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1.  The synergistic effect of cigarette taxes on the consumption of cigarettes, alcohol and betel nuts 
BMC Public Health  2007;7:121.
Background
Consumption of cigarettes and alcoholic beverages creates serious health consequences for individuals and overwhelming financial burdens for governments around the world. In Asia, a third stimulant – betel nuts – increases this burden exponentially. For example, individuals who simultaneously smoke, chew betel nuts and drink alcohol are approximately 123 times more likely to develop oral, pharyngeal and laryngeal cancer than are those who do not.
To discourage consumption of cigarettes, the government of Taiwan has imposed three taxes over the last two decades. It now wishes to lower consumption of betel nuts. To assist in this effort, our study poses two questions: 1) Will the imposition of an NT$10 Health Tax on cigarettes effectively reduce cigarette consumption? and 2) Will this cigarette tax also reduce consumption of alcoholic beverages and betel nuts? To answer these questions, we analyze the effect of the NT$10 tax on overall cigarette consumption as well as the cross price elasticities of cigarettes, betel nuts, and alcoholic beverages.
Methods
To establish the Central Bureau of Statistics demand function, we used cigarette, betel nut, and alcoholic beverage price and sales volume data for the years 1972–2002. To estimate the overall demand price elasticity of cigarettes, betel nuts, and alcoholic beverages, we used a seemingly unrelated regression analysis.
Results
We find that the NT$10 health tax on cigarettes will reduce cigarette consumption by a significant 27.22%. We also find that cigarettes, betel nuts, and alcoholic beverages have similar inherent price elasticities of -0.6571, -0.5871, and -0.6261 respectively. Because of this complementary relationship, the NT$10 health tax on cigarettes will reduce betel nut consumption by 20.07% and alcohol consumption by 7.5%.
Conclusion
The assessment of a health tax on cigarettes as a smoking control policy tool yields a win-win outcome for both government and consumers because it not only reduces cigarette consumption, but it also reduces betel nut and alcoholic beverage consumption due to a synergistic relationship. Revenues generated by the tax can be used to fund city and county smoking control programs as well as to meet the health insurance system's current financial shortfall.
doi:10.1186/1471-2458-7-121
PMCID: PMC1913507  PMID: 17592627
2.  A review of the systemic adverse effects of areca nut or betel nut 
Areca nut is widely consumed by all ages groups in many parts of the world, especially south-east Asia. The objective of this review is to systematically review and collate all the published data that are related to the systemic effects of areca nut. The literature search was performed by an electronic search of the Pubmed and Cochrane databases using keywords and included articles published till October 2012. We selected studies that covered the effect of areca nut on metabolism, and a total of 62 studies met the criteria. There is substantial evidence for carcinogenicity of areca nut in cancers of the mouth and esophagus. Areca nut affects almost all organs of the human body, including the brain, heart, lungs, gastrointestinal tract and reproductive organs. It causes or aggravates pre-existing conditions such as neuronal injury, myocardial infarction, cardiac arrhythmias, hepatotoxicity, asthma, central obesity, type II diabetes, hyperlipidemia, metabolic syndrome, etc. Areca nut affects the endocrine system, leading to hypothyroidism, prostate hyperplasia and infertility. It affects the immune system leading to suppression of T-cell activity and decreased release of cytokines. It has harmful effects on the fetus when used during pregnancy. Thus, areca nut is not a harmless substance as often perceived and proclaimed by the manufacturers of areca nut products such as Pan Masala, Supari Mix, Betel quid, etc. There is an urgent need to recognize areca nut as a harmful food substance by the policy makers and prohibit its glamorization as a mouth freshener. Strict laws are necessary to regulate the production of commercial preparations of areca nut.
doi:10.4103/0971-5851.133702
PMCID: PMC4080659  PMID: 25006276
Adverse effects; areca nut; arecoline; betel nut; systemic effects
3.  Betel Nut Chewing Is Strongly Associated With General and Central Obesity in Chinese Male Middle-aged Adults 
Obesity (Silver Spring, Md.)  2009;17(6):1247-1254.
Betel nut chewing has been reported to increase the risk of cardiovascular disease and all-cause mortality. The reason is unclear. In this study, we investigated the association between betel nut chewing and general obesity (BMI ≥25kg/m2) and central obesity (waist circumference (WC) ≥90 cm). A total of 1,049 male subjects, aged ≥40 years, were recruited from Taichung city in Taiwan in 2004. The relationships between betel nut chewing and general and central obesity were studied by multiple linear and logistic regression analyses. The prevalence of current and former betel nut chewing was 7.0 and 10.5% in our male Taiwanese cohort. Current/former betel nut chewers had a higher prevalence of general and central obesity when compared with individuals who had never chewed betel nut. Adjusted for age, diabetes, hypertension, lipids, smoking, alcohol drinking, physical activity, income, and education level, the odds ratios (ORs; 95% confidence intervals) of general and central obesity among the lower consumption of betel nut chewers were 1.78 (1.07, 2.96) and 1.19 (0.70, 2.02), respectively, compared to 2.01 (1.18, 3.41) and 1.89 (1.10, 3.23), respectively, among higher consumption chewers compared to individuals who had never chewed betel nut. The increasing ORs of general and central obesity with higher betel nut consumption revealed dose–response effects. Using multiple linear regression analyses, after adjusting for potential confounders, betel nut consumption was statistically significantly associated with BMI and WC. In conclusion, betel nut chewing was independently associated with general and central obesity in Taiwanese men. Dose–response effects of the association between betel nut consumption and general obesity as well as central obesity were found.
doi:10.1038/oby.2009.38
PMCID: PMC2879272  PMID: 19247275
4.  Presence of Helicobacter pylori in betel chewers and non betel chewers with and without oral cancers 
BMC Oral Health  2009;9:23.
Background
Betel chewing has been shown to predispose to periodontal disease and oral cancer. Studies show that people with gum disease are more likely to test positive for Helicobacter pylori (H. pylori). It is not known if the lesions produced by betel quid and the resulting, chemical changes predispose to colonization by H. pylori. Further the role of this organism in oral cancer is not known. Our objective was to determine the presence of H. pylori in oral lesions of thirty oral cancer patients and to determine the presence of IgG antibodies to H. pylori in oral cancer patients who are betel chewers and non betel chewers, healthy betel chewers and healthy non-betel chewers and to compare the presence of H. pylori in these four groups. This case control study was conducted at the Cancer Institute Maharagama and the Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura.
Methods
One hundred and seventy three subjects, of whom fifty three were patients presenting with oral cancer to the Cancer Institute Maharagama, sixty healthy betel chewers and sixty healthy non-betel chewers from the Religious and Welfare Service Centre Maharagama were tested for H. pylori by serology. Thirty oral biopsies from oral cancer patients were cultured under microaerophilic condition to isolate H. pylori. The statistic used was Chi-square test.
Results
Of the fifty-three oral cancer patients, forty-four were betel chewers. Among the 53 oral cancer patients examined, ten of forty-four (10/44 = 22.7%) patients who are betel chewers and four of nine (4/9 = 44.4%) patients who are non-betel chewers were detected positive for IgG antibody against H. pylori. In the healthy group (betel chewers and non betel chewers) ten (16.7%) of the healthy betel chewers tested positive for H. pylori by serology. None of the healthy non-betel chewers tested positive for H. pylori
Fourteen [26.4%] of oral cancer patients tested positive for H. pylori by serology, of which two were also culture positive (Only thirty samples were cultured). The presence of H. pylori in betel chewers (with or without cancer) compared to non-betel chewers was statistically significant. (Chi-square test p < 0.05) The use of tobacco and areca nut in betel chewers was significant with the presence of H. pylori (p < 0.05).
Conclusion
There is a significant higher proportion of H. pylori in betel chewers compared to non-betel chewers but not between oral cancer patients compared to patients without oral cancer. Hence Betel chewing may predispose to colonisation with H. pylori in the digestive tract through swallowing the quid or during betel chewing.
doi:10.1186/1472-6831-9-23
PMCID: PMC2755467  PMID: 19772630
5.  Areca nut and its role in oral submucous fibrosis 
Areca nut, commonly called as betel nut or supari, is a fruit of areca catechu palm tree, which is native of South Asia and Pacific Islands. The seed or endosperm is consumed fresh, boiled or after sun drying or curing. Chewing areca nut is thought to have central nervous system stimulating effect and along with this it is known to have salivary stimulating and digestive properties. According to the traditional Ayurvedic medicine, chewing areca nut and betel leaf is a good remedy against halitosis. It is also used for its deworming property. Along with these beneficial effects of areca nut one of its most harmful effects on the human body in general and oral cavity in particular is the development of potentially malignant disorder called Oral Submucous Fibrosis. The present paper discusses in detail the effects of the components of areca nut on pathogenesis of Oral Submucous Fibrosis.
Key words:Areca nut, oral submucous fibrosis, potentially malignant disorder, supari.
doi:10.4317/jced.51318
PMCID: PMC4312688
6.  Arecoline induced disruption of expression and localization of the tight junctional protein ZO-1 is dependent on the HER 2 expression in human endometrial Ishikawa cells 
BMC Cell Biology  2010;11:53.
Background
Approximately 600 million people chew Betel nut, making this practice the fourth most popular oral habit in the world. Arecoline, the major alkaloid present in betel nut is one of the causative agents for precancerous lesions and several cancers of mouth among those who chew betel nut. Arecoline can be detected in the human embryonic tissue and is correlated to low birth weight of newborns whose mothers chew betel nut during pregnancy, suggesting that arecoline can induce many systemic effects. However, few reports exist as to the effects of arecoline in human tissues other than oral cancer cell lines. Furthermore, in any system, virtually nothing is known about the cellular effects of arecoline treatment on membrane associated signaling components of human cancer cells.
Results
Using the human Ishikawa endometrial cancer cell line, we investigated the effects of arecoline on expression, localization and functional connections between the ZO-1 tight junction protein and the HER2 EGF receptor family member. Treatment of Ishikawa cells with arecoline coordinately down-regulated expression of both ZO-1 and HER2 protein and transcripts in a dose dependent manner. Biochemical fractionation of cells as well as indirect immunofluorescence revealed that arecoline disrupted the localization of ZO-1 to the junctional complex at the cell periphery. Compared to control transfected cells, ectopic expression of exogenous HER2 prevented the arecoline mediated down-regulation of ZO-1 expression and restored the localization of ZO-1 to the cell periphery. Furthermore, treatment with dexamethasone, a synthetic glucocorticoid reported to up-regulate expression of HER2 in Ishikawa cells, precluded arecoline from down-regulating ZO-1 expression and disrupting ZO-1 localization.
Conclusion
Arecoline is known to induce precancerous lesions and cancer in the oral cavity of betel nut users. The arecoline down-regulation of ZO-1 expression and subcellular distribution suggests that arecoline potentially disrupts cell-cell interactions mediated by ZO-1, which may play a role in arecoline-mediated carcinogenesis. Furthermore, our study has uncovered the dependency of ZO-1 localization and expression on HER2 expression, which has therefore established a new cellular link between HER2 mediated signaling and apical junction formation involving ZO-1.
doi:10.1186/1471-2121-11-53
PMCID: PMC2910664  PMID: 20604955
7.  Effects of betel nut on cardiovascular risk factors in a rat model 
Background
Areca nut (commonly known as betel nut) chewing has been shown to be associated with metabolic syndrome and cardiovascular disease (CVD). The mechanism by which betel nut ingestion could lead to development of CVD is not precisely known; however, dyslipidemia, hyperhomocysteinemia, hypertriglyceridemia and inflammation could be some of the potential risk factors. This study was undertaken to investigate the effects of two dosages of betel nut on homocysteinemia, inflammation and some of the components of metabolic syndrome, such as hypertriglyceridemia, low HDL-cholesterol, obesity and fasting hyperglycemia in a rat model.
Methods
Thirty-six adult female Sprague Dawley rats, aged 10–12 weeks were divided into three equal groups. Group-1 served as the control group (n = 12) and received water, whereas groups 2 and 3 were given water suspension of betel nut orally in two dosages, 30 mg and 60 mg, respectively for a period of 5 weeks. At the end of the fifth week, the animals were weighed and sacrificed, blood was collected and liver, kidney, spleen and stomach were removed for histological examination.
Plasma/serum was analyzed for glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, homocysteine, folate, vitamin B12 and N-acetyl-β-D-glucosaminidase (NAG) – a marker of inflammation.
Results
When the mean concentration values of 3 groups were compared using one way ANOVA followed by Tukey’s HSD-test, there was a significant increase in the concentration of total cholesterol (p = 0.04) in the group receiving 30 mg/day betel nut compared to the control group. However, administration of a higher dose of betel nut (60 mg/day) had no significant effect on the serum concentrations of glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, and NAG. Histological examination of spleen revealed a dose-dependent extramedullary hematopoiesis. No other remarkable change in the tissues (liver, kidney and stomach) was observed.
Mean serum/plasma levels of folate, vitamin B12 and homocysteine were not found to be significantly different in all the groups. Betel nut ingestion had no effect on the mean body weights of rats.
Conclusions
Low dosage of betel nut is found to be associated with hypercholesterolemia. However, betel nut ingestion is not associated with hyperhomocysteinemia, hypertriglyceridemia, hyperglycemia, inflammation and increase in body weight in a rat model.
doi:10.1186/1471-2261-12-94
PMCID: PMC3506470  PMID: 23095290
Areca nut; Betel nut; Cardiovascular disease; Metabolic syndrome; Rat model
8.  Systematic Review and Meta-Analysis of Association of Smokeless Tobacco and of Betel Quid without Tobacco with Incidence of Oral Cancer in South Asia and the Pacific 
PLoS ONE  2014;9(11):e113385.
Aim
This systematic review and meta-analysis aimed to critically appraised data from comparable studies leading to quantitative assessment of any independent association between use of oral smokeless tobacco in any form, of betel quid without tobacco and of areca nut with incidence of oral cancer in South Asia and the Pacific.
Methods
Studies (case control and/or cohort) were identified by searching Pub Med, CINAHL and Cochrane databases through June 2013 using the keywords oral cancer: chewing tobacco; smokeless tobacco; betel quid; betel quid without tobacco; areca nut; Asia, the Pacific and the reference lists of retrieved articles. A random effects model was used to compute adjusted summary ORRE for the main effect of these habits along with their corresponding 95% confidence intervals. To quantify the impact of between-study heterogeneity on adjusted main-effect summary ORRE, Higgins' H and I2 statistics along with their 95% uncertainty intervals were used. Funnel plots and Egger's test were used to evaluate publication bias.
Results
Meta-analysis of fifteen case–control studies (4,553 cases; 8,632 controls) and four cohort studies (15,342) which met our inclusion criteria showed that chewing tobacco is significantly and independently associated with an increased risk of squamous-cell carcinoma of the oral cavity (adjusted main-effect summary for case- control studies ORRE = 7.46; 95% CI = 5.86–9.50, P<0.001), (adjusted main-effect summary for cohort studies RR = 5.48; 95% CI = 2.56–11.71, P<0.001). Furthermore, meta-analysis of fifteen case control studies (4,648 cases; 7,847 controls) has shown betel quid without tobacco to have an independent positive association with oral cancer, with OR = 2.82 (95% CI = 2.35–3.40, P<0.001). This is presumably due to the carcinogenicity of areca nut. There was no significant publication bias.
Conclusion
There is convincing evidence that smokeless (aka chewing) tobacco, often used as a component of betel quid, and betel quid without tobacco, are both strong and independent risk factors for oral cancer in these populations. However, studies with better separation of the types of tobacco and the ways in which it is used, and studies with sufficient power to quantify dose-response relationships are still needed.
doi:10.1371/journal.pone.0113385
PMCID: PMC4239077  PMID: 25411778
9.  Combined Effects of ICAM-1 Single-Nucleotide Polymorphisms and Environmental Carcinogens on Oral Cancer Susceptibility and Clinicopathologic Development 
PLoS ONE  2013;8(9):e72940.
Background
In Taiwan, oral cancer has causally been associated with environmental carcinogens. Intercellular adhesion molecule (ICAM)-1, a cell adhesion molecule with a key role in inflammation and immunosurveillance, was implicated in carcinogenesis by facilitating instability in the tumor environment. The current study explored the combined effect of ICAM-1 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors.
Methodology and Principal Findings
Four single-nucleotide polymorphisms (SNPs) of the ICAM-1 gene from 595 patients with oral cancer and 561 non-cancer controls were analyzed by a real-time PCR. We found that the ICAM-1 rs5498 polymorphism and the TAGG or TACG haplotype of 4 ICAM-1 SNPs (rs3093030, rs5491, rs281432, and rs5498) combined were associated with oral-cancer susceptibility. Among 727 smokers, ICAM-1 polymorphisms carriers with the betel-nut chewing habit had a 27.49–36.23-fold greater risk of having oral cancer compared to ICAM-1 wild-type (WT) carriers without the betel-nut chewing habit. Among 549 betel-nut chewers, ICAM-1 polymorphisms carriers who smoked had a 9.93–14.27-fold greater risk of having oral cancer compared to those who carried the WT but did not smoke. Finally, patients with oral cancer who had at least 1 T allele of ICAM-1 rs5491 or 1 G allele of rs281432 were at lower risk of developing an advanced clinical stage (III/IV) (p<0.05), compared to those patients with AA or CC homozygotes.
Conclusions
Our results suggest that the ICAM-1 rs5498 SNP and either of 2 haplotypes of 4 SNPs combined have potential predictive significance in oral carcinogenesis. Gene-environment interactions of ICAM-1 polymorphisms, smoking, and betel-nut chewing might alter oral-cancer susceptibility. ICAM-1 rs5491 and rs281432 may be applied as factors to predict the clinical stage in OSCC patients.
doi:10.1371/journal.pone.0072940
PMCID: PMC3771971  PMID: 24069166
10.  Characterization of Aspergillus species on Brazil nut from the Brazilian Amazonian region and development of a PCR assay for identification at the genus level 
BMC Microbiology  2014;14:138.
Background
Brazil nut is a protein-rich extractivist tree crop in the Amazon region. Fungal contamination of shells and kernel material frequently includes the presence of aflatoxigenic Aspergillus species from the section Flavi. Aflatoxins are polyketide secondary metabolites, which are hepatotoxic carcinogens in mammals. The objectives of this study were to identify Aspergillus species occurring on Brazil nut grown in different states in the Brazilian Amazon region and develop a specific PCR method for collective identification of member species of the genus Aspergillus.
Results
Polyphasic identification of 137 Aspergillus strains isolated from Brazil nut shell material from cooperatives across the Brazilian Amazon states of Acre, Amapá and Amazonas revealed five species, with Aspergillus section Flavi species A. nomius and A. flavus the most abundant. PCR primers ASP_GEN_MTSSU_F1 and ASP_GEN_MTSSU_R1 were designed for the genus Aspergillus, targeting a portion of the mitochondrial small subunit ribosomal RNA gene. Primer specificity was validated through both electronic PCR against target gene sequences at Genbank and in PCR reactions against DNA from Aspergillus species and other fungal genera common on Brazil nut. Collective differentiation of the observed section Flavi species A. flavus, A. nomius and A. tamarii from other Aspergillus species was possible on the basis of RFLP polymorphism.
Conclusions
Given the abundance of Aspergillus section Flavi species A. nomius and A. flavus observed on Brazil nut, and associated risk of mycotoxin accumulation, simple identification methods for such mycotoxigenic species are of importance for Hazard Analysis Critical Control Point system implementation. The assay for the genus Aspergillus represents progress towards specific PCR identification and detection of mycotoxigenic species.
doi:10.1186/1471-2180-14-138
PMCID: PMC4051963  PMID: 24885088
Aspergillus section Flavi; Mycotoxin; Mitochondrial small subunit ribosomal RNA gene; PCR-RFLP
11.  Alcohol, betel-nut and cigarette consumption are negatively associated with health promoting behaviors in Taiwan: A cross-sectional study 
BMC Public Health  2013;13:257.
Background
Oral cancer is the 2nd most common cause of death due to cancer in the south-western coastal region of Taiwan; the standardized mortality of oral cancer is higher than elsewhere in the world. According to the evidence, alcohol, betel-nut and cigarette (ABC) consumption cause oral, nasopharyngeal and related cancers. This study describes the relationships between ABC consumers and health promoting behaviors among community adults living around an area with a high prevalence of oral cancer.
Methods
A population-based, cross-sectional study design was conducted in oral cancer epidemic areas in south-western coastal Taiwan in 2010, 6,203 community residents over 20 years of age participated. Demographic data, ABC habits, and health-promoting behaviors were explored. A logistic regression analyses were used to identify factors associated with ABC consumers.
Results
A high percentage of participants consumed alcohol, betel-nut and cigarettes. Betel-nut and cigarette consumers took low levels of exercise, adopted a poor diet, and had poor oral hygiene. After adjusting for potential confounders, the logistic regression model indicated that middle aged males of poor education and low economic status, who did not exercise regularly and had poor oral hygiene, were more likely to chew betel quid and smoke cigarettes.
Conclusions
It has identified that BC consumers are negatively associated with health promoting behaviors. Further research is required to understand the reasons why the subjects consume ABC, and explore ways to prevent initiation and enhance cessation of ABC habits in this population.
doi:10.1186/1471-2458-13-257
PMCID: PMC3607848  PMID: 23517549
Alcohol; Betel-nut; Cigarette; Nursing-led community health; Health promotion; Oral cancer
12.  The association between hyperuricemia and betel nut chewing in Taiwanese men: a cross-sectional study 
BMC Public Health  2013;13:1136.
Background
Studies have associated betel nut chewing with cancers, metabolic syndrome, cardiovascular disorders, chronic kidney disease, and proteinuria. This study investigated whether hyperuricemia is associated with betel nut chewing in men who participated in a health check-up program.
Methods
From hospital records, we identified a total of 11,991 men who participated in the health check-up program from 2003 to 2009. They were divided into hyperuricemic group and non-hyperuricemic group. Laboratory tests, medical history, and status of cigarette smoking, alcohol consumption, and betel nut chewing were compared between the 2 groups. We calculated odds ratio (OR) and 95% confidence interval (CI) of hyperuricemia in association with betel nut consumption and other factors.
Results
Compared with the non-hyperuricemic group, the hyperuricemic group was slightly older (59.4 vs. 58.6 years) but less prevalent with betel nut use (11.8 vs. 13.6%, p = 0.003). Multivariable logistic regression analysis showed that hyperuricemia was negatively associated with betel nut chewing (OR 0.75, 95% CI 0.66-0.84), older age (OR 0.84, 95% CI 0.77-0.93), and diabetes mellitus (OR 0.57, 95% CI 0.50-0.64). On the other hand, hyperuricemia was positively associated with body mass index (OR 1.75, 95% CI 1.62-1.90), drinking (OR 1.36, 95% CI 1.25-1.49), hypertension (OR 1.41, 95% CI 1.30-1.52), mixed hyperlipidemia (OR 1.84, 95% CI 1.33-2.54), chronic kidney disease (OR 3.28, 95% CI 2.94-3.65), and proteinuria (OR 1.22, 95% CI 1.08-1.38). Smoking, hypercholesterolemia, and hypertriglyceridemia had no significant association with hyperuricemia.
Conclusion
Our data suggest that betel nut chewing is negatively associated with hyperuricemia.
doi:10.1186/1471-2458-13-1136
PMCID: PMC4234360  PMID: 24308550
Betel nut; Chronic kidney disease; Comorbidity; Hyperuricemia; Logistic regression analysis
13.  Uncovering the relation between betel quid chewing and cigarette smoking in Taiwan 
Tobacco Control  2005;14(Suppl 1):i16-i22.
Objective: To describe the characteristics of betel quid chewers and to investigate the behavioural and mortality relations between betel quid chewing and cigarette smoking.
Method: Prevalence and mortality risks of betel quid chewers by smoking status were calculated, based on the National Health Interview Survey in 2001 and a community based cohort, respectively. Cox's proportional hazards model was used to adjust mortality risks for age, alcohol use, and education.
Results: Almost all betel quid chewers were smokers, and most started chewing after smoking. Chewers were predominantly male, mostly in their 30s and 40s, more likely being among the lowest educational or income group, and residing in the eastern regions of Taiwan. On average, betel quid chewers who smoked consumed 18 pieces of betel quid a day, and smoked more cigarettes per day. Far more smokers use betel quid than non-smokers (27.5% v 2.5%), but ex-smokers quit betel quid more than smokers (15.1% v 6.8%). The significantly increased mortality of betel quid users who also smoked, for all causes, all cancer, oral cancer, and cancer of the nasopharynx, lung, and liver, was the result of the combined effects of chewing and smoking. Smokers who chewed betel quid nearly tripled their oral cancer risks from a relative risk of 2.1 to 5.9. Increasing the number of cigarettes smoked among betel quid chewers was associated with a synergistic effect, reflective of the significant interaction between the two.
Conclusion: To a large extent, the serious health consequences suffered by betel quid chewers were the result of the combined effects of smoking and chewing. Betel quid chewing should not be considered as an isolated issue, but should be viewed conjointly with cigarette smoking. Reducing cigarette smoking serves as an important first step in reducing betel quid chewing, and incorporating betel quid control into tobacco control may provide a new paradigm to attenuate the explosive increase in betel quid use in Taiwan.
doi:10.1136/tc.2004.008003
PMCID: PMC1766184  PMID: 15923442
14.  CD44 Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan 
PLoS ONE  2014;9(4):e93692.
Background
Oral squamous cell carcinoma (OSCC) is the fourth leading cause of male cancer death in Taiwan. Exposure to environmental carcinogens is the primary risk factor for developing OSCC. CD44, a well-known tumor marker, plays a crucial role in tumor cell differentiation, invasion, and metastasis. This study investigated CD44 single-nucleotide polymorphisms (SNPs) with environmental risk factors to determine OSCC susceptibility and clinicopathological characteristics.
Methodology/Principal Findings
Real-time polymerase chain reaction (PCR) was used to analyze 6 SNPs of CD44 in 599 patients with oral cancer and 561 cancer-free controls. We determined that the CD44 rs187115 polymorphism carriers with the genotype AG, GG, or AG+GG were associated with oral cancer susceptibility. Among 731 smokers, CD44 polymorphisms carriers with the betel-nut chewing habit had a 10.30–37.63-fold greater risk of having oral cancer compared to CD44 wild-type (WT) carriers without the betel-nut chewing habit. Among 552 betel-nut chewers, CD44 polymorphisms carriers who smoked had a 4.23–16.11-fold greater risk of having oral cancer compared to those who carried the WT but did not smoke. Finally, we also observed that the stage III and IV oral cancer patients had higher frequencies of CD44 rs187115 polymorphisms with the variant genotype (AG+GG) compared with the wild-type (WT) carriers.
Conclusion
Our results suggest that gene–environment interactions between the CD44 polymorphisms and betel quid chewing and tobacco smoking increase the susceptibility to oral cancer development. Patients with CD44 rs187115 variant genotypes (AG+GG) were correlated with a higher risk of oral cancer development, and these patients may possess greater chemoresistance to advanced- to late-stage oral cancer than WT carriers do. The CD44 rs187115 polymorphism has potential predictive significance in oral carcinogenesis and also may be applied as factors to predict the clinical stage in OSCC patients.
doi:10.1371/journal.pone.0093692
PMCID: PMC3974805  PMID: 24699672
15.  Areca (Betel) Nut Chewing Practices in Micronesian Populations 
Objective
To describe the areca nut/betel quid chewing practices of Micronesian chewers living in Guam.
Design
Two studies were conducted using qualitative data from focus groups and quantitative cross-sectional data from the 2007 Guam Behavioral Risk Factor Surveillance System (BRFSS). Ten focus groups included 49 men and women aged 18–60 years living in Guam in 2007. Participants were areca nut/betel quid chewers selected to reflect Guam's age and ethnic group (Chamorro, Chuukese, Palauan, and Yapese) distributions. Salient themes were extracted from transcripts of the sessions by three expert reviewers. A second method, latent class analysis, was used to identify unique groups of chewers. The groups were then compared on demographics and chewing-related behaviors.
Results
Areca nut and betel quid recipes collected from the focus groups showed that Chamorros had a preference for the ripe nut and swallowed the nut, whereas, the Chuukese, Palauan, and Yapese groups preferred the unripe nut and did not swallow it. Similarly, latent class analysis resulted in the identification of two groups of areca nut/betel quid chewers. Group 1 was all Chamorros. Compared to Group 2, the chewers in Group 1 preferred red and ripe nuts, did not add slake lime (calcium hydroxide) or tobacco, and swallowed the masticated areca nut (with or without Piper betle leaf).
Conclusion
The quantitative analysis confirmed the qualitative exploration of areca nut/betel quid chewers in Guam, thus providing evidence that chewing practices vary among Micronesian populations.
Implication
If future research should include an intervention, the differences in chewing practices among Micronesian populations should be taken into consideration to ensure programmatic success.
PMCID: PMC4322768
16.  All in the name of flavour, fragrance & freshness: Commonly used smokeless tobacco preparations in & around a tertiary hospital in India 
Background & objectives:
There is a general misconception that smokeless tobacco particularly sweetened and flavoured paan masala and gutkas are safe to use. The present study was undertaken with the objective of highlighting the deceptive and aggressive marketing techniques adopted by the manufacturers of smokeless tobacco preparations exploiting cultural, social and religious values. Another object was to highlight the lack of transparency in terms of content, weight, quality control and warning.
Methods:
All empty pouches of the used paan masalas, gutka, khaini or surti in and around a tertiary care hospital at east Delhi were collected. Their constituents were studied as per written declaration by the manufacturers on each packet. Information on net weight, cost, presence and type of warning, and quality assurance on each brand provided on side of the packets was noted.
Results:
A total of 1136 pouches of 33 brands/varieties were collected. Most of the gutka preparations contained tobacco, betel nut, unknown flavouring agents, undeclared spices and heavy metals. Warning regarding the harmful effect of tobacco was written in 90.9 per cent of brands with 81.8 per cent in English language only in minute font. Contents of the products were mentioned in 84.8 per cent of brands and only 27.3 per cent of those mentioned the net weight of the ingredients.
Interpretation & conclusions:
Seemingly ‘innocuous’ tobacco preparations in the form of paan masalas, gutka, khaini, surti or mouth fresheners contain various harmful substance like tobacco, betel nut, sugar coated fennel, saccharine, heavy metals like silver, unknown flavouring agents and undeclared spices in unknown quantities. Lack of transparency in terms of content, weight, quality control and warning is duping unsuspecting consumers.
PMCID: PMC3573606  PMID: 23287132
Gutkas; paan masala; quality control; smokeless tobacco
17.  Betel nut and tobacco chewing; potential risk factors of cancer of oesophagus in Assam, India 
British Journal of Cancer  2001;85(5):661-667.
Cancer of the oesophagus is the most commonly diagnosed cancer in males in Assam, in north-eastern India, and ranks second for females. The chewing of betel nut, with or without tobacco and prepared in various ways, is a common practice in the region and a case–control study has been designed to study the pattern of risk associated with different ways of preparing and chewing the nuts. 358 newly diagnosed male patients and 144 female have been interviewed together with 2 control subjects for each case chosen at random from among the attendants who accompanied patients to hospital. There were significant trends in risk ratios associated with the frequency of chewing each day, with the duration of chewing in years and with the age at which the habit was started that were apparent for both males and females and which remained significant after allowance was made for other known risk factors, notably tobacco smoking and alcohol consumption. The adjusted ratios, in comparison with non-chewers, were 13.3 M and 5.7 F for chewing more than 20 times a day, 10.6 M and 7.2 F for persons who had chewed for more than 20 years and 10.3 M and 5.3 F for those who had started before the age of 20. Among the different combinations of ingredients that were chewed the adjusted odds ratios were highest for those who had been using fermented betel nut with any form of tobacco (7.1 M and 3.6 F). The risk associated with tobacco smoking and alcohol consumption, which are high in some parts of the world, were less in Assam than those associated with the chewing of betel nut. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1920
PMCID: PMC2364125  PMID: 11531248
oesophageal cancer; betel nut chewing; tobacco chewing; Assam
18.  Chewing Betel Quid and the Risk of Metabolic Disease, Cardiovascular Disease, and All-Cause Mortality: A Meta-Analysis 
PLoS ONE  2013;8(8):e70679.
Background
Betel nut (Areca nut) is the fruit of the Areca catechu tree. Approximately 700 million individuals regularly chew betel nut (or betel quid) worldwide and it is a known risk factor for oral cancer and esophageal cancer. We performed a meta-analysis to assess the influence of chewing betel quid on metabolic diseases, cardiovascular disease, and all-cause mortality.
Methodology/Principal Findings
We searched Medline, Cochrane Library, Web of Science, and Science Direct for pertinent articles (including the references) published between 1951 and 2013. The adjusted relative risk (RR) and 95% confidence interval were calculated using the random effect model. Sex was used as an independent category for comparison.
Results
Of 580 potentially relevant studies, 17 studies from Asia (5 cohort studies and 12 case-control studies) covering 388,134 subjects (range: 94 to 97,244) were selected. Seven studies (N = 121,585) showed significant dose-response relationships between betel quid consumption and the risk of events. According to pooled analysis, the adjusted RR of betel quid chewers vs. non-chewers was 1.47 (P<0.001) for obesity (N = 30,623), 1.51 (P = 0.01) for metabolic syndrome (N = 23,291), 1.47 (P<0.001) for diabetes (N = 51,412), 1.45 (P = 0.06) for hypertension (N = 89,051), 1.2 (P = 0.02) for cardiovascular disease (N = 201,488), and 1.21 (P = 0.02) for all-cause mortality (N = 179,582).
Conclusion/Significance
Betel quid chewing is associated with an increased risk of metabolic disease, cardiovascular disease, and all-cause mortality. Thus, in addition to preventing oral cancer, stopping betel quid use could be a valuable public health measure for metabolic diseases that are showing a rapid increase in South-East Asia and the Western Pacific.
doi:10.1371/journal.pone.0070679
PMCID: PMC3734295  PMID: 23940623
19.  Betel quid use in relation to infectious disease outcomes in Cambodia 
Summary
Objectives
The habitual chewing of betel quid (areca nut, betel leaf, tobacco) is estimated to occur among 600 million persons in Asia and the Asia-Pacific Region. Emerging data from rural Asia indicate that the betel quid is part of traditional medicine practices that promote its use for a wide range of ailments, including infectious disease. In the present study, we examined the association between betel quid, traditional medicine, and infectious disease outcomes.
Methods
For the purpose of a nationwide, interviewer-administered, cross-sectional survey of tobacco use (including betel quid), we conducted a stratified three-stage cluster sampling of 13 988 adults aged 18 years and older from all provinces of Cambodia.
Results
We found an association between the intensity of betel quid use and HIV/AIDS (odds ratio (OR) 2.06, 95% CI 1.09–3.89), dengue fever (OR 2.40, 95% CI 1.55–2.72), tuberculosis (OR 1.50, 95% CI 0.96–2.36), and typhoid (OR 1.48, 95% CI 0.95–2.30). These associations were even stronger in women – the primary users of betel quid in Cambodia. Multivariable analyses that controlled for age, gender, income, education, urban versus rural dwelling, receiving care from traditional medicine practitioners, and cigarette smoking did not alter the betel quid–infectious disease association.
Conclusions
Our findings raise the possibility of a role of betel quid use in the transmission of infectious disease through pathways such as immunosuppression, oral route of entry for a pathogen (i.e., through injury to the oral mucosa), and contamination (i.e., fecal–oral) of the betel quid ingredients.
doi:10.1016/j.ijid.2011.12.006
PMCID: PMC3307941  PMID: 22296863
Smokeless tobacco; Epidemiology; Tuberculosis; HIV
20.  Head and neck squamous cell carcinoma in chronic areca nut chewing Indian women: Case series and review of literature 
Background:
Head and neck squamous cell carcinoma (HNSCC) is an important public health problem in India. Several risk factors such as tobacco, human papilloma virus, alcohol, areca nut usage have been extensively studied as causative agents. Though Areca nut chewing is known cause of oral cancer, its association with hypopharynx cancer has not been previously reported. Since areca nut is mostly consumed along with tobacco, it is uncommon to find patients who consume the areca nut alone.
Materials and Methods:
This is a prospective case series of ten women who presented to us with HNSCC with history of chewing of areca nut alone for several years. We have excluded all those cases where areca nut was consumed along with tobacco in any form. The data were prospectively collected with regard to clinical parameters, duration and frequency of areca nut usage, the socio-economic status and education level.
Results:
All ten females had varying degree of submucous fibrosis and coexisting squamous cell carcinoma either in the oral cavity or hypopharynx. Submucous fibrosis was characterized by burning mouth, unhealthy oral mucosa, buried third molars, trismus, poor oral hygiene, etc. The disease presented in an advanced stage in majority of the cases. All patients were unaware of areca nut's deleterious effects.
Conclusion:
Areca nut chewing is an important risk factor for HNSCC in females. Despite plethora of information, little importance is given to areca nut control in cancer prevention campaigns in India.
doi:10.4103/0971-5851.96966
PMCID: PMC3385276  PMID: 22754206
Areca nut; oral cancer; oral submucous fibrosis; potentially malignant lesion
21.  Carcinogenicity of betel quid ingredients: feeding mice with aqueous extract and the polyphenol fraction of betel nut. 
British Journal of Cancer  1979;40(6):922-926.
Male mice of inbred strains Swiss and C17 were fed daily 5 times a week by intragastric tube 0.1 ml of betel-nut aqueous extract, betel-leaf aqueous extract and the polyphenol fraction of betel nut. Male mice of corresponding strains fed 0.1 ml of distilled water served as controls. Treated and control mice were kept under observation and killed when moribund. Betel-nut aqueous extract induced tumours of the gastrointestinal tract in 58% Swiss mice and 25% C17 mice. The polyphenol fraction by the same route induced tumours at other sites in 17% of the mice. Betel-leaf aqueous extract failed to induce any tumour in the treated mice, which supports an earlier report of the lack of any carcinogenic principle in betel leaf, an essential constituent of betel quid. Results are discussed in relation to the relevant literature.
Images
PMCID: PMC2010148  PMID: 526433
22.  Alcohol Use and Health-Related Quality of Life among Youth in Taiwan 
Purpose
To examine the extent to which the use of the three most commonly consumed drugs in Taiwan (i.e., alcohol, tobacco, and betel nut) is related with health-related quality of life among adolescents. We probe whether the relationship linking alcohol use with health-related quality varies by health-orientated domains (e.g., physical, social, or emotional) and if it differs with other drug involvement.
Method
The data for this study come from a representative sample of 2235 adolescents (aged 12–18 years) collected as part of the 2001 National Health Interview Survey (NHIS), conducted in Taiwan. Recent alcohol, tobacco, and betel nut experiences were assessed by face-to-face interview. The 36-item short form Health Survey (SF-36) was used to assess respondents’ generic health status.
Results
Youth with recent alcohol use tend to experience a poorer level of health-related quality of life. The estimated associations were not constant over the eight domains of general health examined, and multivariate modeling with generalized linear models and generalized estimating equations found that the strongest inverse relationship appears in the domain of role limitation due to emotional problems (β = −10.5, 95% confidence interval [CI]: −16.9–−4.12, p < .001). Greater deleterious effects were not found among youth also using tobacco and/or betel nut.
Conclusions
Alcohol use was shown to be associated with impaired levels of health-related quality of life in adolescents. Although the temporality between alcohol involvement and lower levels of mental health is not explicit, the findings suggest that youth who are actively drinking might be a possible target group to intervene and avert mental health-related problems.
doi:10.1016/j.jadohealth.2006.04.019
PMCID: PMC2278239  PMID: 17046514
Adolescent; Alcohol; Tobacco; Betel nut; Quality of life
23.  Mold Contamination of Untreated and Roasted With Salt Nuts (Walnuts, Peanuts and Pistachios) Sold at Markets of Tabriz, Iran 
Background:
Nuts are one of the main consumed snacks worldwide and a significant component of Iranian’s diet. Natural contamination of nuts with fungus is unavoidable and is a major challenge to nuts safety and quality.
Objectives:
The purpose of this research was to study fungal contamination in commercially available nuts (pistachios, walnuts and peanuts) in the markets of Tabriz, Iran.
Materials and Methods:
100 samples of 50 gr roasted with salt peanuts and pistachios and 300 samples of 50 gr pure pistachios, walnuts and peanuts were collected from different areas of the local markets. After initial preparation, the samples were cultured on Sabouraud’s dextrose agar (SDA). 19 fungal isolates were identified.
Results:
The results show that Aspergillus niger was the predominant mold among pure (44%) and roasted with salt (14%) nuts (P < 0/001). In addition, percentage of mycotoxigenic fungal contamination was 18% for roasted with salt nuts and 11% for pure samples.
Conclusions:
The overall results of the analysed samples showed that the rate of fungal contamination in pure samples was higher than roasted with salt ones (P < 0.005). Results of the current survey could be useful for minimizing fungal contamination and can educate people about the dangers of mold in nuts.
doi:10.5812/jjm.8751
PMCID: PMC4138676  PMID: 25147659
Fungi; Nuts; Contamination; Aspergillus
24.  Role of lime in the generation of reactive oxygen species from betel-quid ingredients. 
The role of lime in the formation of reactive oxygen species (ROS), i.e., O2-., H2O2, and OH., from betel-quid components (extracts of areca nut and catechu) was investigated in vitro using a chemiluminescence technique and an assay for oxidative DNA damage involving analysis of 8-hydroxy-2'-deoxyguanosine. Of the various areca-nut extracts, the catechin fraction, at alkaline pH, was shown to be the most active producer of ROS. The free Ca(OH)2 content and pH of lime samples (a component of betel quid and chewing tobacco) were highly correlated with the generation of ROS from areca-nut extract in vitro and with oxidative base damage to DNA in vitro. While Fe2+ had an enhancing effect on ROS formation, Mg2+ had a marked inhibitory effect. The cytogenetic effects of ROS generated in vivo were measured in Syrian golden hamsters in which the cheek pouch had been painted with lime and an areca-nut extract or catechu, singly or in combination. The frequency of micronucleated cells was increased only in animals that had received both the areca-nut extract and lime. The frequency of micronucleated cells in exfoliated oral mucosal cells from Indian chewers of betel quid with tobacco containing lime or of tobacco with lime was significantly higher than in a control (no habit) group. These studies demonstrate that addition of lime to betel quid constituents generates ROS, which induce cytogenetic damage in hamster cheek pouch and may contribute to the cytogenetic damage observed in the oral cavity of betel-quid chewers. These results implicate ROS in clastogenesis and probably in the etiology of oral cancer.
PMCID: PMC1519632  PMID: 1486850
25.  Sana: democratizing access to quality healthcare using an open mhealth architecture 
Introduction
Sana is a cell phone-facilitated clinical information system that connects community health workers and medical specialists, to improve screening and diagnostics in resource-constrained settings.
Aims and objectives
The platform allows the transmission of any type of medical data—text, audio, video or photo—from a rural health worker to a remote medical specialist for real-time decision support, and for incorporation into an electronic medical record in order to facilitate care, quality control and allow statistical analysis. By functioning as a portable medical record, Sana also offers the ability to track patients more easily. The point-of-care platform is open source and customizable, allowing doctors to encode new assessments onto smart-phones for a specific application, or to use existing ones. The Sana team partners with universities, social enterprises, governments, NGOs and health organizations in resource-poor countries to assist with implementations of the Sana platform. There are currently eight deployments of Sana in Brazil, Greece, India, the Philippines, Swaziland and Zimbabwe, covering a range of clinical areas.
Results
One of the most urgent problems in resource-poor areas of the world is a shortage of doctors, and especially medical specialists. The biggest implementation of the Sana platform so far has been for the early detection of oral cancer in rural south India. It enables frontline community health workers to screen for precancerous and cancerous lesions by using Sana’s clinical decision support tools in dental hospitals and primary health clinics. Diagnosing oral cancer lesions at an early stage can reduce morbidity, mortality and cost of treatment. Screening processes also increase awareness of risk factors for oral cancer among the population, such as smoking and betel nut chewing. The solution was first implemented in June 2010 and more local health workers and support staff were brought on board in February 2011. By August 2010, up to 6000 people had been screened for oral cancer in the state of Karnataka. 300 patients were identified as high risk and their clinical data, including a photo of the inside of their mouth, were reviewed by an oral cancer specialist at a large tertiary care centre. The plan over the next year is to scale the project to screen one and a half million people in the province of Karnataka.
The developed world, meanwhile, is facing a crisis of an ageing population and a growing burden of chronic disease. In Greece, Sana has been deployed to treat one of the complications of a chronic disease, diabetes. Diabetes continues to be the most common underlying cause of nontraumatic lower extremity amputations, mainly due to foot ulcerations. Sana has developed a mobile health platform for diabetic foot tele-health and a pilot clinical trial to evaluate it is under development in Central Greece. The patients are offered home telehealth consultations during a visit by a specialized nurse, to substitute some of the visits to the outpatient vascular clinic of the hospital.
Conclusion
Oral cancer screening in India enabled the identification of 15 patients with pre-cancerous lesions among the 300 high-risk patients. Evaluation of the cost effectiveness and clinical impact of the technology is underway in deployments such as the project in Greece.
PMCID: PMC3571126
mHealth; open source; resource constrained areas

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