lacked the PXXP domain, was overexpressed using a plasmid and adenovirus vector, and HSC70 expression was silenced using siRNA. Co-immunoprecipitation (co-IP) followed by western blot was employed to define the complex of BAG3 binding to its chaperones. The PXXP domain of BAG3 was determined to be critical for BAG3-mediated attenuation of H9C2 cell apoptosis induced by H/R through the binding of PXXP with HSC70. The abolished cellular protection of BAG3 induced by the knockdown of HSC70 is associated with reduced binding to HSC70. Given that the structural domain PXXP of BAG3 is necessary for the cellular protection of BAG3 from I/R injury, the mechanism revealed in this study indicates that BAG3 may be a therapeutic target in patients undergoing reperfusion after myocardial infarction.

BACKGROUND Synovitis is an important disease that cause intractable pain in temporomandibular joint (TMJ), and the inflammation process played a crucial role in the initiation and development of temporomandibular joint disorder. A series of investigations suggested that the increasing expression of interleukin-(IL) 1β secreted by synovial lining cells plays an important role in synovial inflammation and cartilage destruction in TMJ. In this present study, we investigated the signaling pathways which regulate the expression of IL-1β. MATERIAL AND METHODS The occlusal interference animal model was created to induce synovial injury. Forty-eight rats were divided into 4 groups: 1) control group, 2) occlusal interference group, 3) TAK-242 (a specific inhibitor targeting the Toll-like receptor (TLR)-4) group, and 4) SB203580 (a specific inhibitor targeting the p38) group. The inflammation changes were observed, and the expression of p38 and IL-1β in the synovial membranes were assayed. RESULTS The results showed that downstream p38 MAPK (mitogen-activated protein kinase) signaling was triggered following the activation of TLR4. Moreover, the injection of SB203580 could inhibit the inflammatory reactions and the increased expression of IL-1β at both mRNA and protein levels. CONCLUSIONS The results prompted us that TLR4 may stimulates synovial inflammatory reactions and increased expression of IL-1β in rats through the activation of p38 MAPK signaling pathway, p38 was an important mediator in the mechanisms of the initiation and development of synovial injury by regulating the expression of IL-1β in synovial membranes.

Mesenchymal stem cells (MSCs) possess reparative and immunoregulatory properties, representing a hope for stem cell‑based treatments. However, the mechanisms by which transplanted MSCs affect T helper (Th)17/regulatory T cell (Treg) balance in asthma patients remain unclear. The aim of the present study was to assess the therapeutic effects of human placenta MSCs (hPMSCs) in asthma, and explore the underlying mechanisms; in addition, the impact of hPMSCs transplantation on Th17/Treg balance in lymph and serum samples from asthmatic animals was evaluated. Sprague‑Dawley rats were sensitized and challenged with ovalbumin (OVA). Administration of hPMSCs from human placenta resulted in increased Th17 and Treg in lymph samples compared with peripheral blood specimens. Enhanced pause values in OVA‑treated animals were significantly higher than those in the control and hPMSCs treatment groups. The numbers of total cells, macrophages, neutrophils, and eosinophils were markedly increased in the OVA group compared with those of control + hPMSCs and control groups. In addition, interleukin 10, forkhead box P3 (Foxp3) and Treg levels in lymph, peripheral blood and lung tissue samples from asthma rats were increased significantly following hPMSC transplantation. Furthermore, Foxp3 protein levels increased, while those of RAR‑related orphan receptor γ (RORγt) decreased after hPMSCs transplantation compared with the asthma group. Reduced IL‑17, RORγt and Th17 levels were accompanied by reduced inflammatory cell infiltration, sub‑epithelial smooth layer attenuation and mucus production in lung tissues. These results suggest that hPMSCs may improve airway hyperresponsiveness and inflammation by regulating the Th17/Treg balance in rats with asthma.

Accumulating studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for several paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). However, the impact of PRRT2 in tumorigenesis is not known. Based on a large-scale data analysis, we found that PRRT2 was down-regulated in glioma tumor tissues compared with normal brain tissue. Dysregulation of PRRT2 was not induced by mutation, copy number variation and epigenetic modification, but modulated by microRNA-30a-5p. Overexpression of PRRT2 strongly impaired the cell viability and promoted cell apoptosis and these anti-tumor effects could be largely reversed by microRNA-30a-5p. Mechanistically, PRRT2 expression was closely correlated genes involved in unfolded protein response (UPR) pathway and introduction of PRRT2 inhibited gene expression in the three branches of UPR, including PERK axis, IRE1 axis and ATF6 axis. Taken together, our findings identify PRRT2 as a tumor suppressor in glioma and provide a promising target for potential therapeutic intervention.

Interleukin 6 (IL-6), which is elevated in patients with congestive heart failure and acts as both a chronic marker of inflammation and an acute-phase reactant, is associated with myocardial damage. Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and could be a factor for cardiac inflammation and fibrosis. Our previous study has shown that AVP promotes the proliferation of neonatal rat cardiac fibroblasts (NRCFs) throughV 1A vasopressin receptor-mediated G protein–coupled receptor kinase 2 (GRK2) signaling. In the present study, we investigated the impact of the GRK2-dependent signaling. Using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, we measured the levels of interleukin-6 (IL-6) mRNA and protein in NRCFs, respectively. Manipulation of GRK2 activation either pharmacologically or through overexpression of GRK2-ct was used to determine the role of GRK2 in regulating the effects of AVP on IL-6 production. Phosphorylation and activation of nuclear factor κ-B (NF- κ B) evoked by AVP stimulation were measured by immunoblot and NF-kB luciferase reporter gene transfected in NRCFs, respectively. Present studies have found that: 1) AVP increased the level of IL-6 protein and mRNA in a dose- and time-dependent manner in NRCFs; 2) inhibition of GRK2 abolished the AVP-induced IL-6 production and NF- κ B activation; and 3) blocking NF- κ B signaling using the pharmacologic approach diminished AVP-induced IL-6 production. In summary, AVP induces IL-6 production of NRCFs by activating V 1A receptor signaling via a GRK2/NF- κ B pathway. These findings provide a possible molecular mechanism for inflammation that occurs in heart failure and other types of cardiac stress.

To investigate the effect of simvastatin on lipid accumulation and the expression of CXCL16 and Nephrin in murine podocytes induced by oxidized LDL (OxLDL) in order to explore the mechanism of protection.Murine podocytes (MPC5) were incubated with OxLDL (80 μg/ml) at different concentrations of simvastatin (0, 1.0, and 2.0 μg/ml) for 48 hours. Oil red O staining was used for the assessment of lipid accumulation in podocytes, and colorimetric cholesterol detection kit was used for the quantitative measurement. CXCL16 and Nephrin expression were detected by using Western blot.OxLDL-treated MPC5 cells exhibited significantly higher intracellular lipid accumulations compared with the untreated group. Colorimetric detection found that total cholesterol was 90.3 ± 30.1 μg/ml in untreated cells and 226.5 ± 21.6 μg/ml in OxLDL-treated cells. The difference was statistically significant (p.01). While cells were treated with both OxLDL and simvastatin, we observed little lipid accumulation. Total cholesterol in OxLDL + simvastatin cells were 151.8 ± 6.8 μg/ml and 135.5 ± 26.9 μg/ml under 1.0 μg/ml or 2.0 μg/ml of simvastatin treatment, respectively. Both were statistically significantly lower than that of the OxLDL treated cells (p.05). Western blot analysis showed that CXCL16 expression was significantly increased (p.05) in OxLDL-treated cells compared with the untreated cells, and was significantly inhibited by application of simvastatin (p.05). The analysis of nephrin expression showed that there were no changes in group simvastatin compared with that of control group (p.05). Nephrin expression was significantly reduced by treatment with OxLDL (p.01), and was significantly increased by application of simvastatin (p.05).Simvastatin treatment could significantly decrease lipid accumulation in murine podocytes and this protective effect was realized through inhibition of the expression of CXCL16 and increase in the expression of nephrin.

Long noncoding RNAs lncRNAs play an essential role in the epigenetic regulation of colorectal cancer CRC. However, the biological function of lncRNA Long Intergenic Noncoding RNA 00511 LINC00511 in the CRC is unclear. Here, present research found that LINC00511 was significantly up-regulated in the CRC tissue samples and cell lines. Consistently, LINC00011 overexpression was correlated with larger tumor size and advanced tumor stage. Functionally, LINC00511 promoted the proliferation and reduced the apoptosis of CRC cells in vitro, and LINC00511 knockdown repressed tumor growth in vivo. Mechanistically, hypoxia-inducible factor 1α (HIF-1α) bound the promoter region of LINC00511 to active tits transcription. Moreover, LINC00511 functioned as the miR-153-5p sponge in the cytoplasmic portion, and miR-153-5p also targeted the 3'-UTR of HIF-1α. In conclusion, this study identifies the roles of LINC00511 in CRC progression and uncovers the positive feedback loop of HIF-1α/LINC00511/miR-153-5p in CRC, providing a potential therapeutic target.

Dent disease is a rare X-linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low-molecular-weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention.

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

P2X3 receptor plays a role in nociception transmission of orofacial pain in temporomandibular disorder patients. A previous study found that P2X3 receptors in masseter muscle afferent neurons and the trigeminal ganglia were involved in masseter muscle pain induced by inflammation caused by chemical agents or eccentric muscle contraction. In this study, we attempted to investigate changes in P2X3 receptors in the trigeminal subnucleus caudalis (Vc) and midbrain periaqueductal gray (PAG) in relation to the hyperalgesia of masseter muscles induced by occlusal interference. Experimental occlusal interference by crown application was established in 30 rats and another 30 rats were treated as sham controls. On days 1, 3, 7, 14, and 28 after crown application, the mechanical pain threshold was examined by von-Frey filaments. The expression of the P2X3 receptor in Vc and PAG was investigated by immunohistochemistry and quantitative PCR. We found that mechanical pain threshold of bilateral masseter muscles decreased significantly after occlusal interference, which remained for the entire experimental period. The mRNA expression of the P2X3 receptor increased significantly and the number of P2X3R-positive neurons increased markedly in Vc and PAG accordingly. These results indicate that the upregulated expression of P2X3 receptors in Vc and PAG may contribute toward the development of orofacial pain induced by occlusal interference and P2X3 receptors in the PAG may play a key role in the supraspinal antiociception effect.

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Anti-complement factor H (CFH) antibodies were thought to participate in the pathogenesis of aHUS. The aim of this study was to address the functions and properties of CFH autoantibodies in a Chinese Han cohort of aHUS patients. Thirty-six anti-CFH antibody-positive aHUS patients at the acute phase of the disease were involved in this study. Clinical data of the patients were collected. Anti-CFH immunoglobulin G (IgG) subclasses and antibody isotypes were detected by ELISA. Epitope mapping was performed using recombinant CFH fragments (SCRs 1–4, SCR 7, SCRs 11–14, and SCRs 19–20). Purified IgG from plasma from seven patients were used for functional analyses. All patients presented with the classic triad of HUS. The anti-CFH autoantibodies mostly bound to the SCRs 19–20 domains of CFH but not the SCRs 1–4 domains. CFI cofactor activity was not disturbed by the anti-CFH antibody in any of the seven patients. Purified IgG interfered with the binding of CFH to C3b and CFH-mediated sheep erythrocyte protection in all seven patients. IgG from 4/5 (80%) patients tested inhibited the binding of CFH to glomerular endothelial cells. Our study suggests that the properties of CFH antibodies from patients with aHUS, including the recognition of SCRs and IgG subclasses, can influence and impair the biological role of CFH and therefore contribute to aHUS susceptibility.

As a hallmark of platelet activation, mean platelet volume (MPV) has been identified to be associated with various malignancies. However, the correlation between MPV, mean platelet volume/platelet count ratio (MPR), and esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study is to clarify the relevance of MPV and MPR in patients with locally advanced ESCC. Four hundred and fifty-seven cases with newly diagnosed locally advanced ESCC followed by radical surgery and 240 healthy subjects matched for age and gender were included in this study. We retrospectively compared various hematological variables between groups and analyzed the correlation between MPV, MPR, and patients' clinicopathologic characteristics. Preoperative MPV and MPR were found to be significantly decreased in locally advanced ESCC when compared to healthy controls, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P

Synovitis is an important disease that causes intractable pain in TMJ. Some investigations suggested that the increasing expression of IL-1βsecreted by synovial lining cells plays an important role in synovial inflammation and cartilage destruction in TMJ. In our previous research, the results demonstrated that TLR4 is involved in the expression of IL-1βin SFs from TMJ with lipopolysaccharide stimulation. However, the inflammatory response that occurred in synovial membrane is not caused by bacterial infection. In the current study, we investigated whether or not TLR4 participates in the inflammatory responses and the expression of IL-1βin synovial membrane of rats induced by occlusal interference. The results showed that obvious inflammation changes were observed in the synovial membranes and the expression of TLR4 and IL-1βwas increased at both mRNA and protein levels in the occlusal interference rats. In addition, the inflammation reactions and the increased expression of IL-1βcould be restrained by treatment with TAK-242, a blocker of TLR4 signaling. The results prompted us that the activation of TLR4 may be involved in the inflammatory reactions and increased expression of IL-1βin patients with synovitis and participate in the mechanisms of the initiation and development of synovial injury by regulating the expression of inflammatory mediators like IL-1βin synovial membranes.

The aim of the present study was to analyze the diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) in renal injury in asphyxiated preterm infants. In total, 48 cases of asphyxiated preterm infants, 45 cases of premature infants and 45 cases of normal newborn infants were included in the study. Using ELISA we evaluated the level of urine NGAL, kidney injury molecule-1 (KIM-1), cystatin C (Cys-C) and serum creatinine (Scr). We also calculated the estimated glomerular filtration rate (eGFR). Our results showed that NGAL, KIM-1 and Cys-C levels in the group of asphyxiant renal injury within 24 and 48 h were markedly higher than the other two groups (P0.05). Scr level in renal injury group within 48 h was markedly elevated while the eGFR level was visibly reduced (P

Anti-complement factor H (CFH) autoantibody-associated hemolytic uremic syndrome (HUS) is a severe sub-type of HUS. We assessed the clinical and renal pathological features, circulating complement levels, and genetic background of Chinese pediatric patients with this sub-type of HUS. Thirty-three consecutive patients with acute kidney injury who tested positive for serum anti-CFH autoantibodies were enrolled in this study. All of the eight patients who underwent renal biopsies presented with changes typical of thrombotic microangiopathy, especially changes in chronic characteristics. Compared to patients in remission and normal control subjects, patients with acute disease had significantly lower plasma CFH levels and significantly higher plasma complement 3a (C3a), C5a, and terminal complement complex (SC5b-9) levels. The CFH–anti-CFH immunoglobin G (IgG) circulating immunocomplex (CFH-CIC) titers were more closely correlated with CFH plasma levels than anti-CFH IgG levels. Of the 22 patients, four (18%) were homozygous for CFHR3–1Δ and ten were heterozygous for CFHR1 or CFHR3 deletions. Most patients responded well to a combination of plasma and immunosuppressive therapies, with a remission rate of 87%. At the end of the follow-up, nine patients reached the combined end-points, including two with end-stage renal disease and seven with relapses. Plasma C3a, C5a, and SC5b-9 levels predicted disease activity in anti-CFH autoantibody-associated HUS patients enrolled in this study. These patients responded well to plasma therapy combined with immunosuppression.

High-throughput sequencing technology has revolutionized both medical and biological research by generating exceedingly large numbers of genetic variants. The resulting datasets share a number of common characteristics that might lead to poor generalization capacity. Concerns include noise accumulated due to the large number of predictors, sparse information regarding thep≫nproblem, and overfitting and model mis-identification resulting from spurious collinearity. Additionally, complex correlation patterns are present among variables. As a consequence, reliable variable selection techniques play a pivotal role in predictive analysis, generalization capability, and robustness in clustering, as well as interpretability of the derived models.K-dominating set, a parameterized graph-theoretic generalization model, was used to model SNP (single nucleotide polymorphism) data as a similarity network and searched for representative SNP variables. In particular, each SNP was represented as a vertex in the graph, (dis)similarity measures such as correlation coefficients or pairwise linkage disequilibrium were estimated to describe the relationship between each pair of SNPs; a pair of vertices are adjacent, i.e. joined by an edge, if the pairwise similarity measure exceeds a user-specified threshold. A minimumK-dominating set in the SNP graph was then made as the smallest subset such that every SNP that is excluded from the subset has at leastkneighbors in the selected ones. The strength ofk-dominating set selection in identifying independent variables, and in culling representative variables that are highly correlated with others, was demonstrated by a simulated dataset. The advantages ofk-dominating set variable selection were also illustrated in two applications: pedigree reconstruction using SNP profiles of 1,372 Douglas-fir trees, and species delineation for 226 grasshopper mouse samples. A C++ source code that implements SNP-SELECT and uses Gurobi™ optimization solver for thek-dominating set variable selection is available (https://github.com/transgenomicsosu/SNP-SELECT).

To the Editor: A 13-y-old boy was admitted to our hospital because of gross hematuria for 4 h and recurring abnormal urine for 4 y. He was diagnosed as HenochSchonlein purpura (HSP) 4 y back. Gross hematuria occurred after renal biopsy and with active treatment for 3 d, hematuria alleviated. However, gross hematuria re-emerged after vigorous skipping. The blood RT showed Hb decreasing rapidly from 120 g/L to 74 g/L. Renal color doppler ultrasound and contrast-enhanced CT suggested a renal artery pseudoaneurysm (Fig. 1a). Conservative treatment did not work well and we decided to perform renal artery angiography and embolization. A contrast extravasation was found to the descending branch of right renal artery, thus confirmed the diagnosis of pseudoaneurysm rupture (Fig. 1b). We inserted SP micro catheter to the lower pole of the right kidney lesions for infusion of 3–5 0.2×0.2 mm gelatin sponge particles and 2 mm metal coils (Fig. 1c). The interventional treatment turned out to be a success. On follow-up of 6 mo we saw no recurrence of hematuria. The success rate of ultrasound-guided renal biopsy is relatively high and the occurrence rate of severe complications is extremely low. Literature retrieval of post-biopsy renal artery pseudoaneurysm in children shows 3 on the PubMed database [1, 2]. The formation of pseudoaneurysm may be related to factors such as poor compliance of children, application of anticoagulant, inappropriate puncture site, and vascular malformation [3]. There may be no obvious symptom for small pseudoaneurysm in early stage, but without timely treatment, the pseudoaneurysm gradually increases to endanger life. Pseudoaneurysm can be confirmed by imaging examination, including color Doppler ultrasound, CT, MRI, DSA, etc. [4]. Arteriovenous fistula is the most required entity to be differentiated from pseudoaneurysm. Their clinical features are similar, but can be distinguished by color Doppler ultrasonoscopy and DSA. The color Doppler ul t rasonoscopy of pseudoaneurysm shows red-blue face to face rotatory bloodstream (Bto-and-fro^) and diagnostic arteriography can clearly show the shape, size and location [5]. Although development of a pseudoaneurysm is a rare event, we highlight the importance of early recognition and that superselective renal artery embolization is considered to be secure and reliable.