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Background: Asthma is a heterogeneous disease, characterized by chronic airway inflammation. Asthma exacerbations (AE) are episodes characterized by a progressive increase in symptoms of shortness of breath, cough, wheezing, or chest tightness with a decrease in lung function. There have been previous studies that examined the role of eosinophil-derived neurotoxin (EDN) in asthma, but there have been no studies of the role of EDN in children experiencing AE. Objective: In this study, we aimed to examine the association of EDN with lung function and prognosis in children admitted for severe AE. Methods: We enrolled 82 children who were admitted for severe AE at two different university hospitals in South Korea between January 2018 and December 2019. Blood tests, including white blood cell count, myeloperoxidase (MPO), total eosinophil count, EDN, C-reactive protein (CRP) level, and interleukin (IL) 4, IL-5, IL-10 values, and lung function were measured on admission and at discharge in each patient. Results: We observed significant decreases in the levels of MPO, EDN, CRP, and IL-4, with significant improvement in lung function after treatment. We then classified the subjects into two groups of different clinical phenotypes: eosinophilic asthma exacerbation (EAE) group and non-EAE group. EDN levels were higher and lung functions were lower in the EAE group. Also, we found that the EDN level was a significant biomarker useful for predicting the number of days for hospital stay. Conclusion: We found that EDN can act as a biomarker that reflects lung function, and that EDN could act as a prognostic biomarker, which demonstrated the complex role of EDN in children experiencing AE.

STUDY OBJECTIVES: To evaluate whether obstructive sleep apnea (OSA) and its severity are related to dyslipidemia and alanine transaminase elevation as a marker of nonalcoholic fatty liver disease in children. METHODS: The data collected from polysomnography, laboratory measurements (lipid profile and liver enzyme), and body mass index in children aged 0–18 years who visited the pediatric department between 2012 and 2018 were retrospectively analyzed. RESULTS: There were a total of 273 participants in the study (ages 0–6 years, 7–12 years, and 13–18 years: 61.9%, 26.4%, and 11.7%, respectively). In the ages 7–12 and 13–18 years groups, obesity was strongly associated with OSA severity (Cramer’s V = 0.498, P < .001). High-density lipoprotein cholesterol levels were significantly lower in the OSA group than in the non-OSA group, irrespective of the presence of obesity. In addition, high-density lipoprotein cholesterol levels were significantly different between the OSA severity groups after adjusting for body mass index (P = .000). In participants who were obese, moderate and severe OSA were associated with alanine transaminase elevation (P = .023 and P = .045, respectively). CONCLUSIONS: This study suggests that OSA may be an independent risk factor for dyslipidemia and that OSA and obesity have a synergistic effect on alanine transaminase elevation. Early diagnosis and treatment of OSA from childhood, especially in obese children, will reduce metabolic complications. CITATION: Kang EK, Jang MJ, Kim KD, Ahn YM. The association of obstructive sleep apnea with dyslipidemia in Korean children and adolescents: a single-center, cross-sectional study. J Clin Sleep Med. 2021;17(8):1599–1605.

The immunization schedule for the inactivated Japanese encephalitis (JE) vaccine in Korea is a two-dose primary series at 12–24 months of age and three booster doses at 12 months after primary schedule and at 6 and 12 years of age. The aim of this study was to investigate immunogenicity and safety of the third booster dose of the inactivated JE vaccine, as well as the long-term immunogenicity of the second booster dose in Korean children. Healthy children aged 11–13 years, primed and given four doses of inactivated JE vaccines were included. All subjects received the third booster dose of the JE vaccine. Neutralizing antibody (NTAb) titers were assessed before and 4–6 weeks after vaccination using plaque reduction neutralization test (PRNT), and were considered to be protective at ≥ 1:10. Local and systemic adverse events were monitored for 4 weeks after vaccination. Before and after booster vaccination, all seroprotection rates were 100%. Geometric mean titer (GMT) showed a 6.05–fold increase, from 139.11 (95% CI: 110.76, 174.71) to 841.53 (95% CI, 714.25, 991.50). The local tolerability and systemic safety profiles were favorable, with no serious adverse events. In conclusion, the third booster dose of the inactivated JE vaccine was demonstrated to be safe and immunogenic in Korean children when administered according to the current immunization schedule.

Obesity is the state of excessive body fat accumulation and is mainly caused by consuming more calories than are burned through physical activity. Herbal acupuncture (HA), also known as pharmacopuncture, has been increasingly used in clinics of Korean medical to alleviate obesity. This review analyzed four clinical studies and 16 animal studies on the effectiveness of HA as a treatment for obesity. Clinical evidence suggests that various kinds of HA might be beneficial for treating obesity; however, further investigations with well-designed, evidence-based, randomized clinical trials are needed. Animal studies support the idea that HA might be beneficial for the treatment of obesity and provide possible mechanisms, such as anti-inflammation, antioxidation, modulating lipid metabolism and so on, to explain the effect of HA on obesity. This review, based on the evidence collected, suggests that HA could have a beneficial effect for alleviating obesity by modulating inflammation, oxidative stress, lipid metabolism, leptin, and the insulin signal.

A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of Rubinstein–Taybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a −1 Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient's mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome.

H2A.Z is a highly conserved H2A variant, and two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified as products of two non-allelic genes, H2AFZ and H2AFV. H2A.Z has been reported to be overexpressed in breast, prostate and bladder cancers, but most studies did not clearly distinguish between isoforms. One recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. Here we first report that H2A.Z.1 plays a pivotal role in the liver tumorigenesis by selectively regulating key molecules in cell cycle and epithelial-mesenchymal transition (EMT). H2AFZ expression was significantly overexpressed in a large cohort of hepatocellular carcinoma (HCC) patients, and high expression of H2AFZ was significantly associated with their poor prognosis. H2A.Z.1 overexpression was demonstrated in a subset of human HCC and cell lines. H2A.Z.1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins and caused apoptotic cell death of HCC cells. We also observed that H2A.Z.1 knockdown reduced the metastatic potential of HCC cells by selectively modulating epithelial-mesenchymal transition regulatory proteins such as E-cadherin and fibronectin. In addition, H2A.Z.1 knockdown reduced the in vivo tumor growth rate in a mouse xenograft model. In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy.

Background Bronchiectasis is a chronic pulmonary disease characterized by progressive and irreversible bronchial dilatation. The aim of the present study was to investigate the etiologies and clinical features of bronchiectasis in Korean children. Methods We performed a retrospective review of the medical records for children diagnosed with bronchiectasis between 2000 and 2017 at 28 secondary or tertiary hospitals in South Korea. Results A total of 387 cases were enrolled. The mean age at diagnosis was 9.2 ± 5.1 years and 53.5% of the patients were boys. The most common underlying cause of bronchiectasis was preexisting respiratory infection (55.3%), post-infectious bronchiolitis obliterans (14.3%), pulmonary tuberculosis (12.3%), and heart diseases (5.6%). Common initial presenting symptoms included chronic cough (68.0%), recurrent pneumonia (36.4%), fever (31.1%), and dyspnea (19.7%). The most predominantly involved lesions were left lower lobe (53.9%), right lower lobe (47.1%) and right middle lobe (40.2%). No significant difference was observed in the distribution of these involved lesions by etiology. The forced expiratory volume in 1 s (FEV1) levels were lowest in cases with interstitial lung disease-associated bronchiectasis, followed by those with recurrent aspiration and primary immunodeficiency. Conclusions Bronchiectasis should be strongly considered in children with chronic cough and recurrent pneumonia. Long-term follow-up studies on pediatric bronchiectasis are needed to further clarify the prognosis and reduce the disease burden in these patients.

To investigate the genetic background for the emergence of macrolide resistance, we characterized the genetic features of Mycoplasma pneumoniae using multilocus sequence typing. Of the 146 M. pneumoniae strains collected during the 5 consecutive outbreaks of M. pneumoniae pneumonia during 2000–2016 in South Korea, macrolide resistance increased from 0% in the first outbreak to 84.4% in the fifth. Among the 8 sequence types (STs) identified, ST3 (74.7%) was the most prevalent, followed by ST14 (15.1%). Macrolide-susceptible strains comprised 8 different STs, and all macrolide-resistant strains were ST3 (98.3%) except 1 with ST14. The proportion of macrolide-resistant strains in ST3 remained 2.2% (1/46) until the 2006–2007 outbreak and then markedly increased to 82.6% (19/23) during the 2010–2012 outbreak and 95.0% (38/40) during the 2014–2016 outbreak. The findings demonstrated that clonal expansion of ST3 M. pneumoniae was associated with the increase in macrolide resistance in South Korea.

Background Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. Methods In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. Results We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). Conclusions The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Background Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea. Methods A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005. Results Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996–2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001). Conclusion S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children., Graphical Abstract

Background With the emergence of macrolide resistance, concerns about the efficacy of macrolides for the treatment of Mycoplasma pneumoniae (MP) pneumonia in children have been raised. This study aimed to determine the effect of macrolide resistance on the outcome of children who were hospitalized with MP pneumonia. Methods Between 2010 and 2015, we performed culture of MP from nasopharyngeal samples obtained from children who were hospitalized with pneumonia at five hospitals in Korea. Macrolide resistance was determined by the analysis of 23S rRNA gene transition and the minimal inhibitory concentrations of four macrolides. Medical records were reviewed to analyze the clinical response to treatment with macrolides. Results MP was detected in 116 (4.8%) of the 2436 children with pneumonia. MP pneumonia was prevalent in 2011 and 2015. Of the 116 patients with MP pneumonia, 82 (70.7%) were macrolide-resistant. There were no differences in the age distribution, total duration of fever, and chest x-ray patterns between the macrolide-susceptible and macrolide-resistant groups. After macrolide initiation, mean days to defervescence were longer in the macrolide-resistant group than in macrolide-susceptible group (5.7 days vs. 4.1 days, P = 0.021). However, logistic regression analysis revealed that the presence of extrapulmonary signs (P = 0.039), homogeneous lobar consolidation (P = 0.004), or parapneumonic effusion (P

Purpose Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic diseases, but a few allergic patients receive AIT. In this multicenter cross-sectional study, we aimed to explore patient and physician perspectives on AIT through a questionnaire survey. Materials and Methods Allergic patients who received subcutaneous immunotherapy for at least 1 year were asked to answer a questionnaire developed by an expert panel of allergen and immunotherapy workgroup in Korea. Results A total of 267 patients (adults, 60.3%) with allergic rhinitis (91.4%), asthma (42.7%), or atopic dermatitis (20.2%) from referred hospitals completed the survey. Among patients and physicians, respectively, the overall rates of satisfaction with AIT for allergic rhinitis were 86.4% and 83.3% (kappa agreement=0.234, p

In Korea, Mycoplasma pneumoniae was detected in 255/2,089 respiratory specimens collected during 2000–2011; 80 isolates carried 23S rRNA gene mutations, and 69/123 culture-positive samples with the mutation were resistant to 5 macrolides. During 2000–2011, prevalence of the mutation increased substantially. These findings have critical implications for the treatment of children with mycoplasma pneumonia.

Peanut (PN) and tree nuts (TNs) are common causes of anaphylaxis in Western countries, but no information is available in Korea. To feature clinical characteristics of anaphylaxis caused by PN, TNs, and seeds, a retrospective medical record review was performed in 14 university hospitals in Korea (2009-2013). One hundred and twenty-six cases were identified, with the mean age of 4.9 years. PN, walnut (WN), and pine nut accounted for 32.5%, 41.3%, and 7.1%, respectively. The median values of specific IgE (sIgE) to PN, WN, and pine nut were 10.50, 8.74, and 4.61 kUA /l, respectively. Among 50 cases managed in the emergency department, 52.0% were treated with epinephrine, 66.0% with steroid, 94.0% with antihistamines, 36.0% with oxygen, and 48.0% with bronchodilator. In conclusion, WN, PN, and pine nut were the three most common triggers of anaphylaxis in Korean children, and anaphylaxis could occur at remarkably low levels of sIgE.

Background The objective of this study was to assess the prevalence of education about sleep and sleep disorders in medical school education and to identify barriers to providing such education. Methods Surveys were sent to 409 medical schools across 12 countries (Australia, India, Indonesia, Japan, Malaysia, New Zealand, Singapore, South Korea, Thailand, United States, Canada and Viet Nam). Results Overall, the response rate was 25.9%, ranging from 0% in some countries (India) to 100% in other countries (New Zealand and Singapore). Overall, the average amount of time spent on sleep education is just under 2.5 h, with 27% responding that their medical school provides no sleep education. Three countries (Indonesia, Malaysia, and Viet Nam) provide no education, and only Australia and the United States/Canada provide more than 3 h of education. Paediatric topics were covered for a mere 17 min compared to over 2 h on adult-related topics. Conclusion These results suggest that there continues to be very limited coverage of sleep in medical school education despite an incredible increase in acknowledgement of the importance of sleep and need for recognition of sleep disorders by physicians.

The Wnt/beta-catenin signaling pathway regulates various aspects of development and plays important role in human carcinogenesis. Nemo-like kinase (NLK), which is mediator of Wnt/beta-catenin signaling pathway, phosphorylates T-cell factor/lymphoid enhancer factor (TCF/LEF) factor and inhibits interaction of beta-catenin/TCF complex. Although, NLK is known to be a tumor suppressor in Wnt/beta-catenin signaling pathway of colon cancer, the other events occurring downstream of NLK pathways in other types of cancer remain unclear. In the present study, we identified that expression of NLK was significantly up-regulated in the HCCs compared to corresponding normal tissues in five selected tissue samples. Immunohistochemical analysis showed significant over-expression of NLK in the HCCs. Targeted-disruption of NLK suppressed cell growth and arrested cell cycle transition. Suppression of NLK elicited anti-mitogenic properties of the Hep3B cells by simultaneous inhibition of cyclinD1 and CDK2. The results of this study suggest that NLK is aberrantly regulated in HCC, which might contribute to the mitogenic potential of tumor cells during the initiation and progression of hepatocellular carcinoma; this process appears to involve the induction of CDK2 and cyclin D1 and might provide a novel target for therapeutic intervention in patients with liver cancer.

Today, the combined use of Oriental herbal medicines and Western biomedical medicines has been a prevalent yet controversial practice. Case reports and healthy volunteer trials have had conflicting results on the effect Panax ginseng has on warfarin's pharmacologic action, some reporting a reductive and others a potentiating influence.This study investigated the interaction between warfarin and P. ginseng by observing the prothrombin time (PT) and the international normalized ratio (INR) in ischemic stroke patients who did not have a history of taking warfarin.Randomized, open-label, controlled study.Twenty-five (25) patients newly diagnosed with ischemic stroke by brain computed tomography or magnetic resonance imaging in the Korean Medical Hospital, Kyung Hee University (Seoul, Republic of Korea).Ischemic stroke patients were randomized into 2 groups: the ginseng group (n = 12), given both P. ginseng and warfarin, and the control group (n = 13), given only warfarin, both for 2 weeks. The warfarin dose was restricted to 2 mg in the first week and 5 mg in the second week.The peak values and the international normalized ratio (INR) and prothrombin time (PT) areas under the curve (AUC) in both groups significantly increased compared to those at baseline. However, there was no statistically significant difference in peak values and INR and PT AUC between groups in both the first and second weeks.This study suggests that coadministration of P. ginseng and warfarin in ischemic stroke patients does not influence the pharmacologic action of warfarin.

Sasang constitutional medicine classifies mankind into four constitutional types according to individual psychologic and physical traits. We hypothesized that differences among constitutional types might be explained by genetic variations.To evaluate the hypothesis, we determined the possible association in ischemic stroke patients (n = 134) of peroxisome proliferator-activated receptor (PPAR)-gamma with four constitutional types of Sasang medicine. The constitutional type of each patient and control subject (n = 129) was classified and genotyped for PPAR-gamma polymorphism Pro12Ala by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods.The distribution of the Pro/Ala genotypes in the ischemic stroke patients was not significantly different from that of healthy controls [odds ratio (OR)= 0.46; p = 0.1214]. However, very interestingly, we observed that all six Pro/Ala genotypes in ischemic patients were Taeeumin, one of four constitutional types of Sasang medicine. Statistical analysis revealed that Pro/Ala genotype in Taeeumin increases almost 15-fold the susceptibility to ischemic stroke compared to other constitutional types, Taeyangin, Soyangin or Soeumin (OR= 14.72; p = 0.0110).From the results in this study, we might suggest that Pro/Ala genotype in Taeeumin is associated with the susceptibility to ischemic stroke. To the author's best knowledge, this is the first report to study on genetic level the potential relationship between ischemic stroke and Sasang constitutional medicine, one of traditional Korean medicines (TKM). Authors hope that this study could provide a new approach for the study of ischemic stroke and merit further research.

The purpose of this study was to examine sleep patterns in a large sample of infants and toddlers (ages birth to 36 months) in Korea, and to compare sleep patterns, sleep problems, sleep ecology, and parental behaviors to global sleep data on young children in both predominately Asian (P-A) and predominately Caucasian (P-C) countries/regions. We additionally examined parent and child demographic information, parental behaviors, and aspects of the sleep ecology as predictors of sleep patterns among infants and toddlers in Korea. Parents/caregivers of 1,036 Korean infants and toddlers completed an expanded, internet-based version of the brief infant sleep questionnaire. Consistent with other studies of sleep in early childhood, sleep/wake patterns became increasingly consolidated with older child age for the Korea sample. Compared to both P-A and P-C infants and toddlers, children in Korea had the latest bedtimes, shortest total sleep and daytime sleep durations, and the least frequent rates of napping. Even though half of parents perceive their children’s sleep problematic, parental perceptions of severe child sleep problems were the lowest. Within Korea, breastfeeding and bottle-feeding at sleep resumption were associated with increased nocturnal awakenings. Evening television viewing was associated with later bedtimes, which may have implications for sleep hygiene recommendations in clinical practice. The current study provides important information about sleep/wake patterns, parental behaviors, and aspects of the sleep ecology for infants and toddlers for physicians to support healthy sleep in Korea., Graphical Abstract

Background Mastocytosis is characterized by a pathological increase in mast cells in organs such as skin and bone marrow. Transglutaminase 2 (TG2) expressed in mast cells contributes to allergic diseases, but its role in mastocytosis has not been investigated. This study aimed to investigate whether TG2 contributes to pediatric mastocytosis. Methods Serum, various skin tissues or bone marrow (BM) biopsy and aspirates were obtained from pediatric normal control or patients with indolent systemic mastocytosis (SM), mastocytoma, and urticaria pigmentosa (UP). Tryptase, individual cytokines, leukotriene C4 (LTC4), and TG2 activity in the serum were determined by enzyme-linked immunosorbent assay, mast cell population by May–Grunwald–Giemsa, CD 117 by immunofluorescence, cell surface molecules by Western blot, and colocalization of c-kit and TG2 or IL-10-expressing cells, CD25, and FOXP3 by immunohistochemistry. Results Infiltration of CD25+CD117+CD2- mast cells into BM and scalp/trunk/ear dermis; expression of FceRI, tryptase, c-kit, FOXP3, CCL2/CCR2, and vascular cell adhesion molecule-1; and colocalization of c-kit and TG2 were enhanced in patient′s skin tissues or BM, particularly SM, but colocalization of c-kit and IL-10-expressing cells was decreased vs. normal tissues. Amounts of LTC4 and inflammatory cytokines, expression of tryptase or TG2 activity were increased in patient's serum, BM aspirates, or ear/scalp skin tissues, respectively, vs. normal persons, but IL-10 level was decreased. Conclusion The data suggest that mast cells, recruited in the skin and BM by CCL2/CCR, may induce the development of pediatric mastocytosis through reducing IL-10 due to upregulating TG2 activity via transcription factor nuclear factor-κB. Thus, TG2 may be used in diagnosis of pediatric mastocytosis, particularly SM.

Background Nodule-in-nodule-type hepatocellular carcinoma (NIN-HCC) is a useful model to illustrate the multi-step nature of hepatocarcinogenesis. To identify large-scale molecular change in early hepatocarcinogenesis, the expression profile of NIN-HCC was compared with those from three sets of individual high-grade dysplastic nodules (HGDN) and grade 1 hepatocellular carcinomas. Methods We compared expression profiles of inner grade 1 hepatocellular carcinoma nodules and peripheral HGDN in one case of NIN-HCC using spotted-oligonucleotide DNA microarray. The relevant outlier genes assumed to associate with early carcinogenesis in hepatocellular carcinoma were identified by comparative analysis of NIN-HCC and individual cases of HGDN and grade 1 hepatocellular carcinoma, respectively. Results From this analysis we extracted a total of 40 genes, consisting of 28 up-regulated genes and 12 downregulated genes, and more than a two-fold change in grade 1 hepatocellular carcinoma compared with HGDN. Conclusion We assessed the expression profiles of pre-neoplastic lesions and grade 1 hepatocellular carcinoma using oligonucleotide microarray analysis and found high stringent outlier genes that are presumably directly involved in the transition from dysplastic nodule to the early stage of hepatocellular carcinoma by utilizing NIN-HCC.

Accumulated evidence has established that aberrant regulation of histone deacetylases (HDACs) is one of the major causes of the development of human malignancies. Among different iso-enzymes of HDAC and sirtuins grouped as the HDAC super family, little is known as to how histone deacetylase 2 (HDAC2) causes carcinogenesis in solid tumors. Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry. Moderate to strong expression of HDAC2 was found in 44 (62%) out of a total of 71 tumors. The majority of positive tumors, which were detected in the nucleus but not in normal gastric epithelium, did not express HDAC2 or showed only weak positive staining. Interestingly, we also noted that HDAC2 expression appeared to be associated with tumor aggressiveness as HDAC2 expression was observed to be statistically significant in advanced gastric cancer (P=0.0023, Chi-square test) and in positive lymph node metastasis (P=0.0713, Chi-square test). Taken together, these results suggest that HDAC2 may play an important role in the aggressiveness of gastric cancer.

Background Serum levels of eosinophil cationic protein are an indirect measure of airway inflammation in asthma. It is proposed that the extent to which bronchoconstriction or airway inflammation contributes to airflow obstruction in acute asthma may determine responsiveness to bronchodilator therapy. Objective To test the hypothesis that subjects with acute asthma exacerbations who respond poorly to inhaled bronchodilator treatment may have more marked airway inflammation than those who respond well to identical therapy. Methods Forty-eight asthmatic children who visited the emergency room due to acute exacerbations were studied. Serum levels of eosinophil cationic protein were measured at the time of acute exacerbations and of clinical remissions at acute exacerbation, FEV 1 was assessed before and after the administration of aerosolized salbutamol. Results The mean serum level of eosinophil cationic protein at acute exacerbation (41.1 ± 12.8 microgram/L) was significantly higher ( P .01) than that at clinical remission (30.0 ± 8.5 microgram/L) in the study population. The level at acute exacerbation was even higher in group A (n = 18: postbronchodilator FEV 1 1 >/= 75% predicted), whereas both groups showed similar levels at clinical remission. The level at acute exacerbation correlated positively with severity of exacerbation (r = .47, P .01) and negatively with bronchodilator responses (r = −.56, P .01). This negative correlation was valid among subjects with a similar degree of exacerbation. Conclusion A higher level of eosinophil cationic protein at acute asthma exacerbation was associated not only with more severe exacerbation but also with a lower degree of bronchodilator responsiveness. This suggests that degree of airway inflammation may be one determinant of degree of responsiveness to initial bronchodilatory therapy at acute asthma exacerbation.

Background: The objective of this study was to assess the prevalence of education about sleep and sleep disorders in pediatric residency programs and to identify barriers to providing such education. Methods: Surveys were completed by directors of 152 pediatric residency programs across 10 countries (Hong Kong, India, Indonesia, Japan, Singapore, South Korea, Thailand, United States-Canada, and Vietnam). Results: Overall, the average amount of time spent on sleep education is 4.4 hours (median = 2.0 hours), with 23% responding that their pediatric residency program provides no sleep education. Almost all programs (94.8%) offer less than 10 hours of instruction. The predominant topics covered include sleep-related development, as well as normal sleep, sleep-related breathing disorders, parasomnias, and behavioral insomnia of childhood. Conclusions: These results indicate that there is still a need for more efforts to include sleep-related education in all pediatric residency programs, as well as coverage of the breadth of sleep-related topics. Such education would be consistent with the increased recognition of the importance of sleep and under-diagnosis of sleep disorders in children and adolescents.

Immunization to eliminate measles is recommended at 15 months of age with the option of giving vaccine at 6 to 9 months of age during measles outbreaks in Korea. Because of the recent resurgence of measles and concern about the possibility of reduced vaccine efficacy caused by genomic differences between vaccine virus and contemporary wild measles viruses, we conducted a measles vaccine efficacy study involving children with household exposure ages 1 to 5 years during measles outbreak that had occurred 1993 in Seoul and Seong-nam city, with the demographic analysis of patients brought to the hospitals. A total of 380 patients (M:F = 216:164) were included in this study. Two hundred nine cases (55.0%) occurred in children less than 5 years of age, and 167 (43.9%) were younger than 16 months of age. The recorded age-specific incidence rates showed bimodal patterns, i.e. highest peak in those below 16 months of age and second peak in those ages 6 to 9 years of age. Only 9.6% (16 of 167) of the measles cases less than 16 months, 59.5% (25 of 42) of those 16 months to 4 years and 91.8% (157 of 171) of the cases in school age children have been vaccinated. Attack rates among the 122 vaccinated siblings and 12 unvaccinated siblings ages 1 to 5 years who contacted measles were 5.7 and 75%, respectively, and the clinical vaccine efficacy was 92.4% (95% confidence interval, 83.6, 96.4). The high vaccine efficacy in household exposures suggests that measles outbreaks in Korea are not caused by reduced vaccine efficacy.

This study was performed to measure early changes in the serotype distribution of pneumococci isolated from children with invasive disease during the 3-year period following the introduction of 10- and 13-valent pneumococcal conjugate vaccines (PCVs) in Korea. From January 2011 to December 2013 at 25 hospitals located throughout Korea, pneumococci were isolated among children who had invasive pneumococcal disease (IPD). Serotypes were determined using the Quellung reaction, and the change in serotype distribution was analyzed. Seventy-five cases of IPD were included. Eighty percent of patients were aged 3-59 months, and 32% had a comorbidity that increased the risk of pneumococcal infection. The most common serotypes were 19A (32.0%), 10A (8.0%), and 15C (6.7%). The PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and 6A) accounted for 14.7% of the total isolates and the PCV13 minus PCV7 types (1, 3, 5, 7F and 19A) accounted for 32.0% of the total isolates. Serotype 19A was the only serotype in the PCV13 minus PCV7 group. The proportion of serotype 19A showed decreasing tendency from 37.5% in 2011 to 22.2% in 2013 (P = 0.309), while the proportion of non-PCV13 types showed increasing tendency from 45.8% in 2011 to 72.2% in 2013 (P = 0.108). Shortly after the introduction of extended-valent PCVs in Korea, serotype 19A continued to be the most common serotype causing IPD in children. Subsequently, the proportion of 19A decreased, and non-vaccine serotypes emerged as an important cause of IPD. The impact of extended-valent vaccines must be continuously monitored., Graphical Abstract

Children with suspected respiratory syncytial virus infection were examined prospectively in a randomized evaluation of standard ribavirin aerosol therapy (6 gm/300 ml water for 18 hours daily) compared with high-dose, short-duration ribavirin aerosol therapy (6 gm/100 ml water given for a period of 2 hours three times a day) by means of an oxygen hood (n = 20) or a ventilator (n = 12). Viral shedding was quantitated daily; clinical observations were recorded daily by 2 physicians aware and one unaware of treatment assignments. Study characteristics evaluated at entry were not significantly different in the high-dose and the standard-dose groups. Viral titers and clinical scores decreased similarly in both groups during the study; pulmonary function test results were also similar at discharge in children not receiving mechanical ventilation. Potential complications related to aerosol therapy were noted in three patients (one hood patient who was receiving standard therapy; two patients with an endotracheal tube in place who were receiving high-dose therapy); substantial crystallization was noted in the tubing of the patients undergoing intubation and receiving high-dose therapy. Environmental sampling revealed that ribavirin was nearly undetectable near patients supported by mechanical ventilation who were receiving either form of therapy, and was significantly decreased on a daily basis in patients without an endotracheal tube who were receiving high-dose therapy compared with those receiving standard therapy. The effects of high-dose, short-duration aerosol ribavirin therapy were similar to those of standard-dose therapy in our study patients and resulted in a decreased release of ribavirin into the room of patients receiving therapy by means of an oxygen hood. (J P EDIATR 1994;125:635-41)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The number of cases of HCC has continued to increase in recent decades. Previous studies have suggested that S100P, a member of the S100P calcium-binding protein family, is aberrantly regulated in several malignant neoplasms. However, the underlying molecular mechanisms of the dysregulation of S100P remain to be elucidated. To investigate biological effects of S100P on hepatocarcinogenesis, aberrant expression of S100P was investigated by immunohistochemistry (IHC), Western blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) in HCC tissues and cell lines. Endogenous expression of S100P was disrupted by the RNA interference-mediated protein knockdown method in the human Hep3B liver cancer cell line. Then, cell growth and cellular apoptosis were compared with control siRNA transfectants. The effects of S100P-silencing on the major components of cell cycle regulation were assessed by Western blot analysis. As results, elevated levels of S100P were observed in the HCC tissues compared to the corresponding normal tissues. Targeted disruption of S100P suppressed cell growth and augmented cellular apoptosis. In addition, inhibition of S100P resulted in the down-regulation of cyclinD1 and CDK2. In conclusion, this study showed over-expression of S100P in HCC. The aberrant regulation of S100P in HCC might activate cyclin D1 and CDK expression and contribute to the mitogenic potential of tumor cells during HCC carcinogenesis. These findings provide information that suggests new therapeutic strategies for the treatment of liver cancer.

Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents for the treatment of solid and hematological malignancies. However, the best characterized HDAC function concerns the control of gene expression via the regulation of transcription activation or repression. To understand the genome-wide effects of HDAC inhibition on gene regulation, we performed serial gene expression analyses from 0 to 48 h after treating MDA-MB-435, a melanoma-derived highly metastatic tumor cell line, with Apicidin, a HDAC inhibitor. Combined-transcriptomic analysis of large-scale molecular changes induced by Apicidin resulted in the identification of 631 outlier genes that were continuously up- or down-regulated during the 48 h study period. When the 631 outlier genes were mapped to known biological processes, cell-cycle suppression emerged as the function most elicited by Apicidin. In addition comprehensive negative cell-cycle regulation by Apicidin was dissected using gene expression data and validated by Western blot analysis. We suggest the 631 outlier genes as a characteristic molecular signature for Apicidin, and propose concurrent transcriptional suppression of major components of cell-cycle regulatory circuit as potent anti-tumor mechanism of Apicidin. Genetic elements identified during this study also provide the possibility of novel therapeutic interventions in tumor metastasis.

An epidemiologic study was performed to determine the genetic variability of rotaviruses in Seoul, South Korea. In 3,174 stool specimens from children with acute diarrhea at five referral hospitals, 571 (18%) possessed the antigen of group A rotavirus detectable by ELISA—10.8% in 2004 and 28.1% in 2005. VP7 genotyping revealed that the G3 type was found in 25.6% of all typed isolates, G4 in 23.8%, G2 in 21.6%, and G1 in 17.6%. VP4 genotyping showed that the P[8] type was detected in 66.7%, P[6] in 15.6%, P[4] in 13.0%, and P[9] in 0.2%. Because the variant P[8] type could not be amplified initially by conventional P typing primers (1T-1), PCR were performed using newly designed 1T-1S primer, which revealed that 307 specimens were the variant P[8] type. Uncommon combinations such as G4P[6] and G2P[8] were also found with relatively high prevalence, 14.6% and 12.8%, respectively. Variant P[8] types were associated with an outbreak of rotavirus in 2005. J. Med. Virol. 80:1661–1665, 2008. © 2008 Wiley-Liss, Inc.

Graves' disease, the most common cause of hyperthyroidism, is an autoimmune disorder. Antithyroid drugs have been selected as the first-line treatment of Graves' disease in Korea, Japan, and European countries. However, antithyroid drugs such as methimazole (MMI) and prophylthiouracil (PTU) have limitations in clinical applications because of their side effects. In this study, we performed a clinical trial and in vitro study to investigate the clinical effects and action mechanism of Ahnjeonbaekho-tang (AJBHT), an herbal remedy for Graves' disease. In a clinical study of Graves' disease patients who had side effects from antithyroid drugs, we found that treatment by AJBHT resulted in a reduction of serum triiodothyronine (T3) and free thyroxine (FT4) levels and an increase in thyroid stimulating hormone (TSH) levels (T3: p0.0001, FT4: p=0.0012, TSH: p=0.0370, respectively). In vitro, AJBHT significantly inhibits FRTL-5 cell proliferation, DNA synthesis, cyclic AMP production, T4 synthesis, and the expression of thyroglobulin (Tg) mRNA in comparison with the control. These results suggest that AJBHT might suppress T(4) synthesis by modulating adenosine 3',5'-cyclic monophosphate (cAMP) and Tg expression, and therefore, AJBHT could be an alternative therapy for Graves' disease patients who have side effects from antithyroid drugs.

The hygiene hypothesis postulates that infections early in life might influence the development of asthma later in childhood. However, this hypothesis is controversial. The objective of this study was to determine whether there is a relationship between infection-related risk factors during infancy and development of asthma later in childhood.Data were obtained by a nationwide, population-based, cross-sectional study of 26,400 children, 7 to 12 years of age. Parents completed a questionnaire on symptoms of and risk factors for asthma, including the number of fever episodes, acute gastroenteritis, use of antibiotics, and immunization during infancy. The presence of asthma was defined by parental report of "wheeze in the last 12 months" or "asthma ever." Data were analyzed by logistic regression analysis.The occurrence of fever during infancy was weakly associated with the development of asthma (P0.05). A higher frequency of episodes of fever was associated with a higher risk of development of asthma. The relationship between antibiotic use during infancy and development of asthma was also significant (P0.0001). The adjusted odds ratios of childhood asthma increased in proportion to the number of antibiotic courses during infancy. A history of acute gastroenteritis during infancy increased the risk of developing asthma in later life (P0.001). In contrast, immunization in infancy was not related to development of asthma in childhood (P0.05).These data suggest that the development of childhood asthma is associated with episodes of fever, antibiotic use, and acute gastroenteritis during infancy.

To understand comprehensive molecular mechanisms by which Autotaxin (ENPP2) mediates, we identified large-scale molecular changes responsible for aberrant expression of Autotaxin (ATX) on breast cancer cells by using DNA microarrays. Transcriptional over-expression of ENPP2 gene was endogenously silenced by using RNA interference technique, and then recapitulated corresponding molecular changes in MDA435 breast cancer cells. Application of nonparametric Wilcoxon statistical analyses (P0.05) and the selection criteria of 2-fold differential gene expression change resulted in the identification of 368 genes including 133 up-regulated and 235 genes under-expressed in ENPP2-silencing MDA435 cells. Most of the functional categories of identified genes are associated with cellular metabolism, cytoskeleton organization, transcription regulation, signal transduction as well as cellular organization and biogenesis. Our data suggest that the molecular signature identified by the ENPP2-silencing methods may represent potential candidates that can explain the complicated characteristics of ATX and may serve as biomarkers, for the development of molecular-targeting therapy, in human breast cancer.

We analyzed the gene mutations and loss of heterozygosity (LOH) of the HCCS1 gene using intragenic polymorphic markers in a series of 88 primary HCCs. We found two sequence variations at exon 5 and 14 in both normal and tumor DNAs of case 50 and 51, respectively. The variation in case 50 led to a reading frameshift and a premature stop (TGA) at codon 125 and case 51 showed amino acid change at codon 448 (Val-->Ala, GTG-->GCG). Interestingly, these variations were not found in peripheral lymphocytes of 69 normal individuals and 227 cancer patients (86 HCC, 75 unselected gastric cancer, and 66 breast cancer), suggesting that these two variations are mutation, not polymorphism. In addition, we found 14 novel intragenic polymorphic sites in the HCCS1 gene. Thirty-two (47%) of sixty-eight informative cases showed allelic loss at at least one or more intragenic polymorphic sites, but there was no significant relationship between the frequency of LOH and clinicopathologic parameters. These results suggest that mutation of the HCCS1 gene might not be a main inactivation mechanism in the development of Korean HCC and that the HCCS1 gene might be involved in acceleration of the tumorigenic process in Korean HCC.

We present a 22-day-old infant with extensive subcutaneous calcifications due to subcutaneous fat necrosis caused by prolonged exposure to cold.

To validate the prevalence rate of symptoms of asthma produced by the phase I ISAAC (International Study of Asthma and Allergies in Childhood) study, hypertonic saline challenge test was carried out during the phase II study at a year after the phase I study. For the phase II study, six middle schools from three cities in the phase I study were selected. Finally, 499 children who responded to both studies were analyzed. All subjects were asked to complete the written questionnaire (WQ) first, followed by a video questionnaire (AVQ 3.0) during the phase I study. Of the 499 children, only 19 (3.8%) were positive to the hypertonic saline bronchial challenge test. The degree of agreement between responses to the two corresponding questions "wheezing at rest" and "nocturnal wheeze" in the AVQ 3.0 and WQ were moderate and weak with a Kappa indices of 0.45 and 0.23, respectively. The question on "severe wheeze" in the AVQ 3.0 had the highest Youden's index among the five questions related to asthma symptoms in the previous 12 months, but its specificity was low whereas its sensitivity was 1.0. There was no consistency of priority between the two questionnaires in predicting bronchial hyperreactivity in a group of Korean schoolchildren. Therefore we need to develop more appropriate WQ or AVQ to compare the prevalences of asthma to other countries.

Leigh's disease is a rare progressive neurological disorder that is characterized light microscopically by focal spongy necrosis in the brain and electron microscopically by mitochondriopathy. We report an autopsy case of Leigh's disease that showed abnormalities in the liver, kidney and skeletal muscle as well as the central nervous system. The patient was an 18-month-old girl who has carried a diagnosis of cerebral palsy ever since her birth to a 20-year-old mother. The baby was generally hypertonic and mentally retarded. She died of severe metabolic acidosis. Postmortem examination showed growth retardation, fatty liver, fatty kidney and soft brain. Brain section showed multifocal softenings in the brainstem, basal ganglia and periventricular areas. Microscopically increased capillaries with endothelial proliferation, vacuolar degeneration and mild gliosis were seen in the brain. The axons were relatively preserved. Liver and kidneys showed microvesicular fatty change. Myofiber degeneration of the skeletal muscle was also noted. Electron microscopic examination showed markedly increased mitochondria in the parenchymal cells of the brain, liver and kidney. The mitochondria showed round to ovoid ballooned appearance including electron-dense core-like structures and pseudoinclusions of glycogen granules.