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Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk.A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication.A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index1.29 in the treatment-naive cohort. Patients with FIB-41.29, compared to those with FIB-41.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index1.29, ALT level40 U/l, and HBsAg level1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment.In non-cirrhotic patients with chronic HBV infection, FIB-4 index1.29 complements the existing clinical profile to define patients with the lowest HCC risk.

We report a one-pot two-nanoprobe approach coupled to mass spectrometry for simultaneous quantification and post-translational modification (PTM) profiling of targeted protein in biofluid. Using N-glycoprotein as model, the assay employs two nanoprobes, antibody-conjugated SiO2 nanoparticles and lectin-conjugated magnetic Fe3O4 nanoparticles, to achieve target glycoprotein isolation from biofluid and subsequent glycopeptide enrichment in a single tube. As demonstrated on α-fetoprotein (AFP), a serum biomarker for hepatocellular carcinoma (HCC), the assay has high purification specificity (20 glycopeptides) with 2-fold and 10-fold superior total glycopeptide intensity compared to non-one-pot method (9 glycopeptides) or without enrichment (6 glycopeptides), respectively. By multiple reaction monitoring mass spectrometry (MRM-MS) analysis of the nonglycopeptides, the assay can quantify low abundant AFP expression (0.5 ng) with good correlation with conventional ELISA method (Pearson’s r = 0.987). Furthermore...

Background: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC. Methods: We conducted a nested case–control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI). Results: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12–2.11; OR = 4.88 (1.46–16.3); OR = 3.79 (1.10–13.0); OR = 4.13 (1.13–15.1) with each additional quintiles, respectively] with a significant dose–response trend (Ptrend = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62–4.39); OR = 3.85 (1.47–10.1); OR = 2.56 (0.96–6.84); OR = 3.76 (1.33–10.7) for the second, third, fourth, and fifth quintiles, respectively; Ptrend = 0.017] before HCC. Conclusions: Elevated adiponectin levels were independently associated with an increased risk of HCC. Impact: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown. Cancer Epidemiol Biomarkers Prev; 23(8); 1659–71. ©2014 AACR.

The estrogen pathway has long been implicated as a tumor protector in female hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Our previous study identified that estrogen receptor alpha (ERα) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ERα translation. This study aims to delineate the mechanism underlying the upregulation of miR-18a in female HCC. The analysis of 77 female HCC specimens revealed that miR-18a levels were associated with pre-miR-18a rather than pri-miR-18a levels, suggesting an enhanced processing of pri- to pre-miR-18a. Among a panel of factors involved in microRNA processing, p53 was identified as a novel regulator for miR-18a maturation process. Knockdown of p53 by si-RNA decreased the level of miR-18a, whereas overexpression of either wild-type or mutant p53 increased its level. The association between the elevation of miR-18a and the accumulation of p53, mainly caused by somatic mutations, was confirmed in the clinical specimens of HBV-related female HCC. By analyzing the association with clinicopathological features, activation of this p53/miR-18a pathway mainly occurs in younger or noncirrhosis female HCC patients and associated with a trend of worse overall survival. Therefore, this study demonstrated a novel function of elevated/mutant p53 in regulating the amount of ERα protein through its promoting the biogenesis of miR-18a, which could lead to decrease the tumor-protective function of the estrogen pathway in female hepatocarcinogenesis.

Continuous cultivation has been known to decrease soil organic matter content. Application of organic matter to cultivated soil is an important practice from the point of view of maintaining an adequate amount of soil organic matter. Soil organic matter content significantly affects soil microbial activity, which is an important index of soil quality. In this study, a field experiment was conducted to examine the long-term effects of different kinds of organic matter in combination with inorganic nitrogen (N) fertilizer on chemical and biological properties of soils. There were seven treatments, namely (1) CK (without fertilization), (2) Chem-N (applying chemical N fertilizer only), (3) Comp (applying compost with the same rate of N as the Chem-N treatment), (4) Comp + l/3 N (applying compost complemented with 33% of the chemical N fertilizer of the Chem-N treatment), (5) Comp + 2/3 N (applying compost complemented with 66% of the chemical N fertilizer of the Chem-N treatment), (6) GM + 1/3 N (app...

Background and Aims The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear. Methods A retrospective cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV-DNA/HBsAg levels and HBeAg-negative hepatitis/active viral replication (HBV-DNA level ≥ 2000 IU/mL) were investigated. Results In the overall cohort, serum HBV-DNA level served as a better predictor for HBeAg-negative hepatitis compared with HBsAg level. However, in those with HBV-DNA level

Liver cancers and lung cancer are the 2 leading cancer deaths in Taiwan. Thus, these 2 cancers are the most important cancers in Taiwan, and both have been chosen as the main target diseases by National Research Program for Genomic Medicine. For Liver cancers, only the early stage patients (10. Since TLCN has become NHRI Biobank, which is supported by Government fund and has been approved by the Ministry of Health and Welfare, it can accept the application not only from the scientists, but also the industries directly. The final goal of this project is to improve the treatment and survival of liver cancer patients in Taiwan through successful researches in the liver carcinogenetic mechanism, prevention, screening, early detection and therapies.

Arsenic in drinking water has been shown to increase the risk of urothelial carcinoma and lung cancer. However, the lifetime risk of developing urothelial carcinoma and lung cancer caused by exposure to arsenic in drinking water has not been reported. This study aimed to assess the lifetime risk of urothelial carcinoma and lung cancer caused by arsenic exposure from drinking water and cigarette smoking habit for residents living in the arseniasis-endemic area in Northeastern Taiwan. We recruited 8086 residents in 1991–1994 and monitored them for their newly developed types of cancers, identified by computerized linkage with the national cancer registry profile. There were 37 newly diagnosed urothelial carcinoma cases and 223 new lung cancer cases during the follow-up period (until 2007). The lifetime (35–85 years old) cumulative risk of developing urothelial carcinoma from an arsenic concentration in the drinking water of

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR ( P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR ( P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

Background: OSA is frequently coexistent with AMI. However, the impact of OSA in AMI patients was not clear so far. Also, if the impact changed with time after AMI has never been studied. This study aimed to clarify the impact of OSA on AMI with a population-based cohort study. Methods: Totally 9,453 adult patients newly diagnosed of AMI between 2000 and 2012 from Taiwan9s National Health Insurance Research Database (NHIRD) were recruited. Among those, 207 patients (2.2%) were identified as OSA. Comparison group was selected from non-OSA patients based on a 1:5 matching process with propensity score. Two groups were followed until Dec 31, 2012. The primary outcome was major adverse cardiovascular events (MACEs). Results: The follow-up duration was 4.68±3.55 years for OSA group and 4.83±3.82 years for comparison group. OSA patients had a 1.288-fold higher risk for overall MACEs (95%CI:1.067-1.556,p=0.009) including recurrent AMI (re-AMI) or coronary revascularization (HR:1.266,95%CI:1.009-1.588,p=0.042) and hospitalization for ischemic heart disease (IHD) (HR:1.367, 95%CI:1.088-3.251,p=0.021). Moreover, the risk reached highest while the OSA was diagnosed within 6 months after AMI including overall MACEs (HR:2.347,95%CI:1.453-2.790,p Conclusion: OSA within six months after AMI was highly associated with MACEs. Patients with recent AMI should be routinely evaluated with evidence of OSA.

Arsenic in drinking water is associated with hepatomegaly and death from liver cancer. However, confounding factors related to liver diseases have not been carefully studied. We examined associations between exposure of arsenic in drinking water and risk of hepatitis and cirrhosis, and the interaction with chronic viral hepatitis, in people living in the Lanyang Basin of northeastern Taiwan, where well water has an arsenic content that ranges from undetectable to 3590 μg/L.We tested blood samples from 4387 people who lived in arseniasis-endemic areas in northeastern Taiwan from 1991 through 1994 for hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), and antibodies against hepatitis C virus (anti-HCV). We measured arsenic concentrations in well water and collected information on residents' histories of major chronic diseases. Reports of chronic hepatitis or cirrhosis were ascertained using the Taiwan National Health Insurance database. Reports of liver cancer were ascertained using the Taiwan National Cancer Registry.Prevalence odds ratios in the overall study population for chronic hepatitis or cirrhosis for well water arsenic concentrations of ≤10 μg/L were 1.00 (reference), 0.93 for 10.1-49.9 μg/L (95% confidence interval [CI], 0.57-1.52), 1.24 for 50.0-99.9 μg/L (95% CI, 0.68-2.23), 0.98 for 100.0-299.9 (95% CI, 0.52-1.85), and 1.86 for ≥300.0 μg/L (95% CI, 1.08-3.20). Increasing levels of arsenic in drinking water were associated with increasing prevalence of chronic hepatitis or cirrhosis in residents who were seronegative for HBsAg and seronegative for anti-HCV, but not for seropositive for either HBsAg or anti-HCV. In individuals who were seropositive for HBsAg or anti-HCV, we observed an inverse association between hepatitis or cirrhosis and consumption of water with levels of arsenic ≥100.0 μg/L. Among participants who were seropositive for HBsAg or anti-HCV, consumption of water with levels of arsenic ≥100.0 μg/L was associated with a reduced risk of liver cancer (multivariate-adjusted hazard ratio, 0.29; 95% CI, 0.09-0.95; P.05). A higher proportion of individuals exposed to cumulative arsenic level14,000 μg/L ×year were carriers of inactive hepatitis B virus (DNA10,000 copies/mL) and were positive for HBsAg (60%) than individuals exposed to water below this arsenic level (35%).Concentrations of arsenic concentration in drinking water ≥300.0 μg/L significantly increase risk of hepatitis or cirrhosis in people without chronic viral hepatitis. However, in people with chronic viral hepatitis, levels of arsenic ≥100.0 μg/L in drinking water significantly reduce the risk of chronic hepatitis or cirrhosis.

Field measurements at various wetland ecosystems were conducted to investigate the coefficients b for different scalars in the relaxed eddy accumulation method. These measurements were performed at paddy, marsh and lagoon fields using the eddy covariance system to collect data with a sampling rate of 10 Hz. Without the application of a wind deadband, the mean median values of b were found to be 0.55 for paddy, 0.57 for marsh and 0.56 for lagoon for all scalar quantities under unstable and near-neutral conditions. However, the median values of b under stable conditions steadily increase with stability. The results of estimated b were well described by proposed relationships as a function of the dimensionless stability parameter z / L . Scalar similarity between carbon dioxide, temperature and water vapor showed a distinct diurnal pattern and change within the day where good scalar correlations were observed at paddy and marsh during daytime, but poor scalar correlations were observed at lagoon. With the application of wind deadband, the reductions of the normalized b factors, b REA , related to the increase of deadband values were evaluated and the results were compared with the reported relationships in the literature. The relative minimal variability of the normalized b REA was found when the wind deadband was equal to 0.8. From the diurnal variation of b REA , the relative maximum values of b REA factors occurred around noon, and lower values were observed in the early morning and late afternoon. Daily median b 0 values for various scalars under unstable and neutral conditions over paddy from the beginning to the end of the study period were used to verify the independence of the variations in surface roughness.

BACKGROUND AND PURPOSE: The occipital artery is usually a main feeding artery of an intracranial dural arteriovenous fistula. The aim of this study was to establish the role of the OA in the diagnosis of DAVFs by using duplex sonography. MATERIALS AND METHODS: We first compared the clinical features between patients with DAVFs having and not having the OA as one of feeding arteries in 181 consecutive patients with DAVFs. Second, we investigated the OA by using duplex sonography in 60 control subjects to test the accessibility. Finally, we studied 24 DAVF and 60 non-DAVF patients to validate the diagnostic performances of duplex sonography. Hemodynamic parameters, including the resistance index and flow velocity, were analyzed. RESULTS: Half of the DAVFs (51%) had the OA as one of feeding arteries. DAVFs with the OA as one of the feeders were more likely located at noncavernous sinuses; to belong to types IIb, IIa+b, III, IV, or V; and to be associated with aggressive manifestations compared with DAVFs without the OA as a feeder ( P < .05). Accessibility of the OA by using duplex sonography was 100%. The resistance index was lower and flow velocity was higher in the OA among patients with DAVFs compared with control subjects ( P < .001). An OA resistance index

Background. It is unclear whether hepatitis B e antigen (HBeAg) seroconversion induced by nucleos(t)ide analogues (NUC) has a prognosis that is similar to that of spontaneous HBeAg seroconversion. Methods. A total of 148 noncirrhotic NUC-induced HBeAg seroconverters were consecutively enrolled. A historical control of 407 noncirrhotic spontaneous HBeAg seroconverters was also recruited. We compared the rates of HBeAg seroreversion and HBV reactivation between these 2 cohorts. Results. There were 1652.8 and 465.2 person-years of follow-up for spontaneous and NUC-induced HBeAg seroconverters, respectively. Compared with NUC-induced seroconverters, spontaneous seroconverters were younger when achieving HBeAg seroconversion. We thus compared these 2 cohorts according to their age at HBeAg seroconversion. In patients achieving HBeAg seroconversion before 30 years of age, NUC-induced seroconverters had a higher 2-year HBeAg seroreversion rate than spontaneous seroconverters (12.0% vs 2.9%; P= .004) and were at a higher risk of HBV reactivation (hazard ratio, 4.6; 95% confidence interval, 1.5–14.4). Using multivariate analysis, NUC-induced HBeAg seroconversion remained a risk factor of both endpoints in young HBeAg seroconverters. Conclusion. NUC-induced HBeAg seroconverters may not have durable response after stopping therapy. For patients achieving HBeAg seroconversion before 30 years of age, the risk of HBeAg seroreversion and HBV reactivation is higher in NUC-induced seroconverters than spontaneous HBeAg seroconverters. Hepatitis B virus (HBV) infection is a global health

Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3′ untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012)

Heme oxygenase (HO)-1 is up-regulated as a cellular defense responding to stressful stimuli in experimental studies. A GT-repeat length polymorphism in the HO-1 gene promoter was inversely correlated to HO-1 induction. Here, we reported the association of GT-repeat polymorphism with blood pressure (BP) phenotypes, and their interaction on cardiovascular (CV) mortality risk in arsenic-exposed cohorts.Associations of GT-repeat polymorphism with BP phenotypes were investigated at baseline in a cross-sectional design. Effect of GT-repeat polymorphism on CV mortality was investigated in a longitudinal design stratified by hypertension. GT-repeat variants were grouped by S (27 repeats) or L (≥ 27 repeats) alleles. Multivariate analyses were used to estimate the effect size after accounting for CV covariates.Totally, 894 participants were recruited and analyzed. At baseline, carriers with HO-1 S alleles had lower diastolic BP (L/S genotypes, P = 0.014) and a lower possibility of being hypertensive (L/S genotypes, P = 0.048). After follow-up, HO-1 S allele was significantly associated with a reduced CV risk in hypertensive participants [relative mortality ratio (RMR) 0.27 (CI 0.11, 0.69), P = 0.007] but not in normotensive. Hypertensive participants without carrying the S allele had a 5.23-fold increased risk [RMR 5.23 (CI 1.99, 13.69), P = 0.0008] of CV mortality compared with normotensive carrying the S alleles.HO-1 short GT-repeat polymorphism may play a protective role in BP regulation and CV mortality risk in hypertensive individuals against environmental stressors.

BACKGROUND Hepatitis B e antigen (HBeAg) status and serum hepatitis B virus (HBV) DNA levels are major factors affecting the prognosis of adult HBV carriers; however, the impact of viral load on long-term outcomes after spontaneous HBeAg seroconversion remains unclear. METHODS A total of 390 spontaneous HBeAg seroconverters with a long-term follow-up were enrolled. Serum HBV-DNA levels at 1 year after HBeAg seroconversion were determined, and their correlation with long-term adverse outcomes was explored. RESULTS In a mean follow-up of 6.8 years, the average annual incidence rates were 4.4% and 1.9% for HBeAg-negative hepatitis and hepatitis flare, respectively. Compared with patients with HBV-DNA levels

Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (

Waste heat boilers are widely used in the petroleum refining industry to improve energy efficiency. However, improper design, operation or maintenance of these boilers may result in costly failures. Cracking was found repeatedly at the same location on a circumferential weld of a certain waste heat boiler in CPC refinery. Hence a special designed fixture was used to avoid crack extension. Root cause mainly due to improper arrangement of internal tubes and external piping was then mainly found by thermal stress analysis. Recommendations was proposed to shut down the boiler immediately and to rearrange the tubes and piping without changing basic design of the waste heat boiler.

Background and Aims: Metabolic profiles are associated with severity of liver histology in chronic hepatitis C (CHC) infection. However, the influence of hepatitis C virus (HCV) genotypes, especially genotype 1 and 2, on the association between metabolic profiles and hepatic fibrosis remains unknown. Methods: We consecutively enrolled 528 CHC patients infected by HCV genotype 1 or 2, and used univariate and multivariate approaches to determine the influence of HCV genotype on the association of metabolic characteristics with severity of liver histology. Results: In univariate analysis, diabetes mellitus, obesity, higher grades of hepatic steatosis, homeostasis model assessment–insulin resistance index and alanine aminotransferase level, but lower serum total cholesterol and low-density lipoprotein level, were associated with advanced hepatic fibrosis. Advanced hepatic fibrosis was associated with an adjusted odds ratio of 13.72 (95% confidence interval, 2.15–87.7) for serum fasting blood glucose, 1.07 (1.01 to 1.13) for body mass index (BMI), and 0.03 (0.00–0.32) for total cholesterol level. Older age, lower serum total cholesterol level and more necro-inflammatory activity were associated with advanced hepatic fibrosis in both genotype 1 and 2 patients (P

The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 μg/L), whereas studies from lower exposure areas (100 μg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher. Cancer Epidemiol Biomarkers Prev; 19(1); 101–10

Previous epidemiological studies have indicated that ingested inorganic arsenic is strongly associated with a wide spectrum of internal cancers. Little is conducted, however, to assess health effects at long-term low dose exposures by linking biologically based mechanistic models and arsenic epidemiological data. We present an integrated approach by linking the Weibull dose-response function and a physiologically based pharmacokinetic (PBPK) model to estimate reference arsenic guideline. The proposed epidemiological data are based on an 8 years follow-up study of 10,138 residents in arseniasis-endemic areas in southwestern and northeastern Taiwan. The 0.01% and 1% excess lifetime cancer risk based point-of-departure analysis were adopted to quantify the internal cancer risks from arsenic in drinking water. Positive relationships between arsenic exposures and cumulative incidence ratios of bladder, lung, and urinary-related cancers were found using Weibull dose-response model r(2)=0.58-0.89). The result shows that the reference arsenic guideline is recommended to be 3.4 microg L(-1) based on male bladder cancer with an excess risk of 10(-4) for a 75-year lifetime exposure. The likelihood of reference arsenic guideline and excess lifetime cancer risk estimates range from 1.9-10.2 microg L(-1) and 2.84 x 10(-5) to 1.96 x 10(-4), respectively, based on the drinking water uptake rates of 1.08-6.52 L d(-1). This study implicates that the Weibull model-based arsenic epidemiological and the PBPK framework can provide a scientific basis to quantify internal cancer risks from arsenic in drinking water and to further recommend the reference drinking water arsenic guideline.

Adipose tissue is now accepted by the scientific and medical community to be a genuine endocrine organ, in addition to its classical role as an energy store. Adiponectin is one of the many adipocytokines that are secreted almost exclusively by adipose tissue. Alteration in blood adiponectin concentrations has been linked to many human diseases in numerous cross-sectional and prospective studies. In this review, we describe briefly the biological effects of adiponectin as revealed by basic scientific investigations. We also summarize the principles of blood adiponectin assays. Overall, lower blood adiponectin concentration is found in subjects with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. These medical conditions are components of the metabolic syndrome and major risk factors for accelerated atherosclerosis. Plasma adiponectin levels are also expected to be lower in subjects with cardiovascular diseases, such as coronary artery disease, ischemic stroke and peripheral artery disease. Congestive heart failure (CHF) and cardiac arrhythmia are common end points in cardiovascular diseases. Surprisingly, higher blood adiponectin levels are frequently reported to predict mortality associated with CHF. Few human data regarding adiponectin and cardiac arrhythmia are available. Higher blood adiponectin level has been documented only in atrial fibrillation. We also summarize data on the role of the high molecular weight (HMW) iso-forms of adiponectin and the effects of clinical treatment on the levels of total or HMW adiponectin. Whether adiponectin is a risk marker or a risk factor for the diseases reviewed in this article, and in many other human diseases, and their detailed pathogenic links awaits further investigation.

Background Early viral load decline following pegylated interferon-α2a and ribavirin therapy is an important predictor of the treatment responses in chronic hepatitis C (CHC) patients, thus, it is essential to evaluate the influence of host and viral factors on early viral load decline. Methods Clinical and serial virological data were collected from 145 consecutive Asian CHC patients with pegylated interferon-α2a plus ribavirin therapy. A dose of pegylated interferon-α2a was administered at week 1 and then weekly with daily oral ribavirin for 24 or 48 weeks. Genotyping and quantification of hepatitis C virus (HCV) RNA were done using molecular methods. Results A total of 81 patients were infected with HCV genotype 1, 61 with genotype 2 and 3 with both genotypes 1 and 2. At the end of follow-up, 110 patients attained sustained virological response (SVR). In multivariate analyses, body mass index (BMI) and genotype were related to viral load decline at day 2, baseline viral load and high-density lipoprotein (HDL) cholesterol levels were correlated with viral load decline between days 2 and 28. Genotype, baseline viral load, alanine aminotransferase (ALT) levels and BMI independently predicted rapid virological response, whereas only genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR. Conclusions HCV genotype, baseline viral load, pretreatment BMI, HDL and ALT levels have a significant effect on early viral load decline of Asian CHC patients with interferon-based therapy. Only HCV genotype, baseline viral load and viral load decline at day 28 can independently predict SVR.

A hospital-based case-control study was conducted near a former black-foot disease (BFD)-endemic area in southwestern Taiwan to examine the possible risk factors and genetic susceptibility for urinary transitional cell carcinoma (TCC). A total of 221 patients with pathologically confirmed TCC and 223 age–sex-matched control subjects from urology outpatient clinics were recruited between 1998 and 2002. The results showed that residency in the BFD area and consumption of well water for more than 10 years was a strong factor on urinary cancer risk (odds ratio [OR],8.16, 95% confidence interval [CI],3.34–19.90, p

The clinical implications of metabolic profiles in patients with chronic hepatitis C remain controversial. To study the association of metabolic abnormalities with chronic hepatitis C, we conducted a case-control study with special emphasis on serum lipid pattern, fasting blood glucose, and adiponectin.We enrolled 500 patients with chronic hepatitis C and 536 sex and age-matched controls. Unadjusted and adjusted associations of demographic and metabolic variables were estimated.Chronic hepatitis C patients had higher alanine aminotransferase (ALT) and high-density lipoprotein-cholesterol levels, but lower total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol levels than controls. Stratifying ALT level according to its upper limit of normal, HCV infection was associated with younger age, female gender, and higher TC levels in chronic hepatitis C patients with normal ALT levels, but with lower TC and lower TG levels in those with abnormal ALT levels. By using multiple linear regression analyses for subjects with available adiponectin data, presence of HCV infection was independently associated with higher serum adiponectin levels.Metabolic profiles of chronic hepatitis C patients are affected by age, gender, serum adiponectin, and ALT levels. Further longitudinal studies are needed to clarify the complex interplay between HCV infection and metabolic profiles.

Background and Aims: Although insulin resistance affects liver fibrosis progression and treatment response in chronic hepatitis C (CHC), the relationship between chronic hepatitis C virus (HCV) infection and insulin resistance (IR) remains to be firmly established. We thus studied the impact of host, metabolic and viral factors on IR in CHC patients. Methods: A total of 162 CHC patients with complete clinical data were enrolled. Among them, 94 received histological examinations. Quantitative HCV RNA was assayed by a real-time polymerase chain reaction (PCR) assay. Genotyping was performed by reverse transcription PCR with type-specific primers. The pretreatment IR index was determined using homeostasis model assessment (HOMA), and an index value of more than 2.4 was designated IR. Unadjusted and adjusted association of the HCV RNA level and IR was further analysed. Results: In multivariate linear regression analysis, a dose‐ response relationship was observed between the log10HCV RNA level and the presence of IR. IR was positively correlated with body mass index, triglyceride, HCV RNA and alanine aminotransferase levels, but negatively correlated with adiponectin level. Subgroup analysis stratified by HCV genotype showed that there was a trend towards a higher HOMR-IR index value and lower adiponectin levels in genotype 1 patients. Histological analysis showed that IR was positively associated with the severity of hepatic steatosis. Conclusions: Our data indicate that higher HCV RNA levels are associated with the presence of IR in CHC patients. Further studies are needed to clarify the interplays between HCV infection, IR and adiponectin in an attempt to develop new adjuvant therapy for CHC.

Cardiovascular disease is the leading cause of mortality worldwide. Arsenic is a ubiquitous metalloid in the crust of the earth. Chronic arsenic poisoning is becoming an emerging epidemic in Asia. Epidemiological studies have shown that chronic arsenic poisoning through ingestion of arsenic-contaminated water is associated with various cardiovascular diseases in dose-response relationships. These cardiovascular disorders include carotid atherosclerosis detected by ultrasonography, impaired microcirculation, prolonged QT interval and increased QT dispersion in electrocardiography, and clinical outcomes such as hypertension, blackfoot disease (a unique peripheral vascular disease endemic in southwestern Taiwan), coronary artery disease and cerebral infarction. Chronic arsenic poisoning is an independent risk factor for cardiovascular disease. The adverse cardiovascular effects of long-term arsenic exposure may be persistent and/or irreversible. Arsenic-induced cardiovascular diseases in human population may result from the interaction among genetic, environment and nutritional factors. The major adverse cardiovascular effect of chronic arsenic poisoning has been established qualitatively and quantitatively in the high arsenic exposure areas, but the low-dose effect of arsenic on cardiovascular diseases remains to be explored. Cardiovascular death is the major cause of mortality worldwide, and a small increased risk may imply a large quantity of excess mortality.

Background/purposeElevation of C-reactive protein (CRP) level is associated with increased risk of cardiovascular events. The 1059 G > C polymorphism in exon 2 of the CRP gene has been shown to affect plasma concentration of CRP. We want to elucidate the effect of this polymorphism on the development of coronary artery disease (CAD) among the Chinese population in Taiwan.MethodsWe scrutinized 536 patients undergoing coronary angiography (365 patients with CAD and 171 controls with patent coronaries) and evaluated the association of CRP gene 1059 G > C polymorphism with CAD. Genotyping of the polymorphism was performed by polymerase chain reaction and MaeIII restriction enzyme digestion.ResultsThe CC genotype was associated with lower plasma CRP concentration (GG, 6.5 ± 5.8; GC, 3.3 ± 4.4; CC, 2.3 ± 3.1 mg/L; p = 0.02). Subjects with CAD or myocardial infarction (MI) had significantly higher plasma CRP concentration than that in controls (CAD vs. controls, 8.9 ± 18.9 vs. 3.3 ± 7.2 mg/L; p < 0.001), while patients with MI showed higher CRP when compared to those with chronic stable angina (13.5 ± 22.9 vs. 5.2 ± 14.1 mg/L; p < 0.001). However, this polymorphism was not associated with CAD in our population.ConclusionOur data suggest that human CRP gene 1059 G > C polymorphism is associated with plasma CRP concentration among Chinese in Taiwan receiving coronary angiography.

Acute encephalitis is a common CNS infectious disease in children. However, there are limited studies concerning about the correlation between the clinical evaluations and neurological outcome. To investigate the value of neurological evaluations, and the correlation between these evaluations and neurological outcomes of acute encephalitis, in the present study we retrospectively evaluated the neurological outcome of 0- to 16-year-old children with encephalitis or meningoencephalitis between 1999 and 2000. Of 101 children enrolled, 4 died and 25 had other neurological sequelae, including epilepsy, headache, developmental delay, and emotional or behavioral changes during the 5 years of follow-up. The causative organisms in patients with neurological sequelae were herpes virus (HSV) 2/2 (100%), influenza 2/3 (67%), mycoplasma 5/12 (42%), and enterovirus 71 2/7 (29%). The important predictors for adverse outcomes were focal neurological signs, multiple seizures or status epilepticus on admission, leukopenia, focal slow waves or continuous generalized delta waves in electroencephalography (EEG), and focal cortical parenchymal hyperintensity in the magnetic resonance imaging (MRI) (p

Prenatal diagnosis of fetal growth restriction (FGR) is very important, as FGR may have increased risks with perinatal morbidity and mortality. Fetal humerus dysplasia is associated with a variety of congenital syndromes and FGR. For the assessment of the efficacy of fetal humerus volume in predicting FGR, we undertook a prospective cross-sectional study using quantitative three-dimensional (3D) ultrasound (US). In total, 42 fetuses with FGR and 258 fetuses without FGR were included for the humerus volume assessment in utero by 3D US. All the fetuses were singletons and were followed up to delivery to determine whether they were complicated with FGR or not. Our results revealed that fetal humerus volume assessed by 3D US can differentiate fetuses with FGR from fetuses without FGR well. The best predicting threshold for FGR is at the 10th percentile by humerus volume. Using the 10th percentile as the cutoff, the sensitivity of fetal humerus volume in predicting FGR was 97.6%, specificity 87.2%, positive predictive value 55.4%, negative predictive value 99.6% and accuracy 88.7%. In conclusion, fetal humerus volume assessed by quantitative 3D US can be used to predict FGR prenatally. We believe fetal humerus volume assessment by 3D US would be a useful test in detecting fetuses with FGR.

PURPOSE: Allelic loss at chromosome 4q21-23 occurs frequently in human hepatocellular carcinoma, and the putative tumor suppressor gene (TSG) has not yet been identified. We studied the Fas-associated phosphatase-1 (FAP-1) gene as a potential candidate TSG in this region. EXPERIMENTAL DESIGN: The expression level of FAP-1 RNA in hepatocellular carcinomas was evaluated by RNase protection and quantitative PCR. Sodium bisulfite modification and subsequent single-strand conformational polymorphism and sequence analyses were used to assay the methylation of CpGs at FAP-1 promoter. Direct sequencing of the FAP-1 coding region was conducted for detecting the genetic mutations. Two common single nucleotide polymorphisms of FAP-1 were selected for evaluating their association with the hepatocellular carcinoma trait in sporadic and familial hepatocellular carcinomas. Moreover, the functional effect of FAP-1 on cellular proliferation has been evaluated by small interfering RNA approach. RESULTS: Around 50% of hepatocellular carcinomas showed significantly decreased expression of FAP-1 compared with the corresponding nontumorous liver tissues. In most cases, the RNA level was well correlated with the methylation status of promoter CpGs, suggesting that the promoter methylation may contribute to the down-regulation. Several genetic mutations of FAP-1 have been identified in hepatocellular carcinomas. The G/G genotype of FAP-1 cSNP6304 was significantly associated with the increased risk of multiplex familial hepatocellular carcinomas (odds ratio, 2.44; 95% confidence interval, 1.19-5.01). Finally, knockdown expression of FAP-1 was shown to enhance the cellular proliferation in PLC5 cells. CONCLUSIONS: FAP-1 could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation. The genetic mutations and polymorphisms may also confront with the higher hepatocellular carcinoma risk. These results first suggested FAP-1 as a putative TSG in hepatocarcinogenesis.

This article presents a simple method for constructing a singleton fuzzy model from a given set of input/output data. The method consists of three computational steps: the initial phase, the growth phase, and the optional refining phase. The universe of discourse and two linguistic terms for each input variable and a rule base are established during the initial phase. Additional linguistic terms and rules are then appended sequentially during the growth phase to modify the model structure and to elevate the performance. During the optional refining phase the overall modelling performance can be further improved by adjusting the singleton outputs of the rule set in the sense of least squares. The proposed identification method can simultaneously provide an appropriate model structure and parameters without any time-consuming optimisation. Several numerical examples demonstrate the effectiveness of the proposed identification method.

Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (

There has been significant progress recently in the clinical investigation of atopic dermatitis (AD), especially in the recognition of aeroallergens as aggravating factors in AD. However, sensitization to food allergens and aeroallergens in children with AD has not been fully studied.To evaluate the correlation between age and allergens in children with AD.A retrospective cross-sectional study was performed between January 1, 1999, and December 31, 2002, on 262 children with a definitive diagnosis of AD aged 0 to 16 years. Comparison of 3 age groups (2 years, 2-5 years, and5 years) with the correlation of food allergens and aeroallergens using the CAP-FEIA test was made using linear regression and logistic regression analyses.In children younger than 2 years, AD was associated with food allergens. In children aged 2 to 5 years, both food allergens and aeroallergens played an important role. In children older than 5 years, only elevated aeroallergen specific IgE levels were noted (P.02). Age correlated negatively with food allergens and positively with aeroallergens after adjusting for sex (P.04). Sensitization to aeroallergens may correlate with acquisition of the respiratory symptoms of the atopic state.Food allergens may be the major trigger of AD in early life, after which the role of environmental aeroallergens become more important and may be associated with respiratory sensitization.

Adiponectin is an adipose-derived plasma protein. Recently the plasma adiponectin levels have been linked to most variables of metabolic syndrome (MS) and risk factors of coronary artery disease (CAD). However, its relation with blood pressure is yet unclear. Here we report the relationship between the plasma adiponectin levels and blood pressures in 68 female adolescents (age 16.1 +/- 1.8 yr). We found that the plasma adiponectin levels correlated significantly with both the systolic blood pressure (SBP) (gamma = -0.47, P = 0.000) and diastolic blood pressure (gamma = -0.30, P = 0.014). In linear regression models with adjustment for age and the other anthropometric or metabolic factors, only the SBP, but not the diastolic blood pressure, was independently related to the plasma adiponectin levels. The mean plasma adiponectin levels between the subjects in the lowest quartile of SBP (SBPor = 100 mm Hg) and those in the highest quartile (SBPor = 118 mm Hg) were significantly different (P = 0.035). In conclusion, the SBP is inversely related to the plasma adiponectin independent of the other variables of the MS and other risk factors of CAD in healthy adolescent females. This further strengthens the potential roles of adiponectin in the pathophysiology of MS and CAD.

BACKGROUND Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression. METHODS OPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription–polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis. RESULTS Osteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with α-fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high-grade HCC (P < 0.001), late-stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10-year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early-stage HCC, which has no vascular invasion and a lower early tumor recurrence than late-stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003). CONCLUSIONS OPN mRNA overexpression was correlated closely with high-grade, late-stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early-stage HCC. Cancer 2003;98:119–27. © 2003 American Cancer Society. DOI 10.1002/cncr.11487

YANG, WEI-SHIUNG, WEI-JEI LEE, TOHRU FUNAHASHI, SACHIYO TANAKA, YUJI MATSUZAWA, CHIA-LING CHAO, CHI-LING CHEN, TONG-YUAN TAI, AND LEE-MING CHUANG. Plasma adiponectin levels in overweight and obese Asians. Obes Res. 2002;10:1104 –1110. Objective: Hypoadiponectin has been documented in subjects with obesity, diabetes mellitus, or coronary heart disease, suggesting a potential use of plasma adiponectin in following the clinical progress in subjects with metabolic syndrome (MS). In this study, we investigated the plasma adiponectin levels in relation to the variables of MS among overweight/obese Asian subjects. Research Methods and Procedures: The plasma adiponectin, anthropometric and biochemical measurements, oral glucose tolerance tests (OGTT), and modified insulin suppression tests were performed on 180 overweight/obese Asian subjects [body mass index (BMI) 23 kg/m 2 ], including 47 subjects with morbid obesity (BMI 40 kg/m 2 ). Results: The plasma adiponectin levels negatively correlated with BMI, waist-to-hip ratio, fasting plasma glucose, insulin, triglyceride, uric acid levels, hyperinsulinemia, and glucose intolerance in OGTT, but positively with highdensity lipoprotein-cholesterol. In contrast, they were not related to blood pressure and total cholesterol. Moreover, insulin sensitivity, measured by quantitative insulin sensitivity check index (QUICKI) or in insulin suppression tests, significantly correlated with the plasma adiponectin levels. Among morbidly obese subjects, only the waist-to-hip ratio correlated with the plasma adiponectin levels. Using multivariate linear regression models, the area under curve of plasma glucose in OGTT and high-density lipoprotein-cholesterol among the overweight/obese subjects and WHR among the morbidly obese subjects were significantly related to the plasma adiponectin levels after adjustment for other variables. Discussion: In overweight/obese Asians, the plasma adiponectin levels significantly correlated with various indices of MS except hypertension. Whether the plasma adiponectin level could be a suitable biomarker for following the clinical progress of MS warrants further investigation.

OBJECTIVE—To examine whether the presence of diabetes alters the risk of acute urinary tract infection (UTI) in postmenopausal women. RESEARCH DESIGN AND METHODS—A case-control study of the Group Health Cooperative of Puget Sound (GHC), a staff-model nonprofit health maintenance organization in Washington State, was conducted. Subjects were women aged 55–75 years who had been members of GHC for at least 1 year and who had had an acute symptomatic UTI within the preceding month. Laboratory files were used to identify women with a urine culture that grew ≥105 colonies of a urinary pathogen. Medical records were reviewed to confirm the presence of acute, clinically symptomatic UTI. Control subjects were randomly selected from the GHC enrollment file, screened to remove women with recent UTI, and frequency matched to cases by age within 2 years. An interviewer ascertained self-reported clinician-diagnosed diabetes. Diagnosis of diabetes was confirmed by the GHC diabetes registry. A subsample of women underwent measurement of postvoid residual bladder volume (n = 748) and culture of vaginal flora (n = 454). RESULTS—Of the 901 case and 913 control subjects, diabetes was reported in 13.1 and 6.8%, respectively. The health plan diabetes registry confirmed the diagnosis in 92% of women who self-reported the condition. The age-adjusted odds ratio (OR) for UTI in relation to self-reported clinician-diagnosed diabetes was 2.2 (95% CI 1.6–3.0). Adjustment for frequency of sexual intercourse and history of UTI had little effect on this estimate. Compared with nondiabetic women, higher UTI odds were seen in subjects who used oral hypoglycemic agents (OR 2.9 [95% CI 1.7–5.1]) and insulin (2.6 [1.5–4.6]) but not in subjects with untreated diabetes or diabetes treated by lifestyle changes (1.3 [0.7–2.3]). No significant difference was seen in the OR for UTI in diabetic women with disease of shorter duration ( CONCLUSIONS—Diabetes under pharmacologic treatment is associated with increased risk of clinically apparent UTI in postmenopausal women.

Background — Long-term exposure to ingested arsenic has been documented to induce peripheral vascular disease, ischemic heart disease, and cerebral infarction in a dose-response relationship. This study further examined the biological gradient between ingested inorganic arsenic and carotid atherosclerosis. Methods and Results — We studied 199 male and 264 female adult residents from the southwestern area of endemic arseniasis in Taiwan. The extent of carotid atherosclerosis was assessed by duplex ultrasonography. Diabetes mellitus was determined by oral glucose tolerance test, hypertension by mercury sphygmomanometers, and serum lipid profiles by autoanalyzers. Information regarding the consumption of high-arsenic artesian well water, cigarette smoking, and alcohol consumption was obtained through standardized questionnaire interviews. Logistic regression analysis was used to estimate the odds ratio and its 95% CI of carotid atherosclerosis for various risk factors. Three indices of long-term exposure to ingested arsenic, including the duration of consuming artesian well water, the average arsenic concentration in consumed artesian well water, and cumulative arsenic exposure, were all significantly associated with prevalence of carotid atherosclerosis in a dose-response relationship. The biological gradient remained significant after adjustment for age, sex, hypertension, diabetes mellitus, cigarette smoking, alcohol consumption, waist-to-hip ratio, and serum levels of total cholesterol and LDL cholesterol. The multivariate-adjusted odds ratio was 3.1 (95% CI 1.3 to 7.4) for those who had a cumulative arsenic exposure of ≥20 mg/L-years compared with those without exposure to arsenic from drinking artesian well water. Conclusions — Carotid atherosclerosis is associated with ingested inorganic arsenic, showing a significant biological gradient.

Introduction This study aimed to determine the effect of combining positive airway pressure (PAP) therapy and mandibular advancement device (MAD) in patients with severe obstructive sleep apnea (OSA) who were pressure intolerant for PAP and were unresponsive to MAD. Methods This retrospective study reviewed the medical records of severe OSA patients with apnea-hypopnea index (AHI) ≥ 30/hr who were diagnosed between October 1, 2008 and June 30, 2014. Patients were initially treated with 2 weeks of PAP, and those who were intolerant to high-pressure PAP (≥15 cm H2O) were switched to 12 weeks of MAD, which is a monobloc designed at 75% of maximum protrusion. Patients who had high residual AHI (≥15/hr) on MAD underwent 12 weeks of combination therapy (CT) with MAD and CPAP and were enrolled in the present study. Enrolled subjects who completed the 12-week CT were followed-up until June 30, 2016. Results A total of 14 male patients were included. All three treatments effectively reduced AHI, oxygen desaturation index (ODI), and total sleep time with SpO2

Background Lipopolysaccharide-binding protein (LBP) has been reported to associate with metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease. Since chronic hepatitis C virus (HCV) infection is associated with metabolic derangements, the relationship between LBP and HCV deserves additional studies. This study aimed to determine the serum LBP level in subjects with or without HCV infection and investigate the change of its level after anti-viral treatments with or without interferon. Methods and Findings We recruited 120 non-HCV subjects, 42 and 17 HCV-infected subjects respectively treated with peginterferon α-2a/ribavirin and direct-acting antiviral drugs. Basic information, clinical data, serum LBP level and abdominal ultrasonography were collected. All the subjects provided written informed consent before being enrolled approved by the Research Ethics Committee of the National Taiwan University Hospital. Serum LBP level was significantly higher in HCV-infected subjects than non-HCV subjects (31.0 ± 8.8 versus 20.0 ± 6.4 μg/mL; p-value < 0.001). After multivariate analyses, LBP at baseline was independently associated with body mass index, hemoglobin A1c, alanine aminotransferase (ALT) and HCV infection. Moreover, the baseline LBP was only significantly positively associated with ALT and inversely with fatty liver in HCV-infected subjects. The LBP level significantly decreased at sustained virologic response (27.4 ± 6.6 versus 34.6 ± 7.3 μg/mL, p-value < 0.001; 15.9 ± 4.4 versus 22.2 ± 5.7 μg/mL, p-value = 0.001), regardless of interferon-based or -free therapy. Conclusions LBP, an endotoxemia associated protein might be used as an inflammatory biomarker of both infectious and non-infectious origins in HCV-infected subjects.

Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis.251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages.In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67).A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.