Publications by authors named "Ching-Yuang Lin"

126 Publications

Heat Shock Protein-70 Levels Are Associated With a State of Oxidative Damage in the Development of Bronchopulmonary Dysplasia.

Front Pediatr 2021 26;9:616452. Epub 2021 May 26.

Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan.

Heat shock protein-70 (Hsp-70) exhibits cytoprotective effects against oxidative stress-induced airway injury. This study aimed to examine Hsp-70 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) from tracheal aspirates (TA) in very low-birth weight (VLBW) preterm infants to predict the development of bronchopulmonary dysplasia (BPD). This birth cohort study enrolled 109 VLBW preterm infants, including 32 infants who developed BPD. Hsp-70 and 8-OHdG concentrations from TA were measured by immunoassay. The apoptosis of TA epithelial cells obtained on Day 28 after birth was measured using annexin-V staining assay. Hsp-70 and 8-OHdG levels in TA fluid were persistently increased from Day 1 to Day 28 of life in the BPD group. Multiple linear regression analysis demonstrated that BPD was significantly associated with gestational age, respiratory distress syndrome, and TA Hsp-70 and 8-OHdG levels on post-natal Day 28. The TA Hsp-70 level positively correlated with TA 8-OHdG level on the Day 1 ( = 0.47) and Day 28 of life ( = 0.68). Incubation of recombinant Hsp-70 with primary epithelial cells derived from TA of patients decreased hydrogen peroxide-induced epithelial cell death. Hsp-70 levels are associated with a state of oxidative injury in the development of BPD.
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http://dx.doi.org/10.3389/fped.2021.616452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187579PMC
May 2021

Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan.

Medicine (Baltimore) 2021 May;100(20):e25986

Clinical Immunological Center, Children's Hospital, China Medical University, Taichung, Taiwan.

Abstract: Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.
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http://dx.doi.org/10.1097/MD.0000000000025986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137071PMC
May 2021

Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia.

Pediatr Blood Cancer 2020 02 17;67(2):e28075. Epub 2019 Nov 17.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, Changhua Christian Children's Hospital, Changhua City, Taiwan.

Background: This study aimed to investigate the relationship between CD4 regulatory T cells (Tregs) and innate lymphoid cells (ILCs) in children with primary immune thrombocytopenia (ITP) undergoing high-dose intravenous immunoglobulin (IVIG) therapy.

Methods: We enrolled a cohort of 30 children with newly diagnosed ITP and 30 healthy controls and collected blood samples for levels of Tregs, ILCs, relevant cytokines, and Treg suppression assay at the diagnosis, two days, four weeks, and one year (only platelet count) after high-dose IVIG treatment. IVIG partial responders was defined by a platelet count less than 100 × 10 /L at 12 months after IVIG treatment.

Results: Children with newly diagnosed ITP exhibited elevated levels of ILC1, ILC2, ILC3, Th17, myeloid dendritic cells (DCs), plasmacytoid DCs, and serum IFN-γ and IL-17A levels, accompanied by a decrease in IL-10-producing Tregs. High-dose IVIG therapy reversed these aberrations. Platelet counts positively correlated with Tregs (rho = 0.72) and negatively correlated with both ILC1 (rho = -0.49) and ILC3 (rho = -0.60) (P < 0.05). Significantly lower Tregs and higher ILC1, ILC3, DCs, and serum IL-17A levels were noted in the partial responders (n = 8) versus responders (n = 22; P < 0.05). We found that Tregs suppressed proliferation of ILCs and CD4 T cells in CD25-depleted peripheral PBMCs and enhanced the apoptosis of CD4 CD45RO T cells in vitro following IVIG therapy.

Conclusions: Effective high-dose IVIG therapy for children with newly diagnosed ITP appears to result in the induction of Tregs, which suppresses ILC proliferation in vitro and is associated with platelet response.
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http://dx.doi.org/10.1002/pbc.28075DOI Listing
February 2020

Nasal nitric oxide is a useful biomarker for acute unilateral maxillary sinusitis in pediatric allergic rhinitis: A prospective observational cohort study.

World Allergy Organ J 2019 17;12(4):100027. Epub 2019 May 17.

School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Background: Nasal nitric oxide (nNO) could be a biomarker for nasal passage inflammation and sinus ostial patency. We have aimed to investigate the nNO concentration and the effect of antibiotic therapy in children with perennial allergic rhinitis (PAR) children with/without acute bacterial sinusitis.

Methods: We enrolled a cohort of 90 and 31 children with PAR, without and with acute unilateral maxillary sinusitis, and 79 normal children. Acute bacterial maxillary sinusitis was diagnosed based on clinical signs and symptoms, radiographic examination and nasal fibroendoscopy. Rhinitis control assessment test (RCAT), rhinomanometry, nNO and fractional exhaled NO (FENO) measurements were performed before and 2 weeks after antibiotic therapy.

Results: We found significantly higher mean nNO levels, FENO values, and total nasal resistance in children with PAR than in normal children ( ​< ​0.05). Acute unilateral maxillary sinusitis was associated with lower lesion-side nNO levels, higher FENO values, total nasal resistance, and poor RCAT scores ( ​< ​0.05). In multivariate analysis, age, IgE, and acute maxillary sinusitis were significant factors influencing nNO levels in children with PAR. The lesion-side nNO levels, FENO values, total nasal resistance, and RCAT scores were reversed after antibiotic therapy ( ​< ​0.05). The lesion-side nNO levels were significantly correlated to nasal obstructive scores ( ​= ​0.59,  ​< ​0.05) and expiratory nasal resistance ( ​= ​-0.54,  ​< ​0.05) in the acute maxillary sinusitis. A cut-off nNO value of 538 ​ppb showed 100% sensitivity and 94.9% specificity, to predict PAR from normal children. An nNO value of 462 ​ppb showed 100% sensitivity and 100% specificity to discriminate between the lesion-side and the unaffected sinus-side in PAR children with acute unilateral maxillary sinusitis.

Conclusions: We conclude that the obstruction of NO from the sinus into the nasal passage is the likely explanation for the decreased lesion-side nNO levels in acute unilateral maxillary sinusitis. nNO is a non-invasive biomarker with high sensitivity to diagnose and monitor treatment responses of PAR patients with acute rhinosinusitis. Both nNO and FENO levels return to baseline following antibiotic therapy, supporting the "one airway one disease" concept.
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http://dx.doi.org/10.1016/j.waojou.2019.100027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526296PMC
May 2019

Allergen-specific immunotherapy enhances CD8  CD25  CD137 regulatory T cells and decreases nasal nitric oxide.

Pediatr Allergy Immunol 2019 08 30;30(5):531-539. Epub 2019 May 30.

Clinical Immunological Center, China Medical University Hospital, College of Medicine, Division of Pediatric Nephrology, China Medical University, Taichung, Taiwan.

Background: 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8 Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8  CD25  CD137 Treg suppressive function to decrease nasal nitric oxide (nNO) levels.

Methods: Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8  CD25 T cells and suppressive function of CD8  CD25  CD137 Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8  CD25  CD137 T cells was analyzed by Western blotting.

Results: Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8 T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8  CD25  CD137 population in PBMCs. Pam3CSK4-stimulated CD8 CD25 CD137 Tregs induced IL-10 and TGF-β and suppressed CD4 CD25- T-cell proliferation mainly by cell contact inhibition. CD8 CD25 CD137 Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8 CD25 T cells decreased Pam3CSK4-activated Foxp3 expression.

Conclusion: Der p IT expanded CD8 CD25 CD137 Tregs and decreased nNO levels. Induced CD137 expression on CD8 CD25 Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.
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http://dx.doi.org/10.1111/pai.13061DOI Listing
August 2019

Mortality Risks among Various Primary Renal Diseases in Children and Adolescents on Chronic Dialysis.

J Clin Med 2018 Nov 5;7(11). Epub 2018 Nov 5.

Clinical Immunological Center, China Medical University Medical College and Hospital, Taichung 404, Taiwan.

There is little information available on the association between primary renal disease (PRD) and long-term mortality in the pediatric dialysis population. The objective of this study was to explore mortality risks in children and adolescents on chronic dialysis, specifically focused on the risk of various PRDs. The study cohort included children and adolescents with end-stage renal disease (ESRD) (aged < 20 years) who had received dialysis for at least 90 days between 2000 and 2014 and were identified from Taiwan's National Health Insurance medical claims. A total of 530 children and adolescents were included in the study. The median age of the included patients was 13.6 years and 305 (57.5%) patients were males. One hundred and seven patients died during the follow-up period and the median survival time was 6.0 years. Mortality was highest in the youngest patients. For patients with the following PRDs, mortality was significantly higher than that in patients with primary glomerulonephritis: secondary glomerulonephritis (adjusted hazard ratio (aHR): 2.50; 95% confidence interval (CI): 1.03⁻6.08), urologic disorder (aHR: 4.77; 95% CI: 1.69⁻13.46), and metabolic diseases (aHR: 5.57; 95% CI: 1.84⁻16.85). Several kinds of PRDs appear to have high mortality risks in the pediatric dialysis population. These differences in mortality risk highlight the importance of the focused clinical management of these high-risk subgroups.
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http://dx.doi.org/10.3390/jcm7110414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262556PMC
November 2018

Complement regulatory protein CD46 induces autophagy against oxidative stress-mediated apoptosis in normal and asthmatic airway epithelium.

Sci Rep 2018 08 28;8(1):12973. Epub 2018 Aug 28.

Clinical Immunological Center and College of Medicine, China Medical University Hospital, Taichung, Taiwan.

Autophagy plays a major role in defending against oxidative stress in respiratory epithelial cells. The complement regulatory protein CD46 can enhance autophagy and decrease local complement activation at sites of inflammation. This study investigated the mechanism by which CD46 protects against oxidative stress-mediated apoptosis in respiratory epithelium in asthmatic patients. Nasal mucosa samples were obtained from 60 adults with mild asthma who received turbinectomy and 30 controls. A decreased expression of CD46 and increased apoptosis were noted in the damaged nasal epithelium from the asthmatic patients. Primary epithelial cells cultured with Dermatophagoides pteronyssinus 2 showed decreased CD46 and increased cleaved CASPASE-3A expressions. Crosslinking CD46 mAb could induce the formation of autophagosomes and LC3-II expression in primary epithelial cells. CD46 engagement could induce autophagy against hydrogen peroxide-induced epithelial cell death, whereas the autophagy inhibitor 3-methyladenine decreased this effect. In addition, CD46 engagement decreased the expressions of PRO-IL-1β and NLRP3, enhanced the expression of scaffold protein GOPC, and diminished hydrogen peroxide-induced 8-OHdG, IL-1β and IL-6 production. Silencing ATG5 in human lung epithelial A549 cells decreased CD46-activated autophagy with LC3-II. CD46 induced autophagy and decreased the oxidative stress-mediated apoptosis of respiratory epithelium, and this may offer a new therapeutic strategy to treat asthma.
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http://dx.doi.org/10.1038/s41598-018-31317-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113329PMC
August 2018

Cardiac apoptosis induced under high glucose condition involves activation of IGF2R signaling in H9c2 cardiomyoblasts and streptozotocin-induced diabetic rat hearts.

Biomed Pharmacother 2018 Jan 7;97:880-885. Epub 2017 Nov 7.

Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Biological Science and Technology, Asia University, Taichung 41354, Taiwan. Electronic address:

The insulin-like growth factor type 2 receptor (IGF2R) overexpression has been implicated in heart disease progression. Unregulated IGF2R signaling triggers cardiac hypertrophy, apoptosis, and cardiomyopathies. The present study investigated the role of IGF2R in cardiomyocyte apoptosis under high glucose (HG) levels and in streptozotocin (STZ) induced diabetic rat hearts. We found that IGF2 and IGF2R protein expression were highly upregulated under high glucose condition in H9c2 cells as well as in STZ induced diabetic rat hearts. Using immunoblotting and TUNEL assay, we found that elevated glucose condition induced IGF2R expression leads to activation of Gαq mediated calcineurin-dependent signaling pathway, which further leads to downstream activation and expression of cardiac hypertrophy related proteins, ANP and BNP. Further, we found that glucose-induced IGF2R expression downregulated survival protein p-Akt, p-Bad (Ser 155) and enhanced the expression of apoptosis-inducing proteins cytochrome c and cleaved Caspase-3. Our results suggested that hyperglycemic condition leads to cellular cardiomyocyte apoptosis both in vitro and in vivo models, via abnormally increased activation of the IGF2R signaling pathway.
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http://dx.doi.org/10.1016/j.biopha.2017.11.020DOI Listing
January 2018

Regression of Neonatal Cardiac Rhabdomyoma in Two Months Through Low-Dose Everolimus Therapy: A Report of Three Cases.

Pediatr Cardiol 2017 Oct 5;38(7):1478-1484. Epub 2017 Aug 5.

Pediatric Nephrology, China Medical University Children's Hospital, Taichung, 40447, Taiwan.

Cardiac rhabdomyoma (CR) is the most common cardiac tumor in newborns. Approximately 75% of cases are associated with tuberous sclerosis complex. Although these tumors usually spontaneously regress after 2 years of age, they can be life-threatening when they obstruct major cardiac inflow or outflow pathways. Everolimus is an inhibitor of the mammalian target of rapamycin, reducing its production of the proteins harmartin and tuberin. Everolimus has demonstrated a remarkable suppression effect in children with tuberous sclerosis complex at doses of 4.7-5.6 mg/M/day and serum trough levels of 5-15 ng/mL. Since 2012, five case reports of neonates with CR have also reported the tumor-regressing effect of everolimus. However, the optimal dosage for neonates is still unknown. Over the past 2 years, we have deliberately used a low dose everolimus regimen (0.3-0.67 mg/M/day) in three neonates with large CRs, in an effort to maintain serum trough levels at 3-7 ng/mL. In all three cases, the tumors regressed smoothly within 2 months. Regarding the drug's side effect of predisposing patients to infection, we observed that adenovirus pneumonia occurred in one case at 3 months of age, and chicken pox occurred in another case at 9 months of age; both recovered smoothly. Our three cases of neonatal CR demonstrate that a low-dose everolimus regimen is an effective treatment for tumor regression.
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http://dx.doi.org/10.1007/s00246-017-1688-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628183PMC
October 2017

The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3IL-17 T cells.

BMC Nephrol 2017 Jul 10;18(1):225. Epub 2017 Jul 10.

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.

Background: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4 forkhead box P3 (FOXP3) T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3IL-17 T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear.

Methods: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days.

Results: Juxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4FOXP3 T cells increased progressively, along with the number of FOXP3interleukin (IL)-17 T cells, after 14 days, and their numbers then progressively decreased with increasing CD4IL-17 T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4FOXP3IL-17 T cells in splenic single-cell suspensions. FOXP3IL-17 T cells expressed TGF-β1 both in vitro and in vivo, and TGF-β1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-β1-producing cells.

Conclusions: TSA treatment decreased JG hyperplasia, the percentage of FOXP3IL-17 cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.
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http://dx.doi.org/10.1186/s12882-017-0630-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504832PMC
July 2017

High exhaled nitric oxide levels correlate with nonadherence in acute asthmatic children.

Ann Allergy Asthma Immunol 2017 04;118(4):521-523.e2

Clinical Immunological Center and College of Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2017.01.031DOI Listing
April 2017

IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy.

Nephrol Dial Transplant 2018 02;33(2):248-256

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, China.

Background: Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN.

Methods: The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis.

Results: CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes.

Conclusions: IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.
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http://dx.doi.org/10.1093/ndt/gfw397DOI Listing
February 2018

Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation.

J Am Coll Cardiol 2016 Dec;68(23):2554-2563

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; Taiwan Clinical Trial Consortium in Fabry Disease, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Background: Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement.

Objectives: The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD.

Methods: To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults.

Results: LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes.

Conclusions: Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD.
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http://dx.doi.org/10.1016/j.jacc.2016.09.943DOI Listing
December 2016

Correlates of Elevated Interleukin-6 and 8-Hydroxy-2'-Deoxyguanosine Levels in Tracheal Aspirates from Very Low Birth Weight Infants Who Develop Bronchopulmonary Dysplasia.

Pediatr Neonatol 2017 02 30;58(1):63-69. Epub 2016 May 30.

Department of Pediatrics, Changhua Christian Children's Hospital, Changhua City, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; School of Medicine, Chung Shan Medical University, Taichung City, Taiwan. Electronic address:

Background: Bronchopulmonary dysplasia (BPD) remains the most common complication of very low birth weight (VLBW) preterm infants, and inflammatory regulation plays a role in the development of the BPD. Interleukin-6 (IL-6) has an important role in airway inflammation and therefore can be used as a marker of airway injury. The study aimed to compare the changes between IL-6 and oxidative stress marker with 8-hydroxy-2'-deoxyguanosine (8-OHdG) from serum and tracheal aspiration (TA) in VLBW preterm infants following development of BPD.

Methods: This birth cohort study enrolled 80 VLBW preterm infants, including 26 who developed BPD. All infants completed the study and survived at 36 weeks postmenstrual age. IL-6 and 8-OHdG concentrations from serum and TA on Day 1 and Day 28 after birth were measured using immunoassay.

Results: IL-6 and 8-OHdG in serum and TA were higher in the BPD group than in the non-BPD group on the 1 day after birth (p < 0.05). The IL-6 and 8-OHdG levels in TA fluid were persistently increased on the 28 day of life in the BPD group (p < 0.05). The TA IL-6 was positively correlated with 8-OHdG levels on the 1 day (r = 0.64, p < 0.05) and 28 day of life (r = 0.76, p < 0.05). Based on receiver operating characteristic curves as a predictor of BPD development, TA IL-6 (cutoff, 456.8 pg/mg) had 81.5% sensitivity and 77.8% specificity, whereas TA 8-OHdG (cutoff, 4.4 ng/mg) had a sensitivity of 81.5% and a specificity of 64.4%.

Conclusion: Persistent inflammation with oxidative DNA damage in the respiratory tract may be a crucial mechanism in BPD.
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http://dx.doi.org/10.1016/j.pedneo.2016.01.004DOI Listing
February 2017

Childhood Albuminuria and Chronic Kidney Disease is Associated with Mortality and End-Stage Renal Disease.

Pediatr Neonatol 2016 08 1;57(4):280-7. Epub 2016 Feb 1.

Office of Statistics, Department of Health, The Executive Yuan, Taiwan.

Background: We do not yet fully grasp the significance of childhood albuminuria. Based on mass urinary screening (MUS) using albumin-specific dipsticks in school children, we studied the independent association of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in children with chronic kidney disease (CKD).

Methods: A prospective cohort of 5351 children with albuminuria detected by school MSU during the period 1992-1996, followed up to 2009.

Results: Cumulative mortality rate, prevalence of CKD, and ESRD were higher in children with albuminuria than those without. Albuminuria category was associated with the risk of mortality [hazard ratio (HR) 3.4] and ESRD (HR 3.24). Lower eGFR and albuminuria predicted mortality and ESRD among children with albuminuria and CKD. We found that being below a threshold of 45 mL/min/1.73 m(2) was significantly associated with ESRD. The highest renal function decline, along with the steepest slope of cumulative ESRD number, occurred in Stage 3, the critical point in renal progression. Risk factors for renal progression among different age groups with albuminuria were hypercholesterolemia and low serum albumin at 7-17 years of age. Beyond 18 years of age, besides the risk factor, a higher fasting blood sugar (BS) was also noted.

Conclusion: Childhood albuminuria is a risk factor for CKD in later life, albuminuria provides additional prognostic information, and complications of CKD should be defined in each case.
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http://dx.doi.org/10.1016/j.pedneo.2015.09.013DOI Listing
August 2016

Clinical characteristics and prevalence of complications of chronic kidney disease in children: the Taiwan Pediatric Renal Collaborative study.

Pediatr Nephrol 2016 07 5;31(7):1113-20. Epub 2016 Feb 5.

Division of Pediatric Nephrology, Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.

Background: Little information is available regarding the clinical characteristics and prevalence of complications in children with chronic kidney disease (CKD), especially in early disease stages. The objective of this study was to determine the clinical characteristics and prevalence of complications in children with predialytic CKD.

Methods: This multicenter, cross-sectional study enrolled children at all stages of predialytic CKD. Children who were between the ages of 1 year and 18 years and who fulfilled the clinical criteria of CKD were included in the study. Baseline demographic data, previous history, clinical characteristics, and laboratory data were collected.

Results: A total of 757 children were included in the study. The median age at the time of enrollment was 10.6 years; 397 patients (52.4 %) were males. A total of 39.0 % of the patients were in CKD stage 1, 37.6 % were in stage 2, 14.8 % were in stage 3, 3.0 % were in stage 4, and 5.5 % were in stage 5. Nonglomerular renal diseases were the primary cause of CKD, comprising 51.9 % of the patients with CKD. The age at disease onset, gender, CKD stage distribution, and proportion of co-morbidities varied between the glomerular and nonglomerular CKD cases. Anemia, hyperlipidemia, hypocalcemia, and hyperphosphatemia were more prevalent in patients with glomerular CKD. The overall prevalence of complications was as follows: uncontrolled blood pressure, 44.1 %; anemia, 34.2 %; hyperlipidemia, 44.9 %; short stature, 10.3 %; and failure to thrive, 8.2 %. Uncontrolled blood pressure (BP), anemia, and hyperlipidemia were common, even in the early CKD stages. The prevalence of CKD complications generally increased with the worsening stage of CKD.

Conclusions: This study reveals differences in CKD etiology and prevalence of specific complications according to the stage of CKD. Early recognition and awareness of complications are mandatory for clinicians during the follow-up visits of children with CKD.
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http://dx.doi.org/10.1007/s00467-016-3325-5DOI Listing
July 2016

Incidence and Risks of Congenital Anomalies of Kidney and Urinary Tract in Newborns: A Population-Based Case-Control Study in Taiwan.

Medicine (Baltimore) 2016 Feb;95(5):e2659

From the Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan (Y-LT); Department of Mathematical Sciences, Research Center for Mind, Brain, and Learning, National Chengchi University, Taipei, Taiwan (HL); Children's Hospital of China Medical University, Taichung, Taiwan (C-YL); Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (C-NH); and School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (C-NH).

Congenital anomalies of the kidney and urinary tract (CAKUT) are 1 of the major factors in young adults needing renal replacement therapy, but there is little extensive assessment of their incidence and risk factors. This study aimed to evaluate trends in the incidence of and risk factors for CAKUT among all births in Taiwan.This population-based case-control study design was conducted using the Taiwan national births registry, which contains detailed information about maternal health and characteristics of newborns, supplied by health professionals. Of 1,603,794 newborns registered between 2004 and 2014, 668 infants were reported to have CAKUT. Newborns without congenital anomalies were matched with CAKUT cases by birth year, month, and Apgar score in a ratio of 5:1. Odds ratio (OR) and 95% confidence interval (CI) for developing CAKUT were calculated using a conditional multivariate logistic regression model.The incidence of CAKUT was approximately 4.2 per 10,000 births. The adjusted ORs for CAKUT in newborns associated with maternal age of 20 to 29 (OR, 2.18; 95% CI, 1.11-4.28), or 30 to 39 (OR, 2.29; 95% CI, 1.17-4.51), maternal gestational diabetes (OR, 2.22, 95% CI, 1.06-4.67), maternal thalassemia/hemochromatosis (OR, 2.67; 95% CI, 1.35-5.27), polyhydramnios or oligohydramnios (OR, 9.16; 95% CI, 5.46-15.37), birth parity >1 (OR, 0.27; 95% CI, 0.15-0.50), having a gestational age <37 weeks (OR, 1.48; 95% CI, 1.23-1.78), and being a boy (OR, 1.83; 95% CI, 1.53-2.19). Infants of mother with gestational diabetes were more likely to have congenital anomalies, small gestational age (<37 weeks) and low birth weight.CAKUT are associated with several maternal health risk factors. As Taiwan has the highest prevalence and incidence rates of end-stage renal disease in the world, these findings strongly support the need to develop professional guidelines for prenatal counseling and management of women at risk of adverse birth outcomes, to prevent kidney disease progression and reduce complications.
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http://dx.doi.org/10.1097/MD.0000000000002659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748909PMC
February 2016

Effect of superoxide anion scavenger on rat hearts with chronic intermittent hypoxia.

J Appl Physiol (1985) 2016 Apr 14;120(8):982-90. Epub 2016 Jan 14.

School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Occupational Therapy, Asia University, Taichung, Taiwan; and Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan

Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2 (-)-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNEL-positive apoptosis. The superoxide anion scavenger decreased hypoxia-induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis-inducing factor (AIF), and TUNEL-positive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances cardiac survival pathways.
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http://dx.doi.org/10.1152/japplphysiol.01109.2014DOI Listing
April 2016

Etiology and pediatric chronic kidney disease progression: Taiwan Pediatric Renal Collaborative Study.

J Formos Med Assoc 2016 Sep 29;115(9):752-63. Epub 2015 Aug 29.

Department of Pediatrics, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi City, Taiwan.

Background/purpose: This study aims to examine the characteristics of Taiwanese children with chronic kidney disease (CKD) and delineate the factors that lead to disease progression in this population.

Methods: We reviewed the records of the Taiwan Pediatric Renal Collaborative Study, a multicenter database of Taiwanese children with CKD. Multivariate regression analysis was used to identify the main factors associated with disease progression.

Results: A total of 382 children aged 1-18 years were included in the study (median age was 10.6 years; interquartile range: 6.4-13.8). There were 197 males (51.6%) and 185 females. CKD Stage 1 was diagnosed in 159 children (41.6%), Stage 2 in 160 (41.9%), Stage 3 in 51 (13.4%), and Stage 4 in 12 (3.1%). Fifty-six children (14.7%) experienced CKD progression. A multivariate analysis for all patients indicated that the risk for disease progression was increased in children with CKD secondary to a structural abnormality, genetic disease, anemia, elevated diastolic blood pressure, or elevated blood urea nitrogen. Compared with children with Stage 1 CKD, those with Stage 2 and Stage 4 CKD had decreased risk for CKD progression in this short-term cohort follow-up.

Conclusion: CKD etiology affects disease progression. Careful monitoring and treatment of anemia and elevated blood pressure in children with CKD may slow disease progression.
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http://dx.doi.org/10.1016/j.jfma.2015.07.019DOI Listing
September 2016

p-Cresol mediates autophagic cell death in renal proximal tubular cells.

Toxicol Lett 2015 Apr 7;234(1):20-9. Epub 2015 Feb 7.

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taiwan; Clinical Immunological Center and Division of Pediatrics Nephrology, Children's Hospital of China Medical University, Taiwan. Electronic address:

Higher serum level of p-cresol (PC) in chronic kidney disease (CKD) patients has been linked with CKD progression. The toxic effect of PC on diverse cells has been reported by prior studies, except for renal tubular cells. Both autophagy and apoptosis contribute to renal tubular cell death, yet evidence of its response to PC is limited and their crosstalk is still unclear. Autophagy is an important cellular process involved in toxin-induced cell death. Renal tubular cell death in tubular injury is thought to be one of the key events causing the progression of CKD. Thus, we treated rat (NRK-52E) and human (HRPTEC) renal proximal tubular cells (RPTC) with PC and found the cell proliferation was significantly decreased. Cell apoptosis was significantly increased and accompanied with the activation of autophagy as evidenced by increases in LC3-II, beclin 1 and Atg 4. We also found an increase of p62 by c-Jun activation. p62 accumulation could mediate the activation of caspase 8-dependent cell apoptosis. Conversely, knockdown of p62 by siRNA of p62 had the opposite effect by arresting LC3-II accumulation and promoting increasing cell viability. We conclude that PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. PC can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases.
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http://dx.doi.org/10.1016/j.toxlet.2015.02.003DOI Listing
April 2015

Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients.

Nephrology (Carlton) 2014 Nov;19(11):672-8

The Kidney Institute and Division of Nephrology, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.

Aims: Fibroblast growth factor 23 (FGF23) and Klotho are associated with vascular calcification and cardiovascular disease in dialysis patients. Sevelamer has been shown to reduce progression of vascular calcification. This study aimed to determine the long-term effect of sevelamer treatment on serum FGF23 and Klotho levels in chronic haemodialysis (HD) patients.

Methods: In the post-hoc analysis, we measured serum FGF23, Klotho and other biochemical factors (Ca, P, i-PTH, hsCRP, LDL-C) in 50 haemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. Twenty-three patients received sevelamer and 27 patients received calcium carbonate.

Results: After 48-week sevelamer treatment, there were significant changes with lower LDL-C (from 2.82 ± 0.78 to 1.65 ± 0.53 mmol/L, P = 0.000), lower FGF23 (from 2465.97 (2568.88) to 795.61 (1098.39), P = 0.000) and higher s-Klotho levels (from 189.35 (161.88) to 252.94 (517.80) pg/mL, P = 0.000). In calcium carbonate group, there were no significant changes of LDL-C and FGF23, but with a borderline significant increase of s-Klotho level (from 142.34 (265.24) to 188.57 (252.38) pg/mL, P = 0.054). Multivariate analysis showed that FGF23 decrement was associated with sevelamer treatment (β = -0.277, P = 0.005), change of serum phosphate (β = 0.609, P = 0.000) and calcium levels (β = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (β = 0.490, P = 0.019).

Conclusion: Maintenance HD patients had lower serum FGF23 levels, accompanied with significantly increased serum Klotho levels, after 48-week sevelamer treatment. The FGF23 decrement was associated with sevelamer use, the change of serum phosphate and calcium levels. The serum Klotho increment was proportional to the phosphate-lowering power of the binders.
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http://dx.doi.org/10.1111/nep.12319DOI Listing
November 2014

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

JAMA 2014 Aug;312(5):525-34

Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China.

Importance: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown.

Objective: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Design, Setting, And Participants: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia.

Main Outcomes And Measures: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Results: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease.

Conclusions And Relevance: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.
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http://dx.doi.org/10.1001/jama.2014.7859DOI Listing
August 2014

Multidisciplinary care improves clinical outcome and reduces medical costs for pre-end-stage renal disease in Taiwan.

Nephrology (Carlton) 2014 Nov;19(11):699-707

Division of Nephrology, Internal Medicine, Changhua Christian Hospital, Changhua City, Taiwan.

Aim: Multidisciplinary care (MDC) for patients with chronic kidney disease (CKD) may help to optimize disease care and improve clinical outcomes. Our study aimed to evaluate the effectiveness of pre-end-stage renal disease (ESRD) patients under MDC and usual care in Taiwan.

Method: In this 3-year retrospective observational study, we recruited 822 ESRD subjects, aged 18 years and older, initiating maintenance dialysis more than 3 months from five cooperating hospitals. The MDC (n = 391) group was cared for by a nephrologists-based team and the usual care group (n = 431) was cared for by sub-specialists or nephrologists alone more than 90 days before dialysis initiation. Patient characteristics, dialysis modality, hospital utilization, hospitalization at dialysis initiation, mortality and medical cost were evaluated. Medical costs were further divided into in-hospital, emergency services and outpatient visits.

Results: The MDC group had a better prevalence in peritoneal dialysis (PD) selection, less temporary catheter use, a lower hospitalization rate at dialysis initiation and 15% reduction in the risk of hospitalization (P < 0.05). After adjusting for gender, age and Charlson Comorbidity Index score, there were lower in-hospital and higher outpatient costs in the MDC group during 3 months before dialysis initiation (P < 0.05). In contrast, medical costs (NT$ 146,038 vs 79,022) and hospitalization days (22.4 vs 15.5 days) at dialysis initiation were higher in the usual care group. Estimated medical costs during 3 months before dialysis till dialysis initiation, the MDC group yielded a reduction of NT$ 59,251 for each patient (P < 0.001). Patient mortality was not significantly different.

Conclusion: Multidisciplinary care intervention for pre-ESRD patients could not only significantly improve the quality of disease care and clinical outcome, but also reduce medical costs.
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http://dx.doi.org/10.1111/nep.12316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265277PMC
November 2014

Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus-specific immunotherapy.

J Allergy Clin Immunol 2014 Nov 25;134(5):1206-9.e1. Epub 2014 Jul 25.

Clinical Immunological Center, China Medical University Hospital, College of Medicine, China Medical University, Taichung, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.06.005DOI Listing
November 2014

Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4 + 919G > A).

Orphanet J Rare Dis 2014 Jul 1;9:96. Epub 2014 Jul 1.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation

Methods And Results: Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis.

Conclusions: All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation.
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http://dx.doi.org/10.1186/1750-1172-9-96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100491PMC
July 2014

Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes.

J Occup Med Toxicol 2014 Mar 18;9(1):11. Epub 2014 Mar 18.

Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao St., Changhua 500, Taiwan.

Background: Iron is essential not only for erythropoisis but also for several bioenergetics' processes in myocardium. Hepcidin is a well-known regulator of iron homeostasis. Recently, researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. In addition, our previous in vivo study revealed that the left ventricular mass index increased in chronic kidney disease patients with lower serum hepcidin. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions.

Methods: To test this hypothesis, human cardiomyocytes were cultured and treated with ferrous iron. The possible underlying signaling pathways of cardiotoxicity were examined following knockdown studies using siRNAs of hepcidin (siRNA1 was used as a negative control and siRNA2 was used to silence hepcidin).

Results: We found that ferrous iron induces apoptosis in human cardiomyocytes in a dose-dependent manner. This iron-induced apoptosis was linked to enhanced caspase 8, reduced Bcl-2, Bcl-xL, phosphorylated Akt and GATA-4. Hepcidin levels increased in human cardiomyocytes pretreated with ferrous iron and returned to non-iron treated levels following siRNA2 transfection. In iron pretreated cardiomyocytes, the siRNA2 transfection further increased caspase 8 expression and decreased the expression of GATA-4, Bcl-2, Bcl-xL and phosphorylated Akt than iron pretreatment alone, but caspase 9 levels remained unchanged.

Conclusions: Our findings suggest that hepcidin can rescue human cardiomyocytes from iron-induced apoptosis through the regulation of GATA-4/Bcl-2 and the extrinsic apoptotic pathway.
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http://dx.doi.org/10.1186/1745-6673-9-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995429PMC
March 2014

Effect of fibrin sealant aided with Dexon mesh for renal repair in a rat model of partial nephrectomy.

Int J Surg 2014 5;12(4):304-9. Epub 2014 Feb 5.

Division of Urology, Department of Surgery, Changhua Christian Hospital, Taiwan. Electronic address:

Background: To evaluate the clinical efficacy and histochemical impact of a new technique of renal repair using a fibrin sealant and Dexon mesh in rats.

Methods: Ten groups of Sprague-Dawley (SD) rats underwent a bilateral partial nephrectomy 30, 21, 14, 7 to 1 days before sacrifice. Renal repair was accomplished by suturing on one side and using fibrin sealant and Dexon mesh on the opposite side. The time for renal reconstruction was recorded for each approach and compared. In addition to histological evaluations, the isolated renal tissue studies included immunohistochemical analysis, and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR).

Results: In comparison with suturing, renal repair using fibrin sealant and Dexon mesh was much faster. We demonstrated a significant attenuation of the initial inflammatory response in the fibrin-Dexon group. The specific alterations in transforming growth factor-β1 (Tgf-β1) mRNA expression were significantly lower in the fibrin-Dexon group.

Conclusions: The fibrin sealant and Dexon mesh significantly simplified the procedure by reducing the time of renal reconstruction. This approach can diminish the fibrotic reaction and offers a response for renal repair similar to the suturing technique.
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http://dx.doi.org/10.1016/j.ijsu.2014.01.024DOI Listing
January 2015

Inhibition of reverse-mode sodium-calcium exchanger activity and apoptosis by levosimendan in human cardiomyocyte progenitor cell-derived cardiomyocytes after anoxia and reoxygenation.

PLoS One 2014 3;9(2):e85909. Epub 2014 Feb 3.

Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan ; College of Medicine, China Medical University, Taichung, Taiwan.

Levosimendan, a known calcium sensitizer with positive inotropic and vasodilating properties, might also be cardioprotective during ischemia-reperfusion (I/R) insult. Its effects on calcium homeostasis and apoptosis in I/R injury remain unclear. Na(+)/Ca(2+) exchanger (NCX) is a critical mediator of calcium homeostasis in cardiomyocytes, with reverse-mode NCX activity responsible for intracellular calcium overload and apoptosis of cardiomyocytes during I/R. We probed effects and underlying mechanisms of levosimendan on apoptosis and NCX activity in cultured human cardiomyocyte progenitor cells (CPC)-derived cardiomyocytes undergoing anoxia-reoxygenation (A/R), simulating I/R in vivo. Administration of levosimendan decreased apoptosis of CPC-derived cardiomyocytes induced by A/R. The increase in reverse-mode NCX activity after A/R was curtailed by levosimendan, and NCX1 was translocated away from the cell membrane. Concomitantly, endoplasmic reticulum (ER) stress response induced by A/R was attenuated in CPC-derived cardiomycytes treated with NCX-targeted siRNA or levosimendan, with no synergistic effect between treatments. Results indicated levosimendan inhibited reverse-mode NCX activity to protect CPC-derived cardiomyocytes from A/R-induced ER stress and cell death.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911900PMC
December 2014

Addition of immunosuppressive treatment to hemoperfusion is associated with improved survival after paraquat poisoning: a nationwide study.

PLoS One 2014 27;9(1):e87568. Epub 2014 Jan 27.

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan ; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan ; School of Medicine, Chung-Shan Medical University, Taichung, Taiwan ; Graduate Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan ; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Xitun District, Taichung City, Taiwan.

Paraquat poisoning associates very high mortality rate. Early treatment with hemoperfusion is strongly suggested by animal and human studies. Although the survival benefit of additional immunosuppressive treatment (IST) in combination with hemoperfusion is also reported since 1971, the large-scale randomized control trials to confirm the effects of IST is difficult to be executed. Therefore, we designed this nationwide large-scale population-based retrospective cohort study to investigate the outcome of paraquat poisoning with hemoperfusion and the additional effects of IST combined with hemoperfusion. This nationwide retrospective cohort study utilized data retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 1811 hospitalized patients with a diagnosis of paraquat poisoning who received hemoperfusion between 1997 and 2009 were enrolled. The mean age of all 1811 study subjects was 47.3 years. 70% was male. The overall survival rate was only 26.4%. Respiratory failure and renal failure were diagnosed in 56.2% and 36% patients. The average frequency of hemoperfusion was twice. IST was added in 42.2% patients. IST significantly increases survival rate (from 24.3% to 29.3%, P<0.001). The combined IST with methylprednisolone, cyclophosphamide and dexamethasone associates with the highest survival rate (48%, P<0.001). Moreover, patients younger than 45 years of age in the IST group had the best survival (41.0% vs. 33.7%, p<0.001). Our results support the use of IST with hemoperfusion for paraquat-poisoned patients. The best survival effect of IST is the combination of methylprednisolone, cyclophosphamide and daily dexamethasone, especially in patients with younger age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903773PMC
September 2014

CD8⁺ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria.

PLoS One 2014 27;9(1):e81344. Epub 2014 Jan 27.

Division of Pediatric Nephrology, China Medical University Hospital, Taichung, Taiwan ; Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan ; College of Medicine, China Medical University, Taichung, Taiwan.

Unlabelled: We focus on the role of CD8(+) Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4(+)CD25(+)FoxP3(+) and CD8(+)CD25(+)Foxp3(+) Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8(+)FoxP3(+) Treg from PBMCs. IVMP-treated CD8(+)CD25(+) Treg cells directly suppressed CD4(+) T proliferation and induced CD4(+)CD45RO(+) apoptosis. Histologically, CD4(+)FoxP3(+) as well as CD8(+)FoxP3(+) Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8(+)FoxP3(+) Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3(+) Treg cells in PBMNCs (r = -0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4(+)FoxP3(+) Treg cells. CD8(+)Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8(+)CD25(+)Treg-induced CD4(+)CD45RO(+) apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8(+)FoxP3(+) Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN.

Trial Registration: DMR97-IRB-259.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903465PMC
November 2014
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