Towards a replacement therapy for stimulant betel quid dependence: A proof of concept study.

Stimulant betel quid (SBQ) containing Piper betle leaf (L), green unripe Areca catechu nut (AN) and the alkalizing agent, slaked lime, is an addictive, carcinogenic stimulant, with no pharmacotherapy, chewed by millions of people in the Asia/Pacific region. We compared the in vivo physiological profile of chewing (1) non-stimulant P. betle leaf+AN (LAN), (2) SBQ utilizing slaked lime and (3) a novel SBQ utilizing Mg(OH)2 , as an alkalizing agent, by measuring physiological parameters of intoxication and these were correlated with in vitro levels of alkaloids measured by UHPLC-MS/MS. Chewing LAN, which contains high levels of arecoline, had no stimulatory physiological effect. Chewing SBQ containing slaked lime or novel SBQ containing Mg(OH)2 , induced equivalent stimulatory physiological responses. In vitro, slaked lime hydrolyzed muscarinic esters in LAN while Mg(OH)2 did not. The physiological stimulation induced by chewing both SBQ and the lack of physiology to chewing LAN can be explained by changes in lipid solubility of phytochemicals induced by mouth pH during chewing of basic SBQ or acidic LAN. Since antiquity people have added slaked lime to SBQ to enhance absorption of phyto-chemicals across oral membranes to stimulate physiology. The same physiological changes can be induced by substituting slaked lime for less physically and chemically destructive bases. If attitudes regarding SBQ dependence can advance towards the more progressive attitudes already used to help smokers quit tobacco, modern chemistry has the potential to make chewing SBQ safer and quitting programs may become more accessible and efficacious.

Betel-quid addictive use disorders and Oral potentially malignant disorders and Oral cancer in south, southeast, and East Asia: A systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide a comprehensive assessment of the measurement and prevalence of betel-quid (BQ) abuse, dependence, and BQ use disorder (BUD), as well as to evaluate the impact of BQ addiction on oral malignant diseases. METHODS: We used the PRISMA guidelines to perform a systematic review and meta-analysis. We searched for relevant publications up to April 2024 in PubMed, Web of Science, and Embase. The articles were evaluated for BQ addiction and its relationship with oral potentially malignant disorders (OPMD) and oral cancer. RESULTS: The prevalence of BQ abuse, dependence, and BUD in South, Southeast, and East Asia varied between 0.8%-46.3%, 0.4%-43.5%, and 4.7%-39.2%, respectively. Among BQ chewers, the corresponding proportions of these disorders ranged from 40.5%-99.6%, 20.9%-99.6%, and 55.2%-99.3%. The pooled risks of OPMD associated with BQ abuse, dependence, and BUD were 16.3, 18.7, and 9.6-35.5, respectively. The risk of oral cancer for mild, moderate, and severe BUD was 8.5, 8.2, and 42.3, respectively. CONCLUSIONS: BUD mediates the link between BQ use and an increased risk of oral malignant disorders. Addressing and treating BQ addiction is an important component of comprehensive OPMD and oral cancer preventive and intervention programs that go beyond simple cessation efforts.

Evaluation of DSM-5 Diagnostic Criteria for Betel-Quid Use Disorder Using the Addiction Characteristics Defined by American Society of Addiction Medicine.

BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), categorizes betel-quid use disorder (BUD) under Other (Or Unknown) Substance Use Disorder, and the diagnostic criteria used are adapted from those of Substance Use Disorder. Because different substances have different characteristics, an improved set of diagnostic criteria is required to better detect BUD. OBJECTIVE: The objective of this study was to examine the different measures of accuracy for DSM-5 BUD by using the addiction characteristics defined by the American Society of Addiction Medicine (ASAM). METHODS: A certified psychiatrist conducted face-to-face diagnostic interviews. Questionnaires were administered to assess betel-quid use history, patterns of use, and dependence features. All betel-quid users were evaluated for BUD by using the DSM-5 criteria and addiction characteristics defined by the ASAM. RESULTS: One of the DSM-5 diagnostic criteria for BUD, namely large amount of time spent on obtaining and using betel quid and recovering from betel-quid use, showed the lowest sensitivity of 0.14, lowest diagnostic accuracy of 0.63, and lowest diagnostic odds ratio of 2.61. Another DSM-5 diagnostic criterion, namely continued betel-quid use despite knowledge of physical or psychological problems, had the lowest specificity of 0.49. The diagnostic threshold of five or more DSM-5 BUD criteria showed a sensitivity of 0.86 and a specificity of 0.97. CONCLUSIONS: This study is the first to evaluate the different measures of accuracy for DSM-5 BUD. Given that each addictive substance has unique addictive characteristics, the composition and number of criteria for diagnosing DSM-5 BUD must be reconsidered.

This is the first study to evaluate the different measures of accuracy for DSM-5 betel-quid use disorder.The DSM-5 diagnostic criteria, great deal of time spent on obtain, use, and recover from betel-quid use, has the lowest sensitivity, lowest diagnostic accuracy, and lowest diagnostic odds ratio.The DSM-5 diagnostic criteria, continued betel-quid use despite knowing of physical or psychological problems, has the lowest specificity.The diagnostic threshold for DSM-5 betel-quid use disorder at five or more showed the best sensitivity and a specificity.

Skin sympathetic nerve activity as a potential biomarker for overactive bladder.

PURPOSE: Abnormalities in autonomic function are associated with an overactive bladder (OAB). Heart rate variability is generally used as the sole assessment of autonomic activity; however, we utilized neuECG, a novel method of recording skin electrical signals, to assess autonomic nervous function in healthy controls and patients with OAB before and after treatment. METHODS: The prospective sample included 52 participants: 23 patients newly diagnosed with OAB and 29 controls. Autonomic function was assessed in all participants in the morning using neuECG, which analyzed the average skin sympathetic nerve activity (aSKNA) and electrocardiogram simultaneously. All patients with OAB were administered antimuscarinics; urodynamic parameters were assessed before treatments; autonomic and bladder functions using validated questionnaires for OAB symptoms were evaluated before and after OAB treatment. RESULTS: Patients with OAB had significantly higher baseline aSKNA (p = 0.003), lower standard deviation of the normal-to-normal beat intervals, lower root mean square of the successive differences, lower high-frequency, and higher low-frequency than did controls. Baseline aSKNA had the highest value in predicting OAB (AUROC = 0.783, p < 0.001). The aSKNA was negatively correlated with first desire and normal desire in urodynamic studies (both p = 0.025) and was significantly decreased after treatment at rest, stress, and recovery phases, as compared to those before treatment (p = 0.046, 0.017, and 0.017, respectively). CONCLUSION: Sympathetic activity increased significantly in patients with OAB compared to that in healthy controls, and decreased significantly post-treatment. Higher aSKNA is associated with decreased bladder volume at which voiding is desired. SKNA may be a potential biomarker for diagnosing OAB.

Up-regulated small-conductance calcium-activated potassium currents contribute to atrial arrhythmogenesis in high-fat feeding mice.

AIMS: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS AND RESULTS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100 nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). CONCLUSION: Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.

A Study of the Relationship between Phthalate Exposure and the Occurrence of Adult Asthma in Taiwan.

Although phthalate esters contribute to airway remodeling by increasing bronchial cells' migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma (n = 123) and asthma-free (n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder.

Association between gestational abnormal glucose tolerance and maternal-fetal outcomes.

AIM: To investigate the relationship between abnormal glucose tolerance during pregnancy and maternal-fetal outcomes, after categorizing women into groups with different levels of gestational abnormal glucose tolerance. METHODS: A total of 1858 pregnant women who received two-step screening for gestational diabetes mellitus (GDM) at Fooyin University Hospital were categorized into four groups, according to their glucose abnormalities, and their maternal-fetal outcomes were investigated from October 2015 to June 2020. RESULTS: Among the groups having different levels of abnormal glucose tolerance, there were significant differences and trends in mother's age, currently married status, and prepregnancy overweight or obesity, incidences of cesarean section, preterm, and gestational hypertension or preeclampsia; and with respect to neonatal incidence of large for gestational age (LGA), average weight, and average height (p < 0.05). After adjusting for potential factors, there were higher incidences of cesarean section (AOR = 1.71; 95% confidence interval [CI]: 1.12-2.61), preterm (AOR = 2.20; 95% CI: 1.23-3.91), neonatal LGA (AOR = 4.94; 95% CI: 2.87-8.51), and neonatal intensive care unit (NICU) admission (AOR = 2.66; 95% CI: 1.14-6.24) in the GDM group, relative to the control group. Furthermore, the women in the oral glucose tolerance test (OGTT)-1 group had a higher incidence of neonatal LGA when compared with the women in the normal group (AOR = 2.31; 95% CI: 1.02-5.33). CONCLUSIONS: We found higher incidences of cesarean section, preterm, and neonatal LGA and NICU admission in the GDM women, and a higher incidence of neonatal LGA in the OGTT-1 group, relative to control group.

Betel Quid Dependence Effects on Working Memory and Remote Memory in Chewers with Concurrent Use of Cigarette and Alcohol.

OBJECTIVE: The current study asked whether BQ dependence level could affect working memory (WM) and remote memory for the chewers with concurrent use of cigarettes and alcohol, a common phenomenon in Taiwan. METHODS: The standardized neuropsychological tests (Wechsler Memory Scale III (WMS-III) and Remote Memory Test) were adopted to address the BQ chewers' verbal WM, spatial WM and remote memory. The Spatial Span Test and the Digit Span Test from WMS-III and the Remote Memory Test were adopted. The Betel Nut Dependency Scale (BNDS), the Fagerstrom Test for Nicotine Dependence (FTND), and the Alcohol Use Disorders Identification Test (AUDIT) were adopted to measure the dependence levels. RESULTS: The BQ dependence level and Last BQ did not affect spatial WM, verbal WM, and remote memory. Last Cigarette is critical in affecting WM; namely, longer interval led to worse performance. Finally, higher alcohol dependence level could lead to better remote memory. CONCLUSIONS: To our knowledge, there are no BQ studies addressing the effects of concurrent use of cigarettes and alcohol on memory. The current results suggest that cigarette smoking and alcohol drinking, rather than BQ chewing, are critical for memory performance.

Effectiveness of end-stage renal disease communication skills training for healthcare personnel: a single-center, single-blind, randomized study.

BACKGROUND: Given that the consequences of treatment decisions for end-stage renal disease (ESRD) patients are long-term and significant, good communication skills are indispensable for health care personnel (HCP) working in nephrology. However, HCP have busy schedules that make participation in face-to-face courses difficult. Thus, online curricula are a rising trend in medical education. This study aims to examine the effectiveness of online ESRD communication skills training (CST) concerning the truth-telling confidence and shared decision-making (SDM) ability of HCP. METHODS: For this single-center, single-blind study, 91 participants (nephrologists and nephrology nurses) were randomly assigned to two groups, the intervention group (IG) (n = 45) or the control group (CG) (n = 46), with the IG participating in ESRD CST and the CG receiving regular in-service training. Truth-telling confidence and SDM ability were measured before (T0), 2 weeks after (T1), and 4 weeks after (T2) the intervention. Group differences over the study period were analyzed by generalized estimating equations. RESULTS: IG participants exhibited significantly higher truth-telling confidence at T1 than did CG participants (t = 2.833, P = .006, Cohen's d = 0.59), while there were no significant intergroup differences in the confidence levels of participants in the two groups at T0 and T2. Concerning SDM ability, there were no significant intergroup differences at any of the three time points. However, IG participants had high levels of satisfaction (n = 43, 95%) and were willing to recommend ESRD CST to others (n = 41, 91.1%). CONCLUSIONS: ESRD CST enhanced short-term truth-telling confidence, though it is unclear whether this was due to CST content or the online delivery. However, during pandemics, when face-to-face training is unsuitable, online CST is an indispensable tool. Future CST intervention studies should carefully design interactive modules and control for method of instruction.

Epidemic prediction of dengue fever based on vector compartment model and Markov chain Monte Carlo method.

BACKGROUND: Dengue epidemics is affected by vector-human interactive dynamics. Infectious disease prevention and control emphasize the timing intervention at the right diffusion phase. In such a way, control measures can be cost-effective, and epidemic incidents can be controlled before devastated consequence occurs. However, timing relations between a measurable signal and the onset of the pandemic are complex to be discovered, and the typical lag period regression is difficult to capture in these complex relations. This study investigates the dynamic diffusion pattern of the disease in terms of a probability distribution. We estimate the parameters of an epidemic compartment model with the cross-infection of patients and mosquitoes in various infection cycles. We comprehensively study the incorporated meteorological and mosquito factors that may affect the epidemic of dengue fever to predict dengue fever epidemics. RESULTS: We develop a dual-parameter estimation algorithm for a composite model of the partial differential equations for vector-susceptible-infectious-recovered with exogeneity compartment model, Markov chain Montel Carlo method, and boundary element method to evaluate the epidemic periodicity under the effect of environmental factors of dengue fever, given the time series data of 2000-2016 from three cities with a population of 4.7 million. The established computer model of "energy accumulation-delayed diffusion-epidemics" is proven to be effective to predict the future trend of reported and unreported infected incidents. Our artificial intelligent algorithm can inform the authority to cease the larvae at the highest vector infection time. We find that the estimated dengue report rate is about 20%, which is close to the number of official announcements, and the percentage of infected vectors increases exponentially yearly. We suggest that the executive authorities should seriously consider the accumulated effect among infected populations. This established epidemic prediction model of dengue fever can be used to simulate and evaluate the best time to prevent and control dengue fever. CONCLUSIONS: Given our developed model, government epidemic prevention teams can apply this platform before they physically carry out the prevention work. The optimal suggestions from these models can be promptly accommodated when real-time data have been continuously corrected from clinics and related agents.

Contribution of insulin resistance to the relationship between sugar-sweetened beverage intake and a constellation of cardiometabolic abnormalities in adolescents.

BACKGROUND: Insulin resistance (IR) is a pathophysiological construct that derives a series of metabolic disturbances that promote cardiometabolic dysfunction. This study evaluated mediating and modifying effects of homeostatic model assessment-based IR (HOMA-IR) on the association between sugar-sweetened beverage (SSB) consumption and a constellation of adolescent cardiometabolic abnormalities. METHODS: Comprehensive data on sociodemographics, diet, physical activity, and anthropometric and biochemical parameters for 1454 adolescents were obtained from a large-scale representative study for adolescent metabolic syndrome (MetS) conducted in Taiwan. The original (HOMA1-IR) and updated nonlinear (HOMA2-IR) HOMA-IR indicators were used as IR biomarkers. Principal component (PC) analysis was employed to create reduced groups of variables and risk scores for retained PCs. RESULTS: Higher SSB intake was associated with higher levels of HOMA1-IR and HOMA2-IR, and the two IR biomarkers were positively correlated with metabolic dysfunction clustering. Compared with SSB nondrinkers, adolescents who consumed >500 mL/day of hand-shaken high-fructose corn syrup beverages (HHB) had a 0.22 increase in the number of abnormal MetS components, and HOMA-IR mediation explained 33.9-37.9% of the effect. IR biomarkers accounted for 26.5-31.0% of the relationship between >500 mL/day of SSB consumption and bodyweight-enhanced PC scores. The effects of HOMA-IR indicators on all bodyweight-related factors were consistently intensified among >350 mL/day HHB drinkers (all Pinteraction < 0.05). CONCLUSIONS: Fructose-rich SSB intake correlates with a constellation of cardiometabolic abnormalities in adolescents, and this association may be partly mediated by HOMA-IR levels. The adverse effects of HOMA-IR on bodyweight-associated cardiometabolic risk factors depend on the type of SSB consumption, with enhanced risks observed in the intake of high amounts of HFCS-containing SSBs.

Age difference in the combined effect of soda drinks consumption and body adiposity on hyperuricaemia in US adults.

OBJECTIVE: To evaluate age-related differences in the independent/combined association of added sugar intake from soda and body adiposity with hyperuricaemia in gender-stratified US adults. DESIGN: Consumption of added sugar from soda was calculated from 24-h dietary interviews and categorised into none, regular and excessive consumption. Hyperuricaemia was defined as serum uric acid levels >417 mmol/l in men and >357 mmol/l in women. Multiple regression models with interaction terms and logistic models adjusted for covariates were conducted under survey-data modules. SETTING: National Health and Nutrition Examination Survey during 2007-2016. PARTICIPANTS: 15 338 adults without gout, failing kidneys, an estimated glomerular filtration rate < 30 or diabetes were selected. RESULTS: The age-stratified prevalence rate of hyperuricaemia was 18·8-20·4 % in males and 6·8-17·3 % in females. Hyperuricaemia prevalence of approximately 50 % was observed in young and middle age males who consumed excessive added sugar from soda. Excessive added sugar intake was observed to be associated with 1·5- to 2·0-fold and 2·0- to 2·3-fold increased risk of the probability of hyperuricaemia in young and middle age males and middle age females, respectively. Study participants, regardless of age or gender, who were obese and consumed excessive added sugar from soda had the highest risk of having hyperuricaemia. CONCLUSIONS: Our study revealed that the association between hyperuricaemia and consumption of excessive added sugar from soda may vary by age and gender. Obese adults who consumed excessive added sugar from soda had the highest risk of hyperuricaemia, a finding that was found across all age-specific groups for both genders.

Dysphagia and masticatory performance as a mediator of the xerostomia to quality of life relation in the older population.

BACKGROUND: The impact of poor oral health on older adults' quality of life is a public health problem. In this study, the mediating effects of dental status, occlusal condition, dysphagia, and masticatory performance on the association between xerostomia and oral health-related quality of life (OHRQoL) were assessed in the older adult population. METHODS: Stratified cluster sampling was used to recruit 1076 community-dwelling adults aged 65 years and older from Kaohsiung, Taiwan. Community care centers were randomly selected according to their geographic classifications (urban, rural, or mountainous areas). Assessments of dental status and occlusal condition were performed by dentists. Information on demographics, physical function, xerostomia, dysphagia and depression was collected through face-to-face interviews. Masticatory performance was evaluated using color-changeable chewing gum. OHRQoL was measured using the Geriatric Oral Health Assessment Index. Hierarchical regression models were used to assess the relationships between OHRQoL and physical function, dental status and oral function in older adults. Path analysis was used to estimate direct and indirect pathways between xerostomia and OHRQoL. RESULTS: Participants with xerostomia exhibited a 0.20 OHRQoL reduction (p < .001) compared with patients with no xerostomia, and the direct effect accounted for 83.3% of the total effect. Dysphagia and masticatory performance were found to exert significant mediating effects on the association between xerostomia and OHRQoL (ßs = 0.20 and - 0.12, respectively; both p < .001; ßs = 0.06 and - 0.09, respectively; both p < .05). Moreover, potential mediating effects of the number of functional teeth (ßs = - 0.11 and - 0.43, respectively; both p < .001) and occlusal condition (ßs = 0.09 and 0.13, respectively; both p < .05) on the relationship between xerostomia and masticatory performance were noted. CONCLUSIONS: Dysphagia and masticatory performance may serve as pathways through which xerostomia affects quality of life. Early oral function intervention may be a valuable and actionable target for older adults to maintain quality of life. Our results further suggest that checkup and screening for oral dysfunction are essential to prevent or delay the onset of complications.

A haplotype-specific linkage disequilibrium pattern of monoamine oxidase A gene associated with regular smoking in women.

BACKGROUND: Cigarette smoking in women is raising a public health problem. The X-linked monoamine oxidase A (MAOA) was considered as a susceptibility gene to substance abuse of tobacco, but the evolutionary effect of MAOA may lead to a positive or negative association between genetic variations and smoking development among study regions. METHODS: Based on linkage disequilibrium (LD), we performed a haplotype-based association to explore the effect of MAOA gene on women's smoking risk in a case-control study. RESULTS: Genotyped single nucleotide polymorphisms (SNPs) of MAOA gene, rs5953210G>A, rs2283725A>G and rs1137070T>C, were significantly associated with current smoking risk in women, and the increased level of plasma MAO-A activity was raised with per copy increment of risk allele in current smokers (P < .01). The haplotype patterns with minor haplotype frequency >.05 were constructed using the Expectation-Maximization algorithm, and the haplotype-specific A-G-C pattern raised the 2-fold risk to develop regular smoking (P = .0005). In the diplotype analysis based on X-inactivation mechanism relative to no and full dosage compensation, we showed that A-G-C haplotype not only increased regular smoking risk in a dose-dependent manner (Ptrend = .0011) but also contributed to smoking risk in the dosage compensation mechanism. Compared to non-smokers, the effect of A-G-C haplotype on random X-activation was associated with the raised MAO-A activity in women smokers (P < .05) although the lifetime cigarette consumption showed a difference that was not statistically significant. CONCLUSION: This study provides information on MAOA LD-based haplotype and diplotype patterns in women smoking.

Gender-specific factors associated with the suicidal ideation of children in Taiwan: A large-scale cross-sectional study.

We examined the relationship between suicidal ideation (SI) and the depressed mood, life stress and parenting styles in children. A large-scale survey was conducted including 5328 children from 65 elementary schools in Taiwan. SI was measured by asking children if any suicidal thoughts had occurred in the previous month. A series of regression models was analysed separately for male and female students. Compared with boys, girls demonstrated a higher proportion of SI. Among boys, SI was significantly associated with a high level of perceived environmental stress (adjusted odds ratio [aOR] = 2.61), a high degree of depressed mood (aOR = 2.39), authoritative (aOR = 1.72) and authoritarian (aOR = 2.53) parenting styles and two or more life-stress events (aOR = 1.45). A high level of perceived environmental stress (aOR = 2.09), a high degree of depressed mood (aOR = 2.89) and an authoritarian parenting style (aOR = 1.76) were significantly associated with the SI in girls. Gender-specific interventions aimed at preventing SI must enhance support systems at school and at home, particularly for students who suffer from a high degree of stress and depressed mood, and are subjected to an authoritarian parenting style.

PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential.

Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3ß phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated in oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC.

Effects of insulin resistance on the association between the circulating retinol-binding protein 4 level and clustering of pediatric cardiometabolic risk factors.

OBJECTIVES: Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children's susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. METHODS: We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n = 2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. RESULTS: Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310 cm, 1.384 µg/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (ß for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). CONCLUSIONS: HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components.

Endoscopic screening for synchronous esophageal neoplasia among patients with incident head and neck cancer: Prevalence, risk factors, and outcomes.

Esophageal squamous-cell neoplasia (ESCN) is a common second primary neoplasia found in patients with head-and-neck squamous-cell carcinoma (HNSCC). This study sought to identify the risk factors for synchronous ESCN and how they influence survival in HNSCC patient. Eight hundred and fifteen incident HNSCC patients were prospectively recruited for endoscopy screening for ESCN using white-light imaging, narrow-band imaging, Lugol chromoendoscopy, and pathological confirmation. Associated lifestyle and clinicopathological data were collected. The interquartile follow-up period cutoffs were 11.3, 20.5 and 34.9 months. 124 patients (15.2%) were diagnosed as having synchronous ESCN (66 low-grade dysplasia, 29 high-grade dysplasia, and 29 esophageal squamous-cell carcinoma). Consumption of alcohol, but not betel nut or cigarette, was significantly associated with the presence of synchronous ESCN (adjusted odds ratio [aOR] = 7.1 and 10.9 for former and current drinkers, respectively). There was an interaction between cumulative dose of alcohol consumption and alcohol flushing response on the development of ESCN. High-dose drinkers with flush response were 16.9 times more likely to have esophageal high-grade dysplasia/SCC than non-drinkers. Compared with oral cavity cancer patients, those with hypopharyngeal, laryngeal and oropharyngeal cancer were 6.8, 4.6 and 2.8 times more likely to have esophageal high-grade dysplasia/SCC. HNSCC patients with synchronous ESCN had lower overall survival than those without (p < 0.0001). In conclusion, surveillance of ESCN is strongly recommended for the high-risk subpopulation of HNSCC patients, especially drinkers who have a flush response to alcohol, and those with distant metastasis of index cancer and cancers in hypopharynx, oropharynx and larynx.

Fructose-Rich Beverage Intake and Central Adiposity, Uric Acid, and Pediatric Insulin Resistance.

OBJECTIVE: To determine the association between sugar-sweetened beverage (SSB) consumption with biomarkers of insulin resistance (IR) and investigate whether/how this relates to obesity and serum uric acid in adolescents. STUDY DESIGN: Adolescents (n = 1454, aged 12-16 years) were assessed in a study conducted to monitor Multilevel Risk Profiles for Adolescent Metabolic Syndrome in Taiwan. Detailed information about demographics, diet, physical, anthropometric, and clinical variables was collected. An original homeostatic model assessment of IR (HOMA1-IR), updated nonlinear homeostatic model assessment of IR (HOMA2-IR) model, and several IR markers were measured. RESULTS: Adolescents who consumed a greater amount of SSBs were more likely to have elevated fasting serum insulin, HOMA1-IR, and HOMA2-IR (P for trends, ≤.028). Compared with SSB nondrinkers, those with >350 mL/d intake of heavy high-fructose corn syrup-containing SSBs had a 0.52 and 0.30 higher multivariate-adjusted HOMA1-IR and HOMA2-IR, respectively. Waist circumference and serum uric acid were correspondingly found to explain 25.4% and 23.6%, as well as 23.2% and 20.6%, of the increases in the 2 IR markers. Both the elevations of HOMA1-IR and HOMA2-IR for high-fructose corn syrup-rich SSB intake were strengthened among obese adolescents (P for interaction, ≤.033). CONCLUSIONS: Fructose-rich SSB intake is associated with elevated levels of IR, and this relationship may be partially mediated by central adiposity and serum uric acid. Obesity may modify the effect of this type of SSB consumption in intensifying the elevation of IR in adolescents.

Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk.

The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence.