[Show abstract][Hide abstract] ABSTRACT: Objective:
We investigated whether the frequency, phenotype, and suppressive function of CD4+FOXP3+ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls.
Design and methods:
Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4-35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (-) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4+CD25bright were co-cultured with autologous CD4+CD25- target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function.
Despite a lower frequency of CD4+ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+CD25- T cells was significantly impaired in the TS (-) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (-) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group.
The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To investigate the prevalence of thyroid dysfunction, autoimmune thyroid disease (AITD), and simple goiter at goiter diagnosis, and to analyze the natural course of simple goiter and predictors for progression to AITD and/or thyroid dysfunction.
In total, 939 patients (770 females, 5.0-17.9 years) with goiter were reviewed retrospectively. Anthropometrics, pubertal status, goiter grade, and family history (FH) of thyroid disease were investigated. Simple goiter was defined as euthyroid goiter without pathologic cause, after excluding AITD and isolated nonautoimmune hyperthyrotropinemia (iso-NAHT).
At diagnosis, 36.9% of children showed thyroid dysfunction and/or AITD (euthyroid AITD [9.9%], hyper- or hypothyroid AITD [18.4%], iso-NAHT [8.6%]). Risk for subsequent medication was higher in euthyroid AITD than simple goiter (20.4% vs 0.3%, P < .001). Hashimoto thyroiditis (HT) and iso-NAHT developed in 5.2% and 6.6% of patients initially diagnosed with simple goiter during the median 2.0-year follow-up. Compared with the persistent simple goiter group, the HT group had greater FH (54.8% vs 23.6%) and unchanged or increasing goiter size (89.3% vs 71.8%), and the iso-NAHT group had a higher proportion of patients within the upper tertile range of baseline thyrotropin levels (71.8% vs 24.9%) and unchanged or increasing goiter size (86.8% vs 71.8%; all P < .05).
Thyroid disorders were detected in one-third of pediatric patients presenting with goiter. The higher risk for thyroid dysfunction needing medication in patients with euthyroid AITD emphasizes the importance of autoantibody evaluation at diagnosis. During simple goiter follow-up, progression to HT or iso-NAHT occurs, especially in patients with FH or persistent goiter.
No preview · Article · Dec 2015 · The Journal of pediatrics
[Show abstract][Hide abstract] ABSTRACT: Trichomonas vaginalis is a flagellated protozoan parasite that causes vaginitis and cervicitis in women and asymptomatic urethritis and prostatitis in men. Mast cells have been reported to be predominant in vaginal smears and vaginal walls of patients infected with T. vaginalis. Mitogen-activated protein kinase (MAPK), activated by various stimuli, have been shown to regulate the transcriptional activity of various cytokine genes in mast cells. In this study, we investigated whether MAPK is involved in ROS generation and exocytotic degranulation in HMC-1 cells induced by T. vaginalis-derived secretory products (TvSP). We found that TvSP induces the activation of MAPK and NADPH oxidase in HMC-1 cells. Stimulation with TvSP induced phosphorylation of MAPK and p47phox in HMC-1 cells. Stimulation with TvSP also induced up-regulation of CD63, a marker for exocytosis, along the surfaces of human mast cells. Pretreatment with MAPK inhibitors strongly inhibited TvSP-induced ROS generation and exocytotic degranulation. Finally, our results suggest that TvSP induces intracellular ROS generation and exocytotic degranulation in HMC-1 via MAPK signaling.
Preview · Article · Oct 2015 · The Korean Journal of Parasitology
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of type 1 diabetes mellitus (T1DM) in children and adolescents has increased worldwide. However, the epidemiology of T1DM among Korean youth has not been reported since 2001. We investigated the incidence of T1DM in Korean children and adolescents from 2012 to 2014 and compared it with data from 1995 to 2000.
Patients and methods:
Data were obtained from the National Health Insurance Service (NHIS) registry, and age- and sex-specific incidence rates were calculated per 100 000 population.
In total, 706 patients (326 boys and 380 girls, aged <15 yr) with T1DM were registered in the NHIS during 2012-2014. The incidence rate per 100 000 population was 3.19 (95% confidence interval [CI] 2.96-3.43). We found incidence rates of 1.68, 3.16, and 4.46 in children 0-4, 5-9, and 10-14 yr, respectively. The T1DM incidence was 2.84 in boys and 3.56 in girls. A higher T1DM incidence was seen during 2012-2014 than from 1995-2000 (incidence rate ratio 2.33; p < 0.001). The incidence rate ratios between 1995-2000 and 2012-2014 were 2.31, 2.20, and 2.27 in children 0-4, 5-9, and 10-14 yr, respectively. The annual increase in T1DM incidence was 5.6% (95% CI 5.0-6.3%) between 1995 and 2014.
We observed a significant increase in the T1DM incidence. This increase was higher in boys than in girls, and was highest in children aged 0-4 yr. Studies are needed to evaluate the long-term epidemiological trend of T1DM incidence.
No preview · Article · Sep 2015 · Pediatric Diabetes
[Show abstract][Hide abstract] ABSTRACT: We established the timing of peak bone mass acquisition and body composition maturation and provide an age- and sex-specific body composition and bone density reference database using dual-energy X-ray absorptiometry in Korean subjects 10–25 years of age. Reference percentiles and curves were developed for bone mineral content
(BMC), bone mineral density (BMD) of the whole body, the lumbar spine, and the femoral neck, and for fat mass (FM) and lean mass (LM) of 1969 healthy participants (982 males) who participated in the 2009–2010 Korean National Health and Nutrition Examination Survey. Additionally, bone mineral apparent density (BMAD), FM index, and LM index were calculated to adjust for body size. BMC and BMD at all skeletal sites as well as LM increased with age, reaching plateaus at 17–20 years of age in females and 20–23 years of age in males. The femoral neck was the first to reach a bone mass plateau, followed by the lumbar spine and then the whole body. Spine BMAD increased with age in both sexes, but femoral and whole-body BMAD remained the same over time. Females displayed a dramatic increase in FM during puberty, but the FM of males decreased until mid-puberty. These findings indicate that bone health and body composition should be monitored using a normal reference database until the late second to early third decade of life, when statural growth and somatic maturation are completed.
No preview · Article · Jun 2015 · Journal of Bone and Mineral Metabolism
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that overweight or obese children might develop type 1 diabetes mellitus (T1DM) early despite residual beta-cell function. Factors independently associated with preservation of C-peptide level were analyzed.
We retrospectively reviewed the medical data of 135 children aged 2.1-16.5 years with autoimmune T1DM. Body mass index (BMI), pubertal stage, and glycosylated hemoglobin (HbA1c) and C-peptide levels were evaluated. Patients were assigned to underweight (22.2%), normal weight (63.7%), and overweight or obese (14.1%) groups according to their BMI.
Preservation of serum C-peptide levels (≥0.6 ng/mL) was found in 43.0% of subjects. With increasing BMI, the proportions of children with preserved C-peptide levels increased from 33.3% to 41.9% to 63.2%, with marginal significance (P=0.051). Interaction analysis indicated no effect of BMI score on age at onset associated with serum C-peptide levels. The lower the C-peptide level, the younger the age of onset (P<0.001), after adjustment for BMI z-score and HbA1c level. However, no significant relationship between BMI z-score or category and onset age was evident. Upon multivariate-adjusted modeling, the odds that the C-peptide level was preserved increased by 1.2 fold (P=0.001) per year of life, by 3.1 folds (P=0.015) in children presenting without (compared to with) ketoacidosis, and by 5.0 folds (P=0.042) in overweight or obese (compared to underweight) children.
Overweight or obese children had slightly more residual beta-cell function than did underweight children. However, we found no evidence that obesity temporally accelerates T1DM presentation.
[Show abstract][Hide abstract] ABSTRACT: Context: Large-sample studies with long-term follow-up data are limited for pediatric patients with thyroid cancer. Objective: Secular changes in clinicopathological characteristics and outcomes in pediatric patients with thyroid cancer were investigated and compared with those of adults. Design and Patients: A retrospective review of 150 pediatric patients with thyroid cancer managed between 1980 and 2013 was conducted. The long-term outcomes of 124 patients followed up for ≥12 months were evaluated. Predictors of recurrence-free survival (RFS) in pediatric patients with papillary thyroid cancer (ped-PTC group) were compared with those of 3071 adult patients. Results: The proportion of small tumors (<1 cm) increased from 9.0% before 2010 to 36.8% after 2010 (P < 0.001); however, neither pathologic presentations such as multifocality, extrathyroidal extension (ETE), lymph node (LN) metastasis, or lung metastasis nor the RFS rate changed over time. The 5- and 10-year recurrence rates (RRs) were 14.5% and 34.4% in pediatric patients, respectively. In respective analyses of the ped-PTC group and patients of all ages with PTC (all-ages group), rates of ETE, LN metastasis, and lung metastasis were higher with younger age (all P for trend < 0.05). RFS was lower in pediatric than adult patients aged 20-54 years (P < 0.005) and comparable with that of older patients (≥55 years). Only tumor multifocality and size predicted recurrence in the ped-PTC group (P < 0.05), whereas LN metastasis and ETE also predicted recurrence in the all-ages group (P < 0.01). Among patients in the all-ages group with multifocal tumors, pediatric patients had the lowest RFS (P < 0.05). Conclusions: The pathological characteristics and RRs of pediatric thyroid cancer have not changed over 33 years. Although younger patients present with more advanced disease, multifocality rather than age at diagnosis predicted recurrence. Recurrence was higher in pediatric than adult patients with multifocal PTC.
No preview · Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
[Show abstract][Hide abstract] ABSTRACT: Background:
Leukotriene B4 (LTB4) is a proinflammatory lipid mediator that elicits eosinophil exocytosis, leading to allergic inflammation. However, the detailed intracellular signaling mechanisms of eosinophil exocytosis induced by LTB4 are poorly understood. Herein, we report that NADPH oxidase (NOX)2-derived reactive oxygen species (ROS)-mediated BLT1 migration to the cell surface is required for exocytosis in human eosinophils induced by LTB4.
Peripheral blood eosinophils were purified and stimulated for up to 60 min with LTB4. The signaling role of NOX2-derived ROS in BLT1-dependent exocytosis in LTB4-stimulated eosinophils was investigated.
Stimulating eosinophils with LTB4 induced intracellular ROS production and surface upregulation of the exocytosis marker protein CD63 via BLT1-mediated signaling. LTB4 induced p47(phox) phosphorylation and 91(phox) expression required for NOX2 activation in a BLT1-dependent manner. Pretreatment with NOX2 inhibitors, but not mitochondria inhibitor, prevented LTB4-induced ROS generation and exocytosis. At 30 min after stimulation with LTB4, BLT1 expression at the cell surface was upregulated. LTB4-triggered surface upregulation of BLT1 was also blocked by inhibition of ROS generation with NOX2 inhibitors. Moreover, stimulation for 30 min with LTB4 resulted in the interaction of BLT1 with NOX2 by immunoprecipitation. LTB4-induced ROS generation, surface upregulation of BLT1 and exocytosis was also inhibited by pretreatment with a lipid raft disruptor, protein kinase C inhibitor, or Src kinase inhibitor.
These results suggest that NOX2-derived ROS-mediated BLT1 trafficking to the cell surface plays a key role in the exocytosis of human eosinophils induced by LTB4.
No preview · Article · Oct 2014 · International Archives of Allergy and Immunology
[Show abstract][Hide abstract] ABSTRACT: Entamoeba histolytica is a tissue-invasive protozoan parasite causing dysentery in humans. During infection of colonic tissues, amoebic trophozoites are able to kill host cells via apoptosis or necrosis, both of which trigger IL-8-mediated acute inflammatory responses. However, the signaling pathways involved in host cell death induced by E. histolytica have not yet been fully defined. In this study, we examined whether calpain plays a role in the cleavage of pro-survival transcription factors during cell death of colonic epithelial cells, induced by live E. histolytica trophozoites. Incubation with amoebic trophozoites induced activation of m-calpain in a time- and dose-dependent manner. Moreover, incubation with amoebae resulted in marked degradation of STAT proteins (STAT3 and STAT5) and NF-κB (p65) in Caco-2 cells. However, IκB, an inhibitor of NF-κB, was not cleaved in Caco-2 cells following adherence of E. histolytica. Entamoeba-induced cleavage of STAT proteins and NF-κB was partially inhibited by pretreatment of cells with a cell-permeable calpain inhibitor, calpeptin. In contrast, E. histolytica did not induce cleavage of caspase-3 in Caco-2 cells. Furthermore, pretreatment of Caco-2 cells with a calpain inhibitor, calpeptin (but not the pan-caspase inhibitor, z-VAD-fmk) or m-calpain siRNA partially reduced Entamoeba-induced DNA fragmentation in Caco-2 cells. These results suggest that calpain plays an important role in E. histolytica-induced degradation of NF-κB and STATs in colonic epithelial cells, which ultimately accelerates cell death.
Preview · Article · Oct 2014 · The Korean Journal of Parasitology
[Show abstract][Hide abstract] ABSTRACT: Purpose
Whether parental origin of the intact X chromosome and/or the presence of Y chromosome sequences (Yseq) play a role in three-year height response to growth hormone (GH) were investigated.
Paternal (Xp) or maternal (Xm) origin of X chromosome was assessed by microsatellite marker analysis and the presence of hidden Yseq was analyzed. The first-, second-, and third-year GH response was measured as a change in height z-score (Z_Ht) in Turner syndrome (TS) patients with 45,Xp (n=10), 45,Xm (n=15), and 45,X/46,X,+mar(Y) (Xm_Yseq) (n=8).
The mean baseline Z_Ht did not differ according to Xp or Xm origin, however the mean baseline Z_Ht was higher in the Xm_Yseq group than in Xm group, after adjusting for bone age delay and midparental Z_Ht (P=0.04). There was no difference in the height response to GH between the 3 groups. The height response to GH decreased progressively each year (P<0.001), such that the third-year increase in Z_Ht was not significant. This third-year decrease in treatment response was unaffected by Xp, Xm, and Xm_Yseq groups. Increasing GH dosage from the second to third-year of treatment positively correlated with the increase in Z_Ht (P=0.017).
There was no evidence of X-linked imprinted genes and/or Yseq affecting height response to 3 years of GH therapy. Increasing GH dosages may help attenuate the decrease in third-year GH response in TS patients with 45,X and/or 46,X/+mar(Y).
[Show abstract][Hide abstract] ABSTRACT: The enteric protozoan parasite Entamoeba histolytica is the causative agent of human amebiasis. During infection, adherence of E. histolytica through Gal/GalNAc lectin on the surface of the amoeba can induce caspase-3-dependent or -independent host cell death. Phosphorylinositol 3-kinase (PI3K) and protein kinase C (PKC) in E. histolytica play an important function in the adhesion, killing, or phagocytosis of target cells. In this study, we examined the role of amoebic PI3K and PKC in amoeba-induced apoptotic cell death in Jurkat T cells. When Jurkat T cells were incubated with E. histolytica trophozoites, phosphatidylserine (PS) externalization and DNA fragmentation in Jurkat cells were markedly increased compared to those of cells incubated with medium alone. However, when amoebae were pretreated with a PI3K inhibitor, wortmannin before being incubated with E. histolytica, E. histolytica-induced PS externalization and DNA fragmentation in Jurkat cells were significantly reduced compared to results for amoebae pretreated with DMSO. In addition, pretreatment of amoebae with a PKC inhibitor, staurosporine strongly inhibited Jurkat T cell death. However, E. histolytica-induced cleavage of caspase-3, -6, and -7 were not inhibited by pretreatment of amoebae with wortmannin or staurosporin. In addition, we found that amoebic PI3K and PKC have an important role on amoeba adhesion to host compartment. These results suggest that amebic PI3K and PKC activation may play an important role in caspase-independent cell death in Entamoeba-induced apoptosis.
Preview · Article · Aug 2014 · The Korean Journal of Parasitology
[Show abstract][Hide abstract] ABSTRACT: Entamoeba histolytica is an extracellular tissue parasite causing colitis and occasional liver abscess in humans. E. histolytica-derived secretory products (SPs) contain large amounts of cysteine proteases (CPs), one of the important amoebic virulence factors. Although tissue-residing mast cells play an important role in the mucosal inflammatory response to this pathogen, it is not known whether the SPs induce mast cell activation. In this study, when human mast cells (HMC-1 cells) were stimulated with SPs collected from pathogenic wild-type amoebae, interleukin IL-8 mRNA expression and production were significantly increased compared with cells incubated with medium alone. Inhibition of CP activity in the SPs with heat or the CP inhibitor E64 resulted in significant reduction of IL-8 production. Moreover, SPs obtained from inhibitors of cysteine protease (ICP)-overexpressing amoebae with low CP activity showed weaker stimulatory effects on IL-8 production than the wild-type control. Preincubation of HMC-1 cells with antibodies to human protease-activated receptor 2 (PAR2) did not affect the SP-induced IL-8 production. These results suggest that cysteine proteases in E. histolytica-derived secretory products stimulate mast cells to produce IL-8 via a PAR2-independent mechanism, which contributes to IL-8-mediated tissue inflammatory responses during the early phase of human amoebiasis.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Brain magnetic resonance imaging (MRI) findings and factors predictive of pathological brain lesions in boys with precocious puberty (PP) or early puberty (EP) were investigated.
Sixty-one boys with PP or EP who had brain MRI performed were included. PP was classified into the central or peripheral type. Brain MRI findings were categorized into group I (pathological brain lesion known to cause puberty; newly diagnosed [group Ia] or previously diagnosed [group Ib]); group II (brain lesion possibly related to puberty); and group III (incidental or normal findings). Medical history, height, weight, hormone test results, and bone age were reviewed.
Brain lesions in groups I and II were detected in 17 of 23 boys (74%) with central PP, 9 of 30 boys (30%) with EP, and 7 of 8 boys (88%) with peripheral PP. All brain lesions in boys with peripheral PP were germ cell tumors (GCT), and 3 lesions developed later during follow-up. Group I showed earlier pubertal onset (P<0.01) and greater bone age advancement (P<0.05) than group III. Group III had lower birth weight and fewer neurological symptoms than "Ia and II" (all P<0.05).
Earlier onset of puberty, greater bone age advancement, and/or neurological symptoms suggested a greater chance of pathological brain lesions in boys with central PP or EP. All boys with peripheral PP, even those with normal initial MRI findings, should be evaluated for the emergence of GCT during follow-up.