Publications by authors named "Hyun Mi Kang"

113 Publications

Effects of nasopharyngeal microbiota in respiratory infections and allergies.

Clin Exp Pediatr 2021 Apr 15. Epub 2021 Apr 15.

Division of Pediatric Infectious Diseases, Departments of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

The human microbiome, which consists of a collective cluster of commensal, symbiotic, and pathogenic microorganisms living in the human body, plays a key role in host health and immunity. The human nasal cavity harbors commensal bacteria that suppress the colonization of opportunistic pathogens. However, dysbiosis of the nasal microbial community is associated with many diseases, such as acute respiratory infections including otitis media, sinusitis and bronchitis and allergic respiratory diseases including asthma. The nasopharyngeal acquisition of pneumococcus, which exists as a pathobiont in the nasal cavity, is the initial step in virtually all pneumococcal diseases. Although the factors influencing nasal colonization and elimination are not fully understood, the adhesion of opportunistic pathogens to nasopharyngeal mucosa receptors and the eliciting of immune responses in the host are implicated in addition to bacterial microbiota properties and colonization resistance dynamics. Probiotics or synbiotic interventions may show promising and effective roles in the adjunctive treatment of dysbiosis; however, more studies are needed to characterize how these interventions can be applied in clinical practice in the future.
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http://dx.doi.org/10.3345/cep.2020.01452DOI Listing
April 2021

Early Confirmation of Infection by Two Short-Term Serologic IgM Examination.

Diagnostics (Basel) 2021 Feb 20;11(2). Epub 2021 Feb 20.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea.

The aim of the present study is to re-evaluate the clinical application of two-times serologic immunoglobulin M (IgM) tests using microparticle agglutination assay (MAA), an enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR) assay in diagnosing (MP) infection. A retrospective analysis of 62 children with MP pneumonia during a recent epidemic (2019-2020) was conducted. The MAA and ELISA immunoglobulin M (IgM) and IgG measurements were conducted twice at admission and around discharge, and MP PCR once at presentation. Diagnostic rates in each test were calculated at presentation and at discharge. The seroconverters were 39% (24/62) of patients tested by MAA and 29% (18/62) by ELISA. At presentation, the diagnostic positive rates of MAA, ELISA, and PCR tests were 61%, 71%, and 52%, respectively. After the second examination, the rates were 100% in both serologic tests. There were positive correlations between the titers of MAA and the IgM values of ELISA. The single serologic IgM or PCR tests had limitations to select patients infected with MP in the early stage. The short-term, paired IgM serologic tests during hospitalization can reduce patient-selection bias in MP infection studies.
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http://dx.doi.org/10.3390/diagnostics11020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923409PMC
February 2021

The Impact of the Coronavirus Disease-2019 Pandemic on Childhood Obesity and Vitamin D Status.

J Korean Med Sci 2021 Jan 18;36(3):e21. Epub 2021 Jan 18.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: The risk of weight gain as a consequence of school closure in children during the coronavirus disease-2019 (COVID-19) pandemic has been recognized. This study was performed to investigate changes in anthropometric and metabolic parameters in children following a 6-month period of social distancing and school closure due to the pandemic.

Methods: This retrospective cohort study was conducted in school-aged children that were on routine follow-up at the Growth Clinic of Seoul St. Mary's Hospital. Changes in body mass index (BMI) standard deviation scores (z-scores), lipid profiles, and vitamin D levels were investigated. The 1-year period prior to school closure was defined as "pre-COVID-19 period," and the subsequent 6-month period as "COVID-19 period."

Results: Overall, 226 children between 4 to 14 years old without comorbidities were assessed. On average, their BMI z-scores increased by 0.219 (95% confidence interval [CI], 0.167-0.271; < 0.001) in the COVID-19 period compared to the pre-COVID-19 period, and the proportion of overweight or obesity increased from 23.9% in the pre-COVID-19 period to 31.4% in the COVID-19 period. The number of days after school closure ( = 0.004) and being in the normoweight category in the pre-COVID-19 period ( = 0.017) were factors associated with an increased BMI in the COVID-19 period. The mean triglyceride (105.8 mg/dL vs. 88.6 mg/dL, < 0.001) and low-density lipoprotein-cholesterol (100.2 mg/dL vs. 94.0 mg/dL, = 0.002) levels were higher, whereas the calcidiol level (18.9 mg/dL vs. 23.8 mg/dL, < 0.001) was lower in the COVID-19 period compared to the pre-COVID-19 period.

Conclusion: Within 6 months, increased childhood obesity and vitamin D deficiencies were observed. The duration of school closure was significantly associated with an increased BMI and being normoweight does not exclude the risks for gaining weight.
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http://dx.doi.org/10.3346/jkms.2021.36.e21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813584PMC
January 2021

Circulating Respiratory Syncytial Virus Genotypes and Genetic Variability of the G Gene during 2017 and 2018/2019 Seasonal Epidemics Isolated from Children with Lower Respiratory Tract Infections in Daejeon, Korea.

J Korean Med Sci 2020 Dec 21;35(49):e422. Epub 2020 Dec 21.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Respiratory syncytial virus (RSV) is a major pathogen causing respiratory tract infections in infants and young children. The aim of this study was to confirm the genetic evolution of RSV causing respiratory infections in children at Daejeon in Korea, through G gene analysis of RSV-A and RSV-B strains that were prevalent from 2017 to 2019.

Methods: Pediatric patients admitted for lower respiratory tract infections at The Catholic University of Korea Daejeon St. Mary's Hospital in the 2017 and 2018/2019 RSV seasonal epidemics, who had RSV detected via multiplex polymerase chain reaction (PCR) were included. The nucleic acid containing RSV-RNA isolated from each of the patients' nasal discharge during standard multiplex PCR testing was stored. The G gene was sequenced and phylogenetic analysis was performed using MEGA X program and the genotype was confirmed.

Results: A total of 155 specimens including 49 specimens from 2017 and 106 specimens from 2018-2019 were tested. The genotype was confirmed in 18 specimens (RSV-A:RSV-B = 4:14) from 2017 and 8 specimens (RSV-A:RSV-B = 7:1) from 2018/2019. In the phylogenetic analysis, all RSV-A type showed ON1 genotype and RSV-B showed BA9 genotype.

Conclusion: RSV-B belonging to BA9 in 2017, and RSV-A belonging to ON1 genotype in 2018/2019 was the most prevalent circulating genotypes during the two RSV seasons in Daejeon, Korea.
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http://dx.doi.org/10.3346/jkms.2020.35.e422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752254PMC
December 2020

Impact of Antibiotic Prescribing Patterns on Susceptibilities of Uropathogens in Children below 24 Months Old.

Antibiotics (Basel) 2020 Dec 16;9(12). Epub 2020 Dec 16.

Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Monitoring regional antibiotic resistance patterns of uropathogens are important for deciding suitable empirical antibiotics for urinary tract infections (UTIs) in children. This study aimed to investigate regional differences in antimicrobial susceptibility patterns of and spp. in children below 24 months old, diagnosed with their first episode of UTI, and to find factors associated with an increased risk for UTI caused by extended-spectrum β-lactamase (ESBL)-producing uropathogens. This was a retrospective cohort study of children diagnosed between 2011 and 2017 in four different hospitals located in four different regions of South Korea; regions A, B, C, and D. The government's big data repository was used to acquire data on regional antibiotic prescriptions. The pooled antimicrobial susceptibilities of and spp. ( = 2044) were as follows: ampicillin-sulbactam (61.0%), 3rd generation cephalosporin (3C) (82.8%), and trimethoprim-sulfamethoxazole (72.0%). Multivariate analysis showed that children diagnosed at hospital A (OR, 1.8; 95% confidence interval [CI], 1.2-2.6; = 0.002) and every year that increased in the study period (OR, 1.1; 95% CI, 1.1-1.2; < 0.001) were factors associated with an increased risk for UTIs with ESBL-producers. Regions A and B had significantly higher amounts of oral 3Cs prescribed compared to regions C and D ( = 0.009), which correlate with hospitals in the regions that had higher proportions of UTIs with ESBL-producing uropathogens (A and B vs. C and D, < 0.001). Therefore, children in certain regions are at a higher risk for UTIs caused by ESBL-producers compared to other regions, which correlate with regions that had higher amounts of oral 3Cs prescribed.
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http://dx.doi.org/10.3390/antibiotics9120915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767190PMC
December 2020

The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation.

Cell Metab 2021 Feb 9;33(2):379-394.e8. Epub 2020 Dec 9.

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.
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http://dx.doi.org/10.1016/j.cmet.2020.11.011DOI Listing
February 2021

Efficacy of low dose antithymocyte globulin on overall survival, relapse rate, and infectious complications following allogeneic peripheral blood stem cell transplantation for leukemia in children.

Bone Marrow Transplant 2021 Apr 17;56(4):890-899. Epub 2020 Nov 17.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Antithymocyte globulin (ATG) and anti-T lymphocyte globulin (ATLG) have been widely used to prevent graft-versus-host disease (GvHD), each with distinct properties and noninterchangeable doses. However, the optimal dose of ATG in children undergoing allo-PBSCT for leukemia has not yet been established. Therefore, the impact of ATG dose on overall survival (OS), relapse, GvHD, and infectious complications was investigated. Patients administered high dose (unrelated: 7.5 mg/kg, haploidentical: 10.0 mg/kg) and low dose (unrelated: 3.75 mg/kg, haploidentical: 5.0 mg/kg) ATG during two consecutive time periods were compared. There were 78 (39.8%) patients in the low dose group and 118 (60.2%) in the high dose group. OS was superior in the low dose group compared to the high dose group (P = 0.017), and relapse incidence was significantly lower in the low dose group (P = 0.022). Cumulative incidences of acute and chronic GvHD were similar between the groups (P = 0.095 and P = 0.672, respectively). Cytomegalovirus reactivation (70.3% vs. 51.3%, P = 0.007), Epstein-Barr virus reactivation (81.4% vs. 39.7%, P < 0.001), and invasive bacterial infections (12.7% vs. 0%, P = 0.001) post transplant were more frequent in the high dose group compared to the low dose group. Therefore, low dose ATG is more optimal in pediatric allo-PBSCT providing better OS while lowering the risk of relapse and infectious complications.
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http://dx.doi.org/10.1038/s41409-020-01121-9DOI Listing
April 2021

Febrile Urinary Tract Infection in Children: Changes in Epidemiology, Etiology, and Antibiotic Resistance Patterns Over a Decade.

Clin Exp Pediatr 2020 Oct 14. Epub 2020 Oct 14.

Departments of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Understanding the epidemiology and prevalence of febrile urinary tract infection (fUTI) in children is important for risk stratification and selecting appropriate urine sample collection candidates to aid in its diagnosis and treatment.

Purpose: This study aimed to analyze the epidemiology, etiology, and changes in antibiotic susceptibility patterns of the first fUTI in children.

Methods: This retrospective observational cohort study included children younger than 19 years of age who were diagnosed and treated for their first fUTI in 2006-2016. Electronic medical records were analyzed and radiologic images were evaluated.

Results: A total of 359 patients (median age, 5.1 [interquartile range, 3.0-10.5] months) fit the inclusion criteria; of them, 78.0% (n = 280) were younger than 12 months old. The male to female ratio was 5.3:1 for patients aged 0-2 months, 2.1:1 for those 3-5 months, and 1.6:1 for those 6-11 months. Beyond 12 months of age, there was a female predominance. Escherichia coli was the leading cause (83.8%), followed by Enterococcus species (6.7%) and Klebsiella pneumoniae (3.6%). Significant yearly increases in the proportions of multidrug-resistant strains (p < 0.001) and extended-spectrum beta-lactamase (ESBL) producers (p < 0.001) were observed. In patients with vesicoureteral reflux, the overall recurrence rate was 53.6% (n = 15). A significantly higher recurrence rate was observed when the fUTI was caused by an ESBL versus non-ESBL producer (75.0% vs. 30.0%, p = 0.03).

Conclusion: FUTI was most prevalent in children younger than 12 months of age and showed a female predominance in patients older than 12 months of age. The proportion of ESBL producers causing fUTI is increasing. Carbapenems, rather than non-carbapenems, should be considered for treating fUTI caused by ESBL-producing enteric gram-negative rods to reduce short-term recurrence rates.
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http://dx.doi.org/10.3345/cep.2020.00773DOI Listing
October 2020

A new experimental model to study human drug responses.

Biofabrication 2020 09 25;12(4):045029. Epub 2020 Sep 25.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Accurate prediction of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics is critical for drug development. Oral drugs are particularly difficult because they are absorbed by the intestine and metabolized in the liver before systemic metabolism in vivo; this is called the first-pass effect and is a critical factor for predicting oral bioavailability (BA). Here, we fabricated a new networking and circulating cell culture system (NCCS), mimicking the circulatory system and interaction of organs for studying the pharmacokinetic and pharmacodynamics of oral drugs in vitro. NCCS consisted of a micro-pump for circulating fluids, two types of multi-insert culture dishes for culturing different cell types, and an orbital shaker for mixing; flow rate and shaking-speed were controlled by weight-sensors and drivers. A first-pass effect test was performed using functionally differentiated HepaRG and Caco-2 cell lines, using a new modified spheroid forming unit (SFU) protocol. To verify the similarity of PK (first-pass effect) data of NCCS with the data from the human body, 15 reference drugs were chosen and their associated data were obtained by liquid chromatography-mass spectrometry analysis. NCCS generated absorption and metabolism data showed >70% similarity to human data respectively. NCCS can also be used to demonstrate species differences. Animal models are the primary basis for drug discovery, development, and testing. However, the weak correlation between humans and animals, particularly regarding absorption and metabolism, is a substantial limitation for the use of animal models. Here we compare human and mouse acetaminophen (APAP) metabolism using NCCS, and its application can be extended to assess cellular responses, such as efficacy and toxicity, simultaneously.
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http://dx.doi.org/10.1088/1758-5090/abb652DOI Listing
September 2020

Mupirocin and Chlorhexidine Genotypic Resistance Found in Staphylococcus aureus Isolated From Young Infants Below 90 Days Old: A Genetic Basis for Eradication Failure.

Pediatr Infect Dis J 2021 01;40(1):49-54

From the Division of Infectious Diseases, Departments of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Objectives: To investigate the genetic characteristics associated with eradication failure of Staphylococcus aureus in infants below 90 days old.

Methods: S. aureus isolated from clinical specimen cultures (blood, surgical tissue, or drainage, pus, etc.) and routine screening cultures in the neonatal intensive care unit (nasal and axillary skin swab) from patients below 90 days old were collected prospectively for 1 year, from August 2017 to July 2018. The isolates underwent typing and screening for genes associated with chlorhexidine (qacA/B), quaternary ammonium (smr), and mupirocin resistance (iles mutation, mupA, mupB), as well as Panton-Valentine leukocidin (PVL) toxin.

Results: During the study period, 40 nonduplicate isolates were included for analyses, of which 70.0% were methicillin-resistant S. aureus (MRSA). Mupirocin resistance was found in 25% of the total isolates; 17.4% of the colonizers; and 35.3% of the pathogens (P = 0.196). Chlorhexidine resistance gene was found in 3 MRSA isolates colonized in the nares of preterm infants. All isolates harbored the disinfectant quaternary ammonium compound (QAC) resistance gene. PVL toxin gene was found in 57.5%, and the presence of PVL gene among colonizers and pathogens was similar (69.6% vs. 41.2%, P = 0.072).

Conclusions: Mupirocin, chlorhexidine, and QAC-resistant MRSAs harboring the PVL toxin gene were found in the nasal carriages of preterm infants. In this highly vulnerable patient population, one-fourth of the isolates harbored mupirocin-resistant genes, and all were resistant to QAC disinfectants. These strains are associated with persistence in both carriage and environmental reservoirs within the hospitals.
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http://dx.doi.org/10.1097/INF.0000000000002882DOI Listing
January 2021

Immunogenicity and protective efficacy of clade 2.3.2.1c and clade 2.3.4.4c H5Nx avian influenza antigen bank vaccines in mice, Korea.

Vaccine 2020 09 27;38(39):6080-6087. Epub 2020 Jul 27.

Avian Influenza Vaccine Research Laboratory, Avian Influenza Research and Diagnostic Division, Animal and Plant Quarantine Agency, Gimcheon, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2020.07.033DOI Listing
September 2020

Do We Really Need to Isolate All Children with COVID-19 in Healthcare Facilities?

J Korean Med Sci 2020 Jul 27;35(29):e277. Epub 2020 Jul 27.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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http://dx.doi.org/10.3346/jkms.2020.35.e277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384904PMC
July 2020

Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression.

Metabolism 2020 09 24;110:154302. Epub 2020 Jun 24.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Daejeon, Republic of Korea; Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajeong-ro, Daejeon, Republic of Korea. Electronic address:

Background: Intracellular lipid accumulation is associated with various diseases, particularly cancer. Mitochondrial dysfunction is considered as a cause of lipid accumulation; however, the related underlying mechanism remains unclear.

Findings: We found that Von Hippel-Lindau (VHL)-deficiency led to lipid accumulation and mitochondrial dysfunction in renal cell carcinoma cells. Moreover, VHL downregulated ATP-citrate lyase (ACLY), a key enzyme in de novo lipid synthesis, at the transcriptional level, which inhibited intracellular lipid accumulation in human renal carcinoma tissues. We identified PPARγ as the transcription factor regulating ACLY expression by binding to the cis-regulatory site PPRE on its promoter. VHL directly interacted with and promoted ubiquitination of PPARγ, leading to its degradation both in vitro and in vivo, resulting in the downregulation of ACLY. Furthermore, adenovirus-mediated VHL overexpression substantially ameliorated hepatic steatosis induced by a high-fat diet in db/db mice. Importantly, low VHL expression was associated with high ACLY expression and poor prognosis in human liver carcinoma in a dataset in The Cancer Genome Atlas.

Conclusions: VHL plays role in cellular lipid metabolism via regulating mitochondria and targeting PPARγ, a transcription factor for ACLY independent of hypoxia-inducible factor 1α. A novel VHL-PPARγ-ACLY axis and its implication in fatty liver disease and cancer were uncovered.
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http://dx.doi.org/10.1016/j.metabol.2020.154302DOI Listing
September 2020

Protection of layers and breeders against homologous or heterologous HPAIv by vaccines from Korean national antigen bank.

Sci Rep 2020 06 10;10(1):9436. Epub 2020 Jun 10.

Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do, 39660, Republic of Korea.

Korean government has selected and stocked five type antigens of two clades as Korean national antigen bank having high possibility of introduction to Korea. We aimed to evaluate the efficacy of the clade 2.3.2.1c and 2.3.4.4c H5Nx vaccines from the Korean avian influenza (AI) national antigen bank for emergency preparedness for their potency and protective efficacy against lethal homologous and heterologous viruses in layer and breeder chickens practically. The PD (dose of vaccine that protects 50% of chickens from viral challenge) of all vaccinated groups was >50, which was satisfied with minimum antigen requirement of OIE, and the PD levels of the two vaccines differed depending on strain and chicken breed. In homologous challenge, all vaccinated groups exhibited 100% survival with no clinical symptoms and high levels of pre-challenge protective immunity (7.2-8.5 log), although they did not completely prevent virus shedding. On the other hand, against heterologous virus challenge, vaccinated animals exhibited 62.5-80% survival with lower antibody titers (2.3-3.4 log) and a longer period of virus shedding (14 days post infection [dpi]). Our results suggest that the clade 2.3.2.1c and 2.3.4.4c H5Nx vaccines are good candidates for emergency vaccination of commercial chickens and support the idea that close genetic matching between vaccine and challenge virus provides the best protection.
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http://dx.doi.org/10.1038/s41598-020-66343-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287076PMC
June 2020

Sales and immunogenicity of commercial vaccines to H9N2 low pathogenic avian influenza virus in Korea from 2007 to 2017.

Vaccine 2020 04 10;38(16):3191-3195. Epub 2020 Mar 10.

Avian Influenza Research & Diagnostic Division, Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do 39660, Republic of Korea. Electronic address:

The present study was conducted to monitor sales activity and immunogenicity of commercial H9N2 vaccines produced in Korea from 2007 to 2017. Recorded sales of H9N2 vaccine were around 671 million doses, with 10 million doses sold in 2007, rising to a peak of 93 million doses in 2016, with a slight fall in 2017. Multivalent combined vaccines made up around 90% of all vaccine sales, and around 30% of all vaccines were distributed by regional governments for free. The regional vaccination rate was the highest in Gyeonggi and Chungnam, respectively with proportional to the population of layer and breeder chickens. There have been no cases of field infection since 2009. The mean antibody titer was 5.82 log across the study period. Our results suggest that continuous genetic monitoring of H9N2 viruses circulating in the field and updating the vaccine seed strain periodically are necessary in order to control H9N2 outbreaks.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.083DOI Listing
April 2020

Proteomic analyses reveal that ginsenoside Rg3() partially reverses cellular senescence in human dermal fibroblasts by inducing peroxiredoxin.

J Ginseng Res 2020 Jan 13;44(1):50-57. Epub 2018 Aug 13.

Biological Disaster Analysis Group, Korea Basic Science Institute, Daejeon, Republic of Korea.

Background: The cellular senescence of primary cultured cells is an irreversible process characterized by growth arrest. Restoration of senescence by ginsenosides has not been explored so far. Rg3() treatment markedly decreased senescence-associated β-galactosidase activity and intracellular reactive oxygen species levels in senescent human dermal fibroblasts (HDFs). However, the underlying mechanism of this effect of Rg3() on the senescent HDFs remains unknown.

Methods: We performed a label-free quantitative proteomics to identify the altered proteins in Rg3()-treated senescent HDFs. Upregulated proteins induced by Rg3() were validated by real-time polymerase chain reaction and immunoblot analyses.

Results: Finally, 157 human proteins were identified, and variable peroxiredoxin (PRDX) isotypes were highly implicated by network analyses. Among them, the mitochondrial PRDX3 was transcriptionally and translationally increased in response to Rg3() treatment in senescent HDFs in a time-dependent manner.

Conclusion: Our proteomic approach provides insights into the partial reversing effect of Rg3 on senescent HDFs through induction of antioxidant enzymes, particularly PRDX3.
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http://dx.doi.org/10.1016/j.jgr.2018.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033328PMC
January 2020

Effective reconstruction of functional organotypic kidney spheroid for in vitro nephrotoxicity studies.

Sci Rep 2019 11 26;9(1):17610. Epub 2019 Nov 26.

Laboratory of Disease Modeling and Therapeutics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

Stable and reproducible kidney cellular models could accelerate our understanding of diseases, help therapeutics development, and improve nephrotoxicity screenings. Generation of a reproducible in vitro kidney models has been challenging owing to the cellular heterogeneity and structural complexity of the kidney. We generated mixed immortalized cell lines that stably maintained their characteristic expression of renal epithelial progenitor markers for the different lineages of kidney cellular compartments via the BMP7 signaling pathway from a mouse and a human whole kidney. These cells were used to generate functional and matured kidney spheroids containing multiple renal lineages, such as the proximal tubule, loop of Henle, distal tubules, and podocytes, using extracellular matrix and physiological force, named spheroid-forming unit (SFU). They expressed all apical and basolateral transporters that are important for drug metabolism and displayed key functional aspects of the proximal tubule, including protein endocytosis and increased gamma-glutamyltransferase activity, and cyclic AMP responded to external cues, such as parathyroid hormone. Following exposure, cells fluxed and took up drugs via proximal tubule-specific apical or basolateral transporters, and displayed increased cell death and expression of renal injury marker. Here, we developed a new differentiation method to generate kidney spheroids that structurally recapitulate important features of the kidney effectively and reproducibly using mixed immortalized renal cells, and showed their application for renal toxicity studies.
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http://dx.doi.org/10.1038/s41598-019-53855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879515PMC
November 2019

Protective efficacy of vaccines of the Korea national antigen bank against the homologous H5Nx clade 2.3.2.1 and clade 2.3.4.4 highly pathogenic avian influenza viruses.

Vaccine 2020 01 25;38(3):663-672. Epub 2019 Oct 25.

Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do 39660, Republic of Korea. Electronic address:

The occurrence of severe outbreaks of highly pathogenic avian influenza in Korea led to establishment of a national antigen bank for emergency preparedness. Here, we developed five vaccines for this bank (clade 2.3.2.1C, clade 2.3.4.4A, B, C, and D) by reverse genetics, inactivated them with formalin, and evaluated the protective efficacy and potency of serial dilutions against lethal homologous challenge in specific-pathogen-free chickens. After vaccination with one dose, each vaccine resulted in 100% survival, with no clinical symptoms, or lack of detectable virus shedding, and high levels of pre-challenge protective immunity (8.4-10.2 log). After vaccination with one-tenth of the full dose, protection was similar to that with the full dose. After vaccination with one-hundredth of the initial dose, survival was 20-80%, and all vaccines showed virus shedding. Four vaccines (excluding clade 2.3.2.1C) had satisfactory potency. In antibody-persistence tests, all vaccines maintained long-lasting protective immunity. Our results suggest that inactivated reverse-genetics vaccines genetically matched to outbreak viruses provide adequate protection after a single vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2019.10.044DOI Listing
January 2020

Complete mitochondrial genome of the hydrothermal vent stalked barnacle (Cirripedia, Scalpelliforms, Eolepadidae).

Mitochondrial DNA B Resour 2019 Jul 22;4(2):2725-2726. Epub 2019 Jul 22.

Genome Editing Research Center, Korea Research Institute Bioscience and Biotechnology, Daejeon, Korea.

The family Eolepadidae is the only stalked barnacle in hydrothermal vent regions. Here, we determined the mitogenome of the eolepadid . The mitogenome was 17,374 bp long, with 76.6% AT content. Its protein-coding gene organization was identical to that of the deep-sea scalpellid . On the mitogenomic tree, two scalpellomorphan families (Eolepadidae and Scalpellidae) were monophyletic while the other scalpellomorphan family Pollicipedidae did not form the monophyletic group with them. Further mitogenomic analysis of undetermined taxa in hydrothermal vents is required to deepen our understanding of their phylogenetic relationships.
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http://dx.doi.org/10.1080/23802359.2019.1644564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706898PMC
July 2019

Changes in clinical features in Henoch-Schönlein purpura during three decades: an observational study at a single hospital in Korea.

Clin Rheumatol 2019 Oct 8;38(10):2811-2818. Epub 2019 Jun 8.

Departments of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Objective: It is unknown whether epidemiological or clinical characteristics of Henoch-Schönlein purpura (HSP) have changed over time. This study aimed at evaluating the epidemiological and clinical changes of HSP during 3 decades.

Methods: We retrospectively analyzed the data of 515 children with HSP (0-15 years of age) between 1987 and 2015. We compared the two HSP patient groups: those admitted from 1987 to 1996 (group A, 238 cases) and those admitted from 2006 to 2015 (group B, 98 cases), apart a decade.

Results: In total 515 patients, the mean age was 6.5 ± 3.0 years and the male-to-female ratio was 1.2:1 (278:237). The age distribution showed a peak at age 5 with a bell-shaped distribution pattern. The annual number of cases varied in each year with a trend of reduced cases in the recent decade. There were less cases during the summer season. Purpura, gastrointestinal involvement, joint involvement, and renal involvement were found in 100%, 56%, 38%, and 18% of the patients, respectively. In comparison between the two groups, there were similar findings in mean age, age distribution, and seasonal distribution. However, the hospitalization stay was longer, and the proportion of recurrent cases (14 cases vs. 0 case) and proteinuria (15% vs. 3%) were higher in the group A than in the group B.

Conclusions: Long-term epidemiologic features of HSP were similar to those in other countries. Clinical manifestations of HSP showed a trend towards a less severe clinical phenotype over time in Deajeon, Korea. Key Points • It is unknown whether epidemiological and clinical traits of Henoch-Schönlein purpura (HSP) have changed over time. • We reported that clinical manifestations of HSP have changed to milder phenotype through a long-term observation of three decades at a single hospital in Daejeon, South Korea. • Clinical phenotype of infection-related diseases, including HSP, may be changed over time, and the etiology and the reason of clinical changes over time remain to be solved.
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http://dx.doi.org/10.1007/s10067-019-04628-9DOI Listing
October 2019

A Presumed Etiology of Kawasaki Disease Based on Epidemiological Comparison With Infectious or Immune-Mediated Diseases.

Front Pediatr 2019 21;7:202. Epub 2019 May 21.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Kawasaki disease (KD) may be associated with infection of unknown pathogen(s). For predicting of the etiology of KD, we evaluated epidemiological characteristics in KD, common infectious diseases and immune-mediated diseases in childhood. We respectively, reviewed the data of patients with KD, influenza, aseptic meningitis, exanthem subitum (ES), (MP) pneumonia, acute pyelonephritis (APN), Henoch-Schönlein purpura (HSP), acute poststreptococcal glomerulonephritis (APSGN), and childhood asthma. We compared and interpreted epidemiological data across the groups. In age distribution, KD, APN, and ES showed a similar pattern in that majority of patients were infants or young children, and other diseases showed a relatively even age-distribution which had a peak age, mainly 5-6 years, with bell-shape patterns. In annual-case pattern, there were epidemic years in aseptic meningitis and MP pneumonia, and the fluctuated annual cases were seen in other diseases. The trends of decreasing cases were seen in APSGN, HSP, and childhood asthma in recent years. In seasonal frequency, influenza or aseptic meningitis occurred in mainly winter or summer season, respectively. HSP and APSGN cases had less in summer, and KD, APN, and ES showed relatively even occurrence throughout a year without significant seasonal variations. Our results suggest that KD agents may be associated with normal flora that are influenced by environmental changes, since pathogens of APN and ES could be regarded as normal flora that originate from the host itself or ubiquitously existing human reservoirs.
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http://dx.doi.org/10.3389/fped.2019.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536658PMC
May 2019

Early Corticosteroid Therapy for Pneumonia Irrespective of Used Antibiotics in Children.

J Clin Med 2019 May 22;8(5). Epub 2019 May 22.

Departments of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Antibiotics' effect on (MP) infection still remains controversial. A prospective study of 257 children with MP pneumonia during a recent epidemic (2015-2016) was conducted. All MP pneumonia patients were treated with corticosteroids within 24-36 h after admission. Initially, oral prednisolone (1 mg/kg) or intravenous methylprednisolone (IVMP; 1-2 mg/kg) was administered for mild pneumonia patients, and IVMP (5-10 mg/kg/day) for severe pneumonia patients. If patients showed a persistent fever for 36-48 h or disease progression, additive IVMP (5 mg/kg or 10 mg/kg) was given. Thirty-three percent of patients received only a broad-spectrum antibiotic without a macrolide. The mean age and the male-to-female ratio was 5.6 ± 3.1 years and 1:1, respectively. Seventy-four percent of patients showed immediate defervescence within 24 h, and 96% of patients showed defervescence within 72 h with improvements in clinical symptoms. Three percent of patients (8/257) who received additive IVMP also showed clinical improvement within 48 h without adverse reactions. There were no clinical or laboratory differences between patients treated with a macrolide ( = 172) and without ( = 85). Early corticosteroid therapy might reduce disease morbidity and prevent disease progression in MP pneumonia patients without side effects, and antibiotics may have limited effects on MP infection.
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http://dx.doi.org/10.3390/jcm8050726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572103PMC
May 2019

Epidemiological relationship between pneumonia and recurrent wheezing episode in children: an observational study at a single hospital in Korea.

BMJ Open 2019 04 11;9(4):e026461. Epub 2019 Apr 11.

Department of Paediatrics, College of Medicne, The Catholic University of Kora, Seoul, Republic of Korea.

Objective: This study was aimed to evaluate epidemiological and clinical relationship between (MP) infection and childhood recurrent wheezing episode (RWE).

Design: Retrospective case note review.

Setting: Paediatric department at a single Korean institution.

Participants: Consecutive admitted patients with MP pneumonia and RWE (0-15 years of age) between 2003 and 2014.

Methods: The retrospective medical records of patients with (MP) pneumonia (n=793 for epidemiological analysis and n=501 for clinical analysis) and those with RWE (n=384) from 2003 to 2014 were analysed. Diagnosis of MP pneumonia was made based on two-times titration of IgM antibody during hospitalisation. An RWE patient was defined as one with expiratory wheezing with at least one or more wheezing episodes based on medical records.

Results: During three MP pneumonia epidemics, there were no corresponding increases of patients with RWE in the epidemic years. In the 501 MP pneumonia patients, 52 (10.4%) had wheezing at presentation and 15 (3%) had RWE. The MP pneumonia patients with wheezing at presentation (n=52) were younger and were more likely to have an allergic disease history than those without wheezing (n=449). Among wheezing patients at presentation, 10 patients had previously RWE history. In a follow-up study, 13 patients (including 5 RWE) with initial wheezing and 25 patients (including 2 RWE) without wheezing had wheezy episodes after discharge. Among the total 501 patients, it was estimated that at least 31 MP pneumonia patients (6.2%) showed recurrent wheezing after initial MP infection.

Conclusions: A small part of children with MP pneumonia showed recurrent wheezing after MP pneumonia, and patients with RWE had a greater likelihood of experiencing wheezing when they had an initial MP infection. However, there were no increased admitted patients with RWE in MP pneumonia epidemic periods because of rarity of MP reinfection in children including patients with RWE or asthma.
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http://dx.doi.org/10.1136/bmjopen-2018-026461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500193PMC
April 2019

Stabilization of E2-EPF UCP protein is implicated in hepatitis B virus-associated hepatocellular carcinoma progression.

Cell Mol Life Sci 2019 Jul 22;76(13):2647-2662. Epub 2019 Mar 22.

Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Hepatitis B virus (HBV) X protein (HBx) is associated with hepatocarcinogenesis. E2-EPF ubiquitin carrier protein (UCP) catalyzes ubiquitination of itself and von Hippel-Lindau protein (pVHL) for degradation and associates with tumor growth and metastasis. However, it remains unknown whether HBx modulates the enzyme activity of UCP and thereby influences hepatocarcinogenesis. Here, we show that UCP is highly expressed in liver tissues of HBx-transgenic mice, but not non-transgenic mice. UCP was more frequently expressed in HBV-positive liver cancers than in HBV-negative liver cancers. HBx binds to UCP specifically and serotype independently, and forms a ternary complex with UCP and pVHL. HBx inhibits self-ubiquitination of UCP, but enhances UCP-mediated pVHL ubiquitination, resulting in stabilization of hypoxia-inducible factor-1α and -2α. HBx and UCP stabilize each other by mutually inhibiting their ubiquitination. HBx promotes cellular proliferation and metastasis via UCP. Our findings suggest that UCP plays a key role in HBV-related hepatocarcinogenesis.
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http://dx.doi.org/10.1007/s00018-019-03066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586911PMC
July 2019

Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma.

Cell Death Dis 2019 03 22;10(4):279. Epub 2019 Mar 22.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Daejeon, Republic of Korea.

Von Hippel Lindau (VHL) expression is significantly decreased in high-grade RCC, and autophagy, which is involved in tumor growth, invasion, differentiation, and metastasis, is activated in various human cancers. However, the relationship of autophagy and VHL in tumor progression remains controversial. Here, we showed that the expression levels of VHL and microtubule-associated protein 1 light chain 3B (MAP1LC3B, LC3B) were inversely correlated with various tumor grades of RCC tissues. pVHL was found to possess the LIR motif within a beta domain that interacted with MAP1LC3B and ubiquitinated it. The L101A VHL mutant failed to interact with MAP1LC3B, thereby failing to induce ubiquitination. MAP1LC3B-mediated autophagy was inhibited by functional pVHL and the ubiquitination of MAPLC3B was implicated in autophagy-induced cell death. We screened various autophagy inducers to determine the physiological function of the inhibition of LC3B-mediated autophagy by pVHL using VHL-deficient and VHL-expressing cell lines. MLN9708, a proteasome inhibitor, potently induced autophagy via the induction of MAP1LC3B and sensitized the cell to autophagy-mediated cell death in VHL-deficient and VHL-mutant (L101A) cells. In conclusion, our results showed that pVHL interacts with MAPL1LC3B and inhibits LC3B-mediated autophagy via MAP1LC3B ubiquitination. Furthermore, the activation of autophagy by the proteasome inhibitor MLN9708 induced cell death, indicating that MLN9708 can be used for VHL-deficient RCC therapy.
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http://dx.doi.org/10.1038/s41419-019-1520-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430800PMC
March 2019

First report on the complete mitochondrial genome of the deep-water scalpellid barnacle (Cirripedia, Thoracica, Scalpellidae).

Mitochondrial DNA B Resour 2018 Oct 26;3(2):1288-1289. Epub 2018 Oct 26.

Biodiversity Research Center, Academica Sinica, Taipei, Taiwan.

Scalpellids are one of the largest families of Scalpelliformes and reproduce either androdioeciously or dioeciously. Here, we characterized the first mitogenome of a scalpellid barnacle (), which was 15,593 bp in length with a 71.5% AT content. In comparison with the pollicipedids and , the tRNA genes of . were rearranged between ND3 and ND5, between CYTB and ND1, and between 12S rRNA and ND2. On the mitogenomic tree, the Scalpelliformes families Pollicipedidae and Scalpellidae were not monophyletic, which concurs with previous studies.
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http://dx.doi.org/10.1080/23802359.2018.1532844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800395PMC
October 2018

Complete mitochondrial genome of the catophragmid barnacle (Cirripedia, Thoracica, Balanomorpha, Catophragmidae).

Mitochondrial DNA B Resour 2018 Oct 26;3(2):1286-1287. Epub 2018 Oct 26.

Genome Editing Research Center, Korea Research Institute Bioscience and Biotechnology, Daejeon, Korea.

The family Catophragmidae is one of the lower balanomorphs from traditional and recent multiple mitochondrial and nuclear markers molecular analysis. Here, we characterized the first mitogenome of the catophragmid barnacle , which was 15,446 bp in length with a 68.3% AT content. The mitogenome had the typical pancrustacean gene arrangement, which was identical to the mitogenome configurations of the chthamalid sp. and pachylasmatoid . On the mitogenomic tree, the catophragmid formed an independent branch that was basal to the members of the superfamilies Tetraclitoidea and Balanoidea, which was inconsistent with previous findings.
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http://dx.doi.org/10.1080/23802359.2018.1532843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799505PMC
October 2018

Novel reassortants of clade 2.3.4.4 H5N6 highly pathogenic avian influenza viruses possessing genetic heterogeneity in South Korea in late 2017.

J Vet Sci 2018 Nov;19(6):850-854

Avian Influenza Research & Diagnostic Division, Animal and Plant Quarantine Agency, Gimcheon 39660, Korea.

Novel H5N6 highly pathogenic avian influenza viruses (HPAIVs) were isolated from duck farms and migratory bird habitats in South Korea in November to December 2017. Genetic analysis demonstrated that at least two genotypes of H5N6 were generated through reassortment between clade 2.3.4.4 H5N8 HPAIVs and Eurasian low pathogenic avian influenza virus in migratory birds in late 2017, suggesting frequent reassortment of clade 2.3.4.4 H5 HPAIVs and highlighting the need for systematic surveillance in Eurasian breeding grounds.
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http://dx.doi.org/10.4142/jvs.2018.19.6.850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265581PMC
November 2018

Missense mutation of SPAST protein (I344K) results in loss of ATPase activity and prolonged the half-life, implicated in autosomal dominant hereditary spastic paraplegia.

Biochim Biophys Acta Mol Basis Dis 2018 10 11;1864(10):3221-3233. Epub 2018 Jul 11.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Daejeon, Republic of Korea; Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajeong-ro, Daejeon, Republic of Korea. Electronic address:

The spastin protein (SPAST) contains an ATPase with diverse cellular activities (AAA) domain and regulates microtubule dynamics. Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous. Here, SPAST variant with an I344K mutation (I344K-SPAST) was identified in a Korean family with autosomal dominant-type HSP. We investigated the role of the I344K-SPAST in HSP to provide a therapeutic mechanism. The I344K-SPAST mutation prolonged the half-life of the protein compared to wild-type SPAST (WT-SPAST) in cells by modulating post-translational modifications for proteasomal degradation. I344K-SPAST was localized in microtubule but defective in microtubule severing and ATPase activity compared to WT-SPAST in vitro and in cells. Mutant M87 isoform harboring the same mutation with I344K-M1 SPAST also increased protein stability and loss of MT severing activity, but the pathogenicity was not stronger than I344K-M1 SPAST in neurite outgrowth. Overexpression of I344K-SPAST resulted in microtubule accumulation following inhibited neurite growth in neuroblastoma, neural progenitor cells and mouse primary cortical neurons. Conversely, these pathogenic effects of I344K-SPAST were reduced by overexpression of WT-M1 SPAST in a dose dependent manner since WT-SPAST could interact with I344K-SPAST. Our data therefore provide proof-of-concept that gene transfer of WT-M1 SPAST may serve as a valid therapeutic option for HSPs.
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http://dx.doi.org/10.1016/j.bbadis.2018.07.009DOI Listing
October 2018

Characterization of a novel reassortant H5N6 highly pathogenic avian influenza virus clade 2.3.4.4 in Korea, 2017.

Emerg Microbes Infect 2018 Jun 13;7(1):103. Epub 2018 Jun 13.

Avian Influenza Research and Diagnostic Division, Animal and Plant Quarantine Agency, 177, Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do, 39660, Republic of Korea.

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http://dx.doi.org/10.1038/s41426-018-0104-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997646PMC
June 2018