ABSTRACT
Hereditary kidney disease is an important cause of chronic kidney disease in children. With the progress of genome sequencing, single-cell technology, and organoid cultures, the research on hereditary kidney disease has entered a new era. How to integrate big data resources, discover new disease-causing genes, and develop effective treatment methods will be the focus of future research. This article discusses the classification, research progress, challenges and prospects of pediatric hereditary kidney disease, so as to provide valuable insights into the research of hereditary kidney disease in children.
Subject(s)
Kidney Diseases , Humans , Child , Kidney Diseases/genetics , Renal Insufficiency, Chronic/geneticsABSTRACT
Objective: To investigate the clinical phenotype and genetic characteristics of patients with Fabry disease caused by a GLA variant, IVS4+919G>A. Methods: It was a prospective study. Fabry disease screening was conducted among high-risk population in Ninghai from October 2021 to August 2023. Those children with decreased α-galactosidase enzyme activity<2.40 µmol/(L·h) or elavated Lyso-GL-3 level>1.10 µg/L in dried blood spot (DBS) method underwent GLA genetic testing for diagnosis confirmation. Meanwhile, family screening was carried out. A proband and his family members diagnosed with Fabry disease were research subjects. The clinical and genetic characteristics of patients with Fabry disease caused by the GLA variant (IVS4+919G>A) were analyzed. Results: The female proband aged 9.8 years with pain in both lower limbs as the initial symptom was found to have a heterozygous GLA variant IVS4+919G>A among 102 patients. In family screening, there were 4 family members (proband's father, elder sister, elder male cousin and elder female cousin) with Fabry disease and a family member (proband's fifth aunt) with a GLA variant. Among these 4 diagnosed family members, the elder male cousin of the proband, a boy aged 13.2 years had a heterozygous GLA variant, IVS4+919G>A with intermittent pain in both lower limbs as the initial symptom. The proband's father had knee joint pain. The proband's elder sister had decreased vision and his elder female cousin had no obvious symptoms. The proband's fifth aunt with a GLA variant had decreased vision. Conclusions: High-risk screening in children and family screening are helpful for early diagnosis and treatment of Fabry disease. Neuropathic pain may be a early symptom in children with Fabry disease caused by the GLA variant, IVS4+919G>A.
Subject(s)
Fabry Disease , Child , Humans , Male , Female , Aged , Fabry Disease/diagnosis , Fabry Disease/genetics , Fabry Disease/epidemiology , alpha-Galactosidase/genetics , Pedigree , Prospective Studies , Mutation , Phenotype , Heterozygote , PainABSTRACT
Objective: To analyze the nutritional status of progeria, and to provide reference for scientific nutritional management of progeria. Methods: This cross-sectional study included 15 children with progeria who were treated at Children's Hospital, Zhejiang University School of Medicine, between April 2022 and May 2023. Data of medical history, physical examination, laboratory tests, dietary survey and body composition were collected and analyzed. Results: Among 15 patients there were 7 males and 8 females, aged 7.8 (2.3, 10.8) years. Twelve of the 15 patients exhibited signs of malnutrition. A 24-hour dietary survey was carried out in 14 of them. The daily energy intake of 11 cases was below recommended levels. Carbohydrate intake was insufficient in 10 cases, protein intake was insufficient in 7 cases, and fat intake was insufficient in 12 cases. Deficiencies in calcium, magnesium, iron and zinc were noted in 13, 13, 9 and 10 cases, respectively. Body composition was determined by dual-energy X-ray absorptiometry in 8 cases, and the bone mineral density was below average in 5 of them. Conclusions: Malnutrition, characterized by reduced energy intake, micronutrient deficiencies, and alteration in body composition, is prevalent in children with progeria. Regular routine nutritional assessment and proper interventions may benefit their long-term health status.
Subject(s)
Malnutrition , Progeria , Male , Child , Female , Humans , Nutritional Status , Cross-Sectional Studies , Energy IntakeSubject(s)
Nephrotic Syndrome , Child , Humans , Nephrotic Syndrome/diagnosis , Biomarkers , Steroids/therapeutic useABSTRACT
OBJECTIVE: We explored the influences on platelet-rich fibrin (PRF) to rat Bone Mesenchymal Stem Cells (BMSCs), as well as the role of bone morphogenetic protein 2 (BMP2)/maternal signal protein homolog (Smads) pathway. MATERIALS AND METHODS: The proposed research is approved by the ethics board of the Second Affiliated Hospital of Harbin Medical University. The BMSCs were isolated and purified. The BMSCs were assigned to a control group arbitrarily, PRF group, BMP activator group and BMP inhibitor group (hereinafter referred to as activator group and inhibitor group). Each group of BMSCs in the logarithmic growth phase was detected for the alkaline phosphatase (ALP) activity since 3 days and 14 days of culture; CCK-8 assay was conducted for detection of the proliferation of BMSCs; Real time PCR was conducted for detection of the osteogenic differentiation marker collagen I (COL-I), BMP2, Runt-related transcription factor 2(RUNX2), osteocalcin (OCN) mRNA relative expression levels; Western-Blot detection of BMP2, OCN, P-SMAD1/5/8, relative expression level of RUNX2 protein. RESULTS: In contrast to the control group, BMSCs' the ALP activity of the PRF group, activator group, as well as inhibitor group increased for 3 days and 14 days, and the activator group>PRF group>inhibitor group (p≤0.05). ALP activity in each group was elevated with the increase in culture time, the ALP activity of the control group, PRF group, activator group and inhibitor group increased (p≤0.05). In comparison to the control group, the relevant expression levels of COL-I, BMP-2, RUNX2 and OCN in the PRF group, activator group, and inhibitor group increased, and the activator group>PRF group>inhibitor group (p≤0.05). The relative expression levels of BMP2, OCN, p-SMAD1/5/8 and RUNX2 protein in each group were statistically different, the activator group>PRF group>control group>inhibitor group (p≤0.05). CONCLUSIONS: PRF can promote the proliferation and osteogenic differentiation of BMSCs by activating the BMP2/Smads signaling pathway.
Subject(s)
Mesenchymal Stem Cells , Platelet-Rich Fibrin , Animals , Bone Morphogenetic Protein 2/metabolism , Collagen Type I/metabolism , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor Alpha 1 Subunit/metabolism , Humans , Mesenchymal Stem Cells/metabolism , Osteocalcin/metabolism , Osteogenesis , RatsABSTRACT
Objective: To investigate the efficacy and safety of adrenocorticotropic hormone (ACTH) in children with frequently relapsing or steroid-dependent nephrotic syndrome. Methods: The clinical data of 38 children with frequently relapsing or steroid-dependent nephrotic syndrome who were admitted to the Department of Nephrology, the Children Hospital, Zhejiang University School of Medicine from January 2015 to December 2020 were retrospectively analyzed. The general information, clinical manifestations, laboratory data of the children and follow-up (till 12 months after treatment) were collected. The patients were divided into ACTH group and Glucocorticoid (GC) group according to treatment plan. Cumulative remission, average recurrence rate, GC dosage, height and weight change and peripheral blood CD19+B lymphocyte count were compared between the two groups to evaluate the efficacy and adverse reactions of ACTH. Fisher's exact test, t test or rank sum test was used for comparison between groups. Results: Among the 38 patients, 28 were male and 10 were female, aged 84 (24, 180) months; 19 were in ACTH group and 19 were in GC group. The cumulative remission rate of 12 months in ACTH group was higher than that in GC group (9/19 vs. 2/19,χ²=6.81,P=0.009), the average recurrence rate was lower than that in GC group ((0.7±0.8) vs. (1.7±1.1) times, t=-3.27, P=0.011), and the average dosage of GC was lower than that in GC group ((0.27±0.16) vs. (0.51±0.27) mg/(kg·d), t=-3.21, P=0.014). The increase in height was higher than that in the GC group (4 (3,5) vs. 3 (2, 3) cm/year, Z=2.58, P=0.010), and the peripheral blood CD19+B lymphocyte count was lower than that in the GC group ((223±149)×106 vs. (410±213)×106/L,t=-3.35, P=0.009). In safety, 19 cases had transient decreased urine volume, 7 cases had hyperglycemia, and 3 cases had hypertension during the infusion of ACTH, which could be relieved after drug withdrawal. Conclusion: ACTH has a better effect on children with frequently relapsing or steroid-dependent nephrotic syndrome, which can improve cumulative sustained remission rate, lower relapses rate and decrease the dosage of GC, with good safety.
Subject(s)
Nephrotic Syndrome , Adolescent , Adrenocorticotropic Hormone/therapeutic use , Child , Child, Preschool , Female , Glucocorticoids/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Male , Nephrotic Syndrome/drug therapy , Recurrence , Retrospective Studies , Steroids , Treatment OutcomeABSTRACT
BackgroundPrognosis of breast cancer (BC) patients differs considerably and identifying reliable prognostic biomarker(s) is imperative. With evidence that the microbiome plays a critical role in the response to cancer therapies, we aimed to identify a cancer microbiome signature for predicting the prognosis of BC patients.MethodsThe TCGA BC microbiome data (TCGA-BRCA-microbiome) was downloaded from cBioPortal. Univariate and multivariate Cox regression analyses were used to examine association of microbial abundance with overall survival (OS) and to identify a microbial signature for creating a prognostic scoring model. The performance of the scoring model was assessed by the area under the ROC curve (AUC). Nomograms using the microbial signature, clinical factors, and molecular subtypes were established to predict OS and progression-free survival (PFS).ResultsAmong 1406 genera, the abundances of 94 genera were significantly associated with BC patient OS in TCGA-BRCA-microbiome dataset. From that set we identified a 15-microbe prognostic signature and developed a 15-microbial abundance prognostic scoring (MAPS) model. Patients in low-risk group significantly prolong OS and PFS as compared to those in high-risk group. The time-dependent ROC curves with MAPS showed good predictive efficacy both in OS and PFS. Moreover, MAPS is an independent prognostic factor for OS and PFS over clinical factors and PAM50-based molecular subtypes and superior to the previously published 12-gene signature. The integration of MAPS into nomograms significantly improved prognosis prediction.ConclusionMAPS was successfully established to have independent prognostic value, and our study provides a new avenue for developing prognostic biomarkers by microbiome profiling.
Subject(s)
Humans , Female , Unilateral Breast Neoplasms/microbiology , Unilateral Breast Neoplasms/mortality , Microbiota , Biomarkers , Nomograms , Clinical Studies as Topic , Survival RateABSTRACT
BACKGROUND: Prognosis of breast cancer (BC) patients differs considerably and identifying reliable prognostic biomarker(s) is imperative. With evidence that the microbiome plays a critical role in the response to cancer therapies, we aimed to identify a cancer microbiome signature for predicting the prognosis of BC patients. METHODS: The TCGA BC microbiome data (TCGA-BRCA-microbiome) was downloaded from cBioPortal. Univariate and multivariate Cox regression analyses were used to examine association of microbial abundance with overall survival (OS) and to identify a microbial signature for creating a prognostic scoring model. The performance of the scoring model was assessed by the area under the ROC curve (AUC). Nomograms using the microbial signature, clinical factors, and molecular subtypes were established to predict OS and progression-free survival (PFS). RESULTS: Among 1406 genera, the abundances of 94 genera were significantly associated with BC patient OS in TCGA-BRCA-microbiome dataset. From that set we identified a 15-microbe prognostic signature and developed a 15-microbial abundance prognostic scoring (MAPS) model. Patients in low-risk group significantly prolong OS and PFS as compared to those in high-risk group. The time-dependent ROC curves with MAPS showed good predictive efficacy both in OS and PFS. Moreover, MAPS is an independent prognostic factor for OS and PFS over clinical factors and PAM50-based molecular subtypes and superior to the previously published 12-gene signature. The integration of MAPS into nomograms significantly improved prognosis prediction. CONCLUSION: MAPS was successfully established to have independent prognostic value, and our study provides a new avenue for developing prognostic biomarkers by microbiome profiling.
Subject(s)
Breast Neoplasms/microbiology , Microbiota , Breast Neoplasms/mortality , Female , Humans , Prognosis , Survival RateABSTRACT
Objective: To analyze the clinical features and efficacy of enzyme replacement therapy in 4 children with Fabry disease. Methods: A retrospective analysis of the clinical manifestations, laboratory findings, genetic variations and treatment were conducted in 4 children with Fabry disease in Children's Hospital of Zhejiang University School of Medicine from January 2014 to July 2020. Results: All four children (2 males, 2 females) with onset age of 12.4 (6.0-16.8) years were diagnosed based on clinical features, α-Gal A enzyme activity, genetic analysis and family history. The clinical manifestations varied in 4 children. All patients had left ventricular hypertrophy and abnormal urinalysis results, 1 case of neuropathic pain, 2 cases of hypohidrosis, 1 case of insipidus, but no angiokeratomas or hearing abnormalities were found. Three missense mutations of GLA gene were identified: c.424T>C (p.C142R), C.335G>A (p.R112H) and c.644A>G (p.N215S). The first two gene mutations were classical phenotypes, and the last one had also been reported in a classic case. In Case 1, no severe adverse events were reported in the first two months of agalsidase beta treatment. The dosage was 1 mg/kg once every 2 weeks. Symptoms of pain intensity and hypohidrosis were improved. Transiently elevated proteinuria was observed but it returned to normal after a week without any treatment. Conclusions: Clinical manifestations of Fabry disease varied in childhood. Multidisciplinary collaboration is required for its early diagnosis and treatment. Severe adverse events are rare in children with short-term therapy of agalsidase beta.
Subject(s)
Fabry Disease , Adolescent , Age of Onset , Child , Enzyme Replacement Therapy , Fabry Disease/drug therapy , Fabry Disease/genetics , Female , Humans , Male , Retrospective Studies , Treatment OutcomeABSTRACT
Growing evidence suggests that the gut microbiome (GM) plays a critical role in health and disease. However, the contribution of GM to psychiatric disorders, especially anxiety, remains unclear. We used the Collaborative Cross (CC) mouse population-based model to identify anxiety associated host genetic and GM factors. Anxiety-like behavior of 445 mice across 30 CC strains was measured using the light/dark box assay and documented by video. A custom tracking system was developed to quantify seven anxiety-related phenotypes based on video. Mice were assigned to a low or high anxiety group by consensus clustering using seven anxiety-related phenotypes. Genome-wide association analysis (GWAS) identified 141 genes (264 SNPs) significantly enriched for anxiety and depression related functions. In the same CC cohort, we measured GM composition and identified five families that differ between high and low anxiety mice. Anxiety level was predicted with 79% accuracy and an AUC of 0.81. Mediation analyses revealed that the genetic contribution to anxiety was partially mediated by the GM. Our findings indicate that GM partially mediates and coordinates the effects of genetics on anxiety.
Subject(s)
Anxiety/genetics , Anxiety/microbiology , Behavior, Animal , Gastrointestinal Microbiome , Animals , Collaborative Cross Mice , MiceABSTRACT
Objective: To evaluate the effects of adeno-associated virus (AAV) carrying hFâ § by serotype 8 (AAV8/hFâ §) on hemophilia A (HA) mice by gene therapy strategy. Methods: pAAV-CB-EGFP, pH22 (serotype 2) and pfΔ6 (adenovirus helper) were used to package AAV into HEK-293 cells in different conditions (ratios of cells to plasmids). The efficiency of transfection and infection were evaluated using immunofluorescence microscope to seek an optimized package condition. pAAV-TTR-hFâ §, pH 28 (serotype 8) and pfΔ6 were applied to package AAV8/hFâ § in HEK-293 cells using the optimized package condition. The purified AAV8/hFâ § were intravenously injected into HA mice and the effects of gene therapy were estimated. Results: The efficiency of package was evaluated according to the amount and intensity of enhanced green fluorescent protein (EGFP) under immunofluorescence microscope. Four package conditions including 10 cm-dish to transfect 10 µg plasmids, 20 cm-dish to 20 µg, 30 µg and 40 µg plasmids were employed, and the condition of 20 cm-dish to transfect 20 µg plasmids reached the highest transfection efficiency at 24 h, 48 h and 72 h after transfection. The small scale AAV-EGFP was packaged using the optimized condition and an AAV crude extract was harvested by a freeze-thaw method. HEK-293 and 16095 cells were infected by the AAV crude extract, and the preferential infection efficiency was recognized in 16095 cells under immunofluorescence microscope. Then, AAV8/hFâ § was packaged and purified based on the optimized transfection condition, and the high purity of AAV8/hFâ § was detected by Western blot. Fractions of AAV8/hFâ § at the dose of 8×10(12) vg/kg were injected into HA mice through tail vein, an eye-bleeding was performed at every two weeks, and the activity of Fâ § was measured by aPTT assay. Results showed that the activity of Fâ § maintained at the therapeutic level and lasted up to 12 weeks after injection. Conclusion: The purified AAV8/hFâ § based on the optimized package condition could play a role in HA mice gene therapy, and the long-term therapeutic effects of AAV8/hFâ § were observed in vivo.
Subject(s)
Dependovirus , Hemophilia A , Animals , Genetic Therapy , Genetic Vectors , HEK293 Cells , Humans , MiceABSTRACT
Objective: To establish comprehensive laboratory reference intervals for Chinese children. Methods: This was a cross-sectional multicenter study. From June 2013 to December 2014, eligible healthy children aged from 6-month to 17-year were enrolled from 20 medical centers with informed consent. They were assessed by physical examination, questionnaire survey and abdominal ultrasound for eligibility. Fasting blood samples were collected and delivered to central laboratory. Measurements of 15 clinical laboratory parameters were performed, including estradiol (E2), testosterone(T), luteinizing hormone(LH), follicle-stimulating hormone(FSH), alanine transaminase(ALT), serum creatinine(Scr), cystatin C, immunoglobulin A(IgA), immunoglobulin G(IgG), immunoglobulin M(IgM), complement (C3, C4), alkaline phosphatase(ALP), uric acid(UA) and creatine kinase(CK). Reference intervals were established according to central 95% confidence intervals for reference population, stratified by age and sex. Results: In total, 2 259 children were enrolled. Finally, 1 648 children were eligible for this study, including 830 boys and 818 girls, at a mean age of 7.4 years. Age- and sex- specific reference intervals have been established for the parameters. Reference intervals of sex hormones increased gradually with age. Concentrations of ALT, cystatin C, ALP and CK were higher in children under 2 years old. Serum levels of sex hormones, creatinine, immunoglobin, CK, ALP and urea increased rapidly in adolescence, with significant sex difference. In addition, reference intervals were variable depending on assay methods. Concentrations of ALT detected by reagents with pyridoxal 5'-phosphate(PLP) were higher than those detected by reagents without PLP. Compared with enzymatic method, Jaffe assay always got higher results of serum creatinine, especially in children younger than 9 years old. Conclusion: This study established age- and sex- specific reference intervals, for 15 clinical laboratory parameters based on defined healthy children.
Subject(s)
Blood Chemical Analysis , Reference Values , Adolescent , Child , Child, Preschool , Cross-Sectional Studies , Estradiol/blood , Female , Follicle Stimulating Hormone/blood , Humans , Infant , Luteinizing Hormone/blood , MaleABSTRACT
Carrot is generally regarded as a biennial plant with an obligatory vernalization requirement. Early spring cultivation makes plants vulnerable to premature bolting, which results in a loss of commercial value. However, our knowledge of flowering time genes and flowering mechanisms in carrot remain limited. Bolting behavior of D. carota ssp. carota 'Songzi', a wild species sensitive to flower induction by vernalization and photoperiod, and orange cultivar 'Amsterdam forcing', and their offspring were investigated in different growing conditions. We performed RNA-seq to identify the flowering time genes, and digital gene expression (DGE) analysis to examine their expression levels. The circadian patterns of related genes were identified by qPCR. The results showed bolting behavior of carrot was influenced by low temperature, illumination intensity and photoperiod. A total of 45 flowering time-related unigenes were identified, which were classified into five categories including photoperiod, vernalization, autonomous and gibberellin pathway, and floral integrators. Homologs of LATE ELONGATED HYPOCOTYL (LHY) and CONSTANS-LIKE 2 (COL2) were more highly expressed under short day condition than under long day condition. Homologs of COL2, CONSTANS-LIKE 5 (COL5), SUPPRESSION OF OVEREXPRESSION OF CONSTANS 1 (SOC1), FLOWERING LOCUS C (FLC) and GIBBERELLIC ACID INSENSITIVE (GAI) were differentially expressed between 'Songzi' and 'Amsterdam forcing'. The homolog of COL2 (Dct43207) was repressed by light, but that of COL5 (Dct20940) was induced. A preliminary model of genetic network controlling flowering time was constructed by associating the results of DGE analysis with correlation coefficients between genes. This study provides useful information for further investigating the genetic mechanism of flowering in carrot.
Subject(s)
Daucus carota/genetics , Gene Expression Regulation, Plant , Gene Regulatory Networks , Photoperiod , Transcriptome , Circadian Clocks , Daucus carota/growth & development , Daucus carota/physiology , Daucus carota/radiation effects , Flowers/genetics , Flowers/growth & development , Flowers/physiology , Flowers/radiation effects , Gene Expression Profiling , Light , Phylogeny , Time FactorsABSTRACT
BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. OBJECTIVES: We aimed to identify the expression pattern of microRNAs (miRNAs or miRs) at different stages of skin cancer progression in a panel of murine skin cancer cell lines. Owing to the increasing importance of miRNAs in the pathogenesis of cancer, we considered the possibility that miRNAs could help to define the prognosis of CSCC and aimed to evaluate the potential use of miR-203 and miR-205 as biomarkers of prognosis in human tumours. METHODS: Seventy-nine human primary CSCCs were collected at the University Hospital of Salamanca in Spain. We identified differential miRNA expression patterns at different stages of CSCC progression in a well-established panel of murine skin cancer cell lines, and then selected miR-205 and miR-203 to evaluate their association with the clinical prognosis and evolution of human CSCC. RESULTS: miR-205 was expressed in tumours with pathological features recognized as indicators of poor prognosis such as desmoplasia, perineural invasion and infiltrative growth pattern. miR-205 was mainly expressed in undifferentiated areas and in the invasion front, and was associated with both local recurrence and the development of general clinical events of poor evolution. miR-205 expression was an independent variable selected to predict events of poor clinical evolution using the multinomial logistic regression model described in this study. In contrast, miR-203 was mainly expressed in tumours exhibiting the characteristics associated with a good prognosis, was mainly present in well-differentiated zones, and rarely expressed in the invasion front. Therefore, the expression and associations of miR-205 and miR-203 were mostly mutually exclusive. Finally, using a logistic biplot we identified three clusters of patients with differential prognosis based on miR-203 and miR-205 expression, and pathological tumour features. CONCLUSIONS: miR-205 and miR-203 tended to exhibit mutually exclusive expression patterns in human CSCC. This work highlights the utility of miR-205 and miR-203 as prognostic markers in CSCC.