Search

Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Chia-Chi Lung,2 Disline Manli Tantoh,2,5 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11838Fax +886423248179Email Liawyp@csmu.edu.twMing-Chih ChouInstitute of Medicine, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11191Fax +886423248130Email juhan0223@yahoo.com.twPurpose: Ischemic stroke accounts for approximately 85% of all strokes. Risk factors include atrial fibrillation, metabolic disorders, and genetic and lifestyle factors. There is limited evidence to support the association between atrial fibrillation and the risk of ischemic stroke based on genetic variants. We assessed the relationship between ischemic stroke and atrial fibrillation among participants in Taiwan Biobank (TWB) based on the rs2860905 variant of the cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9) gene.Materials and Methods: Using logistic regression analysis, we estimated the odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke among 17,726 biobank adults recruited from 2008 through 2015.Results: Of the eligible participants (n = 17,726), 906 were identified with ischemic stroke. Atrial fibrillation was positively associated with ischemic stroke (OR=3.70; 95% CI, 2.21– 6.20), whereas the rs2860905 variant was not. The OR for ischemic stroke among those with GA/AA genotype was 1.00 (95% CI, 0.82– 1.22) compared to those with the GG genotype. Based on the genotype-stratified analysis, the OR for ischemic stroke was 4.68 (95% CI, 2.70– 8.09) among individuals with GG genotype who had atrial fibrillation compared to those who did not.Conclusion: These results demonstrate that the GG genotype of the CYP2C9 rs2860905 variant appears to enhance the risk of ischemic stroke among adults in Taiwan. It could be essential to factor this genotype-specific contributor to ischemic stroke into clinical and experimental investigations of the disease in Taiwan.Keywords: genetic variation, risk prediction, stroke

Background: The influence of menopausal hormone therapy (MHT) on the probability of developing diabetes mellitus in individuals with prediabetes remains uncertain., Methods: This retrospective cohort study, utilizing the TriNetX U.S. Collaborative Network, investigated cohorts, implemented propensity score matching, and analyzed outcomes associated with diabetes mellitus. The study focused on individuals aged 46-60 with prediabetes prior to menopause, categorizing them into MHT and non-MHT groups. Further stratified analyses, including variables such as age and race, were conducted to thoroughly examine potential variations in outcomes., Results: The study involved 6566 individuals (MHT and non-MHT), with propensity score matching ensuring balanced cohorts. Over a 20-year follow-up, the MHT group demonstrated a lower incidence of diabetes mellitus compared to the non- MHT group, with a Hazard Ratio of 0.693 (95 % CI: 0.577, 0.832). Stratified analyses revealed age-specific nuances, with significant protective effects in individuals aged 46-50 and 55-60. Additionally, ethnicity played a role, with MHT demonstrating significant benefits in White individuals but not in the Black or Asian populations. BMI analysis indicated a significant risk reduction with MHT in individuals with BMI less than or equal to 24.9 and 25-29.9 kg/m 2 , but not in those with BMI greater than or equal to 30 kg/m 2 ., Conclusion: In our study, we demonstrate a sustained 20-year decrease in the risk of diabetes among premenopausal individuals with prediabetes who undergo menopausal hormone therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The COVID-19 pandemic has underscored the importance of its potential long-term health effects, including its link to new-onset asthma in children. Asthma significantly impacts children's health, causing adverse outcomes and increased absenteeism. Emerging evidence suggests a potential association between COVID-19 infection and higher rates of new-onset asthma in adults, raising concerns about its impact on children's respiratory health., Methods: A retrospective cohort study design was employed, using electronic medical records from the TriNetX database, covering January 1, 2021, to December 31, 2022. Two cohorts of children aged 5 to 18 who underwent SARS-CoV-2 RT-PCR testing were analyzed: unvaccinated children with and without COVID-19 infection, and vaccinated children with and without infection. Propensity score matching was used to mitigate selection bias, and hazard ratio (HR) and 95% CI were calculated to assess the risk of new-onset asthma., Results: Our study found a significantly higher incidence of new-onset asthma in COVID-19 infected children compared to uninfected children, regardless of vaccination status. In Cohort 1, 4.7% of COVID-19 infected children without vaccination developed new-onset asthma, versus 2.0% in their non-COVID-19 counterparts within a year (HR = 2.26; 95% CI = 2.158-2.367). For Cohort 2, COVID-19 infected children with vaccination showed an 8.3% incidence of new-onset asthma, higher than the 3.1% in those not infected (HR = 2.745; 95% CI = 2.521-2.99). Subgroup analyses further identified higher risks in males, children aged 5-12 years, and Black or African American children. Sensitivity analyses confirmed the reliability of these findings., Conclusion: The study highlights a strong link between COVID-19 infection and an increased risk of new-onset asthma in children, which is even more marked in those vaccinated. This emphasizes the critical need for ongoing monitoring and customized healthcare strategies to mitigate the long-term respiratory impacts of COVID-19 in children, advocating for thorough strategies to manage and prevent asthma amidst the pandemic., (© 2024. The Author(s).)

We determined the association of vegetarian type and status with bone mineral density (BMD) Z-scores at the spine, hip, and femoral neck. Compared to non-vegetarians, current vegetarians, especially vegans, lacto-vegetarians, and lacto-ovo-vegetarians had lower Z-scores at multiple sites. Sole reliance on a vegetarian diet might be detrimental to the bone., Purpose: The impact of vegetarian diets on BMD is contentious. We determined the association of vegetarian type and status with the spine, hip, and femoral neck BMD Z-scores., Methods: We analyzed data from 20,110 Taiwan Biobank volunteers. BMD was measured using dual-energy X-ray absorptiometry (DXA). The vegetarian status (non-, former, and current vegetarians) and type (non-vegetarians, ovo-vegetarians, lacto-vegetarians, lacto-ovo-vegetarians, and vegans) were determined using questionnaires., Results: The participants consisted of 12,910 women and 7200 men, with a mean age of 55.5 years. Based on vegetarian status (reference: non-vegetarians), current vegetarians had significantly lower BMD Z-scores at the spine (unstandardized regression coefficient, B =  - 0.195, p = 0.006), left hip (B =  - 0.125, p = 0.008), and right hip (B =  - 0.100, p = 0.027), respectively. Based on vegetarian status and type (reference: non-vegetarians), current vegans and non-vegans had notably lower BMD Z-scores at specific skeletal sites. For non-vegans, the BMD Z-scores were significant at the spine (B = -0.184, p = 0.010), left hip (B =  - 0.124, p = 0.010), and left femoral neck (B =  - 0.125, p = 0.012). For current vegans, however, the BMD Z-scores were significant only at the right hip (B =  - 0.232; p = 0.028). Nonetheless, after stratifying vegetarian diet into more subgroups, current vegans exhibited a significant reduction in BMD Z-scores at the spine and right hip, with B-coefficients of - 0.326 and - 0.238, respectively. Current lacto-vegetarians also had significantly lower Z-scores (p < 0.05) at the spine (B =  - 0.459), left hip (B =  - 0.313), and right hip (B =  - 0.214). Moreover, current lacto-ovo-vegetarians had significantly lower Z-scores at the spine (B =  - 0.175) and left hip (B =  - 0.115)., Conclusion: Current vegetarians, particularly vegans, lacto-vegetarians, and lacto-ovo-vegetarians, demonstrated significantly lower BMD Z-scores at various skeletal sites compared to non-vegetarians. Sole reliance on a vegetarian diet might be detrimental to the bone., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Purpose: Peripheral vascular disease (PVD) is a life-threatening condition affecting the lower extremities. Common risk factors include type 2 diabetes (T2D), hypertension, dyslipidemia, smoking, and older age. There is a little-documented research on the genetic basis of the disease in Taiwan. We examined the impact of T2D and the blood pressure-associated rs17367504 variant of the Methylenetetrahydrofolate reductase (MTHFR) gene on PVD risk., Materials and Methods: In this population-based association study, we linked data from 8992 participants in Taiwan Biobank (TWB) to their medical records in the National Health Insurance Research Database (NHIRD). Participants were 30 to 70 years old at recruitment and included those assessed between 2008 and 2015. We tested for association of PVD with rs17367504 and T2D using multiple logistic regression models. The rs17367504 variant was assessed using the Axiom-Taiwan Biobank Array Plate (TWB chip: Affymetrix, Inc., Santa Clara, CA, USA)., Results: Among cases with T2D (n = 1294), 158 (12.21%) were identified with PVD. T2D was associated with PVD (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.21-1.91; p<0.001) whereas rs17367504 variant was not (OR, 0.96; CI, 0.76-1.21; p = 0.728 in AG/GG compared to AA homozygotes). However, T2D and rs17367504 had an interactive effect on PVD (p for interaction = 0.0076). Results from our stratified analyses displayed OR of 1.75 (CI, 1.35-2.26; p<0.001) in AA individuals with DM and 0.94 (CI, 0.56-1.58; p = 0.811) in AG+GG individuals with T2D. Using the AA genotype and no T2D as the reference group, the respective OR of PVD was 1.77 (CI, 1.38-2.28; p<0.001) in AA individuals with T2D; 1.18 (CI, 0.91-1.55; p = 0.215) in AG+GG individuals with no T2D, and 1.03 (CI, 0.66-1.60; p = 0.892) in AG+GG individuals with T2D ., Conclusion: We found that type 2 diabetes was associated with increased risk of peripheral vascular disease, particularly in AA genotype carriers of the rs17367504 variant in Taiwan., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Liu et al.)

Objective: Osteoporosis, the most prevalent bone disorder in humans, is a global public health issue and its relationship with menopause is well-established. The interaction between menopause and genes on osteoporosis risk is, however, yet to be fully elucidated. We assessed the association between menopause and osteoporosis in relation to the SOX6 rs297325 variant in Taiwanese women., Methods: There were 7,581 female participants, aged 30 to 70 years old. Information on SOX6 rs297325 and menopause were obtained from the Taiwan Biobank Database while that on osteoporosis was obtained from the National Health Insurance Research Database., Results: Menopause but not SOX6 rs297325 was significantly associated with a higher risk of osteoporosis (odds ratio [OR] = 1.48; 95% confidence interval [CI] = 1.04-2.10). The interaction between menopause and rs297325 on osteoporosis was significant (P = 0.0216). After stratification by rs297325 genotypes, the risk of osteoporosis was significantly higher in menopausal women having the TT + CC genotype (OR = 2.02; 95% CI = 1.21-3.38). After stratification by menopausal status and rs297325 genotypes, the OR; 95% CI was 0.62; 0.38 to 0.99 in premenopausal women with the TC + CC genotype and 1.24; 0.82 to 1.88 in menopausal women with the TC + CC genotype., Conclusion: SOX6 rs297325 was not significantly associated with osteoporosis but might have modulated the association between menopause and osteoporosis. The risk of osteoporosis was higher in menopausal women with the TC + CC genotype but lower in premenopausal women with the TC + CC genotype.

We examined the association between high-density lipoprotein cholesterol (HDL-C), and exercise and vegetarian diets, in Taiwanese adults, based on the Methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism. Using regression models, we analyzed historical data collected from 9255 Taiwan Biobank (TWB) participants from 2008 through 2015. Exposure to exercise was associated with higher HDL-C ( β = 1.0508 and 1.4011 for GG and GA + AA individuals, respectively), whereas a vegetarian diet was associated with lower HDL-C ( β = -6.2793 and -4.6359 for those with GG and GA + AA genotype, respectively). We found an interaction between exercise and diet among GG individuals ( p = 0.0101). Compared with no exercise/no vegetarian diet, vegetarian diet/no exercise was associated with a 5.1514 mg/dl reduction in HDL-C among those with GG genotype ( β = -5.1514, p < 0.0001) and a 4.8426 mg/dl reduction ( β = -4.8426, p < 0.0001) among those with GA + AA genotype. Vegetarian diets in combination with exercise predicted a 6.5552 mg/dl reduction in HDL-C among GG individuals ( β = -6.5552) and a 2.8668 mg/dl reduction among GA + AA individuals ( p < 0.05). These findings demonstrated that vegetarian diet alone was associated with lower HDL-C, no matter the rs1801133 genotype. However, the inclusion of regular exercise predicted much lower levels among GG individuals, whereas levels among GA + AA individuals were relatively higher., Competing Interests: The authors have no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A complex interplay of several genetic and lifestyle factors influence coronary heart disease (CHD). We determined the interaction between coffee consumption and the tribbles pseudokinase 1 ( TRIB1 ) rs17321515 variant on coronary heart disease (CHD). Data on CHD were obtained from the National Health Insurance Research Database (NHIRD) while genotype data were collected from the Taiwan Biobank (TWB) Database. From the linked electronic health record data, 1116 individuals were identified with CHD while 7853 were control individuals. Coffee consumption was associated with a lower risk of CHD. The multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) was 0.84 (0.72-0.99). Association of CHD with the TRIB1 rs17321515 variant was not significant. The OR (95% CI) was 1.01 (0.72-0.99). There was an interaction between TRIB1 rs17321515 and coffee consumption on CHD risk ( p for interaction = 0.0330). After stratification by rs17321515 genotypes, coffee drinking remained significantly associated with a lower risk of CHD only among participants with GG genotype (OR, 0.62; 95% CI, 0.45-0.85). In conclusion, consumption of coffee was significantly associated with a decreased risk of CHD among Taiwanese adults with the TRIB1 GG genotype.

Objectives: The rs12611091 variant in the BR serine/threonine kinase 1 gene is one of the variants previously associated with age at natural menopause. So far, this variant has not been replicated in Taiwanese women. The purpose of this study was to determine the association between rs12611091 and age at natural menopause based on physical activity., Methods: A total of 1,758 women were eligible for analysis whose information about menopause was collected from the Taiwan Biobank. Multiple linear regression analysis was used for analysis., Results: The mean age (standard deviation) at natural menopause was 50.82 (3.59) years. Of the eligible participants, 56.94% were rs12611091 CC carriers, 36.69% were TC carriers, and 6.37% were TT carriers. Compared to CC carriers, TC and TT carriers were associated with early menopause (β = -0.42, P = 0.02 and -0.87, P = 0.01, respectively). There was a significant interaction between rs12611091 and physical activity (P for interaction = 0.02). Compared to rs12611091 CC carriers, TC and TT carriers who were physically inactive were significantly associated with earlier menopause (β = -0.88, P < 0.01 and -1.25, P = 0.02, respectively)., Conclusion: We demonstrated that rs12611091 variant was associated with age at natural menopause especially among inactive women in Taiwan. That is, women with TC and TT genotypes who were physically inactive were significantly associated with earlier natural menopause compared to those with CC genotype.

Background and objectives: High-density lipoprotein cholesterol (HDL-C) is important for improving risk estimates of atherosclerotic cardiovascular disease. We investigated the effect of omnivore and diverse vegetarian diets in connection with exercise on HDL-C. Materials and Methods: Historical data of 9588 biobank participants (4025 exercisers and 5563 non-exercisers) aged 30-70 years were categorized as omnivores (n = 8589), former vegetarians (n = 544), lacto-ovo vegetarians (n = 417), and strict vegetarians (n = 38). We used multiple linear regression for analyses. Results: HDL-C levels were higher in exercisers compared to non-exercisers. Compared with omnivores, strict vegetarians had decreased levels of HDL-C ( β = -5.705; p = 0.001) followed by lacto-ovo vegetarians ( β = -3.900; p < 0.001) and former vegetarians ( β = -0.329; p = 0.475). The test for trend was significant ( p < 0.001). After categorization by exercise modalities, the β- value was -13.984 for strict vegetarians, -4.419 for lacto-ovo vegetarians, and -1.864 for former vegetarians, respectively ( p < 0.05). There was an interaction between diet and exercise ( p = 0.009). Omnivores who exercised regularly had significantly higher HDL-C, whereas strict vegetarians who exercised regularly had significantly lower HDL-C. Conclusions: In summary, strict vegetarian diets in conjunction with regular exercise might not serve as healthful behaviors to be implemented in everyday life considering the negative impact on HDL-C., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Hyperlipidemia is one of the strong risk factors for ischemic heart disease. Using the Taiwan Biobank (TWB) database, we evaluated the risk of hyperlipidemia and its interaction with sex and rs688 polymorphism on the low-density lipoprotein receptor (LDLR) gene. Data collection in the biobank started in 2008 and is ongoing. Data analysis was performed on the participants' data collected between 2008 and 2015. In general, 27.92% of the 9237 female participants and 32.65% of the 8690 male participants were identified with hyperlipidemia. Compared to the C/C genotype, C/T and T/T genotypes were not significant risk factors for hyperlipidemia (OR = 1.061, CI: 0.976-1.153 for C/T and OR = 1.052, CI: 0.845-1.309 for T/T genotype) in the general model. However, there was a significant interaction between sex and rs6888 on hyperlipidemia risk (p-interaction = 0.0321). With the male sex/CC genotype being the reference group, only the female sex/CT and T/T genotypes were closely associated with hyperlipidemia, with respective ORs of 1.153 (CI: 1.014-1.311) and 1.423 (CI: 1.056-1.917). Our data indicate that rs688 C/T and T/T genotypes may be associated with increased risk of hyperlipidemia in Taiwanese women. These findings may be relevant in lipid-modification therapy., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The nasopharyngeal tract traps mainly coarse particles in inhaled air. Soluble carcinogenic compounds, endotoxins, and trace metals contained in these particles are potential causes of inflammation and oxidative stress which could enhance carcinogenesis. The aim of this study was to determine the association between coarse particulate matter (PM 10-2.5 ) and nasopharyngeal cancer (NPC). A total of 521,098 men (355 cases and 520,743 non-cases), aged ≥40 years were included in this study. Data were retrieved from the Taiwan Cancer Registry, the Adult Preventive Medical Services Database, and the Air Quality Monitoring Database. PM 10-2.5 was significantly associated with a higher risk of NPC after adjusting for SO 2 , NOx, O 3 , age, body mass index, smoking, alcohol drinking, betel nut chewing, exercise, hypertension, diabetes, and hyperlipidemia. With PM 10-2.5 <20.44 μg/m 3 as the reference, the ORs and 95% CIs were 1.47; 1.03-2.11, 1.34; 0.94-1.91, and 1.68; 1.16-2.44 for 20.44≤PM 10-2.5 <24.08, 24.08≤PM 10-2.5 <29.27, and PM 10-2.5 ≥29.27 μg/m 3 , respectively. PM 10-2.5 remained significantly associated with a higher risk of NPC after further adjustments were made for the aforementioned covariates and PM 2.5 The ORs; 95% CIs were 1.42; 0.96 to 2.12, 1.41; 0.94 to 2.10, and 1.71; 1.10 to 2.66 for 20.44≤PM 10-2.5 <24.08, 24.08≤PM 10-2.5 <29.27, and PM 10-2.5 ≥29.27 μg/m 3 , respectively. In conclusion, PM 10-2.5 was significantly associated with a higher risk of NPC in Taiwanese men., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Not much is known regarding the influence of non-smoking-related risk factors on COPD in Taiwan. We examined the relationship between exposure to particulate matter <2.5 μm (PM 2.5 ) and COPD among nonsmokers in Taiwan., Methods: This population-based study involved 3941 nonsmoking Taiwanese adults who were recruited in the Taiwan Biobank project between 2008 and 2015. Air pollution data between 2006 and 2011 were obtained from the air quality monitoring database (AQMD). COPD was the outcome of interest and was identified using the National health insurance Research Database (NHIRD). The data were analyzed using multiple logistic regression models., Results: Compared with the lowest quartile (PM 2.5  = 29.38), exposure to PM 2.5 in the highest quartile (>38.98 μg/m 3 ) was significantly associated with COPD (OR, 1.29; CI 1.01-1.65) after multivariate adjustments. However, exposures to concentrations of 32.07-38.98 μg/m 3 (OR, 1.12 CI 0.88-1.44) and 29.38-32.07 μg/m 3 (OR, 1.09 CI 0.84-1.41) showed positive but non-significant associations. However, the test for trend was significant (Ptrend = 0.043). The ORs for exposure to sulfur dioxide (SO 2 ), ozone (O 3 ), carbon monoxide (CO) and NOx (nitrogen monoxide (NO were not significant., Conclusions: Based on our data, exposure to PM 2.5 at concentrations greater than 38.98 μg/m 3 increased susceptibility to COPD among Taiwanese nonsmokers. Combatting COPD would involve integrating tobacco control and pollution management strategies., (Copyright © 2019. Published by Elsevier GmbH.)

Background: DNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM 2.5 levels., Methods: Data on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM 2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were categorized into northern, north-central, central, and southern regions., Results: Living in PM 2.5 areas was associated with lower methylation levels: compared with the northern area (reference area), living in north-central, central, and southern areas was associated with lower methylation levels at cg05575921. However, only methylation levels in those living in central and southern areas were significant (β = - 0.01003, P = 0.009 and β = - 0.01480, P < 0.001, respectively. Even though methylation levels in those living in the north-central area were not statistically significant, the test for linear trend was significant (P < 0.001). When PM 2.5 was included in the regression model, a unit increase in PM 2.5 was associated with 0.00115 (P < 0.001) lower cg05575921 methylation levels., Conclusion: Living in PM 2.5 areas was inversely associated with blood AHRR methylation levels at cg05575921. The methylation levels were lowest in participants residing in southern followed by central and north-central areas. Moreover, when PM 2.5 was included in the regression model, it was inversely associated with methylation levels at cg05575921. Blood methylation at cg05575921 (AHRR) in non-smokers might indicate different exposures to PM 2.5 and lung cancer which is a PM 2.5 -related disease.

Background: Both SOX2 promoter methylation and air pollution have been associated with lung cancer risk. However, little has been done to assess SOX2 promoter methylation in individuals living in air pollution areas. The aim of this study was to investigate SOX2 promoter methylation in non-smoking Taiwanese adults living in areas with different levels of air pollution especially particulate matter with diameter < 2.5 μm (PM 2.5 )., Methods: A total of 1142 individuals aged 30-70 years were recruited. Data on SOX2 methylation, residence, age, and exposure to second-hand smoke (SHS) among others were extracted from the Taiwan Biobank dataset (2008-2015). After excluding former and current smokers, alongside those with incomplete information, a total of 461 non-smokers comprising 176 men and 285 women were included in the study. Participants' residences were grouped under northern and central/southern areas because air pollution (PM 2.5 ) is lower in northern compared to central and southern areas., Results: The methylation levels in men (0.16310 ± 0.01230) and women (0.15740 ± 0.01240) were significantly different (P < .0001). In both sexes, the SOX2 promoter region was shown to be significantly hypermethylated in central and southern areas compared with the northern areas. The regression coefficient (β) was 0.00331 (P = 0.0257) in men and 0.00514 (P < .0001) in women., Conclusion: SOX2 was significantly hypermethylated in both men and women residing in central and southern areas. The consistency in the results for both sexes shows that SOX2 promoter methylation could serve as a potential biomarker for industrial air pollution exposure. Moreover, it might reflect predisposition to cancer. Hence, healthy non-smokers at precancerous stages who have not been clinically diagnosed could be identified.

CDKAL1 rs10946398 is a type 2 diabetes (T2D)-associated variant. It is a new body mass index (BMI)-associated variant in Asian populations. We investigated the association between rs10946398 and T2D among 9908 participants aged 30-70 years based on BMI: normal weight; 18.5 ≤ BMI < 24 kg/m 2 , overweight; 24 ≤ BMI < 27 kg/m 2 , and obesity; BMI ≥27 kg/m 2 . The CC genotype conferred a higher risk of T2D than the CA genotype. The odds ratios (ORs) were 1.83; 95% confidence interval (CI) 1.49-2.26 and 1.20; 95% CI 1.02-1.40, respectively. The C allele was the significant risk allele compared with A allele (OR = 1.32; 95% CI 1.19-1.47). For normal, overweight and obese participants with CC genotype, the ORs were respectively 1.69; 95% CI 1.02-2.81, 2.34; 95% CI 1.50-3.66, and 1.58; 95% CI 1.02-2.45 among men and 1.22; 95% CI 0.67-2.22, 2.42; 95% CI 1.30-4.52, and 2.3; 95% CI 1.19-4.50 among women. The C allele ORs were higher in obese and overweight women. In conclusion, the rs10946398 CC/CA genotypes, as well as the C allele increased the risk of T2D. The ORs were higher in women who were overweight and obese than in those with normal weight. Nonetheless, significant results were prominent only among those with CC genotype and C allele.

Background: The link between the subcategories of liver cirrhosis and type 2 diabetes is not well known. We investigated the association of type 2 diabetes mellitus with alcoholic cirrhosis and cirrhosis without alcohol., Methods: This nationwide cohort study used the Taiwan National Health Insurance Research Database. Cirrhotic individuals and their matched controls were identified from 2001-2008. In all, 9 313 cirrhotic patients aged 20 years or older were matched by age, sex, and index date with the non-cirrhotic individuals ( n = 37 252). Cirrhosis was categorized into alcoholic cirrhosis and cirrhosis without alcohol. Type 2 diabetes mellitus was identified from January 2001- December 2011., Results: The incidence densities (per 1 000 person-months) of type 2 diabetes were as follows: 1.14 (95% CI: 1.09-1.20) in the non-cirrhotic group, 1.88 (CI 1.76-2.01) in patients with cirrhosis, 1.62 (CI 1.48-1.78) in patients with cirrhosis without alcohol, and 2.92 (CI 2.64-3.23) in patients with alcoholic cirrhosis. The adjusted hazards ratio (aHR) for type 2 diabetes mellitus among cirrhotic individuals was 0.774 (CI: 0.715-0.8934). Alcoholic cirrhotic men had a significantly higher risk of type 2 diabetes (aHR 1.182, CI: 1.046-1.335) compared with non-cirrhotic individuals. Increased risks were seen in men (aHR 1.690; CI: 1.455-1.963) and women (aHR 1.715; CI: 1.113-2.645) with alcoholic cirrhosis compared to those with cirrhosis without alcohol., Conclusions: This study indicates that alcoholic cirrhosis is a significant risk factor for type 2 diabetes mellitus compared with cirrhosis without alcohol., Competing Interests: CONFLICTS OF INTEREST The authors report no conflicts of interest.

Background: Inhaled corticosteroids (ICS) have been associated with decreased lung cancer risk. However, they have been associated with pulmonary infections (tuberculosis [TB] and pneumonia) in patients with chronic obstructive pulmonary disease (COPD). TB and pneumonia have increased lung cancer risk. The association between post-ICS pulmonary infections and lung cancer remains unclear., Methods: We conducted a retrospective cohort study from 2003 to 2010 using the Taiwan National Health Insurance Research Database. Among the 1,089,955 patients with COPD, we identified 8813 new users of ICS prescribed for a period of 3 months or more and 35,252 non-ICS users who were randomly matched for sex, age and date of ICS use from 2003 to 2005. Cox proportional hazard regression was used to estimate the hazard ratio (HR) of pulmonary infections in patients with/without ICS use., Results: The HRs for lung cancer in ICS users with sequential lung infections were as follows; 2.42 (95 % confidence interval [CI], 1.28-4.58) for individuals with TB, 2.37 (95 % CI, 1.01-5.54) for TB and pneumonia, and 1.17(95 % CI, 0.69-1.98) for those with pneumonia. For non-ICS users with pulmonary infections, the HRs were 1.68 (95 % CI, 0.78-3.65) for individual with TB and pneumonia, 1.42 (95 % CI, 0.89-2.26) for TB, and 0.95 (95 % CI, 0.62-1.46) for individuals with pneumonia., Conclusions: COPD patients with TB /or pneumonia who used ICS had increased risk of lung cancer. Because the overall prognosis of lung cancer remains poor, screening tests are recommended for patients with these conditions.

Purpose: To evaluate the association between post-inhaled corticosteroid (ICS) pulmonary tuberculosis (TB), pneumonia and lung cancer in patients with asthma., Methods: The study samples were collected from the National Health Insurance Database. Asthmatic patients who were first-time users of ICS between 2003 and 2005 were identified as cases. For each case, 4 control individuals were randomly matched for sex, age and date of ICS use. Cases and matched controls were followed up until the end of 2010. Cox proportional hazard regression was used to determine the hazard ratio for pulmonary infections and lung cancer risk in the ICS users and non-users., Results: A total of 10,904 first-time users of ICS were matched with 43,616 controls. The hazard ratios for lung cancer were: 2.52 (95% confidence interval [CI], 1.22-5.22; p = 0.012) for individuals with post-ICS TB, 1.28 (95%CI, 0.73-2.26; p = 0.389) for post-ICS pneumonia, 2.31(95%CI, 0.84-6.38; p = 0.105) for post-ICS pneumonia+TB, 1.08 (95%CI, 0.57-2.03; p = 0.815) for TB, 0.99 (95%CI, 0.63-1.55; p = 0.970) for pneumonia, and 0.32 (95%CI, 0.05-2.32; p = 0.261) for pneumonia+ TB, respectively., Conclusions: Post-ICS TB increased lung cancer risk in patients with asthma. Because of the high mortality associated with lung cancer, screening tests are recommended for patients with post-ICS TB.

Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common lung diseases associated with lung cancer mortality. This study evaluated sex disparities in pre-existing pulmonary diseases and stage-dependent lung adenocarcinoma survival.Patients newly diagnosed with lung adenocarcinoma between 2003 and 2008 were identified using the National Health Insurance Research Database and Cancer Registry. Cases with lung adenocarcinoma were followed until the end of 2010. Survival curves were estimated by the Kaplan-Meier method. Cox proportional-hazard regression was used to calculate the hazard ratio (HR) of pre-existing asthma, COPD, and/or TB, and to estimate all-cause mortality risk in patients with different stages of lung adenocarcinoma.A total of 14,518 cases were identified with lung adenocarcinoma. Specifically, among men, the HRs for TB were 1.69 (95% confidence interval [CI], 1.10-2.58), 1.48 (95% CI, 1.14-1.93), and 1.27 (95% CI, 1.08-1.49) for individuals with stage I + II, III, and IV diseases, respectively. The HRs for asthma were 1.41 (95% CI, 1.00-1.99) in women with stage I + II and 1.14 (95% CI, 1.04-1.26) in men with stage IV disease. For pulmonary disease combinations in men, the HRs were 1.45 (95% CI, 1.12-1.89) for asthma + COPD + TB, 1.35 (95% CI, 1.12-1.63) for COPD + TB, 1.28 (95% CI, 1.01-1.63) for TB, and 1.15 (95%CI, 1.04-1.27) for asthma + COPD, respectively. For women with stage I + II disease, the HR was 6.94 (95% CI, 2.72-17.71) for asthma + COPD + TB.Coexistence of pre-existing pulmonary diseases increased mortality risk in men with adenocarcinoma. TB is at elevated risk of mortality among men with different stages of adenocarcinoma. Asthmatic women with early-stage adenocarcinoma had increased risk of mortality., Competing Interests: The authors have no other funding or conflicts of interest to disclose.

Background: Esophageal variceal bleeding (EVB) is a serious and common complication of cirrhosis. Diabetes mellitus (DM) and chronic kidney disease (CKD) increase mortality in patients with cirrhosis. However, whether coexisting DM and CKD increase mortality in cirrhotic patients with EVB remains unclear., Methods: We enrolled cirrhotic patients hospitalized with the first presentation of EVB from 2005 through 2010 using Longitudinal Health Insurance Database 2005. The hazard ratios (HRs) of 42-day and one-year EVB mortality were calculated using Cox regression model., Results: We identified 888 patients hospitalized with the first presentation of EVB. Among the cirrhotic patients with EVB, all-cause mortality at 42-day and one-year were 21.3 and 45.0 %, respectively. The respective HRs for the 42-day and one-year mortality were 1.80 (95 % confidence interval [CI], 1.10-2.97) and 1.52 (95 % CI, 1.06-2.17) for patients with CKD and 0.79 (95 % CI, 0.57-1.10) and 0.88 (95 % CI, 0.71-1.09) for patients with DM. Specifically, coexisting CKD and DM increased the 42-day and one-year mortality with respective HRs of 1.99 (95%CI, 1.03-3.84) and 1.84 (95%CI, 1.14-2.98) compared with those without CKD and DM. The HRs for 42-day and 1-year mortality in female patients with DM and CKD were 4.03 (95%CI, 1.40-11.59) and 2.84 (95%CI, 1.31-6.14) respectively, and were 2.93 (95%CI, 1.14-7.57) and 2.42 (95%CI, 1.28-4.57) in male patients with DM and CKD., Conclusion: We identified that coexisting DM and CKD increased risk of mortality at 42 days and 1 year following EVB.

Background: Good support from and positive relations with institutional staff can enhance the psychosocial wellbeing of residents admitted to a nursing home. Nursing assistants (NAs) interact most frequently with residents and play an important role in developing good rapport with them. Most studies have described the daily interactions between NAs and residents as task oriented. Only few have attempted to explore the perspectives of NAs and residents on their daily interactions. Therefore, the aim of this study was to identify the types of daily interactions perceived by NAs and residents. We also investigated those intentions/beliefs held by NAs and residents that might direct their interactive behaviors., Methods: A descriptive, exploratory, qualitative approach was used to explore the perspectives of 18 NAs (mean age: 51) and 15 residents (mean age: 84.4) on their daily interactions. Unstructured in-depth interviews were used to collect data. All of the interviews were conducted from July to December 2013. The collected data were transcribed verbatim and analyzed by content analysis., Results: Three types of interactions were found that described the NAs' and residents' perspectives on their daily interactions: (1) physiologically-oriented daily interactions; (2) cordial interactions intended to maintain a harmonious atmosphere; and (3) reciprocal social interactions intended to develop closer rapport. One or more themes reflecting the participants' intentions or beliefs were identified from each group to support each type of interaction., Conclusions: An over-emphasis on the formal caring relationship and over-concern about maintaining a harmonious atmosphere contributed to a superficial and distant relationship between the two parties. Building close rapport takes time and involves repeated reciprocal social interactions. The findings showed that with good intentions to establish closer rapport, both NAs and residents did favors for each other. All of those favors were easily integrated in the care provided to the residents without increasing the workload of the NAs. Modifying the training given to NAs and adjusting institutional policies are crucial to raising the competence of the NAs in building good relationships with residents. Positive interactions improve the psychosocial wellbeing of the residents and encourage them to cooperate during the delivery of care, thereby improving their overall health and contributing to the NAs' job satisfaction.

Background: Asthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC)., Methods: This study was a nested case-control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected., Results: From the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56-3.04) and 1.77 (1.22-2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16-1.84) and 1.55 (95 %CI, 1.22-1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteroid was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22-20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05-9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50-5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69-16.81)., Conclusion: Corticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC.

Background: The associations between pulmonary diseases (asthma, chronic obstructive pulmonary disease [COPD], and tuberculosis [TB]) and subsequent lung cancer risk have been reported, but few studies have investigated the association with different histologic types of lung cancer., Methods: Patients newly diagnosed with lung cancer from 2004 to 2008 were identified from the National Health Insurance Research Database in Taiwan. Histologic types of lung cancer were further confirmed using the Taiwan Cancer Registry Database. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of asthma, COPD, and TB and to estimate the risk of specific types of lung cancer., Results: During the study period, 32,759 cases of lung cancer were identified from 15,219,024 insurants aged 20 years and older. In men and women, the adjusted HR estimates of squamous cell carcinoma were respectively 1.37 (95 % confidence interval [CI], 1.21-1.54) and 2.10 (95 % CI, 1.36-3.23) for TB, 1.52 (95 % CI, 1.42-1.64) and 1.50 (95 % CI, 1.21-1.85) for asthma, and 1.66 (95 % CI, 1.56-1.76) and 1.44 (95 % CI, 1.19-1.74) for COPD. Similarly, the adjusted HR estimates of adenocarcinoma were respectively 1.33 (95 % CI, 1.19-1.50) and 1.86 (95 % CI, 1.57-2.19) for TB, 1.13 (95 % CI, 1.05-1.21) and 1.18 (95 % CI, 1.09-1.28) for asthma, and 1.50 (95 % CI, 1.42-1.59) and 1.33 (95 % CI, 1.25-1.42) for COPD. The HRs of small cell carcinoma were respectively 1.24 (95 % CI, 1.01-1.52) and 2.23 (95 % CI, 1.17-4.25) for TB, 1.51 (95 % CI, 1.35-1.69) and 1.63 (95 % CI, 1.16-2.27) for asthma, and 1.39 (95 % CI, 1.26-1.53) and 1.78 (95 % CI, 1.33-2.39) for COPD., Conclusions: Asthma, COPD, and TB were associated with an increased risk of all major subtypes of lung cancer. The risk was the highest among women with TB.

Background: Pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB)] are associated with lung cancer mortality. However, the relationship between coexisting pulmonary diseases and survival in patients with lung squamous cell carcinoma (SqCC) has not been well defined., Methods: Patients newly diagnosed with SqCC between 2003 and 2008 were identified by linking the National Health Insurance Research Database and Taiwan Cancer Registry Database. Cases with SqCC were followed up until death, loss to follow-up, or study end in 2010. Information on health status, date of death and the main causes of death was ascertained from the National Death Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB., Results: During the study period, a total of 5406 cases with SqCC were enrolled. For all cause-mortality, HRs were 1.08 [95% confidence interval (CI), 0.99-1.18], 1.04 (95% CI, 0.97-1.12), and 1.14 (95% CI, 1.00-1.31) for individuals with asthma, COPD, and TB, respectively. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.56 (95% CI, 1.23-1.97) and 1.11 (95% CI, 1.00-1.24) for individuals with asthma+COPD+TB and asthma+COPD, respectively. Among male patients with stage III SqCC, HRs were 3.41 (95%CI, 1.27-9.17) and 1.65 (95%CI, 1.10-2.47) for individuals with asthma+TB and asthma+COPD+TB, respectively. Among male patients with stage IV SqCC, HRs were 1.40 (95%CI, 1.00-1.97) and 1.25 (95%CI, 1.03-1.52) for individuals with asthma+ COPD+TB and asthma. Among female patients with stage I and II, HR was 0.19 (95%CI, 005-0.77) for individuals with asthma., Conclusions: Coexisting pulmonary diseases increased the risk of mortality from SqCC in male patients. For female patients with early stage SqCC, pre-existing asthma decreased mortality. These patients deserve greater attention while undergoing cancer treatment.

Aim: The current study assessed the potential impact of diabetes type 1 and type 2 for female breast cancer risk., Materials and Methods: The health information and medical record of the entire adult female residents in Taiwan were retrieved from Taiwan's National Health Insurance Research Database. Multivariate Cox proportional hazard regression models and descriptive statistics were used to identify potential correlations between type 1/2 diabetes and breast cancer. In addition, this study statistically assessed the possible association of diabetes and breast cancer risk with age, insurance amount (quality of care), and regions., Results: The diabetic status of the entire adult female population was assessed between 2001 and 2003. Of 10,827,079 adult females, 4,738 (0.04%) were diagnosed with type 1 and 830,546 (7.7%) with type 2 diabetes, and 9, 991,795 (92.3%) were free of diabetes. From 2004 to 2010, a total of 57,283 cases of breast cancer were detected, with an average breast cancer incidence rate of 0.53% in the generation population. The actual breast cancer incidence rate was 0.30% (14 of 4,738) in patients with type 1 diabetes, 1.10% (9,105 of 830,546) in patients with type 2 diabetes, and 0.48% (48,164 of 9,991,795) in patients free of diabetes. The breast cancer incidence rate is significantly higher (p < 0.001) in patients with type 2 diabetes than that in patients with type 1 diabetes and in patients free of diabetes. After adjusting for the covariates of age, insurance cost, and region, hazard ratios (HRs) for the association between breast cancer risk and types 1 and 2 DM were 1.01 (CI = 0.60-1.71) and 1.13 (CI = 1.10-1.16), respectively. Women with type 2 diabetes were at a significantly higher risk for development of breast cancer compared with those free of diabetes, but there appeared to have no significant increase in risk for those with type 1 diabetes. Our study also revealed that age, insurance amount (quality of care), and region are significantly associated with diabetes and breast cancer risk (p<0.0001)., Conclusion: Our results demonstrated different implications of diabetes type for the risk of breast cancer with type 2 posing a higher risk than type 1. This is the largest cohort study that assesses the possible correlation between both type 1 and 2 diabetes with breast cancer, and also is the largest cohort study showing that diabetes are associated with age, insurance, and region, which further suggest that living condition and life style may significantly associated with diabetes and breast cancer.

Background: Deficits of learning, memory and cognition have been observed in newborn animals exposed to general anaesthetics. However, conclusions from clinical studies conducted in humans to investigate the relationship between anaesthesia and neurodevelopmental disorders have been inconsistent. Autistic disorder is typically recognised earlier than other neurobehavioural disorders. Although certain genes apparently contribute to autistic disorder susceptibility, other factors such as perinatal insults and exposure to neurotoxic agents may play a crucial role in gene-environmental interaction., Objective: This study was designed to investigate the association of exposure to general anaesthesia/surgery with autistic disorder. We hypothesised that exposure to general anaesthesia and surgery before 2 years of age is associated with an increased risk of developing autistic disorder., Design: A retrospective matched-cohort study., Setting: A medical university. Data from the National Health Insurance Research Database of Taiwan from 2001 to 2010 were analysed., Patients: The birth cohort included 114,435 children, among whom 5197 were exposed to general anaesthesia and surgery before the age of 2 years. The 1 : 4 matched controls comprised 20,788 children., Main Outcome Measures: The primary endpoint was the diagnosis of autistic disorder after the first exposure to general anaesthesia and surgery., Results: No differences were found in the incidence of autistic disorder between the exposed group (0.96%) and the unexposed controls (0.89%) (P = 0.62). Cox proportional regression showed that the hazard ratio of exposure to general anaesthesia and surgery was 0.93 [95% confidence interval (95% CI) 0.57 to 1.53] after adjusting for potential confounders. Age at first exposure did not influence the risk of autistic disorder. No relationship was found between the total number of exposures and the risk of autistic disorder., Conclusion: Exposure to general anaesthesia and surgery before the age of 2 years age at first exposure and number of exposures were not associated with the development of autistic disorder.

Objective: The present study assessed the effects of vegetarian and omnivorous diets on HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), TAG and the ratio of HDL-C to total cholesterol (TC) by gender., Design: HDL-C, LDL-C, TAG and HDL-C:TC were compared among three diet groups (vegan, ovo-lacto vegetarian and omnivorous). Multivariate linear regression analysis was performed to examine factors significantly and independently associated with vegetarian status and to estimate the β value of lipid profiles for the diet groups. Settings A cross-sectional study. Data were obtained from the Taiwanese Survey on the Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension (TwSHHH)., Subjects: The study comprised included 3257 men and 3551 women., Results: After adjusting for confounders, vegan and ovo-lacto vegetarian diets lowered LDL-C levels (β=-10.98, P=0.005 and β=-7.12, P=0.025, respectively) in men compared with omnivorous diet. There was a significant association between HDL-C and vegan diet (β=-6.53, P=0.004). In females, the β values of HDL-C, TAG and HDL-C:TC were -5.72 (P<0.0001), 16.51 (P=0.011) and -0.02 (P=0.012) for vegan diet, and -4.86 (P=0.002), 15.09 (P=0.008) and -0.01 (P=0.026) for ovo-lacto vegetarian diet, when compared with omnivorous diet., Conclusions: Vegan diet was associated with lower HDL-C concentrations in both males and females. Because the ovo-lacto vegetarian diet was effective in lowering LDL-C, it may be more appropriate for males.

Periodontitis and osteoporosis are primary concerns in public health and clinical management. The aim of this study was to investigate the association between periodontitis and osteoporosis by gender.Data were retrieved from the National Health Insurance Research Database, Taiwan. A diagnosis of periodontitis was defined on the basis of subgingival curettage, periodontal flap operation, and gingivectomy (excluding those with restorative or aesthetic indications). Multiple logistic regression was used for analysis. After adjusting for age, sex, income, and geographical region, there was a significant association between periodontitis and osteoporosis among women (odds ratio: 1.96; 95% confidence interval 1.17-3.26). The association between periodontitis and osteoporosis was significant among women.

Purpose: A novel application of infrared-C (IR-C) radiation (3-1000 μm) on hemiparetic stroke patients was evaluated. Hot compresses (HC) were used on the paretic shoulders of patients in this placebo-controlled trial to investigate the effects of IR-C on skin temperature, electrodermal conductance (EC) and pain relief., Materials and Methods: Skin temperature at the center of the middle deltoid (CMD), Quchi (LI11), and the center of the third metacarpal bone on dorsum of hand (COT) of the subjects at Brunnstrom stage 3-5 before and after IR-C HC, were examined. Meanwhile, EC was measured on Hegu (LI4), Quchi and Juanyu (LI15). Pain intensity was evaluated before and after treatment., Results: Skin temperature increased significantly at the CMD and COT on the paretic side in males. In females after treatment, similar skin temperatures were found in each measured region on both the paretic and non-paretic sides. The EC on the paretic side tended to be higher than the non-paretic side before treatment. After treatment, the EC on paretic side declined in both sexes and became even lower than the non-paretic side in females. Pain intensity was lessened after treatment especially in males, which appeared to correspond with an increase in skin temperature and a decrease in EC., Conclusion: IR-C hot compress is a promising method for stroke patients in rehabilitation. Physiological mechanisms of this treatment were proposed and summarized from this research.

Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common pulmonary diseases associated with lung cancer. Besides, smoking is more prevalent in Taiwanese men. This study evaluated gender disparities in coexisting pulmonary diseases on survival of patients with lung adenocarcinoma. Patients newly diagnosed with lung cancer between 2003 and 2008 were identified from Taiwan National Health Insurance Research Database. Cases with lung adenocarcinoma were further confirmed using the Cancer Registry Database and followed up until the end of 2010. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD, and/or TB to estimate all-cause mortality risk. During the study period, 13,399 cases of lung adenocarcinoma were identified. The HRs of adenocarcinoma in men and women were 1.20 (95% confidence interval [CI], 1.10-1.30) and 1.05 (95% CI, 0.95-1.16), respectively, for individuals with asthma, 1.32 (95% CI, 1.16-1.51) and 0.97 (95% CI, 0.89-1.05), respectively, for COPD, and 0.99 (95% CI, 0.93-1.06) and 1.06 (95% CI, 0.86-1.32), respectively, for individuals with TB. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.63 (95% CI, 1.25-2.13), 1.31 (95% CI, 1.08-1.59), and 1.23 (95% CI, 1.11-1.36) for individuals with asthma + COPD + TB, asthma + COPD, and COPD + TB, respectively. However, there was no increase risk of mortality among women with coexisting pulmonary diseases. Coexisting pulmonary diseases are at an elevated risk of mortality among male patients with lung adenocarcinoma. Such patients deserve greater attention while undergoing cancer treatment.

Effects of pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and lung tuberculosis (TB)] on subsequent lung cancer development have been reported. However, whether patients with coexisting pulmonary diseases are at greater risk of developing various histologic types of lung cancer remains elusive. Patients newly diagnosed with lung cancer between 2004 and 2008 were identified from National Health Insurance Research Database (Taiwan). The histologic types of lung cancer were further confirmed using Taiwan Cancer Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB to estimate lung cancer risk by histologic type. During the study period, 32,759 cases of lung cancer were identified from 15,219,024 residents age 20 years and older, who were free from the disease before 2003. Coexisting pulmonary diseases showed stronger association with lung cancer than specific lung disorders. Specifically, among men, the HRs for squamous cell carcinoma (SqCC) were 3.98 (95% CI, 3.22-4.93), 2.68 (95% CI, 2.45-2.93), and 2.57 (95% CI, 2.10-3.13) for individuals with asthma+COPD+TB, asthma+COPD, and COPD+TB, respectively. Among women, the HRs for SqCC were 3.64 (95% CI, 1.88-7.05), 3.35 (95% CI, 1.59-7.07), and 2.21 (95% CI, 1.66-2.94) for individuals with TB, COPD+TB, and asthma+COPD, respectively. Adenocarcinoma HRs for men and women were 2.00 (95% CI, 1.54-2.60) and 2.82 (95% CI, 1.97-4.04) for individuals with asthma+COPD+TB, 2.28 (95% CI, 1.91-2.73) and 2.16 (95% CI, 1.57-2.95) for COPD+TB, and 1.76 (95% CI, 1.04-2.97) and 2.04 (95% CI, 1.02-4.09) for individuals with asthma+TB. Specifically, small cell carcinoma (SmCC) HRs among men were 3.65 (95% CI, 1.97-6.80), 2.20 (95% CI, 1.45-3.36), and 2.14 (95% CI, 1.86-2.47) for those with asthma+TB, asthma+COPD+TB, and asthma+ COPD, respectively. Among women, the HRs of SmCC were 8.97 (95% CI, 3.31-24.28), 3.94 (95% CI, 1.25-12.35) and 3.33 (95% CI, 2.23-4.97) for those with asthma+COPD+TB, COPD+TB, and asthma+COPD, respectively. Patients with coexistence of pulmonary diseases were more susceptible to lung cancer. Affected persons deserve greater attention while undergoing cancer screening.

Background: Vegan diet has been associated with lower risk of cardiovascular diseases and mortality, partly due to its effects on serum lipid profiles. Lipid profiles [high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and triglycerides (TG)] have not been fully elucidated either in pre and postmenopausal vegans or in ovo-lacto vegetarians. This study aimed to compare lipid profiles among vegans, ovo-lacto vegetarians and omnivores., Methods: Demographic data and lipid profiles were obtained from the 2002 Taiwanese Survey on Hypertension, Hyperglycemia and Hyperlipidemia. Multivariate linear regression analysis was used to examine factors significantly and independently associated with different categories of veganism and to estimate the β value of lipid profiles in the dietary types., Results: A total of 2397 premenopausal and 1154 postmenopausal participants who did not receive lipid lowering drugs were enrolled. Premenopausal vegans had significantly lower HDL-C and higher TG, LDL-C/HDL-C, total cholesterol (TC)/HDL-C and TG/HDL-C compared with omnivores. For postmenopausal women, vegans had lower TC while ovo-lacto vegetarians were observed with low HDL-C when compared with omnivores. Multivariate linear regression analyses showed that vegan and ovo-lacto vegetarian diets decreased HDL-C levels in premenopausal women (β = -7.63, p = 0.001 and β = -4.87, p = 0.001, respectively). There were significant associations between lower LDL-C and ovo-lacto vegetarian diets (β = -7.14, p = 0.008) and also between TG and vegan diet (β = 23.37, p = 0.008), compared with omnivorous diet. Post-menopausal women reported to have consumed either a vegan or an ovo-lacto vegetarian diet were at the risk of having low HDL-C unlike those that consumed omnivorous diets (β = -4.88, p = 0.015 and β = -4.48, p = 0.047). There were no significant changes in LDL-C in both pre and postmenopausal vegans., Conclusions: Vegan diet was associated with reduced HDL-C level. Because of its effects on lowering HDL-C and LDL-C, ovo-lacto vegetarian diet may be more appropriate for premenopausal women.

Background: Most cancers share common risk factors. It might provide evidence of shared risk factors with cancers by investigating cross-country and cross-township comparisons., Methods: The data were obtained from International Association of Cancer Registries/World Health Organization and the National Cancer Registration Program of Taiwan. Age standardized incidence rates were calculated among gastric cancer, colorectal cancer and lung adenocarcinoma in 19 countries from 1995 to 1998. The Pearson correlations were also compared among 3 types of cancers for both sexes., Results: The incidence rates of gastric and colorectal cancer throughout different countries show male dominance with a male-to-female sex ratio of around 2 and 1.5, respectively. Significant cross-country correlations in colorectal cancer (r=0.918, p<0.001), gastric cancer (r=0.985, p<0.001) and lung adenocarcinoma (r=0.685, p=0.001) were observed between men and women. There was a significant international correlation between colorectal cancer and lung adenocarcinoma in men (r=0.526, p=0.021), but not in women. In cross-township comparisons of Taiwan, there were significant correlations in colorectal cancer (r=0.451, p<0.001), gastric cancer (r=0.486, p<0.001), and lung adenocarcinoma (r=0.217, p<0.001) between men and women. There were links of lung adenocarcinoma and gastric cancer (r=0.122, p=0.024) and colorectal cancer (r=0.128, p=0.018) in women, and lung adenocarcinoma and colorectal cancer in men (r=0.276, p<0.001)., Conclusions: There were associations between lung adenocarcinoma and colorectal cancer between and in both sexes in Taiwan, but not in cross-country comparisons. The results suggest that some factor, like genes, may be important as determinants for the association between lung adenocarcinoma and colorectal cancer.

Background: Traditional lipid indices have been associated with type 2 diabetes, but it remains uncertain which lipid index is the best discriminator for diabetes. In this study, we aimed to assess lipoproteins, traditional lipid variables, and other variables to discover their association with diabetes in the Taiwanese population., Methods: Data from a nationwide cross-sectional population-based survey of 3087 men and 3373 women in 2002 were analyzed in this study. All participants were assessed for anthropometry, glycosylated hemoglobin, fasting sugar and lipid profiles with triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) and B (ApoB). The ratio of LDL-C/HDL-C, ApoB/ApoA1, ApoB/LDL-C and ApoA1/HDL-C and other variables were analyzed to determine their potential roles in type 2 diabetes in the Taiwanese population. The Odds ratios (ORs) of the risk variables for diabetes were estimated using logistic regression and were adjusted for confounding factors., Results: The increased ratio of ApoA1/HDL-C was significantly associated with diabetes in men (top tertile vs. lowest: OR 2.98; 95% CI: 1.12 - 7.92; P-trend = 0.030) and women (top tertile vs. lowest: OR 2.15; 95% CI: 1.00 - 4.59; P-trend = 0.047). A modest increased diabetic risk was evident with ApoB/LDL-C in women (top tertile vs. lowest: OR 2.03; 95% CI: 1.07- 3.85; P-trend = 0.028), but not in men (top tertile v. lowest: OR 1.69; 95% CI: 0.79- 3.62; P-trend = 0.198)., Conclusions: ApoA1/HDL-C had a significant linear association with diabetes in both sexes and was superior to other lipid and lipoprotein variables among the general Taiwanese population.

Background: To examine the association of anthropometry indices with gout and to compare the performance of indices to predict gout in Taiwanese men., Methods: There were 1443 male subjects aged more than 20 years who participated in the Nutrition and Health Survey in Taiwan (NAHSIT, 1993-1996). Anthropometric evaluation consisted of weight, height, hip and waist circumference (WC) with later body mass index (BMI), waist to height (WHtR) and waist to hip (WHR) estimations. We conducted 4 logistic models to determine the relationships between anthropometric indices and gout. Receiver operating characteristic (ROC) curve were used to compare the predictive performance and to identify the optimal cut-off points, sensitivity and specificity of these indices for gout in men., Results: After controlling for other covariables, the adjusted odds ratios for the mid and top tertiles of WHtR were 2.55 (95% CI: 1.16, 5.59) and 3.01 (95% CI: 1.13, 7.99), respectively, but no linear association was found for BMI, WHR and WC. In ROC curve, the greatest area under curve was 0.684 for WHtR and the cut-off point of WHtR was 0.57., Conclusions: WHtR had a significant linear association with gout in Taiwanese men and was superior to BMI, WHR and WC.

Background: Many studies have examined the risk factors for HCC (including hepatitis B virus, hepatitis C virus, aflatoxin, retinol, cigarette smoking, and alcohol consumption). However, data from previous studies on the association between iron exposure, land subsidence, and HCC mortality/incidence were limited, especially in Taiwanese population. We aimed to explore the geographical distribution of HCC mortality rates by township-specific data and to evaluate the association between HCC mortality, land subsidence, and iron levels in groundwater in Taiwan., Methods: We conducted an ecological study and calculated the HCC age-standardized mortality/incidence rates according to death certificates issued in Taiwan from 1992 to 2001 and incidence data from 1995-1998. The land subsidence dataset before 2005 and iron concentrations in groundwater in 1989 are also involved in this study. Both geographical information systems and Pearson correlation coefficients were used to analyze the relationship between HCC mortality rates, land subsidence, and iron concentrations in groundwater., Results: Township-specific HCC mortality rates are higher in southwestern coastal townships where serious land subsidence and higher township-specific concentrations of iron in groundwater are present. The Pearson correlation coefficients of iron concentrations in groundwater and ASRs of HCC were 0.286 (P = 0.004) in males and 0.192 (P = 0.058) in females for mortality data; the coefficients were 0.375 (P < 0.001) in males and 0.210 (P = 0.038) in females for incidence data., Conclusions: This study showed that HCC mortality is clustered in southwestern Taiwan and the association with the iron levels in groundwater in Taiwanese population warrant further investigation.

Background: Numerous studies have examined the association between heavy metal contamination (including arsenic [As], cadmium [Cd], chromium [Cr], copper [Cu], mercury [Hg], nickel [Ni], lead [Pb], and zinc [Zn]) and lung cancer. However, data from previous studies on pathological cell types are limited, particularly regarding exposure to low-dose soil heavy metal contamination. The purpose of this study was to explore the association between soil heavy metal contamination and lung cancer incidence by specific cell type in Taiwan., Methods: We conducted an ecological study and calculated the annual averages of eight soil heavy metals (i.e., As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) by using data from the Taiwan Environmental Protection Administration from1982 to 1986. The age-standardized incidence rates of lung cancer according to two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]) were obtained from the National Cancer Registry Program conducted in Taiwan from 2001 to 2005. A geographical information system was used to plot the maps of soil heavy metal concentration and lung cancer incidence rates. Poisson regression models were used to obtain the adjusted relative ratios (RR) and 95% confidence intervals (CI) for the lung cancer incidence associated with soil heavy metals., Results: For males, the trend test for lung SCC incidence caused by exposure to Cr, Cu, Hg, Ni, and Zn showed a statistically significant dose-response relationship. However, for lung AC, only Cu and Ni had a significant dose-response relationship. As for females, those achieving a statistically significant dose-response relationship for the trend test were Cr (P = 0.02), Ni (P = 0.02), and Zn (P= 0.02) for lung SCC, and Cu (P < 0.01) and Zn (P = 0.02) for lung AC., Conclusion: The current study suggests that a dose-response relationship exists between low-dose soil heavy metal concentration and lung cancer occurrence by specific cell-type; however, the relevant mechanism should be explored further.

Purpose: Colorectal cancer (CRC) is the second most common cause of cancer death in developed countries among men (after lung cancer) and the third most common among women. This study thus examines the long-term trends of CRC mortality in Taiwan., Methods: CRC cases were collective between patients aged 30 years or older and younger than 85 years from the Taiwan death registries during 1971-2010. Standard descriptive techniques such as age-standardized mortality rates (ASMR), aural percent change, and age-period-cohort analyses were used., Results: The increase of percentage change by each age group in men was higher than in women. The ASMR of CRC increased 2-fold for men and almost 1.5-fold for women during the periods 1971-1975 and 2006-2010. For age-period-cohort analysis, the estimated mortality rate increased steadily with age in both sexes, and plateaued at 175.29 per 100,000 people for men and 128.14 per 100,000 for women in the 80- to 84-year-old group. Period effects were weak in both sexes. Cohort effects were strong. Between 30 and 59 years of age, the sex ratio showed that the female CRC mortality rate was higher than that of their male counterparts. Conversely, the mortality risk of CRC in men was higher than that in women when they were between 60 and 84 years old., Conclusions: The current findings showed a consistent increase in mortality from CRC over the years. Changes in the patient sex ratio indicated an important etiological role of sex hormones, especially in women aged 60 years or younger.

Background: Many studies have examined the association between air pollutants (including sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], nitric oxide [NO], ozone [O3], and particulate matter < 10 μm [PM10]) and lung cancer. However, data from previous studies on pathological cell types were limited, especially for SO2 exposure. We aimed to explore the association between SO2 exposure from outdoor air pollutants and female lung cancer incidence by cell type specificity., Methods: We conducted an ecological study and calculated annual average concentration of 6 air pollutants (SO2, CO, NO2, NO, O3, and PM10) using data from Taiwan Environmental Protection Administration air quality monitoring stations. The Poisson regression models were used to evaluate the association between SO2 and age-standardized incidence rate of female lung cancer by two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]). In order to understand whether there is a dose-response relationship between SO2 and two major pathological types, we analyzed 4 levels of exposure based on quartiles of concentration of SO2., Results: The Poisson regression results showed that with the first quartile of SO2 concentration as the baseline, the relative risks for AC/SCC type cancer among females were 1.20 (95% confidence interval [CI], 1.04-1.37)/1.39 (95% CI, 0.96-2.01) for the second, 1.22 (95% CI, 1.04-1.43)/1.58 (95% CI, 1.06-2.37) for the third, and 1.27 (95% CI, 1.06-1.52)/1.80 (95% CI, 1.15-2.84) for the fourth quartile of SO2 concentration. The tests for trend were statistically significant for both AC and SCC at P = 0.0272 and 0.0145, respectively., Conclusion: The current study suggests that SO2 exposure as an air pollutant may increase female lung cancer incidence and the associations with female lung cancer is much stronger for SCC than for AC. The findings of this study warrant further investigation on the role of SO2 in the etiology of SCC.

Objective: There is a need to develop alternative therapeutic strategies to overcome cisplatin-associated resistance in patients with ovarian cancer. Histone deacetylation (HDAC) associated with inactivation of genes has been implicated in the epigenetic silencing of tumor suppressor genes affecting critical biological activities in cancer cells and may be an important factor in acquired cisplatin-associated resistance. In this report, we tested a combination of cisplatin and LBH589 (histone deacetylation inhibitor) in cisplatin-resistant ovarian cancer cells to explore the reversal effect of cisplatin resistance and changes of gene expression., Materials and Methods: To detect the synergistic effects of antiproliferation between cisplatin and LBH589 in ovarian cancer cells, we performed a cell viability assay and a clonogenic assay. To investigate the differences of gene expression between cells treated by cisplatin alone and cotreated with cisplatin and LBH589, a microarray mRNA analysis was performed., Results: In the presence of low-dose LBH589, the inhibition concentration value of cisplatin for A2780-cp70 cells was much lower than with cisplatin treatment alone. Gene expression profiles identified that a total of 354 genes had been significantly upregulated and a total of 63 genes been downregulated with LBH589 cotreatment., Conclusion: We hypothesized that combination of cisplatin and LBH589 can override cisplatin-associated resistance in ovarian cancer cells. These results provide initial evidence for testing this combination in clinical use., (Copyright © 2011. Published by Elsevier B.V.)

Microtubule is a popular target for anticancer drugs. Chamaecypanone C, is a natural occurring novel skeleton compound isolated from the heartwood of Chamaecyparis obtusa var. formosana. The present study demonstrates that chamaecypanone C induced mitotic arrest through binding to the colchicine-binding site of tubulin, thus preventing tubulin polymerization. In addition, cytotoxic activity of chamaecypanone C in a variety of human tumor cell lines has been ascertained, with IC(50) values in nanomolar ranges. Flow cytometric analysis revealed that chamaecypanone C treated human KB cancer cells were arrested in G(2)-M phases in a time-dependent manner before cell death occurred. Additional studies indicated that the effect of Chamaecypanone C on cell cycle arrest was associated with an increase in cyclin B1 levels and a mobility shift of Cdc2/Cdc25C. The changes in Cdc2 and Cdc25C coincided with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Interestingly, this compound induced apoptotic cell death through caspase 8-Fas/FasL dependent pathway, instead of mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug resistant cancer cell lines overexpressing P-gp170/MDR and MRP were sensitive to Chamaecypanone C. Taken together, these findings indicated that Chamaecypanone C is a promising anticancer compound that has potential for management of various malignancies, particularly for patients with drug resistance., (2009 Elsevier Inc. All rights reserved.)

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrol], a novel selenophene derivative, is a highly potent cytotoxic agent with broad spectrum antitumor activity. The present study was undertaken to explore the mechanism(s) through which D-501036 exerts its action mode on the cancer cell death. D-501036 was found to suppress the growth of KB and HepG(2) cells in an irreversible manner. The results of annexin-V assays and PARP cleavage studies were consistent with the D-501036-induced apoptosis. Findings provided a strong support for the induction of mitochondria-mediated apoptosis by this drug. The examination of two canonical pathways of initiation caspases, those for caspases -8 and -9, revealed that caspase-9 protein and the activities of caspases -9 and -3 were increased in a dose- and time-dependent manner. The concentrations of Fas/Fas-L and procaspase-8 and the activity of caspase-8 were not altered. Furthermore, the mitochondrial membrane potential permeability and the release of cytochrome c to the cytosol were both increased by D-501036. The concentrations of the pro-apoptotic protein Bax and translocation of Bax from the cytosol to the mitochondria were increased in response to D-501036, whereas the concentrations of the anti-apoptotic protein Bcl-2 were decreased. Two DNA damage-related pro-apoptotic proteins, Puma and Noxa, were upregulated in a dose- and time-dependent manner. These pro-apoptotic and anti-apoptotic proteins are downstream effectors of p53. Accordingly, the phosphorylated and total forms of p53 were induced and p53 was translocated from the cytosol to the mitochondria in response to D-501036 treatment. Collectively, we conclude that D-501036 induces cellular apoptosis through the p53-associated mitochondrial pathway.

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G(0)-G(1) and G(2)-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036-induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036-mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036-induced DNA damage activated ataxia telangiectasia-mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21(WAF1) in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036-induced cell death was associated with DNA damage-mediated induction of ataxia telangiectasia-mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers.

Clostridium botulinum neurotoxin type A (BTx-A) is known to inhibit the release of acetylcholine at the neuromuscular junctions and synapses and to cause neuroparalysis and death. In this study, we have identified two monoclonal antibodies, BT57-1 and BT150-3, which protect ICR mice against lethal doses of BTx-A challenge. The neutralizing activities for BT57-1 and BT150-3 were 10(3) and 10(4) times the 50% lethal dose, respectively. Using immunoblotting analysis, BT57-1 was recognized as a light chain and BT150-3 was recognized as a heavy chain of BTx-A. Also, applying the phage display method, we investigated the antibodies' neutralizing B-cell epitopes. These immunopositive phage clones displayed consensus motifs, Asp-Pro-Leu for BT57-1 and Cys-X-Asp-Cys for BT150. The synthetic peptide P4M (KGTFDPLQEPRT) corresponded to the phage-displayed peptide selected by BT57-1 and was able to bind the antibodies specifically. This peptide was also shown by competitive inhibition assay to be able to inhibit phage clone binding to BT57-1. Aspartic acid (D(5)) in P4M was crucial to the binding of P4M to BT57-1, since its binding activity dramatically decreased when it was changed to lysine (K(5)). Finally, immunizing mice with the selected phage clones elicited a specific humoral response against BTx-A. These results suggest that phage-displayed random-peptide libraries are useful in identifying the neutralizing epitopes of monoclonal antibodies. In the future, the identification of the neutralizing epitopes of BTx-A may provide important information for the identification of the BTx-A receptor and the design of a BTx-A vaccine.

A potential mechanism for the increased sensitivity of inflamed tissues to bradykinin is the upregulation of bradykinin receptor expression. We report that recombinant human IFNgamma stimulated a concentration-dependent increase in cell surface bradykinin receptor expression in intact T24 human epithelial-like cells, determined by radioligand binding analysis. Analysis of specific [3H]-bradykinin binding revealed that IFNgamma-treated cells had a two- to threefold increase in bradykinin receptor number compared to the controls with no effect on receptor affinity. The ability of IFNgamma to stimulate increased bradykinin receptor expression was abrogated by treatment with either the transcription inhibitor actinomycin D or the protein synthesis inhibitor cycloheximide. IFNgamma enhanced steady-state human B2 bradykinin receptor mRNA expression in the T24 cells in a dose-dependent manner. B2 bradykinin receptor mRNA expression was increased as early as 1 h following IFNgamma stimulation, and continued to accumulate for 24 h. Bradykinin-stimulated intracellular calcium mobilization was also increased in IFNgamma-treated T24 cells compared to controls. The ability of IFNgamma to upregulate B2 bradykinin receptors in primary epithelial cells was demonstrated using cultured human airway epithelial cells. These observations suggest that increasing IFNgamma levels during inflammation may upregulate the expression of B2 bradykinin receptors, leading to increased sensitivity to bradykinin.

Objective: To identify a Golgi complex autoantigen bound by Sjögren's syndrome (SS) autoantibodies., Methods: Serum from a patient with secondary SS and anti-Golgi antibodies was used as a probe to isolate a complementary DNA (cDNA) insert from a HeLa cDNA library., Results: A 3.7-kb cDNA encoding a 56-kd recombinant protein was immunoprecipitated by the human anti-Golgi serum and immune rabbit serum. Western blot analysis showed that the immune rabbit sera recognized a protein of 97 kd (golgin-97), suggesting that the isolated clone contained a partial cDNA. The 5' upstream sequence was obtained by rapid amplification of the cDNA ends. The complete cDNA contained 4,860 basepairs, encoding a protein with a calculated Mr of 88 kd. Antibodies to golgin-97 were found in 12 (20%) of 60 sera known to have anti-Golgi autoantibodies, and the majority of these sera (8 of 12, or 75%) were from patients who had secondary SS., Conclusion: Golgin-97 is a unique Golgi complex antigen that appears to be a target of SS autoantibodies.

The B2 bradykinin receptor (B2BKR) mediates most of the inflammatory actions of bradykinin. To evaluate its potential role in allergic diseases, we assessed the structure of the human B2BKR gene. Screening a human placenta genomic DNA library identified only clones containing exons 2 and 3. Human placenta and colon tissues were used for 5' rapid amplification of complementary DNA ends to identify nine exon 1 clones, each containing one 9 bp and two 1 bp deletions compared with published sequences. Exon 1 genomic polymerase chain reaction of human leukocyte DNA revealed two distinct products, which were shown to differ by the presence or absence of the 9 bp deletion. Alleles with the 9 bp deletion were designated as (-)21-29, whereas alleles without the deletion were designated as (+)21-29. Genomic polymerase chain reaction in 39 Caucasian, 31 African-American, and 32 Asian normal subjects revealed a highly significant difference in the allelic frequency of the two genotypes, primarily because of an absence of the (+)21-29 allele in Asian subjects. Analysis of steady-state B2BKR messenger RNA levels by reverse-transcription polymerase chain reaction in heterozygous normal subjects revealed consistently higher expression of (-)21-29 transcripts. To investigate the potential clinical significance of the exon 1 polymorphism, 21 patients with angioedema and C1 inhibitor deficiency were genotyped. None were homozygous for the (+)21-29 allele (p = 0.0088 compared with normal subjects). In contrast, two patients with immunochemical evidence of hereditary angioedema without history of clinical angioedema were (+)21-29 homozygous. These results suggest that the B2BKR genotype may influence clinical status in diseases characterized by involvement of bradykinin.

Bradykinin (BK), a pluripotent nonameric peptide, is known for its proinflammatory functions in both tissue injury and allergic inflammation of the airway mucosa and submucosa. To understand the mechanisms by which BK serves as an inflammatory mediator, the human lung fibroblast cell line WI-38 was stimulated with BK and the expression of IL-1beta gene was examined. BK at nanomolar concentrations induced a marked increase in immunoreactive IL-1beta, detectable within 2 h in both secreted and cell-associated forms. BK-induced IL-1beta synthesis was inhibited by a B2-type BK receptor antagonist and by treatment of the cells with pertussis toxin, indicating the involvement of a BK receptor that couples to the G(i)/G(o) class of heterotrimeric G proteins. Whereas cycloheximide and actinomycin D both inhibited BK-induced IL-1beta synthesis, results from Northern blot and nuclear run-on assays suggested that BK acted primarily at the transcription level which led to the accumulation of IL-1beta message in stimulated cells. Gel mobility shift assays were used with nuclear extracts from stimulated WI-38 cells to examine the transcription mechanism for BK-induced IL-1beta expression. A DNA binding activity specific for the decameric kappaB enhancer was detected and was found to contain the p50 and p65 subunits of the NF-kappaB/rel protein family. BK-induced NF-kappaB activation correlated with IL-1beta message upregulation with respect to agonist concentration, time course, sensitivity to bacterial toxins, and blockade by the B2 receptor antagonist. After BK stimulation, a significant increase in the activity of chloramphenicol acetyltransferase was observed in WI-38 cells transfected with a reporter plasmid bearing the kappaB enhancers from the IL-1beta gene. Deletion of the kappaB enhancer sequence significantly reduced BK-induced chloramphenicol acetyltransferase activity. These findings suggests a novel function of BK in the activation of NF-kappaB and the induction of cytokine gene expression.