The impact of reclassification of C3 predominant glomerulopathies on diagnostic accuracy, outcome and prognosis in patients with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis is a recently described entity with heterogeneous histopathological features. This study was conducted to assess the effect of reclassification of C3 glomerulopathies on renal outcomes, mortality, and response to therapy. METHODS: We undertook a retrospective analysis of 857 renal biopsies collected at The Canberra Hospital. Samples with predominant C3 staining were reviewed by a renal histopathologist. Of 31 biopsies with predominant C3 staining, 10 fulfilled histological criteria for C3 glomerulonephritis, while the remaining 21 cases were used as C3 Controls. RESULTS: Aside from a higher incidence of C3 glomerulonephritis in Torres Strait islanders (40% vs 5% C3 Controls, p = 0.04), presentation demographics were similar between the two groups. Median creatinine at diagnosis was higher in patients with C3 glomerulonephritis (253 umol/L IQR 103-333 vs 127 umol/L C3 Controls, IQR 105-182, p = 0.01). Prior to reclassification, a majority of C3 glomerulonephritis cases were diagnosed as membranoproliferative glomerulonephritis (60% vs 5% (C3 Controls) p < 0.01). Electron microscopy demonstrated all C3 glomerulonephritis patients had C3 deposition (100% vs 38% p = 0.02), these deposits were amorphous in nature (50% vs 5% respectively p = 0.007). C3 glomerulonephritis patients had shorter median follow-up (405 days IQR 203-1197 vs 1822 days respectively, IQR 1243-3948, p = 0.02). Mortality was higher in C3 glomerulonephritis patients (30% vs 14% in C3 Controls (log rank p = 0.02)). CONCLUSION: We have devised a diagnostic and treatment algorithm based on the results of literature review and our current study. Further prospective assessment is required to review diagnostic and treatment outcomes for this disease in Australian centres.

Role of lncRNA NEAT1 mediated by YY1 in the development of diabetic cataract via targeting the microRNA-205-3p/MMP16 axis.

OBJECTIVE: We aimed at investigating the possible role and mechanism of NEAT1 in the pathogenesis of diabetic cataract. PATIENTS AND METHODS: YY1 and NEAT1 expressions in anterior lens capsule collected from diabetic cataract (DC) patients and normal controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and their correlation was analyzed. The binding site between YY1 and NEAT1 sequences was predicted by JASPAR and detected by Dual-Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. The proliferation and apoptosis of high-glucose-induced cells with NEAT1 knockdown were detected. Potential downstream targets of NEAT1 were predicted by bioinformatics and detected by Dual-Luciferase reporter assay. RESULTS: YY1 and NEAT1 expressions in the anterior capsule tissue of DC lens were remarkably reduced and positively correlated. Dual-Luciferase reporter assay and ChIP confirmed that YY1 could bind to locus 2 of NEAT1. Knockdown of NEAT1 inhibited proliferation while promoted apoptosis under high glucose conditions. Further mechanism studies revealed that knockdown of NEAT1 could upregulate microRNA-205-3p, and MMP16 was a potential target of miR-205. CONCLUSIONS: The low expression of YY1 induces NEAT1 downregulation, which regulates microRNA-205-3p/MMP16 axis and thus participates in the development of DC.

[Clinical analysis of chest infections caused by streptococcus anginosus group].

Objective: To clarify the clinical characteristics of chest infections caused by streptococcus anginosus group (SAG). Methods: A total of 26 patients diagnosed in Affiliated Hospital of Jining Medical University from January 2014 to October 2019 were enrolled. The analyzed clinical data included baseline data, clinical symptoms, imaging manifestations, therapies, and outcomes. The microbiological diagnosis was established based on the specimens collected by lung needle biopsy, bronchoscopy, artificial airway aspiration, thoracentesis or thoracoscopy. Results: Among the 26 patients, there were 23 (88.5%) males and 3 (11.5%) females aged (63.0±12.5) years, and 21 cases (80.8%) had potential diseases. The distribution of clinical manifestations included 21 cases (80.8%) with fever, 13 cases (50.0%) with pectoralgia, 13 cases (50.0%) with cough, and 13 cases (50.0%) with expectoration. Chest CT displayed 18 cases (69.2%) with nodules, 18 cases (69.2%) with pleural effusion, 17 cases (65.4%) with patchy shadows, 12 cases (46.2%) with consolidation, 4 cases (15.4%) with cavity, 3 cases (11.5%) with spontaneous pneumothorax. 13 cases (50.0%) of Streptococcus constellatus, 12 cases (46.2%) of Streptococcus anginosus and 1 case (3.8%) of Streptococcus intermadius were observed through the bacterial culture. After anti-infection treatment and invasive operation (including tracheoscopy, thoracoscopy, lung puncture, and thoracic puncture drainage), the prognosis of 24 cases (92.3%) became satisfactory, and 2 (7.7%) died. Conclusion: Pulmonary infection caused by SAG is mainly seen in male patients with underlying diseases. No specificity is displayed in clinical manifestations. CT manifestations usually show intrapulmonary nodules, patchy shadows, consolidation and pleural effusion.

Recurrent glomerulonephritis following renal transplantation and impact on graft survival.

BACKGROUND: Recurrence of primary glomerulonephritis in the post-transplant period has been described in the literature but the risk remains poorly quantified and its impact on allograft outcomes and implications for subsequent transplants remain under-examined. Here we describe the rates and timing of post-transplant glomerulonephritis recurrence for IgA nephropathy, focal segmental glomerulosclerosis, mesangiocapillary GN and membranous GN based on 28 years of ANZDATA registry transplant data. METHODS: We investigated the rates of GN recurrence and subsequent graft outcomes in 7236 patient from 28 years of ANZDATA transplant registry data. Data were analysed in R, using Kaplan Meier Survival analysis and adjusted analyses performed using Cox Proportional Hazards methods. A competing risk model was also analysed. RESULTS: GN recurrence occurred in 10.5% of transplants and was most common in mesangiocapillary GN. Median time to recurrence was shorter for FSGS compared to IGAN. GN recurrence was less common in patients over 50 years of age and after unrelated kidney donation. We identified a significantly higher risk of recurrence in secondary grafts following recurrence in a primary allograft for FSGS (RR 5.70, 95 CI: 2.41-13.5, p < 0.001) but not IGAN, MCGN or MN. At 10 years, recurrence occurs in 8.7, 10.8, 13.1, and 13.4% of allografts for FSGS, IGAN, MCGN and MN respectively. In all GN, recurrence significantly reduced death censored graft survival at 5 and 10 years. CONCLUSIONS: GN recurrence occurs in a minority of patients at a significantly different rate for each GN. After a recurrence, there is no evidence for an increased risk of further recurrence in a subsequent graft except in FSGS.

[Various scaffolds for dentine-pulp complex regeneration].

With the rapid development of cell biology and biological materials, the dentine-pulp complex regeneration research has gone further. Scaffolds play important roles in the construction of tissue engineered dentine-pulp complex. At present, scaffolds used in dentine-pulp complex regeneration include not only natural biological materials and synthetic biomaterials, but also various composite materials and cell- or body-based carrier materials. In this paper, the latest research status of various scaffolds for dentine-pulp complex regeneration were reviewed. The advantages and problems of these scaffolds were analyzed. The future development direction was predicted.

[Prognostic analysis of allogeneic hematopoietic stem-cell transplantation in 47 patients with acute myeloid leukemia and MLL rearrangement].

Objective: To investigate the prognosis of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for patients with acute myeloid leukemia and MLL rearrangement. Methods: From September 2009 to May 2016, the clinical data of 47 patients with MLL-rearranged AML undergoing allo-HSCT in the First Affiliated Hospital of Soochow University were retrospectively analyzed. Results: Among 47 MLL-rearranged AML patients, 24 were male and 23 female. The median age was 30 (15-58) years old. There are 36 (76%) patients were FAB-types M4/M5. Two-year overall survival (OS), disease-free survival (DFS), relapse incidence and transplant-related mortality (TRM) were (64.4±8.4)%, (47.3±9.3)%, 41.0% and 17.9%, respectively. Of them, 45 patients were detected with 11q23 translocations, and 2 patients with normal karyotype were MLL partial tandem duplication. According to different chromosome karyotype, 47 patients were divided into three groups: 16 cases of t (6; 11), 15 cases of t (9; 11) and 16 cases of other types. Overall survival was compared between the three groups, there was no significant difference (χ(2)=1.509, P=0.472). On multivariate analysis, independent risk factor on OS was transplant age >45 years [HR=4.454(95%CI 1.314-15.099), P=0.016]. The multivariate analysis also confirmed the higher TRM in patients at non-CR state when transplanted [HR=10.370(95%CI 1.043-103.110), P=0.046]. Positive minimal residual disease (MRD) before transplantation was a negative prognostic factor on DFS [HR=4.236(95%CI 1.238-14.495), P=0.021] and relapse incidence (RI) [HR=5.491(95%CI 1.371-21.995), P=0.016]. Conclusion: Transplant age (>45 years), allo-HSCT in non-CR state adn positive MRD before transplantation were negative prognostic factors in allo-HSCT for MLL-rearranged AML patients.

The protective effect of lidocaine on lipopolysaccharide-induced acute lung injury in rats through NF-κB and p38 MAPK signaling pathway and excessive inflammatory responses.

OBJECTIVE: Acute lung injury is a severe disease with a high rate of mortality, leading to more important illness. We aimed at exploring the protective role and potential mechanisms of lidocaine on lipopolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: Sprague Dawley (SD) rats were randomly assigned to control group receiving 0.9% saline solution, LPS group treated with 4 mg/kg LPS i.p., LPS + lidocaine(treated with 4 mg/kg LPS i.p. followed by giving 1 mg/kg, 3 mg/kg, 5 mg/kg of lidocaine i.v.). Lung specimens and the bronchoalveolar lavage fluid (BALF) were collected for histopathological examination and biochemical analyze 12 h after LPS induction. The cytokines expression of TNF-α, IL-6 and MCP-1 was measured by ELISA. In addition, the malondialdehyde (MDA) content, the activities of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) in lung tissues were also detected using ELISA. The protein expressions of p38, p-p38, p65, p-p65 and IκB were analyzed by Western blot. RESULTS: The results indicated that after lidocaine treatment was able to decrease significantly wet-to-dry (W/D) ratio and ameliorate the histopathologic damage. Additionally, total protein content and the number of leukocytes in BALF significantly decreased. ELISA result indicated that the levels of TNF-α, IL-6 and MCP-1 in BALF were markedly suppressed. Meanwhile, the activities of T-AOC and SOD in lung tissues significantly increased, while the content of MDA significantly decreased after treatment with lidocaine. Moreover, Western blot suggested that lidocaine inhibited phosphorylation of NF-κB p65 and p38 MAPK. CONCLUSIONS: Therefore, lidocaine could ameliorate the LPS-induced lung injury via NF-κB/p38 MAPK signaling and excessive inflammatory responses, providing a potential for becoming the anti-inflammatory agent against lung injury.

[Clinical features and curative effect analysis of patients with myeloid neoplasms and RUNX1 mutations].

Objective: To investigate the survival and prognostic factors of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for patients with myeloid neoplasms and RUNX1 mutations. Methods: From July 2014 to April 2018, the clinical data of forty-two AML/MDS patients with RUNX1 mutations in the First Affiliated Hospital of Soochow University were retrospectively analyzed. The clinical characteristic features and distribution of the mutations frequently observed with RUNX1 mutations were summarized, the prognosis of allo-HSCT for these patients was also analyzed. Results: Among 42 AML/MDS patients with RUNX1 mutations, 27 were male, 15 were female. The median age was 43.5 (16-68) years old. There are 31 patients in allo-HSCT group and 11 patients in chemotherapy group. RUNX1 mutations co-occurred with many other gene mutations, the most frequent mutations were FLT3 (26.2%, 11/42) . Interestingly, FLT3 mutations only occurred in AML patients compared with MDS patients (P=0.014) . ASXL1 (25%, 3/12) mutations were observed as the most frequent co-mutations in MDS patients. One-year overall survival (OS) , disease-free survival (DFS) of allo-HSCT and chemotherapy patients were (70.6±9.0) %, (61.0±9.4) % and (34.4±16.7) %, (22.4±15.3) %, respectively. When OS and DFS between allo-HSCT and chemotherapy patients were compared, significant differences (χ(2)=4.843, 4.320, P<0.05) were showed. In univariate analysis, transplant age >45 years was a negative effect for OS [HR=4.819 (95% CI 1.145-20.283) , P=0.032] and DFS [HR=5.945 (95% CI 1.715-20.604) , P=0.005]. Also, complex chromosome karyotype abnormality was a negative effect for OS [HR=5.572 (95%CI 1.104-28.113) , P=0.038]. Conclusion: Transplant age (>45 years) and complex chromosome karyotype abnormality were negative prognostic factors in allo-HSCT for myeloid neoplasms patients with RUNX1 mutations.

SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/ß-catenin signaling through stabilization of the WNT-receptor complex.

Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/ß-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT-receptor complex stabilization. Activation of WNT/ß-catenin signaling contributes to the SPARCL1-mediated inhibitory effects on OS metastasis. Furthermore, we uncovered a paracrine effect of SPARCL1 on macrophage recruitment through activated WNT/ß-catenin signaling-mediated secretion of chemokine ligand5 from OS cells. These findings suggest that the targeting of SPARCL1 as a new anti-metastatic strategy for OS patients.

Increased glomerulonephritis recurrence after living related donation.

BACKGROUND: Kidney transplantation confers superior outcomes for patients with end stage kidney disease, and live donor kidneys associate with superior outcomes compared to deceased donor kidneys. Modern immunosuppression has improved rejection rates and transplant survival and, as a result, recurrence of glomerulonephritis has emerged as a major cause of allograft loss. However, many glomerulonephritides have significant genetic risk which may manifest through kidney intrinsic or systemic mechanisms. We hypothesise that heritable kidney intrinsic predisposition to glomerulonephritis will result in increased risk of glomerulonephritis recurrence in kidneys transplanted from genetically related donors. METHODS: We investigated the effect of living related donation on rates of recurrence and subsequent graft outcomes in 7236 patient from 28 years of ANZDATA transplant registry data. Data were analysed in R, using Kaplan Meier Survival analysis and adjusted analyses performed using Cox Proportional Hazards methods. A competing risk model was also analysed. RESULTS: Glomerulonephritis recurrence rates were significantly higher in living related donor grafts compared to either living unrelated or deceased donor grafts (p < 0 · 001). In IgA nephropathy, transplantation from living related donor kidneys demonstrated a 10 year recurrence rate of 16 · 7% compared to 7 · 1% in living unrelated donors and 9 · 2% in deceased donors (HR:1 · 7, 95% CI:1 · 26-2 · 26, p = 0 · 0005 for living related vs deceased donors). In focal segmental glomerulosclerosis, risk of recurrence at 10 years was 14 · 6% in living related donors compared to 10 · 8% in living unrelated donors and 6 · 6% in deceased donors (HR:2 · 2, 95% CI 1 · 34-3 · 64, p = 0 · 002) for living related vs deceased donors. Primary glomerulonephritis death censored graft survival was superior for living donor grafts, related or unrelated, compared to deceased donor grafts. CONCLUSIONS: We identified a significant increase in the risk of glomerulonephritis recurrence in IgA Nephropathy and Focal Segmental Glomerulosclerosis in living related donors compared to a deceased donors.

Characterization, expression analysis and localization pattern of toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes in grass carp Ctenopharyngodon idella.

In this study, the toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes of grass carp Ctenopharyngodon idella were cloned and characterized. tlr1 and tlr2 were found to be highly expressed in immune system organs such as spleen, middle kidney and heart kidney. The expression level of tlr1 and tlr2 was found to be up-regulated at the later stage of viral challenge process. Moreover, subcellular localization indicated that Tlr1 and Tlr2 shared similar localization pattern and both of them may locate in the plasma membrane of transfected cells.

Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIP3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIP3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.

Evaluation of dose conversion coefficients for external exposure using Taiwanese reference man and woman.

Reference man has been widely used for external and internal dose evaluation of radiation protection. The parameters of the mathematical model of organs suggested by the International Commission of Radiological Protection (ICRP) are adopted from the average data of Caucasians. However, the organ masses of Asians are significantly different from the data of Caucasians, leading to potentially dosimetric errors. In this study, a total of 40 volunteers whose heights and weights corresponded to the statistical average of Taiwanese adults were recruited. Magnetic resonance imaging was performed, and T2-weighted images were acquired. The Taiwanese reference man and woman were constructed according to the measured organ masses. The dose conversion coefficients (DCFs) for anterior-posterior (AP), posterior-anterior (PA), right lateral (RLAT) and left lateral (LLAT) irradiation geometries were simulated. For the Taiwanese reference man, the average differences of the DCFs compared with the results of ICRP-74 were 7.6, 5.1 and 11.1 % for 0.1, 1 and 10 MeV photons irradiated in the AP direction. The maximum difference reached 51.7 % for the testes irradiated by 10 MeV photons. The size of the trunk, the volume and the geometric position of organs can cause a significant impact on the DCFs for external exposure of radiation. The constructed Taiwanese reference man and woman can be used in radiation protection to increase the accuracy of dose evaluation for the Taiwanese population.