Transcriptome-wide analyses of piRNA binding sites suggest distinct mechanisms regulate piRNA binding and silencing in C. elegans.

PIWI-interacting RNAs (piRNAs) protect genome integrity by silencing transposon mRNAs and some endogenous mRNAs in various animals. However, C. elegans piRNAs only trigger gene silencing at select predicted targeting sites, suggesting additional cellular mechanisms regulate piRNA silencing. To gain insight into possible mechanisms, we compared the transcriptome-wide predicted piRNA targeting sites to the in vivo piRNA binding sites. Surprisingly, while sequence-based predicted piRNA targeting sites are enriched in 3' UTRs, we found that C. elegans piRNAs preferentially bind to coding regions (CDS) of target mRNAs, leading to preferential production of secondary silencing small RNAs in the CDS. However, our analyses suggest that this CDS binding preference cannot be explained by the action of antisilencing Argonaute CSR-1. Instead, our analyses imply that CSR-1 protects mRNAs from piRNA silencing through two distinct mechanisms-by inhibiting piRNA binding across the entire CSR-1 targeted transcript, and by inhibiting secondary silencing small RNA production locally at CSR-1 bound sites. Together, our work identifies the CDS as the critical region that is uniquely competent for piRNA binding in C. elegans. We speculate the CDS binding preference may have evolved to allow the piRNA pathway to maintain robust recognition of RNA targets in spite of genetic drift. Together, our analyses revealed that distinct mechanisms are responsible for restricting piRNA binding and silencing to achieve proper transcriptome surveillance.

APOE-ε4 Alleles Modify the Decline of MMSE Scores Associated With Time-Dependent PM2.5 Exposure: Findings From a Community-Based Longitudinal Cohort Study.

OBJECTIVE: Limited research has explored the long-term effect of reduced PM2.5 exposure on cognitive function. This study aimed to investigate the effects of time-dependent PM2.5 exposure and the interactions of PM2.5 and aging on declines in Mini-Mental State Examination (MMSE) scores, in carriers and non-carriers of the APOE-ε4 allele. METHODS: Participants aged over 60 were recruited for this cohort study, undergoing MMSE tests twice from the Taiwan Biobank Program from 2008 to 2020. Participants with dementia or baseline MMSE scores <24 were excluded. Annual PM2.5 levels were estimated using a hybrid kriging/land use regression model with extreme gradient boosting, treated as a time-dependent variable. Generalized estimating equations were used to assess the impacts of repeated PM2.5 on MMSE decline, further stratified by the presence of APOE-ε4 alleles. RESULTS: After follow-up, 290 participants out of the overall 7,000 community residents in the Biobank dataset demonstrated incidences of MMSE declines (<24), with an average MMSE score decline of 1.11 per year. Participants with ε4/ε4 alleles in the APOE gene had significantly 3.68-fold risks of MMSE decline. High levels of PM2.5 across all visits were significantly associated with worsening of scores on the overall MMSE. As annual levels of PM2.5 decreased over time, the impact of PM2.5 on MMSE decline also slowly diminished. CONCLUSION: Long-term PM2.5 exposure may be associated with increased risk of MMSE decline, despite improvements in ambient PM2.5 levels over time. Validation of these results necessitates a large-scale prospective cohort study with more concise cognitive screening tools.

Determination of potential sources of heavy metals in patients with urothelial carcinoma in central Taiwan: a biomonitoring case-control study.

The clarification of possible exposure sources of multiple metals to identify associations between metal doses and urothelial carcinoma (UC) risk is currently limited in the literature. We sought to identify the exposure sources of 10 metals (Vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, cadmium, and lead) using principal component analysis (PCA) and then linked various principal component (PC) scores with environmental characteristics, including smoking-related indices, PM2.5, and distance to the nearest bus station. In addition, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and DNA hypomethylation markers (5-methyl-2'-deoxycytidine levels; %5-MedC) were investigated in combination with UC risks. We conducted this hospital-based case control study in 359 UC patients with histologically confirmed disease and 718 controls. All data were collected from face-to-face interviews and medical records. Approximately 6 mL blood was collected from participants for analysis of multiple heavy metal and DNA methylation in leukocyte DNA. Further, a 20 mL urine sample was collected to measure urinary cotinine and 8-OHdG levels. In addition, average values for PM2.5 for individual resident were calculated using the hybrid kriging/land-use regression model. In UC patients, significantly higher cobalt, nickel, copper, arsenic, and cadmium (µg/L) levels were observed in blood when compared with controls. Three PCs with eigenvalues > 1 accounted for 24.3, 15.8, and 10.7% of UC patients, and 26.9, 16.7, and 11.1% of controls, respectively. Environmental metal sources in major clusters were potentially associated with industrial activities and traffic emissions (PC1), smoking (PC2), and food consumption, including vitamin supplements (PC3). Multiple metal doses were linked with incremental urinary 8-OHdG and DNA hypomethylation biomarkers. For individuals with high PC1 and PC2 scores, both displayed an approximate 1.2-fold risk for UC with DNA hypomethylation.In conclusion, we provide a foundation for health education and risk communication strategies to limit metal exposure in environment, so that UC risks can be improved potentially.

Association and mediation analyses among multiple metals exposure, plasma folate, and community-based impaired estimated glomerular filtration rate in central Taiwan.

BACKGROUND: Chronic kidney disease (CKD) is increasing, with heavy metal exposure an important risk factor. Additionally, the antioxidant folic acid has been studied for reducing blood arsenic levels and related tissue damage. Therefore, we explored the association and mediation effects among various heavy metal levels in blood, plasma folate, other CKD risk factors, and impaired estimated glomerular filtration rate (eGFR). METHODS: We constructed a community-based cross-sectional study from the Human Biomonitoring and Environmental Health Program in central Taiwan. A total of 1643 participants had lived locally for > 5 years, > 40 years old, and completely received health examinations and biospecimen collections. Impaired eGFR was defined as one single eGFR < 60 mL/min/1.73 m2. Plasma folate and metal levels in blood were determined, as well as urinary 8-hydroxy-2'-deoxyguanosine as an oxidative stress marker. Generalized weighted quantile sum (WQS) regression analysis was used to calculate a WQS score, reflecting overall body-burden of multiple metals (arsenic, cadmium, chromium, nickel, and lead) in blood. RESULTS: Impaired eGFR was identified in 225 participants. Participants with high WQS scores had increased risk of impaired eGFR (odds ratio = 1.67; 95% confidence interval [CI]: 1.34, 2.07). Of five metals, arsenic, lead, and cadmium were weighted highly in impaired eGFR. Participants with high WQS and folate insufficiency (< 6 ng/mL) had 2.38-fold risk of impaired eGFR compared to those with low WQS and high folate (≥6 ng/mL) (95% CI: 1.55, 5.17). Similar increased 4.16-fold risk of impaired eGFR was shown in participants with high WQS and uric acid levels (95% CI: 2.63, 6.58). However, there were no significant WQS-folate (p = 0.87) or WQS-uric acid (p = 0.38) interactions on impaired eGFR risk. As a mediator, uric acid contributed 24% of the association between WQS score and impaired eGFR risk (p < 0.0001). However, no mediation effect of plasma folate was observed. CONCLUSION: WQS analysis could be applied to evaluate the joint effects of multiple metals exposure. High WQS scores may influence impaired eGFR risk through increased uric acid levels. A large-scale and prospective cohort study is necessary to validate these results and demonstrate any causal relationship.

Relationships of multiple metals exposure, global DNA methylation, and urothelial carcinoma in central Taiwan.

The relationship between heavy metal exposure and human health has been investigated mostly for individual metals, failing to consider their potential interactions. In this study, we assessed the joint effects of multiple metals using generalized weighted quantile sum (WQS) regression on the risk of urothelial carcinoma (UC). Also, we performed mediation analysis to evaluate the mediator %5-MedC in DNA involved in the mechanism of urothelial carcinogenesis. We conducted a hospital-based case-control study of 355 UC patients and 710 controls, where diagnosis of UC was histologically confirmed. All data were collected from face-to-face interviews and medical records. Also, we measured six metals and 8-OHdG in urine samples along with %5-MedC in peripheral blood. Ni and Pb levels increased with UC risk in single-pollutant analysis using traditional logistic regression, and similar results were obtained in multi-pollutant analysis, where all metals analyzed were considered. In WQS analysis, the weights of Ni (27%), Pb (20%), Cr (18%), and Co (16%) predominated in the metal mixture index. WQS score and UC risk showed odds ratios of 1.65 (95%CI: 1.26, 2.15) and 1.43 (95%CI: 1.00, 2.05) for a linear and non-linear relationship, respectively. Finally, we did not observe a natural indirect effect of %5-MedC in DNA; however, a marginal effect of WQS score and natural direct effect were still found after considering a natural indirect effect. In conclusion, positive associations between WQS scores and increased risk of UC were observed. Interactions of multiple metals should be considered in assessing human health risk.

The effects of traffic-related air pollutants on chronic obstructive pulmonary disease in the community-based general population.

BACKGROUND: Previous studies have shown inconsistent results regarding the impact of traffic pollution on the prevalence of chronic obstructive pulmonary disease (COPD). Therefore, using frequency matching and propensity scores, we explored the association between traffic pollution and COPD in a cohort of 8284 residents in a major agricultural county in Taiwan. METHODS: All subjects completed a structured questionnaire interview and health checkups. Subjects with COPD were identified using Taiwan National Health Insurance Research Databases. A hybrid kriging/LUR model was used to identify levels of traffic-related air pollutants (PM2.5 and O3). Multiple logistic regression models were used to calculate the prevalence ratios (PRs) of COPD and evaluate the role played by traffic-related indices between air pollutants and COPD. The distributed lag nonlinear model was applied in the analysis; we excluded current or ever smokers to perform the sensitivity analysis. RESULTS: Increased PRs of COPD per SD increment of PM2.5 were 1.10 (95% CI 1.05-1.15) and 1.25 (95% CI 1.13-1.40) in the population with age and sex matching as well as propensity-score matching, respectively. The results of the sensitivity analysis were similar between the single and two pollutant models. PM2.5 concentrations were significantly associated with traffic flow including sedans, buses, and trucks (p < 0.01). The higher road area and the higher PM2.5 concentrations near the subject's residence correlated with a greater risk of developing COPD (p for interaction < 0.01). CONCLUSIONS: Our results suggest that long-term exposure to traffic-related air pollution may be positively associated with the prevalence of COPD.

Exploring the factors related to adolescent health literacy, health-promoting lifestyle profile, and health status.

BACKGROUND: Health literacy has been concerned a key factor for determining the use of health information and promoting health. The study aimed to explore adolescent health literacy, health-promoting lifestyle profile, and health status and related factors. METHODS: A cross-sectional study design was used; 918 first year junior college students were recruited in Taiwan. The measurements were the Chinese Health Literacy Survey Questionnaire (HLS-C-Q), the Chinese Health-Promoting Lifestyle Profile (HPLP-S), and the Health Status Questionnaire. RESULTS: The mean score for health literacy was 36.15 (±6.21), with 30.17% of the participants having insufficient or problematic health literacy. Further, 19.9% of participants were obese and 11.2% experienced emotional instability. Health literacy and health-promoting lifestyle profile showed significant positive and negative correlations with perceived health status and depression, respectively (p < 0.05). An exercise frequency of ≥3 times/week was a predictor of health literacy, health-promoting lifestyle profile, and emotional stability. CONCLUSIONS: Adolescent health literacy, health-promoting lifestyle profile, and health status require careful consideration. In adolescents, developing regular exercise may increase health literacy, thereby developing healthy lifestyle profiles and ameliorating obesity and depression-related issues.

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.

Is combined peritoneal dialysis and hemodialysis redundant? A nationwide study from Taiwan.

BACKGROUND: Combined peritoneal dialysis (PD) and hemodialysis (HD) therapy (combined therapy) has numerous clinical benefits and should be emphasized for PD patients encountering technique failure. METHODS: This 12-year nationwide retrospective study was conducted to compare long-term outcomes (including admission and mortality risks) between combined therapy patients (combined group) and patients directly transferred from PD to HD (transfer group). RESULTS: All 12,407 incidental PD patients from 2000 to 2010 were enrolled and followed up until the end of 2011. A total of 688 patients in the combined group and 688 patients in the transfer group were selected after 1:1 frequency matching based on age, sex, and PD duration. The overall admission and mortality risks of the two groups were comparable in a Cox proportional hazards model (adjusted hazard ratio [HR] = 1.06 [95% confidence interval (CI) = 0.95-1.19] and 1.02 [95% CI = 0.80-1.30]), respectively). Compared with the transfer group, combined group patients with recent peritonitis or frequent hemodialysis (four HD sessions per month) had significantly higher risk of admission while combined group patients without peritonitis had significantly lower risk. The number of incidents in the combined group increased over time. On average, patients stayed on combined therapy for 2 years. CONCLUSIONS: Combined therapy (two HD sessions per month) is not redundant but a rational and cost-effective treatment, particularly for patients without recent peritonitis. Dialysis staff should be familiar with the advantages and disadvantages of combined therapy and consider it an essential part of integrated dialysis care.

Plasma selenium influences arsenic methylation capacity and developmental delays in preschool children in Taiwan.

Inefficient arsenic methylation capacity has been associated with developmental delay in preschool children. Selenium has antioxidant and anti-inflammatory properties that protect experimental animals from chemically induced neurotoxicity. The present study was designed to explore whether plasma selenium levels affects arsenic methylation capacity related to developmental delay in preschool children. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 178 children with a developmental delay and 88 children without a delay were recruited. High-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry were used to determine urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV). Plasma selenium levels were measured by inductively coupled plasma mass spectrometry. As results, plasma selenium concentration was significantly inversely associated with the odds ratio (OR) of developmental delay. Plasma selenium concentration was positively associated with arsenic methylation capacity [percentage of inorganic arsenic and percentage of MMAV (MMAV%) decreased, and percentage of DMAV (DMAV%) increased]. High plasma selenium concentration and high DMA% significantly and additively interacted to decrease the OR of developmental delay; the OR and 95% confidence interval were 0.40 (0.18-0.90). This is the first study to show a combined dose-response effect of plasma selenium concentration and that efficient arsenic methylation capacity decreased the OR of developmental delay in preschool children.

Measurement of urinary arsenic profiles and DNA hypomethylation in a case-control study of urothelial carcinoma.

Environmental exposure to arsenic may be involved in the disturbance of DNA hypomethylation. The aim of this study is the first to explore the effect of interactions of urinary total arsenic levels, arsenic methylation capacity, 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma folate, and global 5-methyl-2'-deoxycytidine (5-MedC) levels on the risk of urothelial carcinoma (UC). A hospital-based case-control study was constructed. The research involved the histological recruitment and pathological verification of 178 UC patients and 356 age-/sex-matched controls without prior history of cancer. Arsenic species were determined by high-performance liquid chromatography (HPLC)-hydride generation and atomic absorption. 5-MedC levels were detected by HPLC and triple-quadrupole mass spectrometry (MS). 8-OHdG was processed by an online solid-phase extraction LC-MS/MS. Plasma folate levels were measured using the chemiluminescent technology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multiple logistic regression analysis. Results indicate that the high levels of total urinary arsenic, inorganic arsenic percentage, and 8-OHdG and the low levels of DMA % and plasma folate were independent factors of UC. In addition, global 5-MedC levels in the first quartile versus fifth quartile significantly increased the twofold OR of UC after potential factors were adjusted (95% CI:1.10-4.03). The interaction of 5-MedC level and high total arsenic level, insufficient arsenic capacity, high 8-OHdG, and low folate levels was insignificant. Results of stepwise logistic regression analysis indicate that high total urinary arsenic levels (Q3 versus Q1), low plasma folate level, and low global 5-MedC (Q4 versus Q5) significantly increased the ORs of UC. The above results suggest that high total arsenic, low plasma folate, and 5-MedC levels affect the ORs of UC independently.

Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan.

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case-control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV %, low InAs %, and high DMAV %). High MMAV % significantly increased and high DMAV % and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83-30.06), 0.21 (0.04-1.23), and 0.20 (0.03-1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

Fuzzy inference system for modeling the environmental risk map of air pollutants in Taiwan.

This study aimed to improve the uncertainty in spatial data of risk assessment through a Fuzzy inference system (FIS) as a way to conduct an environmental risk map of air pollution in Taiwan. In modeling, the feature inputs of FIS included the geographic coordinates and time, while the outputs are the pollutant concentrations. The outputs are supplements to the concentration contour on the map in comparison with Kriging interpolation. In our model, the FIS was designed using the official open data of air pollutants, including Pb and PM2.5 that were collected from the monitoring stations in mid-southern Taiwan. The model involved data filtration and imputation in the preliminary scheme to extract the historical data for analysis. We used the data of Pb (2001-2013) and PM2.5 (2006-2013) for the training process, and then used the data from 2014 to 2015 for validation. Our model was able to compute the smaller errors of inferred and measured values of Pb and PM2.5 than the conventional method. The approach was applied to deduce the exposure of PM2.5 distributed over the Taiwan Island in accordance with the governmental open data of seventy-three stations during 2006-2016 in order to produce our risk map. The designed model upon Fuzzy inference accesses potential risks of spatiotemporal exposures in the unmeasured locations with feasibility and adaptability for environmental management.

Risk of Alzheimer's disease with metal concentrations in whole blood and urine: A case-control study using propensity score matching.

Environmental exposure to heavy metals is suspected to result in neuropathology damage and cognitive impairment. We aimed to explore the association of Alzheimer's disease (AD) risk with the internal dose of heavy metals by constructing a hospital-based case-control study and using propensity-score-matching methods. We investigated 170 patients with AD and 264 controls from the Department of Neurology and Family Medicine, China Medical University Hospital in Taiwan. All patients with AD received clinical neuropsychological examination and cognitive-function assessments, including the mini-mental status examination and clinical dementia rating scale. We also constructed a propensity-score-matched population of 82 patients with AD and 82 controls by matching age, gender, education, and AD-related comorbidity. Blood levels with cadmium, lead, mercury, selenium, and urinary arsenic profile were measured. Logistic regression models and 95% confidence intervals (CIs) were applied to estimate AD risk. After stratification by respective quartile cutoffs of heavy metals, the AD risk of study participants with high urinary inorganic arsenic (InAs%) or low dimethylarsinic acid (DMA%) significantly increased (p < 0.05), as similarly found in the propensity-score-matched population. In addition, people with a low median level of selenium and high median level of InAs%, or/and a low median level of DMA% had approximately two- to threefold significant AD risk. Urinary arsenic profiles may be associated with increased AD risk. Repeat measurements of heavy metals with large sample size and the surveying of potential exposure sources are recommended in future studies.

Activation of liver X receptor suppresses angiogenesis via induction of ApoD.

Liver X receptors (LXRs) are important sensors and regulators for cholesterol, fatty acid, and glucose. LXRs play essential roles in the development and progression of cardiovascular diseases. We examined the effects of T0901317, a potent LXR agonist, on angiogenesis of human umbilical vein endothelial cells (HUVECs). Treatment with T0901317 inhibited the tube formation and migration of HUVECs and reduced the in vivo angiogenesis, as determined by chorioallantoic membrane assay. T0901317 stimulated gene and protein expression of LXR target gene apolipoprotein D (ApoD). Overexpression of ApoD suppressed the tube formation of HUVECs. ApoD interacted with scavenger receptor class B member 1 (SR-B1), while knockdown of SR-B1 blocked suppressive effects of T0901317 on HUVEC migration. T0901317 treatment or overexpression of ApoD lessened expression of proteins regulating angiogenesis, including phospho-eNOS S1177, phospho-Akt T308, phospho-Akt S473, eNOS, mammalian target of rapamycin, VEGF-A, VEGF-C, IL-8, RhoB, matrix metalloproteinase (MMP)-8, -9, and monocyte chemoattractant protein 1. Our study suggested that activation of LXR interferes with angiogenesis through induction of LXR target gene ApoD, which in turn suppresses PI3K-Akt-eNOS signaling, an essential pathway regulating angiogenesis. ApoD may be a potential therapeutic target for tumor angiogenesis.-Lai, C.-J., Cheng, H.-C., Lin, C.-Y., Huang, S.-H., Chen, T.-H., Chung, C.-J., Chang, C.-H., Wang, H.-D., Chuu, C.-P. Activation of liver X receptor suppresses angiogenesis via induction of ApoD.

Clinically diagnosed urticaria and risk of systemic lupus erythematosus in children: A nationwide population-based case-control study.

BACKGROUND: Urticaria is one of the most common diseases seen in clinical practice, whereas several reports have proposed that urticaria may have a link with autoimmune disorders. Few studies have examined the clinical association between urticaria with systemic lupus erythematosus (SLE). By conducting a nationwide population-based case-control study in Taiwan, we evaluated the risk of SLE in children with a prior clinical diagnosis of urticaria. METHODS: Using 2000-2011 claims data from the Taiwanese National Health Insurance Research Database, we identified 2105 SLE children during 2004-2011 as the study group, along with randomly selected 8420 non-SLE patients matched (1:4) for age, sex, and first diagnosis date as the control group. The correlation between urticaria and SLE risk was estimated using conditional logistic regression analysis. RESULTS: The prevalence rates of clinically diagnosed acute and chronic urticaria in SLE patients were 22.09% and 18.24%, respectively. A significant association was found between clinically diagnosed urticaria and childhood SLE, with a stronger risk associated with more episodes of urticaria (≥3 visits, OR: 2.33, 95% CI 1.91-2.84). The risk was higher with chronic urticaria (OR: 2.21, 95% CI 1.85-2.64) than with acute urticaria (OR: 1.54, 95% CI 1.34-1.76). Subgroup analysis stratified by sex or age indicated that the risk associated with SLE was significantly greater among female children and adolescents with urticaria. CONCLUSIONS: Our results suggest that children with urticaria have a significantly higher risk of SLE, with the risk increasing further among those with more episodes of urticaria or chronic urticaria.

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma.

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case-control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2'-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%-12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies.

Association between levels of urinary heavy metals and increased risk of urothelial carcinoma.

OBJECTIVES: To evaluate possible sources of exposure to heavy metals in the general population, and to determine the association between urinary heavy metals and urothelial carcinoma risk. METHODS: We recruited 205 patients with urothelial carcinoma and 406 control participants for a case-control study between June 2011 and December 2013. The control participants were frequency-matched with cases according to sex and age. We measured the urinary levels of arsenic, cadmium, chromium, nickel and lead by using inductively coupled plasma mass spectrometry. We collected environmental exposure-related information through questionnaires. Multivariate logistic regression and 95% confidence intervals were applied to estimate the urothelial carcinoma risk and potential effects of urothelial carcinoma-related risk factors on the levels of urinary heavy metals. RESULTS: Patients with urothelial carcinoma showed higher urinary levels of arsenic, cadmium, chromium, nickel and lead than the controls. After considering other potential risk factors, a significantly increased risk for urothelial carcinoma was observed in patients with increased urinary levels of cadmium, chromium, nickel and lead. Smokers showed a high urinary cadmium level. In addition to cadmium, a high urinary lead level was associated with cumulative cigarette smoking and herbal medicine use. CONCLUSION: Environmental factors might contribute to higher urinary levels of heavy metals and ultimately result in urothelial carcinoma carcinogenesis. These findings can promote proper environmental surveillance of exposure to heavy metals in the general population.

Increased risk of anxiety among patients with urolithiasis: A nationwide population-based cohort study.

OBJECTIVES: To investigate whether patients with urolithiasis are at an increased risk of anxiety and depression. METHODS: We used universal insurance claims data in Taiwan from 2000 to 2011 to identify patients with newly diagnosed urolithiasis (n = 32 617) and those without urolithiasis (n = 130 465). Incidences, hazard ratios, and incidence rate ratios of anxiety and depression were determined in both cohorts in terms of baseline demographic characteristics and comorbidities until December 2011. RESULTS: The urolithiasis cohort yielded a higher incidence of anxiety (11.9 vs 6.91 per 1000 person-years) with an adjusted hazard ratio of 1.5 (95% confidence interval 1.42-1.57) than the non-urolithiasis cohort. The urolithiasis cohort also showed a higher incidence of depression (5.79 vs 3.95 per 1000 person-years) with an adjusted hazard ratio of 1.26 (95% confidence interval 1.18-1.35) than the non-urolithiasis cohort. Regardless of the patients' baseline comorbidities, patients with urolithiasis showed a higher incidence rate ratio of anxiety and depression than those without urolithiasis (with no comorbidities: adjusted hazard ratio 1.62, 95% confidence interval 1.49-1.76] for anxiety and adjusted hazard ratio 1.37, 95% confidence interval 1.23-1.54 for depression). CONCLUSION: Urolithiasis is recurrent, and significantly associated with anxiety and depression. Therefore, urologists should diagnose patients suspected with this disease and provide proper medical care.

Caffeic Acid phenethyl ester is a potential therapeutic agent for oral cancer.

Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.