Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and Macrophage Repolarization-Enhanced Immune Response.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

[Genetic analysis of a child with atypical Hemolytic uremic syndrome and nephrotic-range proteinuria].

OBJECTIVE: To explore the clinical characteristics and genetic etiology for a child with atypical Hemolytic uremic syndrome (aHUS) in conjunct with nephrotic level proteinuria. METHODS: A child patient who had visited the Affiliated Hospital of Qingdao University on June 25, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing of the child and his parents. RESULTS: The child, an 8-month-old male, had presented mainly with edema, oliguria, hematuria, nephrotic level proteinuria, anemia, thrombocytopenia, increased creatinine and urea, hypercholesterolemia but normal complement levels. Genetic testing revealed that he has harbored compound heterozygous variants of the DGKE gene, namely c.12_18dupGAGGCGG (p.P7fs*37) and c.1042G>T (p.D348Y), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were classified as likely pathogenic and variant of uncertain significance, respectively. By combining his clinical manifestations and results of genetic testing, the child was diagnosed with aHUS with nephrotic level proteinuria. CONCLUSION: For infants and young children with aHUS in conjunct with nephrotic level proteinuria, variants of the DGKE gene should be screened. Above finding has expanded the mutational spectrum of the DGKE gene.

Clinical implications of aberrant PD-1 expression for acute leukemia prognosis.

BACKGROUND: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. METHODS: In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. RESULTS: Our results indicated that percentages of CD4+ PD1+ and CD8+ PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+ PD1+ and CD8+ PD1+ T lymphocytes were respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. CONCLUSIONS: Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+ PD1+ and CD8+ PD1+ T lymphocytes positively expressed, respectively.

Delayed diagnosis of pediatric intra-articular epithelioid sarcoma: a case report and literature review.

BACKGROUND: Epithelioid sarcoma (ES) is a rare form of mesenchymal malignancy that rarely occurs in children. Only seven cases of intra-articular epithelioid sarcoma have been reported in the medical literature. CASE PRESENTATION: In this report, we presented the case of a 13-year-old girl with a delayed diagnosis of ES in the left knee. Her initial diagnosis was mistaken for Pigmented Villonodular Synovitis (PVNS) but ruled out later by the first biopsy. However, the lesion rapidly regrew again after arthroscopy, raising suspicions of malignancy. A comprehensive histochemistry examination was conducted again, leading to the diagnosis of INI-1 negative epithelioid sarcoma. Unfortunately, the girl passed away seven months later due to early metastasis of the tumor. CONCLUSION: Careful consideration should be given to the differential diagnosis of pediatric patients presenting with monoarthritis. This report highlights the importance of early and accurate diagnosis and underscores the necessity for effective treatments for epithelioid sarcoma. Surgical resection or radical surgery is recommended, while novel treatment strategies targeting EZH2 show promise.

[Accumulation Pathway of Cd, Pb, and Zn in Chinese Cabbage under the Condition of Exogenous Pollution Superposition in High Geological Background Area].

Northwest Guizhou is a karst area with a high geological background. Affected by historical soil zinc smelting, the heavy metal content of atmospheric dust in the region is high, and soil pollution is severe. In order to explore the accumulation pathway of heavy metals in leafy vegetables, Chinese cabbage was used as the test crop, and the geological high background soil and zinc smelting-contaminated soil with the same contents of Cd, Pb, and Zn were selected. A pot experiment was carried out in the polluted area of zinc smelting and the non-polluting control area. The heavy metal content, enrichment coefficient (BCF), and transport coefficient (TF) of Chinese cabbage were studied under open-air, plastic mulching film, and greenhouse cultivation conditions. The results showed that the contents of Cd, Pb, and Zn in Chinese cabbage in the polluted area and the control area were 0.10-1.01 and 0.10-0.91 mg·kg-1, 0.31-0.62 and 0.23-0.37 mg·kg-1, and 7.50-32.74 and 4.88-21.79 mg·kg-1, respectively. Overall, the contents of heavy metals in the polluted area were relatively high. The contents of Cd and Pb in Chinese cabbage planted in soil with a high geological background met the requirements of the national food safety standard limits. Affected by atmospheric deposition, the contents of Pb and Zn in Chinese cabbage in the polluted area were significantly higher than that in the control area, and the difference in Cd was insignificant. The proportions of weak acid-soluble Cd, Pb, and Zn in the contaminated soil were 48%, 3.0%, and 16%, respectively, which were 3.15, 1.01, and 1.57 times higher than those in the control soil with a high geological background. Affected by the activity of heavy metals, the contents of Cd and Zn in Chinese cabbage planted in the contaminated soil exceeded the national standard and were significantly higher than those in the control soil. The root-soil BCF of Cd, Pb, and Zn in polluted soil was significantly higher than that in the control soil, and the BCF of Cd and Zn was higher than that of Pb. The TF aboveground root Cd and Zn in Chinese cabbage was significantly higher than in the control soil, whereas the TF aboveground root Pb in the polluted area was significantly higher than that in the control area. The Pb content of Chinese cabbage in the two study areas showed open field>plastic mulching film>greenhouse cultivation. In conclusion, the content of Cd and Zn in Chinese cabbage was greatly affected by the activity of heavy metals in soil, and the main accumulation pathway was root absorption and transportation. In addition to root absorption, atmospheric deposition was an important accumulation pathway of Pb. Therefore, in areas with high geological backgrounds, attention should be paid to controlling the exposure risk of Cd and Zn in leafy vegetables planted on exogenously polluted soils. Additionally, greenhouse cultivation could effectively reduce the accumulation of Pb.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Identification of a variant in NLRP3 gene in a patient with Muckle-Wells syndrome: a case report and review of literature.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS), a rare genetic autoimmune disease, is composed of familial cold autoinflammatory syndrome (FCAs), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). MWS is caused by dominantly inherited or de novo gain-of-function mutations in the NOD-like receptor 3 (NLRP3) gene. At present, there is no report about the variation of R262W in China. CASE PRESENTATION: We reported a 3-year-old Chinese boy who had recurrent fever without obvious inducement, bilateral conjunctival congestion, and urticarial-like rash. Laboratory examination showed elevation in leukocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and serum amyloid protein (SAA) levels. Whole exome sequencing identified a missense variation c.784-786delinsTGG (p.R262W) in the coding region of the NLRP3 gene. CONCLUSION: A classical variant of the NLRP3 gene in a patient with MWS was first reported in China.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Mesoporous polydopamine-based nanoplatform for enhanced tumor chemodynamic therapy through the reducibility weakening strategy.

Polydopamine (PDA)-based Fenton agents attract increasing attention in tumor photothermal-enhanced chemodynamic therapy (CDT) due to their good biocompatibility and excellent loading capacity. However, PDA tends to eliminate the Fenton reaction-generated hydroxyl radical (∙OH) by its strong reducibility, which is an intractable hinder to the efficacy of CDT that need to be solved. Herein, a kind of mesoporous PDA-gold-manganese dioxide (MPDA-Au-MnO2, MPAM) nanoplatform was constructed for photothermal-enhanced CDT against tumor through the reducibility weakening strategy. The reducibility of original MPDA is effectively weakened by the oxidation role of HAuCl4 and KMnO4 during the preparation process, reducing the ∙OH scavenging ability of MPDA and benefiting the production of ∙OH. The MnO2 shell could react with GSH to release Mn2+, acting as the Fenton-like agent to generate ∙OH. The exposed Au NPs can further deplete GSH through the Au-S bond interaction. MPDA acts as the photothermal agent to generate hyperthermia under laser irradiation. MPAM shows excellent intracellular GSH scavenging ability and enhanced ∙OH production ability. After intravenous injection, MPAM can significantly suppress the growth of tumors under laser irradiation, meanwhile showing good biosafety. The developed MPDA-based nanoplatform can not only display good potential in further tumor treatments but also provide meaningful enlightenment for developing high-performance PDA or MPDA-based nanoplatforms in CDT-related applications.

Elucidating the role of circNFIB in myocardial fibrosis alleviation by endogenous sulfur dioxide.

BACKGROUND: To investigate the role of circNFIB in the alleviation of myocardial fibrosis by endogenous sulfur dioxide (SO2). METHODS: We stimulated cultured neonatal rat cardiac fibroblasts with transforming growth factor-ß1 (TGF-ß1) and developed an in vitro myocardial fibrosis model. Lentivirus vectors containing aspartate aminotransferase 1 (AAT1) cDNA were used to overexpress AAT1, and siRNA was used to silence circNFIB. The SO2, collagen, circNFIB, Wnt/ß-catenin, and p38 MAPK pathways were examined in each group. RESULTS: In the in vitro TGF-ß1-induced myocardial fibrosis model, endogenous SO2/AAT1 expression was significantly decreased, and collagen levels in the cell supernatant and type I and III collagen expression, as well as α-SMA expression, were all significantly increased. TGF-ß1 also significantly reduced circNFIB expression. AAT1 overexpression significantly reduced myocardial fibrosis while significantly increasing circNFIB expression. Endogenous SO2 alleviated myocardial fibrosis after circNFIB expression was blocked. We discovered that circNFIB plays an important role in the alleviation of myocardial fibrosis by endogenous SO2 by inhibiting the Wnt/ß-catenin and p38 MAPK pathways. CONCLUSION: Endogenous SO2 promotes circNFIB expression, which inhibits the Wnt/ß-catenin and p38 MAPK signaling pathways, consequently alleviating myocardial fibrosis.

Contamination Evaluation and Source Analysis of Heavy Metals in Karst Soil Using UNMIX Model and Pb-Cd Isotopes.

Karst terrain is the typical area covered with a high background of heavy metals under geochemical anomaly. This research explored the accumulation of geochemical elements and soil sources in karst terrain from rock and soil exposed in carbonate areas. The comprehensive ecological risk and enrichment of heavy metals from parent rock weathered to soil was investigated in 11 formations in the carbonate and clastic areas of the Weining and Hezhang counties in northwest Guizhou. The single factor pollution index, geoaccumulation index, and the potential risk coefficient were used to assess the environmental risk. The results revealed that the heavy metals in an overall geologically high background level of soil in northwest Guizhou is at a slight risk level. However, except for Cd, the heavy metals did not exceed the standard pollution reference. Moreover, the UNMIX model and Cd and Pb isotopes were used to analyze the source of heavy metals, comprising of cadmium (Cd), arsenic (As), lead (Pb), chromium (Cr), copper (Cu), nickel (Ni), and zinc (Zn), and the geochemical elements of silicon (Si), aluminum (Al), iron (Fe), magnesium (Mg), and calcium (Ca). The study showed that most elements in the soil carbonate area exceed the national standard, and the heavy metals in the soil showed a strong enrichment, while the major elements Si and Mg display strong loss. Heavy metal concentrations in soil in the carbonate area were higher than in the clastic area. Geological sources and atmospheric deposition were the main contributors to heavy metal concentrations in both carbonate and clastic areas, and their concentrations differ according to soils developing in different formations.

Source Identification and Superposition Effect of Heavy Metals (HMs) in Agricultural Soils at a High Geological Background Area of Karst: A Case Study in a Typical Watershed.

Exogenous sources and the superposition effect of HMs in agricultural soils made the idenfication of sources complicated in a karst area. Here, a typical watershed, a research unit of the karst area, was chosen as the study area. The smaller-scale study of watersheds allowed us to obtain more precise results and to guide local pollution control. In this study, sources of HMs in agricultural soil were traced by a CMB model. Superposition effects were studied by spatial analysis of HMs and enrichment factor (EF) and chemical fraction analysis. The average concentrations of Cd, Pb, Cr, Cu, Ni and Zn in surface soils were 8.71, 333, 154, 51.7, 61.5 and 676 mg∙kg-1, respectively, which exceeded their corresponding background values. The main sources of Cd, Pb and Zn in agricultural soil were rock weathering, atmospheric deposition and livestock manure, and their contributions were 47.7%, 31.0% and 21.2% for Cd; 7.63%, 78.7% and 13.4% for Pb; and 17.0%, 52.3% and 28.1% for Zn. Cr mainly derived from atmospheric deposition (73.8%) and rock weathering (20.0%). Cu and Ni mainly came from livestock manure (81.3%) and weathering (87.5%), respectively, whereas contributions of pesticides and fertilizers were relatively limited (no more than 1.04%). Cd, Pb, Zn and Cu were easily enriched in surface soils near the surrounding pollution sources, whereas Cr and Ni were easily enriched in the high-terrain area, where there was less of an impact of anthropogenic activities. The superposition of exogenous sources caused accumulation of Cd, Pb and Zn in topsoil, contaminated the subsoil through leaching and improved bioavailability of Cd and Pb, causing high ecological risk for agricultural production. Therefore, Cd and Pb should be paid more attention in future pollution control.

Serum levels of degraded monosaccharides in children with Henoch-Schönlein purpura. / è¿‡æ•æ€§ç´«ç™œæ‚£å„¿è¡€æ¸ é™è§£å•ç³–æ°´å¹³çš„å˜åŒ–åŠæ„ä¹‰.

OBJECTIVES: To examine the serum levels of degraded monosaccharides in children with Henoch-Schönlein purpura (HSP) and to study the clinical significance of degraded monosaccharides in HSP. METHODS: A prospective analysis was performed on 132 children who were diagnosed with HSP from September 2019 to January 2022, and 132 healthy children were enrolled as the control group. High-performance liquid chromatography was used to determine the content of degraded monosaccharides in serum in both groups. The receiver operating characteristic (ROC) curve was used to evaluate the efficiency of degraded monosaccharides for the diagnosis of HSP. RESULTS: Compared with the control group, the HSP group had significantly higher serum levels of mannose, glucosamine, aminogalactose, and galactose (P<0.001). The four degraded monosaccharides had an area under the ROC curve of 0.919, 0.913, 0.832, and 0.932 respectively for the diagnosis of HSP (P<0.05). CONCLUSIONS: Children with HSP have higher serum levels of mannose, glucosamine, aminogalactose, and galactose than the healthy population. The levels of degraded monosaccharides may have an important value for the diagnosis of HSP.

Efficacy and safety of belimumab for the treatment of refractory childhood-onset systemic lupus erythematosus: A single-center, real-world, retrospective study.

Objective: This study aimed to investigate the efficacy and safety of belimumab for treating children with refractory childhood-onset systemic lupus erythematosus (cSLE). Methods: Twenty-six cSLE patients who received belimumab treatment in our hospital from January 2020 to September 2021 (23 of them for more than 52 weeks) were enrolled in this study. Their clinical and laboratory data, assessment of disease activity, glucocorticoid dosage, and treatment-emergent adverse events (TEAEs) were retrieved for analysis. The paired samples t-test and the nonparametric test were used to compare the baseline and post-treatment data. Results: The mean age of onset was 10.3 ± 2.4 years old; the mean disease duration was 41.6 ± 37.4 months; the median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 10 (P 25, P 75: 3, 17); and the mean Physician's Global Assessment (PGA) score at baseline was 1.9 ± 1.0. Compared with the baseline values, there was a significant decrease in the 24-h urine protein quantifications at 24 and 52 weeks of treatment (P<0.05) as well as an elevated complement (C) 3 and C4 levels at 4, 12, 24, and 52 weeks of treatment. In addition, the SLEDAI-2K and PGA scores as well as the percentage of CD19+ B cells were significantly decreased at 12, 24, and 52 weeks of treatment compared with the baseline values (P<0.05). The dosage of glucocorticoid at 4, 12, 24, and 52 weeks of treatment was significantly less than that at baseline or the previous follow-up (P<0.05). At 52 weeks, 14 subjects (53.8%) achieved Lupus Low Disease Activity State (LLDAS), and 4 subjects (15.4%) reached clinical remission (CR). At the last follow-up, 16 subjects (61.5%) achieved LLDAS, and 10 subjects (38.5%) reached CR. Conclusions: Belimumab treatment can significantly improve laboratory indicators, reduce disease activity, and decrease the dosage of glucocorticoid required in children with cSLE. Moreover, it has a good safety profile.

TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.

Clinical Features and Familial Mutations in an Autosomal-Inherited Alport Syndrome Patient With the Presentation of Nephrotic Syndrome.

Background: The aim of this study was to report the clinical features and mutations in a patient with autosomal-inherited Alport syndrome (AS). Methods: We examined the clinical data, mutation analysis results, and family tree of a patient with autosomal-inherited AS, who had nephrotic syndrome as her first manifestation. Results: The proband was a girl of 11 months who presented with nephritic and nephrotic syndromes including gross hematuria but had a normal renal function. Her treatment course was complicated by steroid resistance and a poor response to cyclosporine A and cyclophosphamide pulse therapy. Renal biopsy was performed 2 years after disease onset; light microscopy showed glomerular segmental mesangio-proliferative lesions, and type IV collagen staining showed the loss of the α3 chain in the glomerular and tubular basement membrane (GBM and TBM) and α5 chain loss in the GBM. Electron microscopy showed uneven GBM thickness, with the dense basement membrane (BM) layer obviously delaminated and torn, showing a typical "lace-like" change. The segmental BM was loosened and widened. Her father did not develop microscopic hematuria until 10 years later, while her grandmother had asymptomatic hematuria and proteinuria when the proband was diagnosed. We detected a new COL4A4 mutation in the proband, namely c.1715delG (p.G572Vfs * 81) in exon 24. Her father and grandmother carried the same mutation, but her mother and sister did not. Conclusions: We found a new potentially pathogenic mutation of COL4A4 in a patient with autosomal-inherited AS, which presented as nephrotic syndrome in infancy.

Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study.

Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched. Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively. Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The "recurrent variants" included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection. Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.

An electro-Fenton process to treat waste liquor of a hyperaccumulator that contains potentially toxic elements and the COD.

Rapid and safe treatment of harvested fresh biomass of hyperaccumulators is essential for phytoremediation of metal-contaminated soils. Here, an electro-Fenton (EF) process was used to remove cadmium (Cd) and chemical oxidation demand (COD) from waste liquor from the dewatering of biomass of the hyperaccumulator Sedum plumbizincicola after flocculation precipitation. The results showed that the order of impact of the factors on the removal rate of COD and Cd was pH > electrical current density > H2O2 dosage. Increasing pH promoted Cd removal but hindered COD removal. As current density and H2O2 dosage increased the removal rates of both Cd and COD initially increased and then decreased. Compared to an electrocoagulation process, the addition of H2O2 in EF process greatly enhanced Cd and zinc (Zn) removal. Speciation analysis showed that most of the Cd and Zn in the initial liquor were organically and inorganically complexed. At optimal conditions, e.g., pH 5, current density 15 mA cm-2 and H2O2 dosage 9 g L-1, the removal efficiencies of Cd, Zn and COD reached 99.4, 99.9 and 55.5% after 80 min of EF treatment. Electro-Fenton process can therefore be used to quickly remove trace metals from the waste liquor of the hyperaccumulator.

IPDN-China promotes the development of pediatric dialysis in China.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

[Role of hypomethylation of suppressor of cytokine signaling in T helper 17 cell/regulatory T cell imbalance in children with Henoch-Schönlein purpura].

OBJECTIVE: To investigate the association between suppressor of cytokine signaling (SOCS) hypomethylation and T helper 17 (Th17) cell/regulatory T (Treg) cell imbalance in children with Henoch-Schönlein purpura (HSP) and the immune pathogenesis of HSP. METHODS: A total of 32 children in the acute stage of HSP who were hospitalized from May 2014 to January 2015 were enrolled as subjects, and 28 children who underwent physical examination were enrolled as normal control group. ELISA was used to measure the plasma level of interleukin-6 (IL-6). Flow cytometry was used to measure the percentages of CD4+ IL-17A+ T cells (Th17 cells) and CD4+CD25+ Treg cells (Treg cells) in peripheral blood and mean fluorescence intensity (MFI) for phosphorylated-STAT3 (pSTAT3) protein in CD4+ T cells. Quantitative real-time PCR was used to measure the mRNA expression of suppressor of cytokine signaling-1 (SOCS1) and suppressor of cytokine signaling-3 (SOCS3) in CD4+ T cells. High-resolution melting (HRM) was used to evaluate the methylation level of the CpG islands in SOCS1 exon 2 and the CpG islands of the potential bind sites for STAT3 in the 5'-untranslated region (5'-UTR) of SOCS3 in peripheral blood mononucleated cells. RESULTS: Compared with the normal control group, the HSP group had significant increases in plasma IL-6 concentration and MFI for pSTAT3 in CD4+ T cells, as well as a significant increase in the percentage of Th17 cells and a significant reduction in the percentage of Treg cells (P<0.05). The HSP group had significantly higher mRNA expression of SOCS1 and SOCS3 in peripheral blood mononucleated cells than the normal control group (P<0.05). In the HSP group, the mRNA expression of SOCS1 and SOCS3 was negatively correlated with Th17/Treg ratio (P<0.05). The HSP group had hypomethylation of the CpG islands in SOCS1 exon 2 and the potential binding site for STAT3 in SOCS3 5'-UTR, while the normal control group had complete demethylation. CONCLUSIONS: Low relative expression of SOCS1 and SOCS3 caused by hypomethylation may be a factor for Th17/Treg imbalance in children with HSP.