Blackfoot Disease Endemic Area Research Articles

In situ X-ray absorption spectroscopic studies of photocatalytic oxidation of As(III) to less toxic As(V) by TiO2 nanotubes.

Arsenic in groundwater caused the black-foot disease (BFD) in many countries in the 1950-1960s. It is of great importance to develop a feasible method for removal of arsenic from contaminated groundwater in BFD endemic areas. Photocatalytic oxidation of As(III) to less toxic As(V) is, therefore, of significance for preventing any arsenic-related disease that may occur. By insitu synchrotron X-ray absorption spectroscopy, the formation of As(V) is related to the expense of As(III) disappearance during photocatalysis by TiO2 nanotubes (TNTs). Under UV/Vis light irradiation, the apparent first-order rate constant for the photocatalytic oxidation of As(III) to As(V) is 0.0148 min-1. Itseems that As(III) can be oxidized with photo-excited holes while the not-recombined electrons may be scavenged with O2 in the channels of the well defined TNTs (an opening of 7 nm in diameter). In the absence of O2, on the contrary, As(III) can be reduced to As(0), to some extent. Cu(II) (CuO), as an electron acceptor, was impregnated on the TNTs surfaces in order to gain a better understanding of electron transfer during photocatalysis. It appears that As(III) can be oxidized to As(V) while Cu(II) is reduced to Cu(I) and Cu(0). The molecular-scale data are very useful in revealing the oxidation states and interconversions of arsenic during the photocatalytic reactions. This work has implications in that the toxicity of arsenic in contaminated groundwater or wastewater can be effectively decreased via solar-driven photocatalysis, which may facilitate further treatments by coagulation.

Comparative analysis of patients with upper urinary tract urothelial carcinoma in black-foot disease endemic and non-endemic area

BackgroundA high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival.MethodsThe records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups.ResultsFemale predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2–1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease.ConclusionsA higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

Aberrant β-catenin expression in urothelial carcinomas in blackfoot disease-endemic areas

Arsenic is a well-known toxic element and carcinogenic agent. The aim of this study was to investigate p63, E-cadherin, and β-catenin proteins in urothelial carcinoma (UC) in both arsenic contaminated areas [so-called blackfoot disease (BFD) area] and non-BFD areas. The expressions of p63, E-cadherin, and β-catenin proteins in 20 UC cases of blackfoot disease and 22 UC cases in non-BFD areas were detected using immunohistochemical methods. The results revealed a high p63 expression in 20 (47.6%) UC cases and high E-cadherin expression in six (14.3%) UC cases. Expressions of p63 and E-cadherin showed no significant correlations with clinicopathologic parameters. However, all 20 BFD cases and 12 of 22 (54.5%) non-BFD cases showed aberrant β-catenin expression. Ten out of 22 (45.5%) non-BFD cases also had normal membranous immunoreactivity. The β-catenin staining pattern significantly differed between cases in endemic and nonendemic areas of BFD (p=0.001). Tumor sites also significantly correlated with β-catenin expression (p=0.044). In addition, membranous localization of β-catenin was lower in UC from BFD-endemic areas compared with those from non-BFD endemic areas. In conclusion, it is suggested that relocalization of β-catenin from membrane to cytoplasm may be involved in the tumorigenesis of UC from BFD-endemic areas.

Relationship between arsenic-containing drinking water and skin cancers in the arseniasis endemic areas in Taiwan.

Artesian well-water had high concentrations of arsenic that led to the well-known black foot disease in Taiwan around the 1950s, and the associated cancers including skin cancer, bladder cancers and lung cancers. We sought to estimate the standardized morbidity ratio (SMR) and age-standardized incidence rate (ASIR) of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in the black foot disease endemic areas (BFDEA) in Taiwan. A nationwide retrospective population-based survey was done with the data from the National Taiwan Cancer Registry Center between 1979 and 2007. Among the 29-year period, there were 11191 cases with SCC and 13684 cases with BCC diagnosed pathologically. The incidence rates were 4-6-fold higher for SCC and 3-4-fold higher for BCC in the BFDEA compared with the rest of Taiwan. The SMR decreased after stopping arsenic-containing well-water drinking in the 1970s. The arsenic level in the drinking water, amount of contaminated water intake, occupation and sun-exposure time were not documented. This is the first nationwide, population-based study that shows the relationship between arsenic intoxication and non-melanoma skin cancers (SCC and BCC) through comparing the data in people living in the BFDEA and non-BFDEA in Taiwan.

Characteristics of arsenic-related bladder cancer: A study from Nationwide Cancer Registry Database in Taiwan

ObjectiveTo investigate the clinical and pathological characteristics of arsenic-related bladder cancer. MethodsFrom 2008 through 2011, data on 7699 patients with bladder cancer were extracted from the Taiwan Cancer Registry Database. A diagnosis of bladder cancer (International Statistical Classification of Diseases and Related Health Problems, 9th Revision: 188) was confirmed in all patients. Using birth residency codes, patients were divided into three groups: the core zone (CZ; an arsenic endemic area with well water arsenic levels of 350–1100 ng/mL); zone 1 (Z1; an area with well water arsenic levels of≥350 ng/mL but not a blackfoot disease-endemic area); and zone 2 (Z2; an area with well water arsenic levels of<350 ng/mL). Clinicopathological characteristics and survival outcomes were compared between the three groups. ResultsIn this cohort, 119 (1.5%), 1145 (14.9%), and 6435 (83.6%) patients were born in the CZ, Z1, and Z2, respectively. A higher proportion of female patients (35.3%, 31.4%, and 27.5%; p = 0.014) and lower smoking rates (29%, 34.8%, and 35.9%; p = 0.694) were noted in the CZ compared with Z1 and Z2. CZ patients had more high-grade differentiated (80.9%, 69.9%, and 63.0%; p < 0.001) and high clinical stage (stages II–IV, 52.8%, 38.1%, and 31.8%; p < 0.001) tumors compared with Z1 and Z2 patients. Radical cystectomy was infrequently performed for clinical stage II (19.6%) and stage III (25.2%) bladder cancer patients. CZ patients had significantly shorter overall and cancer-specific survival durations compared with Z1 and Z2 patients. Older age, female sex, higher tumor grade or stage, and higher arsenic levels were associated with both poorer overall and cancer-specific survival in a multivariate analysis with a Cox proportional model. ConclusionIn Taiwan, patients with arsenic-related bladder cancer may have poorer tumor characteristics and decreased overall and cancer-specific survival rates.

Discontinuity in the cancer slope factor as it passes from high to low exposure levels--arsenic in the BFD-endemic area.

The ingestion of inorganic arsenic causes bladder and lung cancers demonstrably at >400-500ug/L but questionably below 100-200ug/L. Using the standard 42-village cancer mortality dataset from the Blackfoot-disease (BFD) endemic area of southwest Taiwan (Wu et al., 1989), we examined the risk from low exposures by excluding the high exposures. Poisson regression analyses with the sequential removal of the highest exposure village have been performed using the median, mean, or maximum village well water arsenic level and demonstrated graphically. Risk estimates are positive when villages with exposures of 200-400ug/L are included and significantly so when villages with >400ug/L are included. Risk estimates for exposures below 100ug/L are negative but rarely significantly so. The inflection point where the slope is no longer positive occurs in the range of 100-200ug/L, depending upon whether the exposure metric used is the median, the mean or the maximum. There is a discontinuity in the cancer slope factor or risk from arsenic exposure that occurs in the range of 100-200ug/L. Above these levels, there are significantly positive risks, while below these levels there are not. The analysis reveals within this dataset an intrinsic non-linearity in the cancer risk. The literature speaks to this discontinuity, but this is the first demonstration within a single dataset that shows the discontinuity across the full exposure range and where the low-dose data are not compromised with high-dose data.

Depth-resolved abundance and diversity of arsenite-oxidizing bacteria in the groundwater of Beimen, a blackfoot disease endemic area of southwestern Taiwan

The role of arsenite oxidizers in natural attenuation of arsenic pollution necessitates studies on their abundance and diversity in arsenic-contaminated aquifers. In this study, most probable number-polymerase chain reaction (MPN-PCR) and denaturing gradient gel electrophoresis (DGGE) was applied to monitor depth-wise abundance and diversity of aerobic arsenite oxidizers in arsenic-enriched groundwater of Beimen, southwestern Taiwan. The results revealed that the abundance of arsenite oxidizers ranged from 0.04 to 0.22, and the lowest ratio was observed in the most arsenic-enriched and comparatively more reduced groundwater (depth 200 m) of Beimen 1. The highest ratio was observed in the less arsenic-enriched and less reduced groundwater (depth 60 m) of Beimen 2B. DGGE profiles showed a shift in diversity of arsenite oxidizers, consisting of members of the Betaproteobacteria (61%), Alphaproteobacteria (28%) and Gammaproteobacteria (11%), depending on mainly arsenic concentration and redox level in groundwater. Groundwater with the lowest arsenic and highest dissolved oxygen at Beimen 2B harbored 78% of the arsenite oxidizers communities, while groundwater with the highest arsenic and lowest dissolved oxygen at Beimen 1 and Beimen–Jinhu harbored 17 and 22% of arsenite oxidizers communities, respectively. Pseudomonas sp. was found only in groundwater containing high arsenic at Beimen 1 and Beimen–Jinhu, while arsenite oxidizers belonging to Alpha- and Betaproteobacteria were dominated in groundwater containing low arsenic.

Removal of arsenic from groundwater by using a native isolated arsenite-oxidizing bacterium

Arsenic (As) contamination of groundwater is a significant public health concern. In this study, the removal of arsenic from groundwater using biological processes was investigated. The efficiency of arsenite (As(III)) bacterial oxidation and subsequent arsenate (As(V)) removal from contaminated groundwater using bacterial biomass was examined. A novel As(III)-oxidizing bacterium (As7325) was isolated from the aquifer in the blackfoot disease (BFD) endemic area in Taiwan. As7325 oxidized 2300μg/l As(III) using in situ As(III)-contaminated groundwater under aerobic conditions within 1d. After the oxidation of As(III) to As(V), As(V) removal was further examined using As7325 cell pellets. The results showed that As(V) could be adsorbed efficiently by lyophilized As7325 cell pellets, the efficiency of which was related to lyophilized cell pellet concentration. Our study conducted the examination of an alternative technology for the removal of As(III) and As(V) from groundwater, indicating that the oxidation of As(III)-contaminated groundwater by native isolated bacterium, followed by As(V) removal using bacterial biomass is a potentially effective technology for the treatment of As(III)-contaminated groundwater.

Arsenic-induced Aurora-A activation contributes to chromosome instability and tumorigenesis

Arsenic may cause serious environmental pollution and is a serious industrial problem. Depending on the dosage, arsenic may trigger the cells undergoing either proliferation or apoptosis-related cell death. Because of lack of the proper animal model to study arsenic induced tumorigenesis, the accurate risk level of arsenic exposure has not been determined. Arsenic shows genotoxic effect on human beings who uptake water contaminated by arsenic. Chromosome aberration is frequently detected in arsenic exposure-related diseases and is associated with increased oxidative stress and decreased DNA repairing activity, but the underlying mechanism remains elusive.Aurora-A is a mitotic kinase, over-expression of Aurora-A leads to centrosome amplification, chromosomal instability and cell transformation. We revealed that Aurora-A is over-expressed in the skin and bladder cancer patients from blackfoot-disease endemic areas. Our cell line studies reveal that arsenic exposure between 0.5μM and 1μM for 2–7days are able to induce Aurora-A expression and activation based on promoter activity, RNA and protein analysis. Aurora-A overexpression further increases the frequency of unsymmetrical chromosome segregation through centrosome amplification followed by cell population accumulated at S phase in immortalized keratinocyte (HaCaT) and uroepithelial cells (E7). Furthermore, Aurora-A over-expression was sustained for 1–4weeks by chronic treatment of immortalized bladder and skin cells with NaAsO2. Aurora-A promoter methylation and gene amplification was not detected in the long-term arsenic treated E7 cells. Furthermore, the expression level of E2F1 transcription factor (E2F1) is increased in the presence of arsenic, and arsenic-related Aurora-A over-expression is transcriptionally regulated by E2F1. We further demonstrated that overexpression of Aurora-A and mutant Ha-ras or Aurora-A and mutant p53 may act additively to trigger arsenic-related bladder and skin cancer formation, respectively. It indicates that from chromosome instability proceeding to tumorigenesis, the simultaneous action of Aurora-A with activated oncogenic factor or inactivated tumor suppressor is required.In summary, we hypothesize that low concentration (0.5–1μM) of arsenic-induced E2F1-Aurora-A signaling pathway results in aberrant chromosome distribution during cell mitosis, the abnormal mitotic cells proceed to cancer cells only after acquiring additional tumorigenic factors. Our studies suggest that inhibition of low concentration of arsenic induced Aurora-A expression may provide a new theraputical strategy for the prevention and treatment of arsenic-related cancers.

Bladder/lung cancer mortality in Blackfoot-disease (BFD)-endemic area villages with low (

ObjectiveTo examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. MethodPoisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. ResultsUse of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. ConclusionThe cancer rates are higher among the low-dose (<150μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.

Assessing the mechanisms controlling the mobilization of arsenic in the arsenic contaminated shallow alluvial aquifer in the blackfoot disease endemic area

High levels of arsenic in groundwater and drinking water represent a major health problem worldwide. Drinking arsenic-contaminated groundwater is a likely cause of blackfoot disease (BFD) in Taiwan, but mechanisms controlling the mobilization of arsenic present at elevated concentrations within aquifers remain understudied. Microcosm experiments using sediments from arsenic contaminated shallow alluvial aquifers in the blackfoot disease endemic area showed simultaneous microbial reduction of Fe(III) and As(V). Significant soluble Fe(II) (0.23±0.03mM) in pore waters and mobilization of As(III) (206.7±21.2nM) occurred during the first week. Aqueous Fe(II) and As(III) respectively reached concentrations of 0.27±0.01mM and 571.4±63.3nM after 8 weeks. We also showed that the addition of acetate caused a further increase in aqueous Fe(II) but the dissolved arsenic did not increase. We further isolated an As(V)-reducing bacterium native to aquifer sediments which showed that the direct enzymatic reduction of As(V) to the potentially more-soluble As(III) in pore water is possible in this aquifer. Our results provide evidence that microorganisms can mediate the release of sedimentary arsenic to groundwater in this region and the capacity for arsenic release was not limited by the availability of electron donors in the sediments.

Reduction in arsenic intake from water has different impacts on lung cancer and bladder cancer in an arseniasis endemic area in Taiwan

Excessive arsenic intake has a detrimental effect on human health, as reflected in an increase in cancer incidence. In an area on the southwest coast of Taiwan, arsenic intake from well water since the 1920s had caused an exceptionally high mortality from cancer. Municipal water has become available to people living in the arseniasis endemic area since the early 1970s. This study explored the impacts of reduction in arsenic intake from water on lung cancer and bladder cancer in the arseniasis endemic area in Taiwan. Chart records of 23,013 patients diagnosed with bladder cancer and 93,633 patients with lung cancer from 1979 to 2003 were retrieved from the Taiwan Cancer Registry Center. We used the age-period-cohort model to study the changes in the incidence of lung cancer and bladder cancer in the arseniasis endemic area and the rest of Taiwan. Three decades after municipal water supply to the arseniasis and black foot disease endemic area (BFDEA), we saw a marked decrease in the incidence of both bladder cancer and lung cancer in the area, especially for those in the later cohorts. The relative risk (RR) of getting a bladder cancer for people living in BFDEA when compared with those in the rest of Taiwan has dropped from 20 for the early cohorts to 5 for the late cohorts. As to lung cancer, the RR has decreased from 8 to between 1.5 and 2. Reduction in arsenic intake from water has a positive impact on the incidence of both lung and bladder cancer; however, while RR for lung cancer has dropped to below 2, RR for bladder cancer remained at around 5. The difference may be because (1) there are other risk factors beside the well-water intake or (2) bladder cancer may have longer latency period for excessive arsenic exposure than lung cancer. More studies are required to understand the causes behind the difference in RR for these two types of cancer.

Assessing the characteristics of groundwater quality of arsenic contaminated aquifers in the blackfoot disease endemic area

Redox couples approach and multivariate statistical techniques, including factor analysis, cluster analysis and discriminant analysis, were applied to evaluate and to interpret the complex groundwater quality in the blackfoot disease endemic area, Taiwan. Most groundwater samples were characterized as Na–Ca–HCO 3 with HCO 3 − as the dominant anion. Total arsenic (As) concentration, predominantly as As 3+, ranged from <1.0 to 562.7 μg/L. The patterns of measured reducing potential were consistent with those values calculated from As couple, revealing the in situ environment enhanced the accumulation of As concentration in the groundwater. Factor analysis proposed a four-factor model, comprising salination, reductive dissolution of Fe/Mn oxyhydroxides, As reduction and chemical potential factor, and explained 89.94% of total variance in groundwater. Furthermore, two factors, reductive dissolution of Fe/Mn oxyhydroxides and As reduction, suggested that the decoupled reductive processes accounted for high As concentration in this area. Cluster analysis was adopted to spatially categorize the sampled wells into three main clusters and characterized by the factor scores of the four-factor model. Two-parameter (pH and Eh) model derived from discriminant analysis can be used for preliminary assessment to determine whether the As concentration exceeds 10 μg/L with simple field measurements in this area .

Extraction of arsenic from a soil in the blackfoot disease endemic area with ionic liquids

Abstract Speciation of arsenic extracted with room temperature ionic liquids (RTILs) ([bmim][BF 4 ] (1-butyl-3-methylimidazolium tetrafluoroborate) and [bmim][PF 6 ] (1-butyl-3-methylimidazolium hexafluorophosphate)) from an As-humic acid (As-HA) complex contaminated soil (As-HA/soil) in a blackfoot disease endemic area has been studied by X-ray absorption (near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS)) spectroscopy. About 45% of arsenic in the As-HA/soil can be extracted with [bmim][BF 4 ] while the relatively less hydrophilic [bmim][PF 6 ] extracts 25% of arsenic. The extracted arsenic in the [bmim][BF 4 ] and [bmim][PF 6 ] from the As-HA/soil possesses mainly As(III) species, suggesting that at least two reaction paths may be involved in the extraction process: (1) splitting of As-HA and (2) reduction of As(V) to As(III). The refined EXAFS spectra also indicate that the As(III) extracted in the RTILs possesses the AsO 2 − structure, which has the As–O bond distances of 1.77–1.79 A and coordination numbers of 4.0–4.2.

The association between arsenic exposure from drinking water and cerebrovascular disease mortality in Taiwan

Background Chronic arsenic exposure is associated with a variety of diseases, including cancer, peripheral vascular disease, and diabetes. However, its association with cerebrovascular diseases (CVD) has not yet been resolved. The aim of this study is to explore this association in Taiwan using nation-wide data. Materials and methods We analyzed mortality data in Taiwan from 1971 to 2005 and choose two geographic areas with populations suffering from chronic exposure to arsenic in drinking water for study, the blackfoot disease endemic area (BFDEA) in the southwest and Lan-Yang Basin (LYB) in the northeast parts of Taiwan. The Chia-Yi and Tainan Counties, which surround the BFDEA, and the nation of Taiwan as a whole were used as reference populations. Direct standardized mortality rates and gender-specific indirect standardized mortality ratios (SMRs) were calculated for the four populations. Results The direct standardized mortality rate for CVD in Taiwan decreased from 2.46/10 3 person-year in 1971 to 0.63/10 3 person-year in 2005, and women had significantly lower mortality than men (SMR = 0.80; p < 0.05). The CVD mortality rates of populations with chronic arsenic exposure were significantly higher than the reference populations (SMR ranging from 1.06 to 1.09 in men and 1.12 to 1.14 in women; p < 0.05). The BFDEA had higher CVD mortality rates than the LYB, with SMR = 1.05 ( p < 0.05) in men and SMR = 1.04 ( p = 0.05) in women. Conclusion In Taiwan, while CVD mortality decreased in both genders between 1971 and 2005, chronic arsenic exposure from drinking water was associated with increased risks of CVD.

The Association Between Arsenic Exposure and Cerebrovascular Disease-A Study in the Blackfoot Disease Endemic Area in Taiwan

ISEE-0480 Background and Objective: Epidemiological studies have demonstrated that chronic arsenic exposure may cause various health effects, but previous studies on the association between arsenic exposure from drinking water and cerebrovascular diseases (CVD) in different regions in Taiwan yielded inconsistent results. The objective of this study is to evaluate the possible association between arsenic exposure and mortality of CVD in Taiwan with the data from the whole country, trying to solve the problem with a more complete database. Methods: We analyzed the national death registry data of Taiwan from 1971 to 2005. Two areas were defined as the exposed group: one is the blackfoot disease (BFD) endemic area, and the other is the Lan-Yang Basin (LYB) area. The arsenic levels in the drinking water in the BFD area were generally higher than those in the LYB area. Standardized mortality ratios (SMRs) adjusted for gender and age were calculated using the whole population in Taiwan and the population in the Chiayi-Tainan area as the reference populations respectively. Results: The standardized mortality rate of CVD in Taiwan decreased from 2.46/103 in 1971 to 0.63/103 in 2005. Women had lower rates than men, with SMR = 0.80. The exposure group had higher SMRs of CVD in comparison with the reference populations, with SMRs from 1.06 to 1.09 in men and 1.12 to 1.14 in women. The BFD endemic area had higher mortality rates of CVD than the LYB area, with SMR = 1.05 in men and SMR = 1.04 in women. Conclusion: In Taiwan, women had lower mortality rates of CVD, and the rate has been constantly decreasing in both genders from 1971 to 2005. Exposure to arsenic in drinking water is associated with a higher risk of CVD.

Clinicopathological Characteristics and Survival Outcome of Arsenic Related Bladder Cancer in Taiwan

We compared clinicopathological characteristics and outcomes in patients with bladder cancer who were exposed to graded arsenic levels in drinking water. From 1993 through 2006, 977 patients with bladder cancer in Taiwan were studied retrospectively. Patients were from 3 areas, including the core zone (arsenic related blackfoot disease endemic area with a well water arsenic level of 350 to 1,100 ng/ml), zone 1 (a well water arsenic level of 350 ng/ml or greater but not a blackfoot disease endemic area) and zone 2 (a well water arsenic level of less than 350 ng/ml). Clinicopathological characteristics and survival outcome were compared among the groups. Of these patients 81 (8.3%), 246 (25.2%) and 650 (66.5%) lived in the core zone, and zones 1 and 2, respectively. More high grade and high stage tumors were observed in core zone patients than in those in zones 1 and 2, including high grade in 48.7% vs 41.4% and 39.2% of patients, advanced disease in 39.5% vs 31.0% and 18.5% and nodal metastasis in 8.6% vs 3.3% and 3.4%, respectively. Median overall and cancer specific survival in core zone patients was significantly shorter than in patients in zones 1 and 2, including 69 vs 119 and 113-month overall survival and for the 75th percentile of cancer specific survival 34.5 vs 119 and 113 months, respectively. On multivariate analysis with adjustment for tumor grade and stage the zonal difference was not a significant factor for overall or cancer specific survival. Patients with arsenic related bladder cancer may have decreased overall and cancer specific survival because they have more unfavorable tumor phenotypes than patients in other areas in Taiwan.

Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan

To evaluate the clinical and epidemiological characteristics of patients with genitourinary (GU) tract transitional cell carcinoma (TCC) in an endemic area of blackfoot disease (BFD), the arsenic-exposed group, to compare them with characteristics among other non-BFD endemic areas (unexposed group). In all, 474 patients with pathologically diagnosed GU-TCC were enrolled in the study. All follow-up data were prospectively collected and entered into a database throughout the study period. Statistical analysis was used to determine the association between clinical variables and prognosis, and multivariate regression models were used to assess the association between arseniasis and mortality from GU-TCC. There were no significant differences between the groups in age, sex, tumour stage and grade. However, the exposed group had a significantly higher proportion of females. The overall 5-year survival rate of patients with upper urinary tract (UUT) TCC was 49%, and the two groups had similar 5-year survival rates. The overall 5-year survival rate of patients with urinary bladder (UB) TCC was 68.3%, and there was a statistically significant difference in survival between the groups, with a 5-year survival rate of 58.7% for the exposed and 72.4% for the unexposed group. For patients with early-stage (pTa and pT1) UB cancers, the death rate was five times higher in exposed patients with tumour progression and recurrence after transurethral resection of bladder tumour than in the unexposed group. There was a significantly higher mortality rate for UB-TCC among exposed patients in the area endemic for arseniasis than in those from other non-endemic areas. The arsenic content of artesian-well water might contribute to the increased ratio of female patients with GU-TCC and the unusually high incidence of UUT-TCC in the BFD endemic area in Taiwan.

Hypoplastic Aortoiliac Syndrome in the Arseniasis Area (Southwestern Coast) of Taiwan

Objective: The hypoplastic aortoiliac syndrome (HAIS) has been well documented in the literature and it is unusually found in the population of atheroslerosis with aortoiliac occlusive disease. In the arseniasis area, so-called Blackfoot Disease (BFD) endemic area in the southwestern coast of Taiwan, we encountered HAIS patients in whom the patho-etiology was not been clear, but the surgical revascularization for limb salvage was feasible. Methods: From Jan. 2001 through Jan. 2007, 8 cases of HAIS were recognized among 288 patients in the BFD endemic area. The image study showed hypoplasia of the infrarenal aorta and iliofemoral system with mild to moderate degree of atherosclerotic change in the distal runoff. Clinically, all patients presented with severe intermittent hip or thigh claudication associated with ischemic changes of the foot or toes. The area ratio of the sum of cross-sectional areas of common iliac arteries/cross-sectional area of aorta above the bifurcation ranged between 0.39 and 0.7 (normal range 0.78 to 1.2). Results: Of the 8 HAIS patients, 1 patient underwent an aorto-bifemoral bypass with lumbar sympathectomy (LS), 2 received an aorto-unifemoral bypasses with LS, 1 had an iliofemoral bypass with LS, 3 had profundaplasty with LS, and the remaining one had a unilateral thoracic sympathectomy for finger ischemia and constant poikilothermia of both hands, but declined vascular reconstruction. There was no operative or perioperative mortality. The operative complications included minor wound infection, wound hematoma, paralytic ileus, and atelectasis. The preexistent pregangrenous toes needed amputation in the post-operative days when demarcation became clear. Conclusions: The hypoplastic aortoiliac syndrome (HAIS) associated with ischemia of toes should be treated as aortoiliac occlusive disease without delay. We believe the bypass grafting through a retroperitoneal approach with adjunct lumbar sympathectomy is the treatment of choice if patients' general condition permits.

Humic acid induced genotoxicity in human peripheral blood lymphocytes using comet and sister chromatid exchange assay

Humic acid (HA) in well water used by the inhabitants for drinking is one of the possible etiological factors for blackfoot disease (BFD). Moreover, within BFD endemic areas cancers occur at significantly higher rates than in areas free of BFD. In this study, the genotoxic potential of HA is assessed using human peripheral blood lymphocytes. The cells were exposed to HA (0–200 μg/mL for 2 h), and the induction of DNA primary damage in cellular DNA was evaluated by single-cell gel electrophoresis (comet assay). HA-induced DNA damage was decreased by superoxide (O 2 −), hydrogen peroxide (H 2O 2), and reactive oxygen species (ROS) scavengers (superoxide dismutase, catalase, and Trolox), and nitric oxide (NO) synthase inhibitors ( N G-nitro- l-arginine methyl ester and N G-methyl- l-arginine). Moreover, formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Endo III), known to catalyze the excision of oxidized bases, increase the amount of DNA migration in HA-treated cells. Pretreatment of the cells with both the Ca 2+-chelator BAPTA and EGTA completely inhibited HA-induced DNA damage, indicating that HA-induced changes in Ca 2+-homeostasis are the predominant pathways for the HA induction of genotoxicity. Furthermore, sister chromatid exchange was found in the HA-treated lymphocytes. Our findings suggest that HA can induce oxidative DNA damage and genotoxicity in human lymphocytes.