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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Molecular biology of glucose-6-phosphate dehydrogenase and UDP-glucuronosyltransferase 1A1 in the development of neonatal unconjugated hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and variants of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are the most common genetic causes of neonatal unconjugated hyperbilirubinemia (NUH). In this review, we searched PubMed for articles on the genetic causes of NUH published before December 31, 2022, and analyzed the data. On the basis of the results, we reached eight conclusions: (1) 37 mutations of the G6PD gene are associated with NUH; (2) the clinical manifestation of G6PD deficiency depends not only on ethnicity but also on the molecular mechanisms underlying the deficiency (and thus its severity); (3) of mutations in the UGT1A1 gene, homozygous c.-53A(TA)6TAA > A(TA)7TAA is the main cause of NUH in Caucasians and Africans, whereas homozygous c.211G > A is the main genetic cause of NUH in East Asians; (4) in Indonesian neonates, homozygous c.-3279T > G is the most common cause of NUH development, and neither c.-53 A(TA)6TAA > A(TA)7TAA nor c.211G > A causes it; (5) in breast-fed East Asian neonates, the TA7 repeat variant of the UGT1A1 gene protects against the development of NUH; (6) G6PD deficiency combined with homozygous c.211G > A variation of the UGT1A1 gene increases the risk of severe NUH; (7) in Pakistani and Caucasian patients with Crigler-Najjar syndrome type 2 (CN-2), point mutations of the UGT1A1 gene are widely distributed and frequently occur with variation at nucleotide -53, whereas in Asian patients with CN-2, compound homozygous variations in the coding region are frequently observed; and (8) records of G6PD deficiency and UGT1A1 variation status for a neonate offer useful pharmacogenomic information that can aid long-term care. These results indicate that timely diagnosis of NUH through molecular tests is crucial and that early initiation of treatment for the neonates and educational programs for their parents improves outcomes.

Formoterol Acting via ß2-Adrenoreceptor Restores Mitochondrial Dysfunction Caused by Parkinson's Disease-Related UQCRC1 Mutation and Improves Mitochondrial Homeostasis Including Dynamic and Transport.

Formoterol, a ß2-adrenergic receptor (ß2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson's disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of ß2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD.

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

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.

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

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.

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

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.

Bilirubin metabolism and UDP-glucuronosyltransferase 1A1 variants in Asians: Pathogenic implications and therapeutic response.

In the Asian general population, at least six single-nucleotide variants (SNVs) in the UDP-glucuronosyltransferase (UGT) 1A1 gene have been identified: -3279T>G, -53A(TA)6 TAA>A(TA)7 TAA, 211G>A, 686C>A, 1091C>T, and 1456T>G. Each of these six SNVs was observed in at least four ethnic groups of the 12 Asian populations studied. In East Asian populations, the descending frequency of these six SNVs was as follows: -3279G>[-53A(TA)7 TAA, 211A]>(686A, 1091T)>1456G. Because of the presence of linkage disequilibrium and the expulsion phenomenon, when the SNVs -3279G, -53A(TA)7 TAA, 211A, and 686A were simultaneously involved, 15 instead of the estimated 81 genotypes were observed. Those carrying 686AA or 1456GG developed Gilbert's syndrome or Crigler-Najjar syndrome type 2. Both -53A(TA)7 TAA/A(TA)7 TAA and 211AA are the main causes of Gilbert's syndrome in East Asian populations. In East Asian populations, the 211AA genotype is the main cause of neonatal hyperbilirubinemia, whereas -53A(TA)7 TAA/A(TA)7 TAA exerts a protective effect on hyperbilirubinemia development in neonates fed with breast milk. Both 211A and -53A(TA)7 TAA are significantly associated with adverse drug reactions induced by irinotecan (one of the most widely used anticancer agents) in Asians. However, at least three common SNVs (-3279G, -53A(TA)7 TAA, and 211A) should be comprehensively analyzed. This study investigated the clinical significance of these six SNVs and demonstrated that examining UGT1A1 variants in Asian populations is considerably challenging.

The relationship between pulse pressure with plasma PCSK9 and interleukin-6 among patients with acute ischemic stroke and dyslipidemia.

BACKGROUND AND PURPOSE: A high plasma concentration of proprotein convertase subtilisin/kexin type 9 is characteristic of a prothrombotic state in cardiovascular diseases. Elevated inflammatory markers, such as interleukin-6, are associated with worse outcomes after ischemic stroke. We aimed to study the role of plasma PCSK9 and IL-6 in acute ischemic stroke with dyslipidemia. METHODS: We divided 123 enrolled patients with first-ever acute ischemic stroke into normotensive and high blood pressure groups and further into high and low pulse pressure subgroups. Clinical characteristics and inflammatory and metabolic parameters, including plasma PCSK9 and IL-6, were recorded. RESULTS: After the analysis of the normotensive and BP groups, there were positive correlations between PP and carotid stenosis (P = 0.031) and plaque numbers (P = 0.013) and between National Institute of Health Stroke Scale scores (P = 0.019) and carotid stenosis severity (P = 0.021) and resistance index (P = 0.04). There was a significant association between plasma cholesterol and PCSK9 (P = 0.044) in the low PP subgroup and IL-6 (P = 0.042) in the high PP subgroup. CONCLUSIONS: Our findings indicated that plasma PCSK9 levels were associated with the low PP subgroup, while IL-6 was associated with the high PP subgroup. Dyslipidemia control is also necessary for those who had a stroke and who have high PP. Further investigation to assess the role of PCSK9 and IL-6 in patients with stroke is required for early treatment and secondary prevention.

Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Bilirubin concentrations in thalassemia heterozygotes in university students.

OBJECTIVES: To investigate the difference of bilirubin concentrations between α- and ß-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 ß-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 ß-thalassemia, respectively. Between the α- and ß-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 ß-thalassemia heterozygotes). Compound heterozygous variations/homozygous variation in the UGT1A1 gene and anemia were the main causes of hyperbilirubinemia in α- and ß-thalassemia heterozygotes, respectively. CONCLUSIONS: The difference in bilirubin concentrations between α- and ß-thalassemia heterozygotes may be attributable to more bilirubin being produced in ß-thalassemia heterozygotes than in α-thalassemia heterozygotes, while variation status of the UGT1A1 gene affects bilirubin concentrations in both α- and ß-thalassemia heterozygotes.

Gluten sensitivity: associated sporadic cerebellar ataxia in 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.

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

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)7TAA/A(TA)7TAA is not, while the 211AA is a risk factor for the development of neonatal hyperbilirubinemia in Taiwanese.

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

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.

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

Variations at the six nucleotides -3279 (T > G), -53 (A[TA]6 TAA > A[TA]7 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.

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

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.