Changes in serum bone turnover markers and bone mineral density Z-score in children with osteogenesis imperfecta after zoledronic acid treatment.

The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with osteogenesis imperfecta (OI) after intravenous bisphosphonate therapy and their association with age and estimated glomerular filtration rate (eGFR). This retrospective study analyzed data from 10 pediatric OI patients treated with intravenous zoledronic acid for over 1 year. Patients' clinical data were collected. The levels of BTMs and BMD Z-score before and after zoledronic acid treatment were analyzed. Significant improvement in BMD Z-score was observed after 6 and 12 months of treatment compared to baseline (all p < 0.05). The N-terminal propeptide of type I procollagen (PINP) levels decreased over time (all p < 0.05), indicating that zoledronic acid treatment decreased bone turnover. The levels of beta-C-terminal telopeptide of type I collagen remained stable after treatment. No correlation was found between PINP level and age, eGFR, or BMD (all p > 0.05). Bisphosphonate treatment can improve BMD and decrease bone turnover (indicated by decreased levels of PINP) in pediatric OI patients. PINP may serve as an independent indicator for monitoring the efficacy of bisphosphonate treatment in pediatric OI patients, particularly in those under the age of 6, where standardized BMD Z-score criteria are lacking.

Gut Microbiota Moderates Multimodal Brain Structure-Function Integration and Behavioral Cognition in Growth Hormone Deficient Children.

INTRODUCTION: Previous brain studies of growth hormone deficiency (GHD) often used single-modal neuroimaging, missing the complexity captured by multimodal data. Growth hormone affects gut microbiota and metabolism in GHD. However, from a gut-brain axis (GBA) perspective, the relationship between abnormal GHD brain development and microbiota alterations remains unclear. The ultimate goal is to uncover the manifestations underlying GBA abnormalities in GHD and idiopathic short stature (ISS). METHODS: Participants included 23 GHD and 25 ISS children. The fusion independent component analysis was applied to integrate multimodal brain data (high-resolution structural, diffusion tensor, and resting-state functional MRI) covering regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and white matter fractional anisotropy (FA). Gut microbiome diversity and metabolites were analyzed using 16S sequencing and proton nuclear magnetic resonance (1H-NMR). Associations between multimodal neuroimaging and cognition were assessed using moderation analysis. RESULTS: Six independent components (IC) of ReHo, ALFF, and FA differed significantly between GHD and ISS patients, with three functional components linked to the processing speed index. GHD individuals showed higher levels of acetate, nicotinate, and lysine in microbiota metabolism. Higher alpha diversity in GHD strengthened connections between ReHo-IC1, ReHo-IC5, ALFF-IC1, and the processing speed index, while increasing agathobacter levels in ISS weakened the link between ALFF-IC1 and the speech comprehension index. CONCLUSIONS: Our findings uncover differing brain structure and functional fusion in GHD, alongside microbiota metabolism of short-chain fatty acids. Additionally, microbiome influences connections between neuroimaging and cognition, offering insight into diverse GBA patterns in GHD and ISS, enhancing our understanding of the disease's pathophysiology and interventions.

Impact of different growth hormone levels on gut microbiota and metabolism in short stature.

BACKGROUND: Growth hormone deficiency(GHD) and idiopathic short stature(ISS) are the primary causes of short stature in children. Animal experiments have revealed a link between growth hormone(GH), gut microbiota and metabolism, however, limited information is available from human trials. METHODS: Fecal samples collected from GHD (n = 36), ISS (n = 32) and healthy control (HC) children(n = 16) were subjected to microbiome (16 S rRNA gene sequencing) and metabolome (nuclear magnetic resonance,NMR) analyses. RESULTS: GHD, ISS and HC exhibit distinct differences in beta diversity of gut microbiota.In addition, short stature (GHD and ISS) exhibit higher relative abundance of Prevotellaceae_NK3B31_group at genus level compared to HC, whereas Rodentibacter, Rothia, and Pelomonas showed lower abundance. Additionally,Fusobacterium_mortiferum was identified as the characteristic species of GHD. Moreover, glucose metabolism, pyruvate metabolism and pyrimidine metabolism might play significant roles for distinguishing between GHD and normal GH groups (ISS and HC). Furthermore, a disease prediction model based on differential bacteria and metabolites between GHD and ISS exhibited high diagnostic value. CONCLUSION: These findings highlight the characteristics of different GH levels on the gut microbiota and metabolism in children, providing novel perspectives for early diagnosis and prognostic treatment of short stature with abnormal GH levels. IMPACT: The key message of our study is to identify human-relevant gut microbiota and host metabolic patterns that are interfered with growth hormone levels, and to develop biomarker models to identify short stature associated with growth hormone deficiency. We used idiopathic short stature as a control group for growth hormone deficiency, complementing the absence of height as a factor in the existing literature. Our study ultimately hopes to shed new light on the diagnosis and treatment of short stature children associated with growth hormone deficiency.

Novel homozygous mutations in AIRE leading to APS-1 and potential mechanisms based on bioinformatics analysis.

Background: Autoimmune Poly-endocrine Syndrome Type 1 (APS-1), also known as autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a single-gene hereditary disorder usually characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenocortical insufficiency. This syndrome is very rare in China. Methods: For our reported patient, we employed clinical and laboratory examinations along with genetic identification. For previously reported cases, we summarized findings based on meta-analysis principles. To investigate the AIRE gene's role in disease, we utilized bioinformatics analysis with existing databases and R language processing. Results: Nucleotide sequence analysis revealed two novel homozygous missense mutations (c.74C > G; c.1612C > T) in the patient's AIRE gene, confirming APS-1 diagnosis. The 3D structure of these mutation sites was described for the first time, showing that altered side chains could affect AIRE protein function. We analyzed 16 genetically diagnosed APS-1 Chinese patients, summarized the AIRE genetic spectrum, and found that exons 1, 2, 3, and 5 were most commonly affected. Hypoparathyroidism and adrenal insufficiency were the most common clinical manifestations (56%-93%), followed by hypothyroidism (31.25%), hypogonadism (12.5%), type 2 diabetes (6.25%), and type 1 diabetes (6.25%). Bioinformatics analysis indicated that AIRE mutations cause antigen presentation abnormalities in immune cells, leading to excessive endogenous and reduced exogenous antigen presentation. Conclusions: Our study summarized the clinical features of APS-1 caused by AIRE gene mutations and explored underlying mechanisms. For some patients, the prophylactic use of antimicrobial agents may be beneficial. These findings guide early genetic screening and inform potential research directions for treatment strategies.

Gastrodin ameliorates acute pancreatitis by modulating macrophage inflammation cascade via inhibition the p38/NF-κB pathway.

Acute pancreatitis (AP) is a prevalent, destructive, non-infectious pancreatic inflammatory disease, which is usually accompanied with systemic manifestations and poor prognosis. Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-d-glucopyranoside) has ideal anti-inflammatory effects in various inflammatory diseases. However, its potential effects on AP had not been studied. In this study, serum biochemistry, H&E staining, immunohistochemistry, immunofluorescence, western blot, real-time quantitative PCR (RT-qPCR) were performed to investigate the effects of Gastrodin on caerulein-induced AP pancreatic acinar injury model in vivo and lipopolysaccharide (LPS) induced M1 phenotype macrophage model in vitro. Our results showed that Gastrodin treatment could significantly reduce the levels of serum amylase and serum lipase while improving pancreatic pathological morphology. Additionally, it decreased secretion of inflammatory cytokines and chemokines, and inhibited the levels of p-p38/p38, p-IκB/IκB as well as p-NF-κB p-p65/NF-κB p65. Overall our findings suggested that Gastrodin might be a promising therapeutic option for patients with AP by attenuating inflammation through inhibition of the p38/NF-κB pathway mediated macrophage cascade.

Longitudinal unraveling: The impact of recombinant human growth hormone on spontaneous brain activity in children with short stature-A resting-state fMRI study.

Recombinant human growth hormone (rhGH) is an approved method to improve the growth and ameliorate behavioral issues in children with short stature. However, the data concerning the effects of rhGH treatment on spontaneous brain activity remains unclear. This study included 35 children with short stature, categorized into two groups: the treated group (n = 14) and the untreated group (n = 21). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessments at baseline and at the end of a one-year follow-up. The rs-fMRI based amplitude of low frequency fluctuation (ALFF) analysis method was employed to assess spontaneous brain activity. Interaction effects between rhGH and time on ALFF were detected using a mixed-effects analysis. Additionally, Stepwise regression analysis was conducted to investigate the associations between ALFF values and significant clinical indicators. The treated group exhibited significant improvements in height, weight, insulin-like growth factor-1 (IGF-1) levels, insulin-like growth factor binding protein 3 (IGFBP-3) levels, and processing speed index (PSI) when reevaluated from baseline. The interaction effect of rhGH × time was evident in the right putamen (RPUT), where the ALFF value showed a significant increase following rhGH treatment, while also demonstrating a notable positive correlation with height. Moreover, The main effect of time was manifested as a significant decrease in the ALFF value of the left dorsolateral superior frontal gyrus (LSFG) within the untreated group during the follow-up period, concurrently displaying a positive correlation with age. In conclusion, rhGH treatment not only has a positive effect on the growth, cognition, and behavior of children with short stature, but also improves and normalizes spontaneous brain activity.

Clinical heterogeneity and therapeutic options for idiopathic infantile hypercalcemia caused by CYP24A1 pathogenic variant.

OBJECTIVES: Infantile hypercalcemia-1 (HCINF1) is a rare disease caused by pathogenic variants in the CYP24A1 gene, resulting in the inability to metabolize active vitamin D. This leads to hypercalcemia and severe complications. CONTENT: On December 8th, 2022, a systematic literature search was conducted in PubMed, Wanfang, and CNKI using the keywords "hypercalcemia" and "CYP24A1". Data extraction included patient demographics, clinical presentation, treatment medications, and outcomes. The findings were synthesized to identify common patterns and variations among cases and to assess the efficacy of different therapies in reducing serum calcium. Our findings revealed two distinct peaks in the incidence of HCINF1 caused by CYP24A1 pathogenic variant. Kidney stones or renal calcifications were the most common clinical manifestations of the disease, followed by polyuria and developmental delay. Laboratory investigations showed hypercalcemia, elevated vitamin D levels, hypercalciuria, and low parathyroid hormone. Genetic analysis remains the only reliable diagnostic tool. Although there is no definitive cure for HCINF1, multiple drugs, including bisphosphonates, calcitonin, and rifampicin, have been used to control its symptoms. Blocking the production and intake of vitamin D is the preferred treatment option. SUMMARY AND OUTLOOK: Our review highlights the basic clinical and biochemical features of HCINF1 and suggests that targeted diagnostic and therapeutic strategies are needed to address the clinical heterogeneity of the disease. The insights gained from this study may facilitate the development of innovative treatments for HCINF1.

Successful treatment of hypercalcemia in a Chinese patient with a novel homozygous mutation in the CYP24A1 gene using zoledronic acid: a case report.

OBJECTIVES: To emphasize the significance of genetic mutations in idiopathic infantile hypercalcemia and the potential therapeutic effectiveness of zoledronic acid in managing hypercalcemia attributed to gene mutations. CASE PRESENTATION: A 1-year-old female infant was referred to our hospital. The patient developed hypercalcemia despite no vitamin D prophylaxis or intake. In the acute phase, conventional calcium-lowering treatments showed limited efficacy, while the administration of zoledronic acid demonstrated effectiveness in controlling hypercalcemia. Subsequently the patient maintained normal calcium levels via a low-calcium diet and avoiding vitamin D intake. Genetic testing confirmed a homozygous mutation (c.476G>C) in the CYP24A1 gene. CONCLUSIONS: Family screening and genetic counseling are crucial for early detection and prevention of hypercalcemia. This case emphasizes the importance of genetic mutations in disease development and the potential therapeutic efficacy of zoledronic acid in managing hypercalcemia attributed to gene mutations.

Activating calcium-sensing receptor gene variants in China: a case report of hypocalcaemia and literature review.

OBJECTIVES: Autosomal dominant hypocalcaemia 1 (ADH1) is a rare autosomal dominant genetic disease, due to the activating mutations of the calcium-sensing receptor (CASR) gene. The current paper presents a severe case of ADH1 with intellectual backwardness, and systematically reviews the reported 17 ADH1 patients in China. CASE PRESENTATION: A 7 years old boy with recurrent seizures over 1 year was admitted at Yuying children' hospital, the clinical centre of south province of Zhejiang. Auxiliary examinations demonstrated hypocalcaemia, hyperphosphatemia, hypomagnesemia, hypercalciuria, low parathyroid hormone (PTH), basal ganglia calcifications, normal range of serum creatinine, and 25-hydroxyvitamin D. Wechsler's intelligence test result indicated intellectually backward. The patient's genotype found a heterozygous variant in CASR gene, c.T416C p. (Ile139Thr). This article also systematically reviews the literatures on ADH1 in China and summarises the clinical characteristics and treatment. CONCLUSIONS: ADH1 can be a cause of idiopathic hypoparathyroidism. Recognition and rational treatment is important for symptom improvement and reducing high potential adverse effects.

The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway.

Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic ß cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic ß cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic ß cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic ß cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.

Downregulation of ACAN is Associated with the Growth hormone pathway and Induces short stature.

BACKGROUND: ACAN heterozygous mutations can cause short stature in patients with or without advanced bone age and have recently attracted researchers' attention. Growth hormone can be used to treat short stature induced by ACAN mutations; however, few studies have focused on the underlying mechanism of this treatment. METHODS: Four patients with new mutations were reported based on clinical data and genetic tests. We investigated the expression and Gene Ontology biological process enrichment of ACAN and GH pathways based on GTEx databases through bioinformatics analyses. The effect of ACAN on the growth hormone response evaluated in ATDC5 cells with a growth hormone stimulation test. RESULTS: Four mutations were reported in this study: c.619C > A, c.1967A > G, c.1888G > A, and c.1308_1309del. All patients' heights were under -2.5 SD, with one had advanced bone age, and two had GH deficiency. Two individuals received growth hormone therapy acquired variable levels of height SD score improvement. ACAN and the GH pathway were strongly associated; ACAN does not affect GHR but regulates the response to GH. Downregulating ACAN inhibited ATDC5 cell proliferation induced by GH. CONCLUSION: ACAN is associated with the GH pathway, revealing the potential mechanism underlying GH-targeted treatment for ACAN mutation-induced short stature. GH-promoting therapies may increase patients' heights.

Altered gray matter volume in children with newly diagnosed type 1 diabetes mellitus.

BACKGROUND: Type 1 diabetes mellitus (T1DM) affects the development of cognitive function in children, which may be due to deficits in brain structures or functions. It is unclear whether children with T1DM experience alterations in the gray matter (GM) structure at the initial stages of the disease. This study investigated GM structure alterations in children with newly diagnosed T1DM. METHODS: Based on 3D T1-weighted MR images, we investigated the gray matter volume (GMV) of 35 newly diagnosed T1DM children and 35 age- and sex-matched healthy controls using voxel-based morphometry. The brain regions with significant differences in GMV between the newly diagnosed T1DM children and the controls were extracted and the correlation with clinical data was assessed. RESULTS: Compared with the control group, children with newly diagnosed T1DM had a lower GMV in the right inferior and middle temporal gyri, right lingual gyrus, and left superior frontal gyrus. In T1DM subjects, the GMV of the right middle temporal gyrus was positively correlated with IQ but was negatively correlated with HbA1c. CONCLUSIONS: Our findings provide compelling evidence that GM abnormalities occur during early disease stages in T1DM children, which may be a potential neurobiological mechanism underlying cognitive deficits. IMPACT: Using an efficient method to analyze gray matter changes in T1DM is very important. The anterior, posterior, and temporal brain regions are susceptible to T1DM in children. Recent glucose variability may affect regional gray matter volume in children with newly diagnosed T1DM. Structural changes were documented in the gray matter of the brain even at the early stages of the disease in children with T1DM.

Prognostic and immunological significance of peroxisome proliferator-activated receptor gamma in hepatocellular carcinoma based on multiple databases.

Background: Peroxisome proliferator-activated receptor gamma (PPARG) plays some roles in preventing liver disease progression to hepatocellular carcinoma. However, there is limited information about the function of PPARG of in hepatocellular carcinoma. This study aimed to determine the significance of PPARG in immunological response and as a biomarker for hepatocellular carcinoma survival. Methods: We investigated the expression, prognosis, Kyoto Encyclopedia of Genes and Genomes/Gene Ontology biological process enrichment, and immune significance of PPARG using data from three databases-The Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus-through bioinformatics analysis as well as experimental verification in proliferation function of PPARG in HepG2 cell. Results: High PPARG expression in hepatocellular carcinoma tissues positively correlated with TP53 mutation, and predicted poor prognosis. The results of enrichment and immune infiltration showed that PPARG negatively correlated with the complement system and macrophage infiltration, and laboratory results support that PPARG regulate proliferation of HepG2 cell. Conclusions: PPARG is upregulated in hepatocellular carcinoma and it correlates with a worse prognosis. Moreover, PPARG may play an important role in the cell proliferation, complement system and immune cell infiltration in hepatocellular carcinoma.

Growth hormone deficiency interferes with dynamic brain networks in short children.

PURPOSE: This study aimed to explore the disparities in dynamic brain networks between children with growth hormone deficiency (GHD) and idiopathic short stature (ISS, non-growth hormone deficiency). METHODS: This study enrolled 65 children with GHD and 60 sex- and age-matched children with ISS. Resting-state functional magnetic resonance imaging (rs-fMRI) was performed for all participants to obtain information on dynamic regional homogeneity (dReHo) and functional connectivity (FC) in dynamic (dFC) or static (sFC) state. The rs-fMRI metrics were subsequently compared between the GHD and ISS groups. RESULTS: Compared to the ISS group, the GHD group showed significant dynamic abnormalities in intra-networks of the central executive and cerebellar networks and in inter-networks of the central executive network to attentional, sensorimotor, and visual networks, as well as cerebellar network to default mode, sensorimotor, and visual networks. In addition, FC changes in the dynamic state were different from those in the static state. CONCLUSIONS: The abnormal dynamics in intra- and inter-networks involved in cognitive, emotional, and motor functions in children with GHD extend the knowledge on brain functional alterations in children with GHD as reflected by dynamic changes in macroscopic neural activity patterns. These findings may help explain how GHD leads to various behavioral and cognitive deficits in children with short stature.

Role of angiogenesis in beta-cell epithelial-mesenchymal transition in chronic pancreatitis-induced diabetes.

Clinical evidence suggests that patients with chronic pancreatitis (CP) are prone to development of diabetes (chronic pancreatitis-related diabetes; CPRD), whereas the underlying mechanisms are not fully determined. Recently, we showed that the gradual loss of functional beta-cells in a mouse model for CPRD, partial pancreatic duct ligation (PDL), results from a transforming growth factor ß1 (TGFß1)-triggered beta-cell epithelial-mesenchymal transition (EMT), rather than from apoptotic beta-cell death. Here, the role of angiogenesis in CPRD-associated beta-cell EMT was addressed. We detected enhanced angiogenesis in the inflamed pancreas from CP patients by bioinformatic analysis and from PDL-mice. Inhibition of angiogenesis by specific antisera for vascular endothelial growth factor receptor 2 (VEGFR2), DC101, did not alter the loss of beta-cells and the fibrotic process in PDL-pancreas. However, DC101-mediated inhibition of angiogenesis abolished pancreatitis-induced beta-cell EMT and rendered it to apoptotic beta-cell death. Thus, our data suggest that angiogenesis promotes beta-cell survival in the inflamed pancreas, while suppression of angiogenesis turns beta-cell EMT into apoptotic beta-cell death. This finding could be informative during development of intervention therapies for CPRD.

Age and Gender-Specific Reference Intervals for Uric Acid Level in Children Aged 5-14 Years in Southeast Zhejiang Province of China: Hyperuricemia in Children May Need Redefinition.

Context: Hyperuricemia is defined when the plasma uric acid concentration is above 416 µmol/L (7 mg/dl) in male adults, or 357 µmol/L (6 mg/dl) in female adults. However, there are no explicit criteria yet for children. Objective: It is necessary to set up reference intervals for the uric acid level in different age groups among children. Materials and Methods: A total of 5,439 individuals (3,258 males, 2,181 females) were included in the final statistical analysis. Reference values of all age groups were determined by statistical descriptions. Multiple linear regression analysis was applied to determine the relationship between uric acid level, BMI, and age. Results: The level of uric acid increased with age. Gender differences in uric acid level occurred after the onset of puberty. Additionally, linear regression revealed a positive correlation between the uric acid level and BMI. Discussion and Conclusion: The reference range of the uric acid level in children is inconsistent with the previous viewpoint. Body mass index plays an important role in uric acid metabolism.

[Genetic analysis of a juvenile with maturity-onset diabetes of the young type 12].

OBJECTIVE: To explore the genetic basis for a juvenile with maturity-onset diabetes of the young type 12(MODY12). METHODS: High-throughput sequencing was carried out to screen for the variants. Candidate variant was verified by Sanger sequencing. Pathogenity of the variant was predicted by searching the genetic databases and analysis by using bioinformatic software. RESULTS: Genetic testing indicated that the patient and his mother have both carried a heterozygous c.3976G>A variant (p.Glu1326Lys) in exon 32 of the ABCC8 gene. Prediction of the protein structure suggested the variant to be deleterious. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be uncertain significance. CONCLUSION: Whether the c.3976G>A variant of the ABCC8 gene is the cause of the disease in this patient or not depends on the functional studies and more case data. Above finding has enriched the spectrum of ABCC8 gene variants.

Cardiac dysfunction associated with consumptive hypothyroidism in a case of hepatic haemangioma.

Not required for Clinical Vignette.

Establishment of an induced pluripotent stem cell line from a Noonan syndrome patient with the heterozygote mutation p.S257L (c.770C > T) in RAF1 gene.

Noonan Syndrome (NS) is an inherited autosome dominant disorder syndrome, which can be caused by the mutations of serine/threonine kinase rapidly accelerated fibrosarcoma 1 (RAF1) gene. Here, an induced pluripotent stem cell (iPSC) line named WMUi022-A derived from urine cells (UCs) of a 9-year-old male NS patient with the heterozygote RAF1 gene mutation p.S257L (c.770C > T) was established through the commercial Sendai virus reprogramming kit. The pluripotent markers like OCT4 and SOX2 can be expressed positively in WMUi022-A, which can be induced into three germ layers in vitro as well as maintain a normal karyotype (46, XY).