[Clinical phenotype characteristics and genetic analysis in children with nephronophthisis and related syndromes caused by different gene mutations]. / ä¸åŒåŸºå› çªå˜è‡´è‚¾å•ä½è‚¾ç—¨åŠç›¸å ³ç»¼åˆå¾æ‚£å„¿ä¸´åºŠè¡¨åž‹ç‰¹ç‚¹åŠåŸºå› åˆ†æž.

OBJECTIVES: To improve the understanding of the clinical phenotypes and genetic characteristics of nephronophthisis (NPHP) and related syndromes in children. METHODS: A retrospective analysis was performed on the medical data of eight children with NPHP and related syndromes who were diagnosed and treated in the Department of Pediatrics of the Second Hospital of Hebei Medical University, from January 2018 to November 2022. The clinical characteristics and genetic testing results were analyzed. RESULTS: Among these eight children, there were five boys and three girls, with an age of onset ranging from 15 months to 12 years. All 8 children exhibited different degrees of renal function abnormalities when they attended the hospital. Among the eight children, two had the initial symptom of delayed development, two had the initial symptom of anemia, and two were found to have abnormal renal function during physical examination. The extrarenal manifestations included cardiovascular abnormalities in two children, skeletal dysplasia in two children, liver dysfunction in one child, retinitis pigmentosa in one child, and visceral translocation in one child. All eight children had renal structural changes on ultrasound, and four children had mild to moderate proteinuria based on routine urine test. Of all eight children, five had NPHP1 gene mutations and one each had a gene mutation in the NPHP3, IFT140, and TTC21B genes, and four new mutation sites were discovered. CONCLUSIONS: Children with NPHP and related syndromes often have the initial symptom of delayed development or anemia, and some children also have extrarenal manifestations. NPHP and related syndromes should be considered for children with unexplained renal dysfunction, and high-throughput sequencing may help to make a confirmed diagnosis.

The changes of Treg and Th17 cells relate to serum 25(OH)D in patients with initial-onset childhood systemic lupus erythematosus.

Background: T helper 17 (Th17) cells and regulatory T cells (Treg) are known to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Improving the balance between Treg and Th17 cells can be a promising new therapeutic target in SLE patients. Vitamin D has a significant impact on the immune inflammatory process and the immune cells involved in this process. The purpose of this study is to investigate the relationship between Th17, Treg, cytokines, and serum 25 hydroxyvitamin D [25(OH)D] in patients with initial-onset childhood SLE. Methods: A total of 82 children aged <18 years with initial-onset SLE were included, as well as 60 healthy subjects during the same period at the Pediatrics Department of the Second Hospital of Hebei Medical University. The chemiluminescence method was performed to detect serum 25(OH)D levels. Flow cytometry was used to evaluate Treg and Th17 cells. An enzyme-linked immunosorbent assay kit was used to evaluate plasma interleukin (IL)-23, IL-17, IL-10, IL-6, and tumor necrosis factor alpha (TNF-α) concentrations. Result: The serum 25(OH)D levels in patients with initial-onset childhood SLE were significantly lower than those in the healthy controls. The proportion of lupus nephritis (LN) was higher in the vitamin D insufficiency group (71.4%) compared with the vitamin D sufficiency group (30.3%) (p < 0.05). The SLE disease activity index (SLEDAI) was higher in the vitamin D insufficiency group (median = 14) than that in the vitamin D sufficiency group (median = 9) (p < 0.05).The 25(OH)D level was positively correlated with the Treg ratio (r = 0.337, p = 0.002), and it was negatively correlated with the Th17 cell ratio (r = -0.370, p = 0.001). The serum 25(OH)D level had a negative correlation with IL-23 (r = -0.589, p < 0.001), IL-17(r = -0.351, p = 0.001), TNF-α (r = -0.283, p = 0.01), IL-6 (r = -0.392, p < 0.001), and IL-10 (r = -0.313, p = 0.004) levels. Conclusion: The serum 25(OH)D levels decreased in patients with initial-onset childhood SLE. There was a negative correlation between the serum 25(OH)D levels and SLEDAI. The serum 25(OH)D levels in patients with initial-onset childhood SLE were negatively correlated with the Th17 ratio and related cytokines, while positively correlated with the Treg ratio.

Stormorken Syndrome Caused by a Novel STIM1 Mutation: A Case Report.

Objective: To identify the gene mutation of Stormorken syndrome and review the published Stromal Interaction Molecule 1 (STIM1) mutation phenotype. Methods: We described the clinical and molecular aspects of a Chinese female with Stormorken syndrome by laboratory tests, muscle biopsies, and genetic analysis. We used this information to summarize all the mutation sites reported in the literature. We also reviewed the clinical features of published cases with a gain of function mutations of STIM1. Results: A 12-year-old Chinese female presented with skin purpura in the lower limbs and stroke-like episodes. Muscle biopsy and microscopic examination revealed atrophy in her skeletal muscle. Genetic analysis identified a novel heterozygous missense mutation, a c.1095G>C transition (NM_003156.3), which caused a p.K365N amino acid substitution in the protein and affected a STIM1-orai1-activation region (SOAR). Conclusions: The novel variant c.1095G>C transition (NM_003156.3) was located in the SOAR, which expands the phenotypic spectrum of STIM1 variants in human disorders and may define the molecular basis of Stormorken syndrome.

[Association between autophagy and systemic juvenile idiopathic arthritis and related mechanism: a preliminary study].

OBJECTIVE: To study the role of autophagy in the development of systemic juvenile idiopathic arthritis (sJIA) by analyzing the expression of microtubule-associated protein 1 light chain 3-II (LC3-II), myeloid differentiation factor 88 (MyD88), and suppressor of T-cell receptor signaling 1 (STS-1) in peripheral blood lymphocytes of children with sJIA. METHODS: A total of 26 children with sJIA were enrolled as the sJIA group, and 26 healthy children were enrolled as the control group. Western blot was used to measure the protein expression of LC3-II, STS-1, and MyD88 in peripheral blood lymphocytes. Immunofluorescence assay was used to measure the expression of LC3-II in the cytoplasm of lymphocytes. Pearson correlation analysis was used to assess the correlation between indices. RESULTS: Compared with the control group, the sJIA group had significant increases in the expression of LC3-II, STS-1, and MyD88 (P<0.05). In the sJIA group, the expression of LC3-II was positively correlated with that of MyD88 (r=0.478, P<0.05), and the expression of STS-1 was also positively correlated with that of MyD88 (r=0.817, P<0.05). CONCLUSIONS: There is high expression of LC3-II in peripheral blood lymphocytes of children with sJIA, suggesting that the development of sJIA may be associated with excessive expression of autophagy. STS-1 may induce autophagy by activating some signaling pathways, and MyD88 may participate in autophagy through the Toll-like receptor signaling pathway.

[The expression of suppressor of cytokine signaling-1/3 in renal tubular epithelial cells induced by high glucose].

OBJECTIVE: To observe the morphologic changes and the expression of suppressor of cytokine signaling-1/3 (SOCS-1/3) in renal tubular epithelial cells induced by high glucose (HG) and to investigate their significance. METHODS: The renal tubular epithelial cell line (HKCs) cultured in vitro were divided into blank control group, HG group, and Janus kinase 2 inhibitor AG490 group. HKC of blank control group was cultured for 8 hours in 5.5 mmol/L glucose, and the other two groups were cultured in 300.0 mmol/L glucose or 300.0 mmol/L glucose+10 µmol/L AG490 for 2, 4, 6, 12, 24, 48 hours (n=6). The morphology and ultrastructure were observed with inversion microscope and electron microscope at different time points. Protein expression of SOCS-1/3 was assayed by immunocytochemistry and Western blotting; SOCS-1/3 mRNA was assessed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Under inversion microscope it was showed that 12 hours after being cultured with HG, the cells assumed a spindle-shape, with irregular protrusions, and cellular membrane became indistinguishable with prolongation of time, with increase of intracellular granules. Under the electron microscope, it was seen that there was distinct decrease in microvilli on the cell membrane and mitochondria, with an increase in rough endoplasmic reticulum. The cellular changes were not obvious in AG490 group. Furthermore, immunocytochemistry and Western blotting showed that the immunoreactivity was localized in the cytoplasm as well as in the nuclei, and there was basic expression of SOCS-1/3 protein in normal HKC (0.218±0.023, 0.337±0.009). HG was shown to induce up-regulation of the expression of SOCS-1/3 protein at 4, 6, 12, 24 hours compared with blank control group. The expression of SOCS-1 was highest at 4 hours (1.022±0.072), and that of SOCS-3 was highest at 6 hours (1.256±0.105, both P<0.01), while the expression of SOCS-1/3 protein in AG490 group was lower than that in HG group (4 hours SOCS-1: 0.589±0.167, 6 hours SOCS-3 : 0.656±0.075, both P<0.05). However, HG induced a higher expression of SOCS-1/3 mRNA at 2, 4, 6, 12 hours compared with blank control group. The expression of SOCS-1 was highest at 4 hours (1.716±0.098 vs. 0.475±0.045, P<0.05), and that of SOCS-3 was highest at 6 hours (2.848±0.116 vs. 0.749±0.086, P<0.01), while the expression of SOCS-1/3 mRNA in AG490 group was lower (4 hours SOCS-1: 0.865±0.075, 6 hours SOCS-3: 0.923±0.116, both P<0.05). CONCLUSION: HG could produce morphology and ultrastructure changes in renal tubular epithelial cell, and it induces up-regulation of SOCS-1/3 expression. These changes might be related with negative regulation of Janus kinase (JAK)/signal transducers and activators of transcription (STAT)/SOCS pathway.

[Expression and clinical implication of platelet-derived growth factor-D and platelet-derived growth factor-beta in childhood IgA nephropathy].

OBJECTIVE: To investigate the clinical implication of platelet-derived growth factor (PDGF)-D and PDGF-beta in IgA nephropathy in childhood. METHODS: Forty-seven children with IgA nephropathy and 26 controls were enrolled for study, and their serum, urine and renal biopsy specimens were examined. The patients were divided into control group [including serum, urine specimens of 13 healthy children and 13 renal biopsy samples of non-IgA nephropathy in children], mild proliferation (MP) group (13 patients), focal proliferation (FP) group (19 patients), and proliferation sclerosis (PS) group (15 patients). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to determine contents of PDGF-D, PDGF-beta and PDGF-B in blood, urine and renal tissues. The levels of 24-hour urinary protein excretion, serum albumin (Alb), serum blood urea nitrogen (BUN) and creatinine (Cr) were also determined. RESULTS: Compared with control group, levels of PDGF-D and PDGF-B were progressively elevated in blood and urine of IgA nephropathy children with increase in severity of glomerular damage (all P<0.01). Serum as well as urinary PDGF-D and PDGF-B levels were positively correlated with 24-hour urinary protein excretion (PDGF-D blood: r=0.546, urine: r=0.760; PDGF-B blood: r=0.634, urine: r=0.577, respectively, P<0.01), while negatively correlated with serum Alb levels in IgA nephropathy patients (PDGF-D blood: r=-0.649, urine: r=-0.528; PDGF-B blood: r=-0.613, urine: r=-0.531, respectively, P<0.01). Contents of PDGF-D and PDGF-beta in renal tissue were much higher than those of control group (P<0.01). Along with the increase in severity of glomerular pathology, their contents increased gradually. PDGF-B was only significantly expressed in renal tissue in FP group and PS group. CONCLUSION: PDGF-D might significantly enhance the development of mesangial proliferation and tubulointerstitial fibrosis. In comparison with PDGF-B, PDGF-D appears to reflect more sensitive to the severity and prognosis of IgA nephropathy.