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Diabetic ketoacidosis (DKA) is associated with dehydration and which can cause acute kidney injury (AKI). The proportion of AKI in children and adolescents with DKA has not been reported in East Asian population. This study aimed to identify the prevalence of AKI and to determine whether there is an association between AKI severity and recovery time from metabolic acidosis in children and adolescents with DKA. Medical records of children and adolescents (aged 1.5 times the calculated expected baseline creatinine level. Patients were divided into three groups based on AKI severity: no AKI, mild AKI, and severe AKI. In total, 170 (56.5%) patients with DKA presented AKI (mild AKI, 116 [38.5%]; severe AKI, 54 [18.0%]). Heart rate and laboratory parameters related to dehydration, such as corrected sodium level and blood urea nitrogen, were strongly associated with AKI development (P<0.01). Blood pH, plasma glucose, and potassium levels were also associated with AKI. A negative correlation with borderline significance between the estimated glomerular filtration rate (eGFR) and recovery time from metabolic acidosis was observed in the severe AKI group. AKI was highly prevalent in children and adolescents with DKA. An association between AKI and biomarkers indicating dehydration was noted. The recovery time from metabolic acidosis following treatment may be longer in children with a decreased eGFR who present with severe AKI. AKI is a common complication in children with DKA.

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21-1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15-1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27-2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22-2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D' = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.

Graves disease (GD) is the most common cause of thyrotoxicosis in children and adolescents, accounting for 15% of all thyroid diseases during childhood. Anti-thyroid drugs (ATD) are recommended as the first-line treatment in children and adolescents. However, the remission rate is lower in children than in adults, and the optimal treatment duration and favorite factors associated with remission remain unknown. We aimed to investigate long-term outcomes of pediatric GD patients receiving ATD. We retrospectively reviewed medical charts of 300 pediatric GD subjects, who were initially treated with ATD and followed up for more than one year, from 1985 to 2017 at MacKay Children’s Hospital. The 300 patients comprised 257 (85.7%) females and 43 (14.3%) males, median age at diagnosis was 11.6 (range 2.7-17.8) years, and median follow-up period was 4.7 (range 1.1-23.9) years. Overall, 122 patients achieved the criteria for discontinuing ATD treatment, seven-nine (39.9%) patients achieved remission, with a median follow-up period of 5.3 (range 1.5-20.1) years. Patients in the remission group were more likely to be aged < 5 years (remission vs relapse vs. ongoing ATD; 11.4 vs. 0 vs. 2.6%, P=0.02), less likely to have a family history of thyroid disease (24.1 vs. 42.1 vs. 52.6%, P=0.001), and had lower TRAb levels (42.8 vs. 53.6 vs. 65.1%, P=0.02). Conclusion: Long-term ATD remains an effective treatment option for GD in children and adolescents. Pediatric GD patients aged < 5 years, having no family history of thyroid disease and having lower TRAb levels were more likely to achieve remission.

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has one of the poorest prognosis. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined that IL-24, an IL-20 subfamily cytokine member, was increased both in the serum of IPF patients and the bronchoalveolar lavage fluid (BALF) of mice following bleomycin (BLM)-induced pulmonary fibrosis. As a result, IL-24 deficiency protected mice from BLM-induced lung injury and fibrosis. Specifically, loss of IL-24 significantly attenuated transforming growth factor β1 (TGF-β1) production and reduced M2 macrophage infiltration in the lung of BLM-induced mice. Mechanistically, IL-24 alone did not show a perceptible impact on the induction of M2 macrophages, but it synergized with IL-4 to promote M2 program in macrophages. IL-24 suppressed IL-4-induced expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, through which it enhanced signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma (STAT6/PPARγ) signaling, thereby promoting IL-4-induced production of M2 macrophages. Collectively, our data support that IL-24 synergizes with IL-4 to promote macrophage M2 program contributing to the development of pulmonary fibrosis.

Background The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. Methods Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. Results 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. Conclusions Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.

Lung metastasis and relapse in osteosarcoma (OS) patients indicate poor prognosis. Here, we identified significantly decreased expression of miR-382 in highly metastatic OS cell lines and relapsed OS samples compared to their parental cell lines and primary OS samples, respectively. In addition, our clinical data showed that the miR-382 expression level was inversely associated with relapse and positively associated with metastasis-free survival in OS patients. The overexpression of miR-382 suppressed epithelial–mesenchymal transition (EMT) and metastasis. This overexpression also decreased the cancer stem cell (CSC) population and function in OS cells. In contrast, inhibition of miR-382 stimulated EMT and metastasis and increased CSC population in OS cells. In addition, our in vivo experiments showed that the overexpression of miR-382 inhibited CSC-induced tumor formation, and the combination of miR-382 with doxorubicin prevented disease relapse in OS patients. Furthermore, we demonstrated that miR-382 exerted its tumor-suppressing potential by directly targeting Y box-binding protein 1 (YB-1) in OS. Taken together, our findings suggest that miR-382 functions as a tumor suppressor function and that the overexpression of miR-382 is a novel strategy to inhibit tumor metastasis and prevent CSC-induced relapse in OS.

Background Neonatal hypoxic-ischemic brain damage (HIBD), a leading cause of neonatal mortality, has intractable sequela such as epilepsy that seriously affected the life quality of HIBD survivors. We have previously shown that ion channel dysfunction in the central nervous system played an important role in the process of HIBD-induced epilepsy. Therefore, we continued to validate the underlying mechanisms of TRPV1 as a potential target for epilepsy. Methods Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. Primarily cultured astrocytes were used to assess the expression of TRPV1, glial fibrillary acidic protein (GFAP), cytoskeletal rearrangement, and inflammatory cytokines by using Western blot, q-PCR, and immunofluorescence. Furthermore, brain electrical activity in freely moving mice was recorded by electroencephalography (EEG). TRPV1 current and neuronal excitability were detected by whole-cell patch clamp. Results Astrocytic TRPV1 translocated to the membrane after OGD. Mechanistically, astrocytic TRPV1 activation increased the inflow of Ca 2+ , which promoted G-actin polymerized to F-actin, thus promoted astrocyte migration after OGD. Moreover, astrocytic TRPV1 deficiency decreased the production and release of pro-inflammatory cytokines (TNF, IL-6, IL-1β, and iNOS) after OGD. It could also dramatically attenuate neuronal excitability after OGD and brain electrical activity in HIBD mice. Behavioral testing for seizures after HIBD revealed that TRPV1 knockout mice demonstrated prolonged onset latency, shortened duration, and decreased seizure severity when compared with wild-type mice. Conclusions Collectively, TRPV1 promoted astrocyte migration thus helped the infiltration of pro-inflammatory cytokines (TNF, IL-1β, IL-6, and iNOS) from astrocytes into the vicinity of neurons to promote epilepsy. Our study provides a strong rationale for astrocytic TRPV1 to be a therapeutic target for anti-epileptogenesis after HIBD.

Background Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. Results Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery ( P  = 1.27 × 10 − 6 , OR = 1.55) and validation ( P  = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). Conclusions Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. Trial registration Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Astrocytes are critical regulators of the immune/inflammatory response in several human central nervous system (CNS) diseases. Emerging evidence suggests that dysfunctional astrocytes are crucial players in seizures. The objective of this study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in 4-aminopyridine (4-AP)-induced seizures and the underlying mechanism. We also provide evidence for the role of Yes-associated protein (YAP) in seizures. 4-AP was administered to mice or primary cultured astrocytes. YAP-specific small interfering RNA (siRNA) was administered to primary cultured astrocytes. Mouse brain tissue and surgical specimens from epileptic patient brains were examined, and the results showed that TRPV4 was upregulated, while astrocytes were activated and polarized to the A1 phenotype. The levels of glial fibrillary acidic protein (GFAP), cytokine production, YAP, signal transducer activator of transcription 3 (STAT3), intracellular Ca2+([Ca2+]i) and the third component of complement (C3) were increased in 4-AP-induced mice and astrocytes. Perturbations in the immune microenvironment in the brain were balanced by TRPV4 inhibition or the manipulation of [Ca2+]i in astrocytes. Knocking down YAP with siRNA significantly inhibited 4-AP-induced pathological changes in astrocytes. Our study demonstrated that astrocytic TRPV4 activation promoted neuroinflammation through the TRPV4/Ca2+/YAP/STAT3 signaling pathway in mice with seizures. Astrocyte TRPV4 inhibition attenuated neuroinflammation, reduced neuronal injury, and improved neurobehavioral function. Targeting astrocytic TRPV4 activation may provide a promising therapeutic approach for managing epilepsy.

Background Lung function is constantly changing over the life course. Although the relation of cross-sectional lung function measure and adverse outcomes has been reported, data on longitudinal change and subsequent cardiovascular (CV) events risks are scarce. Therefore, this study is to determine the association of longitudinal change in lung function and subsequent cardiovascular risks. Methods This study analyzed the data from four prospective cohorts. Subjects with at least two lung function tests were included. We calculated the rate of forced respiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decline for each subject and categorized them into quartiles. The primary outcome was CV events, defined as a composite of coronary heart disease (CHD), chronic heart failure (CHF), stroke, and any CV death. Cox proportional hazards regression and restricted cubic spline models were applied. Results The final sample comprised 12,899 participants (mean age 48.58 years; 43.61% male). Following an average of 14.79 (10.69) years, 3950 CV events occurred. Compared with the highest FEV1 quartile (Q4), the multivariable HRs for the lowest (Q1), 2nd (Q2), and 3rd quartiles (Q3) were 1.33 (95%CI 1.19, 1.49), 1.30 (1.16, 1.46), and 1.07 (0.95, 1.21), respectively. Likewise, compared with the reference quartile (Q4), the group that experienced a faster decline in FVC had higher HRs for CV events (1.06 [95%CI 0.94–1.20] for Q3, 1.15 [1.02–1.30] for Q2, and 1.28 [1.14–1.44] for Q1). The association remained robust across a series of sensitivity analyses and nearly all subgroups but was more evident in subjects < 60 years. Conclusions We observed a monotonic increase in risks of CV events with a faster decline in FEV1 and FVC. These findings emphasize the value of periodic evaluation of lung function and open new opportunities for disease prevention.