Cellular mechanisms underlying extraordinary sulfide tolerance in a crustacean holobiont from hydrothermal vents.

The shallow-water hydrothermal vent system of Kueishan Island has been described as one of the world's most acidic and sulfide-rich marine habitats. The only recorded metazoan species living in the direct vicinity of the vents is Xenograpsus testudinatus, a brachyuran crab endemic to marine sulfide-rich vent systems. Despite the toxicity of hydrogen sulfide, X. testudinatus occupies an ecological niche in a sulfide-rich habitat, with the underlying detoxification mechanism remaining unknown. Using laboratory and field-based experiments, we characterized the gills of X. testudinatus that are the major site of sulfide detoxification. Here sulfide is oxidized to thiosulfate or bound to hypotaurine to generate the less toxic thiotaurine. Biochemical and molecular analyses demonstrated that the accumulation of thiosulfate and hypotaurine is mediated by the sodium-independent sulfate anion transporter (SLC26A11) and taurine transporter (Taut), which are expressed in gill epithelia. Histological and metagenomic analyses of gill tissues demonstrated a distinct bacterial signature dominated by Epsilonproteobacteria. Our results suggest that thiotaurine synthesized in gills is used by sulfide-oxidizing endo-symbiotic bacteria, creating an effective sulfide-buffering system. This work identified physiological mechanisms involving host-microbe interactions that support life of a metazoan in one of the most extreme environments on our planet.

Designing the antimicrobial peptide with centrosymmetric and amphipathic characterizations for improving antimicrobial activity.

Antibiotic-resistant bacterial infections are becoming a serious health issue and will cause 10 million deaths per year by 2050. As a result, the development of new antimicrobial agents is urgently needed. Antimicrobial peptides (AMPs) are found in the innate immune systems of various organisms to effectively fend off invading pathogens. In this study, we designed a series of AMPs (THL-2-1 to THL-2-9) with centrosymmetric and amphipathic properties, through substituting different amino acids on the hydrophobic side and at the centrosymmetric position to improve their antimicrobial activity. The results showed that leucine as a residue on the hydrophobic side of the peptide could enhance its antimicrobial activity and that glutamic acid as a centrosymmetric residue could increase the salt resistance of the peptide. Thus, the THL-2-3 peptide (KRLLRELKRLL-NH2 ) showed the greatest antimicrobial activity (MIC90 of 16 µM) against Gram-negative bacteria and had the highest salt resistance and cell selectivity among all the designed peptides. In summary, the results of this study provide useful references for the design of AMPs to enhance antimicrobial activity.

Association between Cesarean section delivery and increased risk of childhood Kawasaki disease.

AIM: Cesarean section delivery is associated with microbiota disruption and immuno-dysregulation during childhood, but the association with Kawasaki disease remains uncertain. We aimed to evaluate the association between Cesarean section and Kawasaki disease. METHODS: We examined the association between Kawasaki disease between six and eighteen months and Cesarean section within a birth cohort of 15,796 mother-infant pairs in Taiwan. The associations were assessed with Poisson regression in the study population, in the 1:2 propensity score-matched subpopulation, and compared with febrile convulsion, trauma and accidents during the same interval as negative control outcomes. RESULTS: Cesarean section was found to increase the risk of Kawasaki disease among overall population (adjusted relative risk [aRR]: 2.22, 95 % confidence interval (CI): 1.14-4.34) and the matched subpopulation (aRR: 2.29, 95 % CI: 1.14-4.68 in PS-matched subpopulation). Meanwhile, there was no association between Cesarean section and the clinic visits for febrile convulsion, trauma and accidents. CONCLUSION: In conclusion, this study identified a potential association between Cesarean section delivery and a higher risk of Kawasaki disease during six-to eighteen months of the prospective birth cohort in Taiwan.

Associations Between Infant Developmental Delays and Secondhand Smoke Exposure Modified by Maternal Prepregnancy Overweight and Obesity Status.

INTRODUCTION: Secondhand smoke exposure during pregnancy has long been associated with adverse health outcomes in children, but only a few studies have examined its effect modifiers. In this study, we applied effect modification analysis for maternal prepregnancy weight status on detrimental neurodevelopmental effect of secondhand smoke exposure during pregnancy and infancy in a nationwide representative population. AIMS AND METHODS: Term singleton mother-infant pairs with nonsmoking mothers were included for main analysis (N = 15 987) from the Taiwan Birth Cohort Study (TBCS), and were further matched with propensity score (n = 5434). We extracted secondhand smoke exposure during pregnancy and infancy, and eight neurodevelopmental milestones from the responses in the baseline visit at 6 months, and 18-month follow-up of TBCS. The associations between secondhand smoke exposure and neurodevelopmental achievement were analyzed with multivariable logistic regression and Cox model. Propensity score weighting and matching were applied for high-versus-low analysis, and relative excess risk due to interaction were used to estimate effect modification. RESULTS: Higher secondhand smoke exposure was associated with increased likelihood of delayed milestone achievement across gross motor, fine motor, language-related, and social-related domains. The associations in fine motor domains remained observable in propensity score-weighted and -matched models. We identified additive interaction with self-reported maternal overweight and obesity status before pregnancy in milestone development for walking with support, scribbling, and waving goodbye. CONCLUSIONS: Secondhand smoke exposure during pregnancy and infancy were associated with delayed neurodevelopmental milestone achievement at 18 months, and the associations were modified by maternal prepregnancy overweight and obesity status. IMPLICATIONS: The study results suggested the association between maternal secondhand smoke exposure during pregnancy and infancy and delayed fine motor and language-related milestone achievement at 18 months in multivariable, propensity score weighting, and matching populations. The results of positive effect modifications for maternal prepregnancy overweight and obesity status suggested the importance of concurrent interventions on smoke-free environment and maternal health during pregnancy.

Intrauterine exposure to per- and polyfluoroalkyl substances may harm children's lung function development.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUA), are common persistent environmental organic pollutants. Animal studies have indicated that PFAS influence inflammatory responses and lung development. However, whether prenatal or childhood PFAS exposure affects children's lung function remains unclear. This study aimed to investigate both in utero exposure and childhood exposure to PFAS and the relationships between them and lung function development in childhood. METHODS: In total, 165 children were recruited from the Taiwan Birth Panel Study (TBPS). Cord blood plasma and children's serum were collected when they were eight years old. PFAS levels were analysed by ultra-high-performance liquid chromatography/tandem mass spectrometry. When these children reached eight years of age, we administered detailed questionnaires and lung function examinations. RESULTS: The mean concentrations of PFOA, PFOS, PFNA and PFUA in cord blood among the 165 study children were 2.4, 6.4, 6.0, and 15.4 ng/mL, respectively. The mean concentrations in serum from eight-year-olds were 2.7, 5.9, 0.6, and 0.3 ng/mL, respectively. At eight years of age, the mean FEV1 (forced expiratory volume per sec), FVC (forced vital capacity), PEF (peak expiratory flow) and FEV1/FVC values were 1679 mL, 1835 mL, 3846 mL/s and 92.0%, respectively. PFOA, PFOS, PFNA and PFUA levels in cord blood were inversely associated with FEV1, FVC and PEF values. The PFOS concentration in cord blood was the most consistently correlated with decreasing lung function before and after adjusting for confounding factors. The PFOS concentration was also significantly inversely correlated with lung function in subgroups with lower birth weight and allergic rhinitis. CONCLUSIONS: Our cohort study revealed that the concentrations of PFOA, PFOS, PFNA and PFUA were higher in cord blood than in serum from eight-year-olds. Some trends were also noted between intrauterine PFOS exposure and children's decreasing FEV1, FVC and PEF, especially in subgroups with lower birth weight and allergic rhinitis. Therefore, intrauterine PFAS exposure, especially PFOS, may play a vital role in lung development.

Associations between household incense burning and delayed motor development among preterm infants modified by gestational age and maternal educational status.

BACKGROUND: Household incense burning is a common ritual behavior in the Asia-Pacific region but has been associated with inferior developmental outcomes in term infants. We aimed to examine these associations among preterm infants. METHODS: Information from 1190 mother-infant pairs during 6- and 18-month follow-up to the Taiwan Birth Cohort Study was examined for associations between household incense burning exposure and infant neurodevelopmental milestone achievement using multivariable Cox proportional hazard model with propensity score weighting, along with stratified, sensitivity, and decomposition analysis. RESULTS: Household incense burning exposure was associated with delayed gross motor milestone achievement among all preterm infants according to the Cox model and after propensity score weighting. Meanwhile, associations for delayed development were found in gross motor domain milestones among late preterm infants, while fine motor domain delay was found among other preterm infants. Furthermore, the associations between household incense burning status and gross motor milestone delays were attenuated by the interaction between higher education level and household incense burning exposure status. CONCLUSIONS: Household incense burning exposure was associated with delays, and the motor domains affected differed according to degree of prematurity. These associations were modified by the attenuation upon higher maternal educational status and exposure status interaction.

Enhanced home palliative care could reduce emergency department visits due to non-organic dyspnea among cancer patients: a retrospective cohort study.

BACKGROUND: Dyspnea is a common trigger of emergency department visits among terminally ill and cancer patients. Frequent emergency department (ED) visits at the end of life are an indicator of poor-quality care. We examined emergency department visit rates due to dyspnea symptoms among palliative patients under enhanced home palliative care. METHODS: Our home palliative care team is responsible for patient management by palliative care specialists, residents, home care nurses, social workers, and chaplains. We enhanced home palliative care visits from 5 days a week to 7 days a week, corresponding to one to two extra visits per week based on patient needs, to develop team-based medical services and formulate standard operating procedures for dyspnea care. RESULTS: Our team cared for a total of 762 patients who exhibited 512 ED visits, 178 of which were due to dyspnea (mean ± SD age, 70.4 ± 13.0 years; 49.4% male). Dyspnea (27.8%) was the most common reason recorded for ED visits, followed by pain (19.0%), GI symptoms (15.7%), and fever (15.3%). The analysis of Group A versus Group B revealed that the proportion of nonfamily workers (42.9% vs. 19.4%) and family members (57.1% vs. 80.6%) acting as caregivers differed significantly (P < 0.05). Compared to the ED visits of the Group A, the risk was decreased by 30.7% in the Group B (P < 0.05). CONCLUSIONS: This study proves that enhanced home palliative care with two additional days per week and formulated standard operating procedures for dyspnea could significantly reduce the rate of ED visits due to non-organic dyspnea during the last 6 months of life.

Gluconeogenesis and glycogen metabolism during development of Pacific abalone, Haliotis discus hannai.

In lecithotrophic larvae, egg yolk nutrients are essential for development. Although yolk proteins and lipids are the major nutrient sources for most animal embryos and larvae, the contribution of carbohydrates to development has been less understood. In this study, we assessed glucose and glycogen metabolism in developing Pacific abalone, a marine gastropod mollusc caught and cultured in east Asia. We found that glucose and glycogen content gradually elevated in developing abalone larvae, and coincident expression increases of gluconeogenic genes and glycogen synthase suggested abalone larvae had activated gluconeogenesis and glycogenesis during this stage. At settling, however, glycogen sharply decreased, with concomitant increases in glucose content and expression of Pyg and G6pc, suggesting the settling larvae had enhanced glycogen conversion to glucose. A liquid chromatography-mass spectrometry (LC/MS)-based metabolomic approach that detected intermediates of these pathways further supported active metabolism of glycogen. Immunofluorescence staining and in situ hybridization suggested the digestive gland has an important role as glycogen storage tissue during settlement, while many other tissues also showed a capacity to metabolize glycogen. Finally, inhibition of glycolysis affected survival of the settling veliger larvae, revealing that glucose is, indeed, an important nutrient source in settling larvae. Our results suggest glucose and glycogen are required for proper energy balance in developing abalone and especially impact survival during settling.

Children's environmental health based on birth cohort studies of Asia (2) - air pollution, pesticides, and heavy metals.

The life style and child raising environment in Asia are quite different compared with Western countries. Besides, the children's environmental threats and difficulties in conducting studies could be different. To address children's environmental health in Asia area, the Birth Cohort Consortium of Asia (BiCCA) was co-established in 2011. We reviewed the mercury, polychlorinated biphenyls, perfluoroalkyl substances, phthalates, and environmental tobacco smoke in pervious based on birth cohort studies in Asia. The aim of this study was to summarize the traditional environmental pollution and the target subjects were also based on the birth cohort in Asia area. Environmental pollutants included air pollutants, pesticides focusing on organochlorine pesticides, diakylphosphates, and pyrethroid, and heavy metals including lead, arsenic, cadmium, manganese, vanadium, and thallium. Fetal growth and pregnancy outcomes, childhood growth and obesity, neurodevelopment and behavioral problems, and allergic disease and immune function were classified to elucidate the children's health effects. In total, 106 studies were selected in this study. The evidences showed air pollution or pesticides may affect growth during infancy or childhood, and associated with neurodevelopmental or behavioral problems. Prenatal exposure to lead or manganese was associated with neurodevelopmental or behavioral problems, while exposure to arsenic or cadmium may influence fetal growth. In addition to the harmonization and international collaboration of birth cohorts in Asia; however, understand the whole picture of exposure scenario and consider more discipline in the research are necessary.

Increased risk of ischemic stroke among women with bladder pain syndrome/interstitial cystitis: a cohort study from Taiwan.

AIM: Vascular factors are proposed in the etiology of bladder pain syndrome/interstitial cystitis (BPS/IC). In this study, we investigated the risk of stroke among women following a diagnosis of BPS/IC over 3 years of follow-up, compared to controls without a BPS/IC diagnosis. METHODS: This retrospective cohort study used data retrieved from the Taiwan "Longitudinal Health Insurance Database 2000." We identified 847 women who received a diagnosis of BPS/IC between January 1, 2001 and December 31, 2008 (study group) and 4,235 comparison women (women without a BPS/IC diagnosis matched on age and other selected demographic variables. All subjects were tracked for 3 years following the index date to identify those who received a diagnosis of stroke during follow-up. RESULTS: The stroke incidence rate was 20.86 (95% confidence interval (CI): 15.78-27.07) and 11.65 (95% CI: 9.88-13.64) per 1,000 person-years among the study and comparison cohorts, respectively. Cox regression analysis showed a stroke hazard ratio (HR) of 1.52 (95% CI: 1.09-2.14) in the BPS/IC group relative to the comparison group over 3-year follow-up, after adjusting for hypertension, diabetes, coronary heart disease, atrial fibrillation, hyperlipidemia, and chronic kidney disease. The adjusted HR of ischemic stroke was 1.52 (95% CI: 1.02-2.27). However, there was no significant difference between the two groups in hemorrhagic stroke risk. CONCLUSIONS: Our study demonstrates an association between BPS/IC and a subsequent ischemic stroke diagnosis among women in Taiwan.

Obstructive sleep apnea increases the risk of bladder pain syndrome/interstitial cystitis: a population-based matched-cohort study.

AIMS: Previous studies indicated a possible association between bladder pain syndrome/interstitial cystitis (BPS/IC) and sleep disorders including sleep abnormalities with delayed onset of sleep, waking up before needed, and snoring. Nevertheless, no previous study has reported the association between obstructive sleep apnea (OSA) and BPS/IC. In this retrospective cohort study, we examined the risk of BPS/IC among subjects with OSA during a 3-year follow-up in Taiwan using a population-based dataset. METHODS: This study comprised 2,940 study subjects with OSA, and 29,400 randomly selected comparison subjects. We individually followed-up each sampled subject (n = 32,340) for a 3-year period to identify those subjects who subsequently received a diagnosis of BPS/IC. A Cox proportional hazards regression model was constructed to estimate the risk of subsequent BPS/IC following a diagnosis of OSA. RESULTS: Incidences of BPS/IC during the 3-year follow-up period were 13.61 (95% confidence interval [CI] = 7.37-23.13) and 3.60 (95% CI = 2.06-4.39) for subjects with and those without OSA, respectively. After adjusting for diabetes, hypertension, coronary heart disease, obesity, hyperlipidemia, chronic pelvic pain, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, depression, panic disorder, migraines, sicca syndrome, allergies, endometriosis, asthma, tobacco use disorder, and alcohol abuse, the stratified Cox proportional hazards regressions revealed that the hazard ratio for BPS/IC among subjects with OSA was 3.71 (95% CI = 1.81-7.62, P < 0.001) that of comparison subjects. CONCLUSIONS: This study provides epidemiological evidence of a link between OSA and a subsequent BPS/IC diagnosis. We suggest that clinical practitioners treating subjects with OSA be alert to urinary complaints in this population.

Bladder pain syndrome/interstitial cystitis increase the risk of coronary heart disease.

AIM: Vascular factor was proposed as being involved in the etiology of bladder pain syndrome/interstitial cystitis (BPS/IC). However, few studies have attempted to investigate the relationship between BPS/IC and cardiovascular disease. This study aimed to investigate the risk of coronary heart disease (CHD) among BPS/IC subjects during a 3-year follow-up period. METHODS: Data for this retrospective matched-cohort study were retrieved from the Taiwan "Longitudinal Health Insurance Database 2000." There were 752 BPS/IC female subjects in the study cohort and 3,760 randomly selected female subjects in the comparison cohort. We individually tracked each subject for 3 years and identified each subject that received a subsequent diagnosis of CHD during that follow-up period. RESULTS: Results showed that incidence rates of CHD during the 3-year follow-up period were 19.50 (95% confidence interval (CI): 14.35-25.95) and 8.87 (95% CI: 7.25-10.74) per 1,000 person-years for the study and comparison cohorts, respectively. The Cox proportional hazards regression suggested that the hazard ratio for CHD in subjects with BPS/IC was 1.65 (95% CI: 1.09-2.48) within the 3-year follow-up period following the index date compared to the comparison subjects after adjusting for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, chronic kidney disease, bladder outlet obstruction, urinary tract infection, chronic pelvic pain, overactive bladder, and number of physician visits during the 3-year follow up period. CONCLUSIONS: Our study demonstrated an association between BPS/IC and a subsequent CHD diagnosis. We advise clinicians to screen subjects with BPS/IC for modifiable risk factors for CHD.

Low birth weight and environmental tobacco smoke increases the risk of wheezing in adolescents: a retrospective cohort study.

BACKGROUND: Low birth weight (LBW) and environmental tobacco smoke (ETS) exposure are each associated with wheezing in children. This study was designed to examine the combined association of LBW and ETS with wheezing. METHODS: A retrospective birth cohort analysis linked with a national survey of allergic disorders among 1,018,031 junior high school students in Taiwan (1995-1996) was analyzed. The reported incidence of wheezing (yes or no) and ETS exposure (4 categories: 0, 1-20, 21-40 and greater than or equal to 41 household cigarettes per day) were obtained from validated questionnaires. Multiple logistic regression models were used to assess the associations of interest. RESULTS: There were 844,003 (83%) subjects analyzed after the exclusion criteria. LBW was associated with an increased risk of reporting ever wheezing (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.01-1.16), current wheezing (OR = 1.09, 95% CI = 1.00-1.20) and wheezing with exercise (OR = 1.11, 95% CI = 1.02-1.21) within the smoke-free cohort. Higher ETS exposure correlated to a higher risk of wheezing (ever, current and with exercise). With ETS exposure, adolescents from the lowest birth weight cohorts were more likely to report wheezing (ever, current and with exercise). CONCLUSIONS: ETS and LBW each has been related to increasing public health risk for respiratory symptoms among adolescents. Furthermore, LBW may aggravate the risk among those exposed to ETS. LBW, ETS and associated respiratory impairments may deserve special attention as part of a comprehensive environmental health risk assessment directed toward prevention and intervention.

Percutaneous nephrolithotomy increases the risk of diabetes: a 5-year follow-up study.

OBJECTIVE: To examine the risk of diabetes mellitus within a 5-year period among patients with nephrolithiasis undergoing percutaneous nephrolithotomy . METHODS: A total of 304 patients who underwent percutaneous nephrolithotomy were included in the study cohort. A total of 3040 patients with nephrolithiasis who did not undergo percutaneous nephrolithotomy were used as a comparison cohort. All participants included in the present study were individually tracked for a 5-year period in order to identify those who developed diabetes mellitus during this timeframe. RESULTS: The incidence rate of diabetes mellitus was 3.03 per 100 person-years in participants who underwent percutaneous nephrolithotomy and 1.65 per 100 person-years in participants who did not undergo percutaneous nephrolithotomy. After adjusting for the participants' monthly income, geographic location, urbanization level, hypertension, hyperlipidemia and alcohol abuse/alcohol dependence syndrome, the hazard ratio of receiving a first diagnosis of diabetes mellitus during the 5-year follow-up period was 1.96 (95% confidence interval 1.40-2.77) for participants who underwent percutaneous nephrolithotomy. Furthermore, compared with extracorporeal shock wave lithotripsy or endoscopic intervention, participants who underwent percutaneous nephrolithotomy had a significantly increased hazard of developing diabetes mellitus (adjusted hazard ratio 1.79 for a percutaneous nephrolithotomy vs extracorporeal shockwave lithotripsy, and adjusted hazard ratio 1.71 for a percutaneous nephrolithotomy vs an endoscopic intervention). CONCLUSIONS: The present results suggest an association between patients with nephrolithiasis who undergo a percutaneous nephrolithotomy and a subsequent diabetes mellitus diagnosis.

Association between parabens exposure and neurodevelopment in children.

OBJECTIVE: Parabens are a group of substances commonly employed as antimicrobial preservatives. The effect of parabens on the development of neurotoxicity in children is still controversial. This study aimed to explore the associations between parabens exposure and children's neurodevelopmental performance, emphasizing potential sex differences and the combined effects of parabens. METHODS: We used the long-term follow-up study of Taiwanese generation, Taiwan Birth Panel Study II (TBPS II). We recruited the group of children at 6-8 years old. And, we measured parabens in children urine, including methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP). Children's attention-related performance was evaluated using the Conners Kiddie Continuous Performance Test 2nd Edition (K-CPT 2). The study employed both linear regression and mixture analysis quantile g-computation (QGC) methods to discern associations. A stratified analysis by sex and QGC was implemented to delve deeper into the cumulative effects of parabens. RESULTS: A total of 446 subjects completed both the parabens analysis and the K-CPT 2 survey. The overall association between parabens and neurodevelopmental performance was not pronounced, but discernible sex differences emerged. In the single pollutant analysis, elevated PP concentrations were associated with higher K-CPT 2 scores particularly in detectability (d') (ß = 0.92 [95 % CI = 0.15 to 1.69]) and commissions (ß = 0.95 [95 % CI = 0.12 to 1.78]), among girls. Further, in the mixture analysis, a significant association between PP and detectability (d') was observed in girls (ß = 1.68 [95 % CI = 0.11 to 3.26]). CONCLUSIONS: This study identified sex-specific associations between parabens and attention performance. Consistent outcomes across single and mixture analysis methods. Further research is crucial to clarify these causal associations.

Gluconeogenesis in the extraembryonic yolk syncytial layer of the zebrafish embryo.

Yolk-consuming (lecithotrophic) embryos of oviparous animals, such as those of fish, need to make do with the maternally derived yolk. However, in many cases, yolk possesses little carbohydrates and sugars, including glucose, the essential monosaccharide. Interestingly, increases in the glucose content were found in embryos of some teleost fishes; however, the origin of this glucose has been unknown. Unveiling new metabolic strategies in fish embryos has a potential for better aquaculture technologies. In the present study, using zebrafish, we assessed how these embryos obtain the glucose. We employed stable isotope (13C)-labeled substrates and injected them to the zebrafish embryos. Our liquid chromatography-mass spectrometry-based isotope tracking revealed that among all tested substrate, glutamate was most actively metabolized to produce glucose in the zebrafish embryos. Expression analysis for gluconeogenic genes found that many of these were expressed in the yolk syncytial layer (YSL), an extraembryonic tissue found in teleost fishes. Generation 0 (G0) knockout of pck2, a gene encoding the key enzyme for gluconeogenesis from Krebs cycle intermediates, reduced gluconeogenesis from glutamate, suggesting that this gene is responsible for gluconeogenesis from glutamate in the zebrafish embryos. These results showed that teleost YSL undergoes gluconeogenesis, likely contributing to the glucose supplementation to the embryos with limited glucose source. Since many other animal lineages lack YSL, further comparative analysis will be interesting.

A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver.

UNLABELLED: The mechanisms that mediate the initiation and development of intrahepatic cholangiocarcinoma (ICC) associated with hepatitis B and C virus (HBV and HCV, respectively) infection remain largely unclear. In this study we conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins in zebrafish livers, which caused fibrosis and consequently contributed to ICC formation at the age of 3 months. Suppressing the transgene expression by doxycycline (Dox) treatment resulted in the loss of ICC formation. The biomarker networks of zebrafish ICC identified by transcriptome sequencing and analysis were also frequently involved in the development of human neoplasms. The profiles of potential biomarker genes of zebrafish ICC were similar to those of human cholangiocarcinoma. Our data also showed that the pSmad3L oncogenic pathway was activated in HBx and HCP-induced ICC and included phosphorylation of p38 mitogen-activated proteinbase (MAPK) and p44/42 mitogen-activated protein kinase (ERK1/2), indicating the association with transforming growth factor beta 1 (TGF-ß1) signaling pathway in ICC. Bile duct proliferation, fibrosis, and ICC were markedly reduced by knockdown of TGF-ß1 by in vivo morpholinos injections. CONCLUSION: These results reveal that TGF-ß1 plays an important role in HBx- and HCP-induced ICC development. This in vivo model is a potential approach to study the molecular events of fibrosis and ICC occurring in HBV and HCV infection.

Obstructive sleep apnea and increased risk of glaucoma: a population-based matched-cohort study.

PURPOSE: Previous studies had reported an increased prevalence of glaucoma in patients with obstructive sleep apnea (OSA). However, the risk of open-angle glaucoma (OAG) among patients with OSA remains unclear. Using a nationwide, population-based dataset in Taiwan, this study aimed to examine the prevalence and risk of OAG among patients with OSA during a 5-year follow-up period after a diagnosis of OSA. DESIGN: A retrospective, matched-cohort study. PARTICIPANTS AND CONTROLS: This study used data sourced from the Longitudinal Health Insurance Database 2000. We included 1012 subjects with OSA in the study cohort and randomly selected 6072 subjects in the comparison group. METHODS: Each subject in this study was individually traced for a 5-year period to identify those subjects who subsequently received a diagnosis of OAG. Cox proportional hazards regression was performed to calculate the 5-year risk of OAG between the study and comparison cohorts. MAIN OUTCOME MEASURES: The incidence and risk of OAG between the study and comparison groups. RESULTS: During the 5-year follow-up period, the incidence rate per 1000 person-years was 11.26 (95% confidence interval [CI], 8.61-14.49) and 6.76 (95% CI, 5.80-7.83) for subjects with and without OSA, respectively. After adjusting for monthly income, geographic region, diabetes, hypertension, coronary heart disease, obesity, hyperlipidemia, renal disease, hypothyroidism, and the number of outpatient visits for ophthalmologic care during the follow-up period, stratified Cox proportional hazards regression revealed that the hazard ratio for OAG within the 5-year period for subjects with OSA was 1.67 (95% CI, 1.30-2.17; P<0.001) that of comparison subjects. CONCLUSIONS: Our results suggest that OSA is associated with an increased risk of subsequent OAG diagnosis during a 5-year follow-up period. FINANCIAL DISCLOSURES(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

A case-control study on the association between bladder cancer and prior bladder calculus.

BACKGROUND: Bladder calculus is associated with chronic irritation and inflammation. As there is substantial documentation that inflammation can play a direct role in carcinogenesis, to date the relationship between stone formation and bladder cancer (BC) remains unclear. This study aimed to examine the association between BC and prior bladder calculus using a population-based dataset. METHODS: This case-control study included 2,086 cases who had received their first-time diagnosis of BC between 2001 and 2009 and 10,430 randomly selected controls without BC. Conditional logistic regressions were employed to explore the association between BC and having been previously diagnosed with bladder calculus. RESULTS: Of the sampled subjects, bladder calculus was found in 71 (3.4%) cases and 105 (1.1%) controls. Conditional logistic regression analysis revealed that the odds ratio (OR) of having been diagnosed with bladder calculus before the index date for cases was 3.42 (95% CI = 2.48-4.72) when compared with controls after adjusting for monthly income, geographic region, hypertension, diabetes, coronary heart disease, and renal disease, tobacco use disorder, obesity, alcohol abuse, and schistosomiasis, bladder outlet obstruction, and urinary tract infection. We further analyzed according to sex and found that among males, the OR of having been previously diagnosed with bladder calculus for cases was 3.45 (95% CI = 2.39-4.99) that of controls. Among females, the OR was 3.05 (95% CI = 1.53-6.08) that of controls. CONCLUSIONS: These results add to the evidence surrounding the conflicting reports regarding the association between BC and prior bladder calculus and highlight a potential target population for bladder cancer screening.

In utero exposure to environmental lead and manganese and neurodevelopment at 2 years of age.

BACKGROUND AND OBJECTIVE: Manganese, lead, arsenic and mercury are common neurotoxic metals in the environment. Nonetheless, the relationship between prenatal exposure to low doses of neurotoxic metals and neurodevelopment in children is not clear. The objective of this study was to explore the relationship between in utero exposure to environmental neurotoxic metals and neurodevelopment at 2 years of age. METHODS: The population of this study came from the Taiwan Birth Panel Study. We included 230 pairs of non-smoking mothers without any occupational exposure and their singleton full-term children. The information about exposure during pregnancy was obtained using a structured questionnaire, and the manganese, lead, arsenic and mercury levels in umbilical cord blood samples were analyzed using inductively coupled plasma mass spectrometry. We used the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) to evaluate the developmental status of each child at 2 years of age, and we examined the association of in utero exposure to environmental metals and neurodevelopment using linear regression models. RESULTS: The median concentrations of manganese, lead, arsenic and mercury in the cord blood samples in this study were 47.90 µg/L (range, 17.88-106.85 µg/L), 11.41 µg/L (range 0.16-43.22 µg/L), 4.05 µg/L (range, 1.50-12.88 µg/L) and 12.17 µg/L (range, 1.53-64.87 µg/L), respectively. After adjusting for maternal age, infant gender, environmental tobacco smoke during pregnancy and after delivery, Home Observation for Measurement of the Environment Inventory results, and arsenic and mercury levels in cord blood, we found that manganese and lead levels above the 75th percentile had a significant adverse association with the overall (ß=-7.03, SE=2.65, P=0.0085), cognitive (ß=-8.19, SE=3.17, P=0.0105), and language quotients (ß=-6.81, SE=2.73, P=0.0133) of the CDIIT. CONCLUSIONS: In utero exposure to environmental manganese and lead may have an adverse association with neurodevelopment at 2 years of age, and there is an interaction effect between the manganese and lead levels in the cord blood that could aggravate the effect.