Publications by authors named "Ching-Shan Huang"

44 Publications

Effects of variation status and enzyme activity for UDP-glucuronosyltransferase 1A1 gene on neonatal hyperbilirubinemia.

Pediatr Neonatol 2020 10 4;61(5):506-512. Epub 2020 Jun 4.

Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan. Electronic address:

Background: We found that Taiwanese adults carrying genotypes of UDP-glucuronosyltransferase (UGT) 1A1 with enzyme activity ≤40% of normal were at high risk for developing Gilbert's syndrome. However, the relationship between UGT1A1 activity and neonatal hyperbilirubinemia has never been evaluated for Taiwanese.

Methods: We enrolled 141 hyperbilirubinemic neonates partially fed supplementary infant formula and 432 controls; and 112 hyperbilirubinemic neonates exclusively breastfed and 493 controls. The five single nucleotide polymorphisms (SNPs) at nucleotides -53, 211, 686, 1091 and 1456 in the UGT1A1 gene were determined and UGT1A1 activity was estimated. Odds ratios (ORs) of variation status in the UGT1A1 gene and enzyme activity for the development of neonatal hyperbilirubinemia were calculated, respectively.

Results: For neonates partially fed supplementary infant formula, the adjusted OR (AOR) for the development of hyperbilirubinemia was significantly higher in the neonates carrying the homozygous variation (211AA) in the UGT1A1 gene than for those carrying the wild type (AOR = 6.00, p < 0.001). Only the AOR of those carrying UGT1A1 activity ranked 31-40% of normal was statistically significant (AOR = 3.16, p < 0.001). For the hyperbilirubinemic neonates exclusively breastfed, AOR for the development of hyperbilirubinemia is positively correlated to degree of variation (AOR = 1.95, 2.19 and 4.53; with p = 0.003, 0.05 and < 0.001, respectively), while the effect of UGT1A1 enzyme activity was varied (AOR = 1.02-3.72, with p = 0.95∼<0.001).

Conclusion: The estimated enzyme activity depending on combination of SNPs (genotypes) in the UGT1A1 gene could not be utilized to explain the development of neonatal hyperbilirubinemia. We reconfirm that the -53 A(TA)TAA/A(TA)TAA is not, while the 211AA is a risk factor for the development of neonatal hyperbilirubinemia in Taiwanese.
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http://dx.doi.org/10.1016/j.pedneo.2020.05.009DOI Listing
October 2020

Association of cyclophilin A level and pulse pressure in predicting recurrence of cerebral infarction.

Kaohsiung J Med Sci 2020 Feb 31;36(2):122-128. Epub 2019 Oct 31.

Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.

Cyclophilin A (CypA), secreted from vascular smooth muscle cells and inflammatory cells in response to oxidative stress, promotes vascular atherosclerosis and development of carotid stenosis. Increased concentration of plasma CypA in acute cerebral infarction was demonstrated clinically. The primary aim of this study was to investigate the prognostic impact between CypA level and outcome in patients with acute ischemic stroke. Admission serum CypA concentrations were detected in 66 acute cerebral infarction patients and in 52 healthy individuals. Inflammatory biomarkers, including high-sensitivity C-reactive protein, adhesion molecules, interleukins, and matrix-metalloproteases, were also assessed. We also examined the relationship between plasma biomarkers, blood pressure (BP), pulse pressure, the carotid artery velocity, the prognostic assessment with modified Rankin scale, and stroke recurrence. Plasma CypA concentration was higher on the first day of hospitalization in the high BP stroke group than in normal BP stroke group, which was statistically significant, which was observed even in the third month and sixth month follow-up outpatient periods. For stroke recurrence prediction, there was an important association between the higher (>60) pulse pressure on the seventh day of hospitalization and CypA level on the third month and sixth month follow-up outpatient periods. Our study revealed higher circulating serum levels of CypA in the hypertensive stroke group than in the non-hypertensive stroke group. We expect that elevated plasma CypA level and raised pulse pressure during hospitalization to become valuable biomarkers in predicting stroke recurrence in the sixth month assessment of acute cerebral infarction.
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http://dx.doi.org/10.1002/kjm2.12143DOI Listing
February 2020

Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases.

BMC Nephrol 2019 10 28;20(1):391. Epub 2019 Oct 28.

Vascular & Genomic Research Center, Changhua Christian Hospital, Changhua, Taiwan.

Introduction: Cell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients.

Methods: One hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA.

Results: Patients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months.

Conclusions: Urinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.
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http://dx.doi.org/10.1186/s12882-019-1549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816217PMC
October 2019

Effect of UDP-glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome.

Kaohsiung J Med Sci 2019 Jul 24;35(7):432-439. Epub 2019 Apr 24.

Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan.

Variations at the six nucleotides -3279 (T > G), -53 (A[TA] TAA > A[TA] TAA), 211 (G > A), 686 (C > A), 1091 (C > T), and 1456 (T > G) in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene were determined in 178 Taiwanese patients with Gilbert's syndrome and in 200 healthy adults. Every subject was classified as a genotype depending on variation status of the six nucleotides in the UGT1A1 gene. The UGT1A1 activity for each genotype was calculated and then those genotypes were divided into 10 subgroups (Q1~Q10) according to their UGT1A1 activities, by using 10% as an interval. There were 24 genotypes observed, with UGT1A1 activity ranged 9%~100% of normal. There were two and six subjects with Gilbert's syndrome and none of healthy controls carrying genotypes in the Q1 and Q2 subgroups, respectively. The odds of developing Gilbert's syndrome were significantly higher for subjects carrying genotypes in the Q3, Q4, and Q5 subgroups than for those with genotype in the Q10 subgroup (odds ratios: 240.22, 59.80, and 14.67, respectively, P < .001 for each). Among the 178 patients of Gilbert's syndrome, serum bilirubin value was inversely correlated with UGT1A1 activity (r = -.306, P < .001). The sensitivity was 72.0% and the specificity was 90.5% by using UGT1A1 activity ≦40% of normal as the cut-off point to distinguish between healthy subjects and patients of Gilbert's syndrome. Our results demonstrate that UGT1A1 activity is certainly a determinate for serum bilirubin value and UGT1A1 activity ≦40% of normal is a proper risk factor for the development of Gilbert's syndrome.
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http://dx.doi.org/10.1002/kjm2.12077DOI Listing
July 2019

Favourable renal outcomes after intravenous thrombolytic therapy for acute ischemic stroke: Clinical implication of kidney-brain axis.

Nephrology (Carlton) 2019 Sep 29;24(9):896-903. Epub 2019 Apr 29.

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

Aim: Recombinant tissue plasminogen activator (rt-PA) administration is the most prevalent treatment for acute ischemic within golden time. However, the effects of rt-PA on the kidney function in such patients remain unknown. This study determined long-term renal outcomes in patients with acute ischemic stroke receiving systemic rt-PA.

Methods: We enroled patients who were hospitalized for acute ischemic stroke from January 2001 to January 2017. We applied 1:2 propensity score matching to eliminate various confounding variables. We defined surrogate renal outcomes as declining of estimated glomerular filtration rate (eGFR) greater than 30% and 50%, and chronic kidney disease (CKD) with eGFR less than 60 mL/min. We then compared the 1-year eGFR with paired t-test in patients treated with or without rt-PA.

Results: Overall, 343 of 1739 patients received rt-PA within golden time. After 1:2 propensity score matching, their baseline characteristics were grouped as treated with rt-PA (n = 235) or not (n = 394). rt-PA-treated patients exhibited slower renal progression, including the risk of eGFR declining greater than 30% (hazard ratio (HR), 0.72; P = 0.03), risk of declining eGFR greater than 50% (HR, 0.63; P = 0.046) and risk of CKD (HR, 0.61; P = 0.005). After 1-year cohort, the rt-PA group exhibited an improved renal outcome by the paired t-test (propensity match: ΔGFR = 9.1 (95% confidence interval: 6.3, 11.8), P < 0.001 in rt-PA group; ΔGFR = -1.1 (95% confidence interval: -2.9, 0.7), P = 0.23 in non-rt-PA group). In patients with eGFR less than 45 mL/min (n = 34), intracerebral haemorrhage was not reported.

Conclusion: Patients receiving rt-PA for acute ischemic stroke exhibit favourable renal outcomes, and no increased incidence of intracerebral haemorrhage occurs in rt-PA patients with advanced CKD.
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http://dx.doi.org/10.1111/nep.13516DOI Listing
September 2019

Increased cumulative doses and appearance of hand-foot skin reaction prolonged progression free survival in sorafenib-treated advanced hepatocellular carcinoma patients.

Kaohsiung J Med Sci 2018 Jul 4;34(7):391-399. Epub 2018 Apr 4.

Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Sorafenib has been recommended as a new palliative therapy for advanced hepatocellular carcinoma (HCC). However, the clinical outcome of patients receiving sorafenib therapy varies. This study sought to identify which clinical method could be used to predict clinical outcome of sorafenib monotherapy in patients with advanced HCC. A total of 146 advanced HCC patients with Child-Pugh A liver function were enrolled from June 2011 to September 2015. Sorafenib doses ranged from 200 mg once daily to 400 mg twice daily. Clinical and pathological parameters were collected. There was no predefined primary endpoint. Tumor response rate, adverse events, overall survival (OS), and progression-free survival (PFS) were analyzed. The follow-up period was 1718 days (median: 859 days). The median dosage of sorafenib was 562.35 mg.Forty patients (27.4%) had stable disease and 106 patients (72.6%) had progression disease. The OS was 432.21 ± 360.52 days (median: 329 days) and PFS was 167.05 ± 166.50 days (median: 102.5 days). No sorafenib toxic effect-related mortality was encountered. The most common severe adverse events (≧grade 3) were hand-foot skin reactions (HFSR) (16, 11.0%), diarrhea (7, 4.8%), and alopecia (1, 0.7%). The following patients had longer median PFS (mPFS): those receiving total dosage > 55000 mg (217 vs.63 days; HR = 0.20,95%CI = 0.11-0.38; p < 0.001), those receiving daily dosage <562 mg (140 vs.69 days; HR = 0.27, 95%CI = 0.17-0.46; p < 0.001), those with treatment durations > 112 days (231vs.64 days; HR = 0.37, 95%CI = 0.19-0.74; p < 0.001), and those with HFSR (105 vs.75 days; HR = 0.60,95% CI = 0.6-0.98; p = 0.04). In conclusion, increased cumulative doses of sorafenib as well as the appearance of HFSR were indicators of prolonged mPFS in sorafenib-treated advanced HCC patients.
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http://dx.doi.org/10.1016/j.kjms.2018.03.006DOI Listing
July 2018

High particulate matter 2.5 levels and ambient temperature are associated with acute lung edema in patients with nondialysis Stage 5 chronic kidney disease.

Nephrol Dial Transplant 2019 08;34(8):1354-1360

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

Background: Numerous studies have shown that exposure to air pollution, especially particulate matter (PM) with a diameter <2.5 μm (PM2.5), was associated with various diseases. We tried to determine the impact of PM2.5 and other weather factors on acute lung edema in patients with Stage 5 nondialysis chronic kidney disease (CKD Stage 5-ND).

Methods: In total, 317 CKD Stage 5-ND (estimated glomerular filtration rate 6.79 ± 4.56 mL/min) patients residing in central Taiwan who developed acute lung edema and initiated long-term dialysis were included in this case-crossover study. Pearson's correlation test was used to examine the relationship of acute lung edema cases with PM2.5 levels and ambient temperature separately.

Results: The average PM2.5 level within the 7-day period correlated with acute lung edema incidence in the fall [adjusted odds ratio (OR) 3.23, P = 0.047] and winter (adjusted OR 1.99, P < 0.001). In winter, even a 3-day exposure to PM2.5 was associated with increased risk (adjusted OR 1.55, P < 0.001). The average temperatures within 3 days in spring and summer were correlated positively with the risk (adjusted OR 2.77 P < 0.001 and adjusted OR 2.72, P < 0.001, respectively). In the fall and winter, temperatures were correlated negatively with the risk (adjusted OR 0.36, P < 0.001 and adjusted OR 0.54, P < 0.001, respectively).

Conclusions: A high PM2.5 level was associated with an increased risk of acute lung edema. High ambient temperature in hot seasons and low ambient temperature in cold seasons were also associated with increased risk. It is essential to educate these patients to avoid areas with severe air pollution and extreme ambient temperature.
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http://dx.doi.org/10.1093/ndt/gfy144DOI Listing
August 2019

Cyclophilin A: A Predictive Biomarker of Carotid Stenosis in Cerebral Ischemic Stroke.

Curr Neurovasc Res 2018 ;15(2):111-119

Department of Neurology, Changhua Christian Hospital, Changhua 500, Taiwan.

Background: Cyclophilin A plays a pathogenic role in the development and progression of atherosclerosis, which can be assessed by measuring carotid intima-media thickness. The primary aim of this study was to examine the interaction between plasma Cyclophilin A level and carotid intima-media thickness in patients with acute ischemic stroke.

Method: Plasma concentration of Cyclophilin A was measured on admission in 66 consecutive patients who had been hospitalized for acute cerebral stroke and in 52 case-control subjects without a history of acute stroke. Subjects in both groups also underwent ultrasound B-mode imaging to measure the mean and maximum intima-media thickness of the carotid artery. Inflammatory biomarkers including high-sensitivity C-reactive protein and fibrinogen were also assessed.

Results: We found that the plasma concentration of Cyclophilin A was significantly higher in patients with acute ischemic stroke (p = 0.042). Increased Cyclophilin A was also correlated with carotid intima-media thickness in the patient group (p < 0.001). Among the risk factors for cerebral stroke examined in this study, only hypertension was significantly associated with plasma Cyclophilin A level.

Conclusion: Increased plasma Cyclophilin A levels might be involved in the pathophysiology of acute ischemic stroke and Cyclophilin A might serve as a biomarker in risk assessment of acute stroke patients.
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http://dx.doi.org/10.2174/1567202615666180516120959DOI Listing
May 2019

Interaction between cytochrome P450 2A6 and Catechol-O-Methyltransferase genes and their association with smoking risk in young men.

Behav Brain Funct 2017 May 4;13(1). Epub 2017 May 4.

Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City, 40601, Taiwan.

Background: Although some effects of gene-gene interactions on nicotine-dopamine metabolism for smoking behavior have been reported, polymorphisms of cytochrome P450 (CYP) 2A6 and catechol-O-methyltransferase (COMT) have not been studied together to determine their effects on smokers. The aim of this study was to investigate the effects of the interaction between the CYP 2A6 and COMT genes on smoking behavior in young Taiwanese men.

Results: A self-report questionnaire regarding smoking status was administered to 500 young men. Polymorphisms of the CYP 2A6 and COMT genes as well as urinary nicotine and urinary cotinine levels were determined. The odds ratio for starting smoking was significantly lower in subjects carrying a CYP2A6 low activity/variant COMT rs4680 genotype than in those possessing a CYP2A6 wild-type/variant COMT rs4680 genotype (0.44, 95% confidence interval = 0.19-0.98, P = 0.043). Comparisons of Fagerstrom Test for Nicotine Dependence (FTND), Physiological Cigarette Dependence Scale (PCDS), and Cigarette Withdrawal symptoms (CWS-21) among the smokers with different CYP2A6/COMT polymorphisms were not significantly different. The adjusted urinary nicotine concentrations were not significantly different between the two groups carrying different genotypes. The adjusted urinary cotinine level was significantly different between the COMT rs4680 wild-type group and COMT rs4680 variant group [92.46 ng/μL vs. 118.24 ng/μL (median value), P = 0.041] and between the COMT rs4680 wild-type/COMT rs165599 variant group and COMT rs4680 variant/COMT rs165599 variant group (97.10 ng/μL vs. 122.18 ng/μL, P = 0.022).

Conclusions: These findings suggest that a single nucleotide polymorphism (rs4680) of the COMT gene and the interaction between the CYP 2A6 and COMT genes affect smoking status in young Taiwanese men.
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http://dx.doi.org/10.1186/s12993-017-0127-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418756PMC
May 2017

Relationship among methadone dose, polymorphisms of dopamine D2 receptor and tri-dimensional personality questionnaire in heroin-addicted patients.

Behav Brain Funct 2016 Aug 31;12(1):24. Epub 2016 Aug 31.

Administration Center of Research and Education Innovation, Changhua Christian Hospital, Changhua, Taiwan.

Background: We investigated whether variation in the dopamine D2 receptor gene (DRD2) and tri-dimensional personality questionnaire (TPQ) scores could be used to aid adjustment of daily methadone requirements of heroin addicts. DRD2 TaqI B polymorphisms and TPQ scores were determined in 138 male Taiwanese heroin addicts who were receiving methadone treatment. Borderline index (harm avoidance + novelty seeking-reward dependence) was calculated for each subject, and three groups were defined: high (mean from all subjects plus 1 standard deviation, or greater), low (half of the calculated high score, or lower) and medium (all values between the high and low scores).

Results: No significant differences in age (p = 0.60), mean methadone dose (p = 0.75) or borderline index group (p = 0.25) were observed between subjects bearing the B1/B1, B1/B2 and B2/B2 DRD2 TaqI genotypes. Among the individuals with low (≤10), medium (11-20) and high (≥21) borderline index scores, there was a significant difference in mean methadone dose (p = 0.04), but not age (p = 0.90). Further analysis showed that mean methadone dose was significantly higher in subjects with low borderline index scores than in those with high scores (62.5 vs. 47.0 mg/day, p = 0.03). The odds ratio for a daily methadone requirement ≥60 mg (median dose across the 138 subjects) was 2.64-fold greater in the low borderline index group than in the high group (p = 0.04).

Conclusions: Although the DRD2 TaqI B genotype was not associated with methadone use requirements, borderline index was revealed as a potential predictive marker for the adjustment of methadone dosage requirements in heroin addicts.
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http://dx.doi.org/10.1186/s12993-016-0109-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007696PMC
August 2016

High plasma coenzyme Q10 concentration is correlated with good left ventricular performance after primary angioplasty in patients with acute myocardial infarction.

Medicine (Baltimore) 2016 Aug;95(31):e4501

Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital Institute of Statistics and Information Science, National Changhua University of Education Vascular and Genomic Research Center Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua School of Medicine, Chung Shan Medical University, Taichung Department of Neurology, Changhua Christian Hospital, Changhua Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan.

Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia-reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI).We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers.Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline.Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction.
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http://dx.doi.org/10.1097/MD.0000000000004501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979854PMC
August 2016

Prolonged Hyperbilirubinemia in a Neonate with a Novel Mutation in the UDP-glucuronosyltransferase 1A1 Gene.

Neonatology 2016 10;109(3):235-8. Epub 2016 Feb 10.

Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital and School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan, ROC.

The total bilirubin value of a male infant was 385 μmol/l on day 5. Liver function test results were normal and there was no evidence of sepsis and no hemolysis reaction. Phototherapy was administered and on day 8 the patient's total bilirubin level was 255 μmol/l. Intermittent episodes of hyperbilirubinemia occurred without phototherapy, with the total bilirubin level reaching 335 μmol/l on day 19. A 3-day regimen of phenobarbital was administered and on day 24 his total bilirubin level was 180 μmol/l. The patient was discharged. At the age of 2 months, the total bilirubin value was 27 μmol/l. His direct bilirubin value was <15% of total bilirubin in every determination. A family study of the UDP-glucuronosyltransferase(UGT)1A1 gene showed that the infant carries a homozygous mutation at nucleotide -3279 plus compound heterozygous mutations at nucleotides 782 and 1091. The mutation at nucleotide 782 is a novel finding. Gilbert's syndrome was diagnosed.
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http://dx.doi.org/10.1159/000443365DOI Listing
November 2016

Cyclophilin A in Ruptured Intracranial Aneurysm: A Prognostic Biomarker.

Medicine (Baltimore) 2015 Sep;94(39):e1683

From the Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (HWK); Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (HWK, CPL); Department of Medical Imaging (KWL, WLC); Vascular and Genomic Center (KWL, WLC, CLK, CSH, WMT, CSL); Department of Neurology (CSL), Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan (CSL); and Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan (CPL).

Cyclophilin A (CyPA), an oxidative stress-induced factor, was found to play an important role in the aneurysm formation. Our working hypothesis was that the plasma level of CyPA in ruptured intracranial aneurysm could predict the neurological outcome. From 2011 to 2013, a total of 36 patients with ruptured saccular intracranial aneurysm were recruited in our study. Before coil embolization, we draw blood samples at the orifice of a culprit aneurysm and in the remote peripheral vein for measurements of the CyPA levels. We utilized the modified Rankin scale 30 days after aneurysm rupture as the outcome measure. Generalized linear models were used to estimate the adjusted odds ratios of the poor neurological outcome given the presence of high plasma level of CyPA. The aneurysmal and venous CyPA levels were significantly associated with the initial clinical severity (P = 0.004 and 0.03, respectively) and 30-day outcome (P = 0.01 and 0.02, respectively). The aneurysmal CyPA levels modestly correlated with age and high Fisher grade (ρ = 0.39 and 0.41; P = 0.02 and 0.01, respectively). The aneurysmal CyPA levels strongly correlated with the venous counterpart (ρ = 0.89; P < 0.001). Patients with high levels of aneurysmal CyPA were 15.66 times (95% CI, 1.48-166.24; P = 0.02) more likely to have worse neurological outcome than those with the low levels after adjustment of the age, gender, and the documented confounding factors. High plasma level of CyPA is a significant prognostic biomarker for poor neurological outcome in patients with ruptured intracranial aneurysm.
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http://dx.doi.org/10.1097/MD.0000000000001683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616861PMC
September 2015

Interleukin-6 as a Prognostic Biomarker in Ruptured Intracranial Aneurysms.

PLoS One 2015 15;10(7):e0132115. Epub 2015 Jul 15.

Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan.

Background: Interleukin-6 (IL-6), a proinflammatory cytokine, was found to surge in the cerebral spinal fluid after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the plasma level of IL-6 could be an independent biomarker in predicting clinical outcome of patients with ruptured intracranial aneurysm.

Methods: We prospectively included 53 consecutive patients treated with platinum coil embolization of the ruptured intracranial aneurysm. Plasma IL-6 levels were measured in the blood samples at the orifices of the aneurysms and from peripheral veins. The outcome measure was the modified Rankin Scale one month after SAH. Multiple logistic regression analyses were used to evaluate the associations between the plasma IL-6 levels and the neurological outcome.

Results: Significant risk factors for the poor outcome were old age, low Glasgow Coma Scale (GCS) on day 0, high Fisher grades, and high aneurysmal and venous IL-6 levels in univariate analyses. Aneurysmal IL-6 levels showed modest to moderate correlations with GCS on day 0, vasospasm grade and Fisher grade. A strong correlation was found between the aneurysmal and the corresponding venous IL-6 levels (ρ = 0.721; P<0.001). In the multiple logistic regression models, the poor 30-day mRS was significantly associated with high aneurysmal IL-6 level (OR, 17.97; 95% CI, 1.51-214.33; P = 0.022) and marginally associated with high venous IL-6 level (OR, 12.71; 95% CI, 0.90-180.35; P = 0.022) after adjusting for dichotomized age, GCS on day 0, and vasospasm and Fisher grades.

Conclusions: The plasma level of IL-6 is an independent prognostic biomarker that could be used to aid in the identification of patients at high-risk of poor neurological outcome after rupture of the intracranial aneurysm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503596PMC
April 2016

Effects of Interaction Between Dopamine D2 Receptor and Monoamine Oxidase A Genes on Smoking Status in Young Men.

Biol Res Nurs 2015 Jul 26;17(4):422-8. Epub 2015 May 26.

Administration Center of Research and Education, Changhua Christian Hospital, Changhua Christian Medical Foundation, Changhua, Taiwan

Although the effect of gene-gene interaction on nicotine-dopamine metabolism for smoking behavior has been reported, polymorphisms of dopamine D2 receptor (DRD2) and monoamine oxidase A (MAOA) have not been simultaneously examined among smokers. In this study, 481 young Taiwanese men completed a self-report questionnaire on smoking status, and data were obtained on polymorphisms of DRD2 rs1800497, DRD2 rs1079597, MAOA rs309850, and MAOA rs1137070, urinary nicotine, and urinary cotinine. In a comparison of 261 current smokers and 220 never smokers, odds ratios (ORs) for the development of smoking in all genotypes were not statistically significant. Among smokers with DRD2 rs1079597 GG//MAOA rs309850 3-repeat, the OR of heavier smoking was 2.67 times higher (95% confidence interval [CI]: [1.08, 6.59], p = .031) and the score on the Fagerstrom test for nicotine dependence was higher (4.26 vs. 2.83) than in those with DRD2 rs1079597 AA//MAOA rs309850 3-repeat. Adjusted urinary cotinine concentration was significantly different between those two groups (median value: 95.83 ng/μl vs. 133.24 ng/μl, respectively, p = .045). These findings suggest that the interaction of DRD2 rs1079597 and MAOA rs309850 3-repeat affects smoking intensity in young Taiwanese men.
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http://dx.doi.org/10.1177/1099800415589366DOI Listing
July 2015

Decrease in plasma cyclophilin A concentration at 1 month after myocardial infarction predicts better left ventricular performance and synchronicity at 6 months: a pilot study in patients with ST elevation myocardial infarction.

Int J Biol Sci 2015 1;11(1):38-47. Epub 2015 Jan 1.

5. Vascular and Genomic Research Center, Changhua Christian Hospital, Changhua 500, Taiwan ; 6. Department of Neurology, Changhua Christian Hospital, Changhua 500, Taiwan ; 7. Graduate Institute of Integrative Medicine, China Medical University, Taichung 404, Taiwan.

Background: Cyclophilin A (CyPA) concentration increases in acute coronary syndrome. In an animal model of acute myocardial infarction, administration of angiotensin-converting-enzyme inhibitor was associated with lower left ventricular (LV) CyPA concentration and improved LV performance. This study investigated the relationships between changes in plasma CyPA concentrations and LV remodeling in patients with ST-elevation myocardial infarction (STEMI).

Methods And Results: We enrolled 55 patients who underwent percutaneous coronary intervention for acute STEMI. Plasma CyPA, matrix metalloproteinase (MMP), interleukin-6 and high-sensitivity C-reactive protein concentrations were measured at baseline and at one-month follow-up. Echocardiography was performed at baseline and at one-, three-, and six-month follow-up. Patients with a decrease in baseline CyPA concentration at one-month follow-up (n = 28) had a significant increase in LV ejection fraction (LVEF) (from 60.2 ± 11.5% to 64.6 ± 9.9%, p < 0. 001) and preserved LV synchrony at six months. Patients without a decrease in CyPA concentration at one month (n = 27) did not show improvement in LVEF and had a significantly increased systolic dyssynchrony index (SDI) (from 1.170 ± 0.510% to 1.637 ± 1.299%, p = 0.042) at six months. Multiple linear regression analysis showed a significant association between one-month CyPA concentration and six-month LVEF. The one-month MMP-2 concentration was positively correlated with one-month CyPA concentration and LV SDI. Conclusions : Decreased CyPA concentration at one-month follow-up after STEMI was associated with better LVEF and SDI at six months. Changes in CyPA, therefore, may be a prognosticator of patient outcome.
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http://dx.doi.org/10.7150/ijbs.10271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278253PMC
September 2015

Multiple variants in UGT1A1 gene are factors to develop indirect hyper-bilirubinemia.

Hepatobiliary Surg Nutr 2014 Aug;3(4):194-8

1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan.

Most Taiwanese patients with hyper-bilirubinemia have genetic abnormalities in the uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene beyond the variants in the TATA box upstream of UGT1A1 associated with Gilbert's syndrome. To investigate the role of UGT1A1 in the pathogenesis of indirect hyper-bilirubinemia, we prospectively studied 97 consecutive patients with indirect hyper-bilirubinemia for genotypes of promoter [(TA)6TAA6, (TA)7TAA7] and coding region [nucleotide (nt)-211, nt-686, nt-1,091 and nt-1,456] of UGT1A1. Thirty-six of the patients (45.6%) were found to have Gilbert's syndrome with 7/7 genotype; among them, 14 also carried variants at nt-686. Forty-two patients (43.3%) had the 6/7 genotype; among them, 36 patients were found to have one or more variants in the coding region. Patients with higher serum total bilirubin are associated with higher likelihood of carrying Gilbert's syndrome genotype: 60.0% (P=0.007) patients with serum total bilirubin level ≥2.5 mg/dL carried the Gilbert's syndrome genotype, while only 23.9% of patients with serum total bilirubin level <2.5 mg/dL carry the same genotype (P=0.0006). Forty-one of the 61 non-Gilbert's patients had one homogenous variants or two or more heterozygous variants in UGT1A1. Further studies are necessary to confirm the role of one homo-zygous variant or two or more hetero-zygous variants in UGT1A1 gene as factors for indirect hyper-bilirubinemia.
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http://dx.doi.org/10.3978/j.issn.2304-3881.2014.08.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141289PMC
August 2014

Serum iron concentration, but not hemoglobin, correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction.

PLoS One 2014 6;9(8):e104495. Epub 2014 Aug 6.

Vascular and Genomic Research Center, Changhua Christian Hospital, Changhua, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan.

Objective: Anemia is associated with high mortality and poor prognosis after acute coronary syndrome (ACS). Increased red cell distribution width (RDW) is a strong independent predictor for adverse outcomes in ACS. The common underlying mechanism for anemia and increased RDW value is iron deficiency. It is not clear whether serum iron deficiency without anemia affects left ventricular (LV) performance after primary angioplasty for acute myocardial infarction (AMI). We investigated the prognostic value of serum iron concentration on LV ejection fraction (EF) at 6 months and its relationship to thrombolysis in myocardial infarction (TIMI) risk score in post MI patients.

Methods: We recruited 55 patients who were scheduled to undergo primary coronary balloon angioplasty after AMI and 54 age- and sex-matched volunteers. Serum iron concentration and interleukin-6 levels were measured before primary angioplasty. LVEF was measured by echocardiography at baseline and after 6 months. TIMI risk score was calculated for risk stratification.

Results: Serum iron concentration was significantly lower in those in whom LVEF had not improved ≥ 10% from baseline (52.7 ± 24.1 versus 80.8 ± 50.8 µg/dl, P = 0.016) regardless of hemoglobin level, and was significantly lower in the AMI group than in the control group (62.5 ± 37.7 versus 103.0 ± 38.1 µg/dl, P<0.001). Trend analysis revealed that serum iron concentration decreased as TIMI risk score increased (P = 0.002). In addition, lower serum iron concentrations were associated with higher levels of inflammatory markers. Multiple linear regression showed that baseline serum iron concentration can predict LV systolic function 6 months after primary angioplasty for AMI even after adjusting for traditional prognostic factors.

Conclusion: Hypoferremia is not only a marker of inflammation but also a potential prognostic factor for LV systolic function after revascularization therapy for AMI, and may be a novel biomarker for therapeutic intervention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104495PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123974PMC
November 2015

Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults.

Biomarkers 2014 Mar 22;19(2):109-13. Epub 2014 Jan 22.

Department of Internal Medicine, Division of Infectious Diseases, Changhua Christian Hospital , Changhua , Taiwan .

Objective: Investigate the latent cytomegalovirus (CMV) infection as a biomarker of oxidative stress and atherosclerosis.

Methods: Latent CMV infection was diagnosed in healthy individuals with PCR-evidence of CMV DNA in peripheral leucocytes. Oxidative stress and atherosclerosis were measured by mitochondrial DNA oxidative damage index (mtDNA(ΔCT)) and intima media thickness (IMT).

Results: The CMV DNA positive subjects had a higher mean mtDNA(ΔCT) and greater IMT than subjects in the control group.

Conclusions: Presence of CMV DNA in leucocytes, as a marker of latent CMV infection, was associated with increased levels of oxidative stress and subclinical atherosclerosis in healthy adults.
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http://dx.doi.org/10.3109/1354750X.2013.877967DOI Listing
March 2014

Cyclophilin-A: a novel biomarker for untreated male essential hypertension.

Biomarkers 2013 Dec 28;18(8):716-20. Epub 2013 Oct 28.

Department of Neurology, Changhua Christian Hospital , Changhua , Taiwan .

Vascular cytokines, total nitrite, and cyclophilin-A (CyP-A) may be related to the pathogenesis of untreated hypertension. Forty males with normotensive and untreated essential hypertension were recruited in this cytokines survey. Body mass index (BMI), hyperlipidemia, and plasma CyP-A were increased in the hypertensive group (p < 0.05). However, only BMI (p = 0.022) and plasma CyP-A (p = 0.020) were found to be significant contributors to hypertension by multiple regression analysis. CyP-A was also positively correlated with systolic blood pressure (p = 0.029) and diastolic blood pressure (p = 0.047). These findings indicated that plasma CyP-A is a critical molecular biomarker in the early pathogenesis of essential hypertension.
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http://dx.doi.org/10.3109/1354750X.2013.847122DOI Listing
December 2013

Using oxidized low-density lipoprotein autoantibodies to predict restenosis after balloon angioplasty in patients with acute myocardial infarction.

PLoS One 2013 3;8(10):e74726. Epub 2013 Oct 3.

Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan ; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.

Objectives: Oxidized low-density lipoproteins (oxLDL) and oxidized low-density lipoprotein autoantibodies (OLAB) have been detected in human plasma and atherosclerotic lesions. OLAB appear to play a role in the clearance of oxLDL from circulation. Higher levels of OLAB appear to be associated with a reduced risk of a wide range of cardiovascular diseases. We investigated the prognostic value of plasma oxLDL and OLAB in patients undergoing primary coronary balloon angioplasty for acute ST-elevation myocardial infarction (STEMI).

Methods: Plasma oxLDL and OLAB concentrations were measured in 56 patients with acute STEMI before primary angioplasty, and then 3 days, 7 days and 1 month after the acute event. Follow-up angiography was repeated 6 months later to detect the presence of restensosis (defined as >50% luminal diameter stenosis). The thrombolysis in myocardial infarction (TIMI) risk score was calculated to determine the relationship between OLAB/oxLDL ratio and TIMI risk scores.

Results: Of the 56 patients, 18 (31%) had angiographic evidence of restenosis. Plasma OLAB concentrations were significantly lower in the restenosis group before angioplasty (181±114 vs. 335±257 U/L, p = 0.003), and at day 3 (155±92 vs. 277±185 U/L, p<0.001) and day 7 (177±110 vs. 352±279 U/L, p<0.001) after the acute event. There was no difference in oxLDL concentration between the two groups. The ratio of OLAB/oxLDL positively correlated with TIMI risk scores before angioplasty (p for trend analysis, p = 0.004), at day 3 (p = 0.008) and day 7 (p<0.001) after STEMI.

Significance: A relative deficit of OLAB, and hence likely impaired clearance of oxLDL, is associated with the risk of arterial restenosis after primary angioplasty for acute STEMI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074726PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789725PMC
June 2014

Efficacy of copper-silver ionization for controlling fungal colonization in water distribution systems.

J Water Health 2013 Jun;11(2):277-80

Department of Internal Medicine, Changhua Christian Hospital, Chinese Taiwan.

The purpose of this study was to identify the prevalence of fungal colonization in water systems and to evaluate the effect of decreasing fungal colonization by a copper-silver ionization system. Environmental samples were collected for fungal culture prospectively during a 1-year period (2011-2012) at the study hospital. A total of 392 water samples were examined from five buildings on March 1, 2011 and February 29, 2012. Fungi were isolated in 13 (3.4%) of 392 water samples from five buildings. The prevalence of fungal colonization in buildings was decreased from 4.76% (9/189) to 1.97% (4/203), a reduction of more than 40%, in pre-ionization and post-ionization treatment (p < 0.001). Thirteen (3.4%) of 392 water samples yielded fungi including Fusarium species (n = 7), Penicillium species (n = 2), Scedosporium species (n = 2), Aspergillus species (n = 1), and one unidentifiable mold. The number of isolated Fusarium species in ionized water samples (0.5% (1/203)) was statistically lower than those in nonionized (3.2% (6/189)) (p = 0.003). Our finding may determine if this ionization method can be applied for control of waterborne fungi colonization in hospital water systems.
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http://dx.doi.org/10.2166/wh.2013.139DOI Listing
June 2013

Endogenous granulocyte colony-stimulating factor: a biomarker in acute ischemic stroke.

Biomarkers 2012 Jun 23;17(4):319-24. Epub 2012 Mar 23.

Department of Neurology, Kuang-Tien General Hospital, Taichung, Taiwan.

Granulocyte colony-stimulating factor (G-CSF) may protect ischemic brain injury either in animal or human. No studies have reported that endogenous G-CSF (enG-CSF) level is related to the severity of ischemic stroke. This study was designed to assess the severity of ischemic patients correlated with the alteration of enG-CSF on the 1st day after an ischemic event. Patient's plasma enG-CSF and scoring of National Institute of Health Stroke Scale were measured on the 1st day after ischemic stroke. The acute ischemic stroke could significantly induce enG-GCF secretion as compared with healthy control group (16.77 vs. 22.86 μg/L, p = 0.001). Elevated enG-CSF concentration was positively correlated with the severity of stroke patients on day 1 after the event (p = 0.006; Spearman correlation coefficient = 0.268). The enG-CSF is a good biomarker for prediction of severity of acute ischemic stroke.
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http://dx.doi.org/10.3109/1354750X.2012.668712DOI Listing
June 2012

Bilirubin concentrations in thalassemia heterozygotes in university students.

Eur J Haematol 2011 Apr;86(4):317-23

Department of Laboratory Medicine, Taipei District, Cathay General Hospital, Taipei, Taiwan.

Objectives:   To investigate the difference of bilirubin concentrations between α- and β-thalassemia carriers and the role of variation status in the UDP-glucuronosyltransferase (UGT) 1A1 gene on such a difference.

Methods:   A total of 2713 university freshmen who attended a regular physical examination were enrolled in underwent screenings for thalassemias. Finally, 123 subjects whose mean corpuscular volume was ≤80 fL and who had no iron deficiency anemia were tested by PCR and PCR-restriction fragment length polymorphism (RFLP) for α- and β-thalassemias, respectively, and tested by PCR-RFLP for the five known variations of the UGT1A1 gene.

Results:   Among the 123 subjects, 76 and 47 were diagnosed with heterozygous α-thalassemia and with heterozygous β-thalassemia, respectively. Between the α- and β-thalassemia heterozygotes, variation status of the UGT1A1 gene was not statistically different (P = 0.898), while hemoglobin and bilirubin concentrations differed significantly (P = 0.005 and 0.001, respectively). Bilirubin concentrations were significantly higher among individuals with compound heterozygous variations/homozygous variation in the UGT1A1 gene than in those possessing the wild type and heterozygous variation (P < 0.001 for both α- and β-thalassemia heterozygotes). Compound heterozygous variations/homozygous variation in the UGT1A1 gene and anemia were the main causes of hyperbilirubinemia in α- and β-thalassemia heterozygotes, respectively.

Conclusions:   The difference in bilirubin concentrations between α- and β-thalassemia heterozygotes may be attributable to more bilirubin being produced in β-thalassemia heterozygotes than in α-thalassemia heterozygotes, while variation status of the UGT1A1 gene affects bilirubin concentrations in both α- and β-thalassemia heterozygotes.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01578.xDOI Listing
April 2011

Gluten sensitivity: associated sporadic cerebellar ataxia in Taiwan.

Acta Neurol Taiwan 2010 Dec;19(4):263-9

Department of Neurology, Vascular and Genomics Center, Changhua Christian Hospital, No. 135, Nanhsiao Street, Changhua 500, Taiwan.

Purpose: Gluten sensitivity (GS) is related to the pathogenesis of sporadic or hereditary ataxia.

Methods: Total of 194 healthy controls and patients with either hereditary ataxia (n=207) or sporadic ataxia (n=361) were tested for the circulating gluten-related autoantibodies which serve as biomarkers to interpret the existence of GS.

Results: The incidences of GS in each population were 1% in normal subjects, 2% in hereditary ataxia patients and 9% in sporadic ataxia patients. High serum level of anti-gliadin IgG/IgA and t-transglutaminase IgA were disclosed at the sporadic ataxia patients compared with normal subjects. However, the anti-gliadin IgG is more specific to the disease of sporadic ataxia.

Conclusion: Relatively higher incidence of GS was found in the population of sporadic ataxia patients but not in either normal subjects or hereditary ataxia patients in Taiwan. Anti-gliadin IgG still is a very powerful indicator to implicate the immune-related sporadic ataxia and we conclude that GS-related sporadic ataxia exists in Taiwan with linkage to autoimmune events.
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December 2010

Variations in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese.

Pharmacogenomics 2008 Sep;9(9):1229-35

Department of Laboratory Medicine, Cathay General Hospital, No 280, Section 4, Jen-Ai Road, Taipei 106, Taiwan.

Introduction: Results of several studies have indicated that the variation of c.-3279T>G in the UDP-glucuronosyltransferase (UGT)1A1 gene could be a further factor for the development of hyperbilirubinemia. However, this variant has not been reported in the Taiwanese population.

Materials & Methods: PCR-restriction fragment length polymorphism was utilized to determine variants at nucleotides -3279 (*60), -53 (*28) and 211 (*6) in the UGT1A1 gene for 178 Taiwanese hyperbilirubinemic patients and 200 controls.

Results: A total of ten and nine diplotypes were observed in the hyperbilirubinemic patients and controls, respectively. Subjects possessing diplotypes of compound haplotypes (*60/*28, *60/*6, *1/*60 plus *1/*28 plus *1/*6); *60/*60; *60/*60 plus 1/*28 and *6/*6 were significantly related to hyperbilirubinemia development, with an odds ratio of 7.83-188.00 (p = 0.012 approximately <0.001). A subgroup possessing diplotypes of *60/*60 plus *28/*28 were only found in hyperbilirubinemic patients, not in the controls. Bilirubin concentration amongst these patients carrying a diplotype of *60/*60 plus *28/*28 (mean [SD]: 39.2 [10.77] micromol/l) was significantly higher than that in the diplotype subgroups of *60/*60 plus *1/*28 (30.4 [4.10] micromol/l) and *6/*6 (30.3 [3.08] micromol/l) (p = 0.046 and 0.034, respectively).

Conclusions: The c.-3279T>G variant is a further factor for the development of hyperbilirubinemia. Our results also demonstrate that possessing the *60/*60 plus *28/*28 diplotype in the UGT1A1 gene is a determinant of relatively higher bilirubin values amongst hyperbilirubinemic patients.
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http://dx.doi.org/10.2217/14622416.9.9.1229DOI Listing
September 2008

Higher infection of dengue virus serotype 2 in human monocytes of patients with G6PD deficiency.

PLoS One 2008 Feb 13;3(2):e1557. Epub 2008 Feb 13.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University (NTU), Taipei, Taiwan, Republic of China.

The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency is high in Asia. An ex vivo study was conducted to elucidate the association of G6PD deficiency and dengue virus (DENV) infection when many Asian countries are hyper-endemic. Human monocytes from peripheral mononuclear cells collected from 12 G6PD-deficient patients and 24 age-matched controls were infected with one of two DENV serotype 2 (DENV-2) strains-the New Guinea C strain (from a case of dengue fever) or the 16681 strain (from a case of dengue hemorrhagic fever) with a multiplicity of infection of 0.1. The infectivity of DENV-2 in human monocytes was analyzed by flow cytometry. Experimental results indicated that the monocytes of G6PD-deficient patients exhibited a greater levels of infection with DENV-2 New Guinea C strain than did those in healthy controls [mean+/-SD:33.6%+/-3.5 (27.2% approximately 39.2%) vs 20.3%+/-6.2 (8.0% approximately 30.4%), P<0.01]. Similar observations were made of infection with the DENV-2 16681 strain [40.9%+/-3.9 (35.1% approximately 48.9%) vs 27.4%+/-7.1 (12.3% approximately 37.1%), P<0.01]. To our knowledge, this study demonstrates for the first time higher infection of human monocytes in G6PD patients with the dengue virus, which may be important in increasing epidemiological transmission and perhaps with the potential to develop more severe cases pathogenically.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2216061PMC
February 2008

Oxidized low-density lipoproteins, autoantibodies against oxidized low-density lipoproteins and carotid intima media thickness in a clinically healthy population.

Cardiology 2008 12;110(4):252-9. Epub 2007 Dec 12.

Institute of Nutritional Science, Chung Shan Medical University, Taichung, Taiwan.

Background: Oxidized low-density lipoproteins (oxLDLs) play an important role in the progress of atherosclerosis. Autoantibodies (oxLDL Ab) against oxLDLs may reflect the extent of LDL oxidation in vivo. Our aim was to investigate the correlation between oxLDLs, oxLDL Ab and intima media thickness of the common carotid arteries (CCA-IMT) in a clinically healthy population.

Methods: Two hundred subjects were recruited, and demographic and clinical characteristics of the subjects were recorded. By use of tertile classification of plasma oxLDLs and oxLDL Ab, 9 groups including 4 extreme subject groups were generated. CCA-IMT was measured as an indicator of carotid atherosclerosis.

Results: Age and plasma LDL concentration contributed significantly to CCA-IMT (p < 0.05). Body mass index, smoking index and plasma LDL concentration were significantly positively related to the plasma oxLDLs concentration; by contrast, plasma oxLDL Ab were significantly negatively related to the plasma oxLDL concentration (p < 0.05). Subjects in the group with low oxLDL Ab/high oxLDLs had the greatest CCA-IMT and the highest level of LDL; by contrast, subjects in the group with high oxLDL Ab/low oxLDLs had the least CCA-IMT and the lowest level of LDL.

Conclusions: Both plasma oxLDLs and oxLDL Ab contribute, although in opposite ways, to the LDL metabolism and development of atherosclerosis. Immune response to oxLDLs may exert a protective role at an early stage of atherosclerosis.
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http://dx.doi.org/10.1159/000112409DOI Listing
July 2008

UDP-glucuronosyltransferase 1A7 polymorphisms are associated with liver cirrhosis.

Biochem Biophys Res Commun 2008 Feb 3;366(3):643-8. Epub 2007 Dec 3.

Department of Medical Technology, Fooyin University, Kaohsiung, Taiwan.

Variations in the UDP-glucuronosyltransferase (UGT) 1A7 gene have been found to be related to the development of hepatocellular carcinoma (HCC). Since the pathogenesis of liver cirrhosis is not dissimilar to that of HCC, we hypothesized that UGT1A7 genetic polymorphisms may be associated with liver cirrhosis. PCR-restriction fragment length polymorphism was utilized to determine UGT for 1A7 genotypes for the 159 patients with liver cirrhosis and 263 gender/age matched controls. Simple logistic regression analysis revealed that significant risk factors for liver cirrhosis were (1) hepatitis B virus (HBV) infection, (2) hepatitis C virus (HCV) infection, (3) HBV infection plus HCV infection and (4) low-activity UGT1A7 genotypes. The results of further multivariate logistic regression confirmed these associations. Interaction of low-activity UGT1A7 genotypes and HBV (or HCV) infection produced an additive effect upon the risk for the development of liver cirrhosis [observed odds ratio (OR) (54.59) greater than the expected OR (18.05)]. UGT1A7 low/low genotype was also related to advanced liver cirrhosis (Child-Pugh classes C and/or B) (OR=7.50, P=0.009). This study demonstrates the novel findings that carriage of low-activity UGT1A7 genotypes represents a risk factor for the development and functional severity of liver cirrhosis.
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http://dx.doi.org/10.1016/j.bbrc.2007.11.125DOI Listing
February 2008

The MTHFR 677 C/T polymorphism influences plasma levels of adhesion molecules and nitric oxide.

Thromb Res 2008 16;121(4):549-54. Epub 2007 Aug 16.

Graduate Institute of Medical Genetics, Kaohsiung Medical University, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Background: Hyperhomocysteinemia is an independent risk factor for cardiovascular events. The T allele of 677 C/T polymorphism at the methylenetetrahydrofolate reductase (MTHFR) gene has been reported to induce mild hyperhomocysteinemia. In the present study, we investigated the relationship between this polymorphism and adhesion molecules and total nitric oxide (NOx).

Methods: The adhesion molecules tested in the present study were soluble E-selectin (sE-selectin), vascular adhesion molecule (sVCAM), and intercellular adhesion molecule (sICAM). A total of 297 subjects had data on these atherosclerotic biomarkers and the MTHFR genotypes. The genetic effect was estimated in the multivariate regression models with adjustment of covariates. Homocysteine, folate, vitamin B6 and vitamin B12 levels were measured in 181 subjects for the test of association between the biomarkers and homocysteine levels.

Results: The genotype distribution was in Hardy-Weinberg equilibrium. The sVCAM levels increased with the number of the T allele, while the NOx levels decreased with the number of the T allele. We found that the T allele was significantly associated with high sVCAM levels (p=0.002) and low NOx levels (p=0.011) in the regression models. The MTHFR genotypes were associated with homocysteine levels (p=0.031). Mild hyperhomocysteinemia (>12 micromol/L) was significantly associated with sVCAM levels (p=0.036). The NOx levels were lower in the hyperhomocysteinemia group than in the normal homocysteine group, but the difference was not significant. The genotypes were not significantly associated with either sE-selectin or sICAM.

Conclusions: The detrimental T allele exerted an additive effect to increase sVCAM and decrease NOx concentrations, which may contribute to atherosclerosis.
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http://dx.doi.org/10.1016/j.thromres.2007.06.006DOI Listing
April 2008