Prospective cohort study of respiratory effects at ages 14 to 26 following early life exposure to arsenic in drinking water.

BACKGROUND: We previously reported chronic respiratory effects in children who were then 7-17 years of age in Matlab, Bangladesh. One group of children had been exposed to high concentrations of arsenic in drinking water in utero and early childhood (average 436 µg/L), and the other group of children were never known to have been exposed to >10 µg/L. The exposed children, both males and females, had marked increases in chronic respiratory symptoms. METHODS: The current study involves a further follow-up of these children now 14-26 years of age with 463 located and agreeing to participate. They were interviewed for respiratory symptoms and lung function was measured. Data were collected on smoking, body mass index (BMI), and number of rooms in the house as a measure of socioeconomic status. RESULTS: Respiratory effects were still present in males but not females. In the high exposure group (>400 µg/L in early life) the odds ratio (OR) among male participants for dry cough in the last 12 months was 2.36 (95% confidence interval [CI] = 1.21, 4.63, P = 0.006) and for asthma OR = 2.51 (95% CI = 1.19, 5.29, P = 0.008). Forced vital capacity (FVC) was reduced in males in the early life high-exposure group compared with those never exposed (-95ml, P = 0.04), but not in female participants. CONCLUSIONS: By the age range 14-26, there was little remaining evidence of chronic respiratory effects in females but pronounced effects persisted in males. Mechanisms for the marked male female differences warrant further investigation along with further follow-up to see if respiratory effects continue in males.

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population.

Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411-422, 2017. © 2017 Wiley Periodicals, Inc.

Telephone Smoking-Cessation Counseling for Smokers in Mental Health Clinics: A Patient-Randomized Controlled Trial.

INTRODUCTION: People with a mental health diagnosis have high rates of tobacco use and encounter limited availability of tobacco treatment targeted to their needs. This study compared the effectiveness of a specialized telephone smoking-cessation intervention developed for mental health patients with standard state quit-line counseling. DESIGN: RCT. SETTING/PARTICIPANTS: The study was conducted at six Veterans Health Administration facilities in the Northeast U.S. Participants were 577 mental health clinic patients referred by their providers for smoking-cessation treatment. INTERVENTION: From 2010 to 2012, the study implemented a telephone program that included patient referral from a mental health provider, mailed cessation medications, and telephone counseling. Participants were randomized to receive a specialized multisession telephone counseling protocol (n=270) or transfer to their state's quit-line for counseling (n=307). MAIN OUTCOME MEASURES: Participants completed telephone surveys at baseline, 2 months, and 6 months. The study's primary outcome was self-reported 30-day abstinence at 6 months. Secondary outcomes were self-reported 30-day abstinence, counseling satisfaction and counseling content at 2 months, and self-reported use of cessation treatment and quit attempts at 6 months. Logistic regression was used to compare treatment groups on outcomes, controlling for baseline cigarettes per day and site. Inverse probability weighting and multiple imputation were used to handle missing abstinence outcomes. Data were analyzed in 2014-2015. RESULTS: At 6 months, participants in the specialized counseling arm were more likely to report 30-day abstinence (26% vs 18%, OR=1.62, 95% CI=1.24, 2.11). There was no significant group difference in abstinence at 2 months (18% vs 14%, OR=1.31, 95% CI=0.49, 3.49). Participants in the specialized arm were more likely to be assisted with developing a quit plan; receive follow-up calls after quitting; and receive counseling on several domains, including motivation, confidence, smoking triggers, coping with urges, and mental health symptoms (all p<0.05). Specialized counseling participants were more satisfied with treatment and more likely to find the counseling useful (p<0.05). CONCLUSIONS: The specialized counseling intervention was more effective at helping patients quit than transfer to a state quit-line. Patients were more satisfied with the specialized counseling program. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT00724308.

Acceptance and commitment therapy smoking cessation treatment for veterans with posttraumatic stress disorder: a pilot study.

OBJECTIVE: Veterans with PTSD smoke at rates two to three times higher than the general population, while their quit rate is less than half that of the general population. The present study evaluated the feasibility, acceptability, and preliminary efficacy of Acceptance and Commitment Therapy for Veterans With Posttraumatic Stress Disorder (PTSD) and Tobacco Addiction (ACT-PT), which focuses on helping veterans overcome emotional challenges to quitting smoking. METHODS: Veterans with current PTSD who smoked 15 or more cigarettes/day (N = 19) participated in an open trial of ACT-PT. Participants attended nine weekly individual counseling sessions and received eight weeks of nicotine patch therapy. Primary outcomes included feasibility and acceptability of the intervention, and secondary outcomes included expired-air carbon monoxide confirmed seven-day point prevalence abstinence, cravings, and PTSD symptoms. RESULTS: The retention rate for ACT-PT was good (74%) and client satisfaction ratings were high. Participants made multiple quit attempts (M = 3.6, SD = 4.2) during the study period and were significantly more confident that they could quit smoking at three-month follow-up. At the end of treatment, 37% of participants were abstinent from smoking and 16% were abstinent at three-month follow-up. Overall, participants reduced their smoking by 62% at the end of treatment and 43% at three-month follow-up. PTSD symptoms and smoking urges significantly decreased from baseline to the end of treatment and three-month follow-up. CONCLUSIONS: ACT-PT appears to be a promising smoking cessation treatment for veterans with PTSD. Future research should evaluate ACT-PT in a randomized controlled trial.

Smoking topography in Korean American and white men: preliminary findings.

UNLABELLED: This is the first study of Korean Americans' smoking behavior using a topography device. Korean American men smoke at higher rates than the general U.S. POPULATION: Korean American and White men were compared based on standard tobacco assessment and smoking topography measures. They smoked their preferred brand of cigarettes ad libitum with a portable smoking topography device for 24 h. Compared to White men (N = 26), Korean American men (N = 27) were more likely to smoke low nicotine-yield cigarettes (p < 0.001) and have lower Fagerstrom nicotine dependence scores (p = 0.04). Koreans smoked fewer cigarettes with the device (p = 0.01) than Whites. Controlling for the number of cigarettes smoked, Koreans smoked with higher average puff flows (p = 0.05), greater peak puff flows (p = 0.02), and shorter interpuff intervals (p < 0.001) than Whites. Puff counts, puff volumes, and puff durations did not differ between the two groups. This study offers preliminary insight into unique smoking patterns among Korean American men who are likely to smoke low nicotine-yield cigarettes. We found that Korean American men compensated their lower number and low nicotine-yield cigarettes by smoking with greater puff flows and shorter interpuff intervals than White men, which may suggest exposures to similar amounts of nicotine and harmful tobacco toxins by both groups. Clinicians will need to consider in identifying and treating smokers in a mutually aggressive manner, irrespective of cigarette type and number of cigarette smoked per day.

Occurrence of trivalent monomethyl arsenic and other urinary arsenic species in a highly exposed juvenile population in Bangladesh.

Following reports of high cytotoxicity and mutagenicity of monomethyl arsonous acid (MMA(III)) and early reports of urinary MMA(III) in arsenic-exposed individuals, MMA(III) has often been included in population studies. Use of urinary MMA(III) as an indicator of exposure and/or health risk is challenged by inconsistent results from field studies and stability studies, which indicate potential artifacts. We measured urinary arsenic species in children chronically exposed to arsenic in drinking water, using collection, storage, and analysis methods shown to conserve MMA(III). MMA(III) was easily oxidized in sample storage and processing, but recoveries of 80% or better in spiked urine samples were achieved. Attempts to preserve the distribution of MMA between trivalent and pentavalent forms using complexing agents were unsuccessful and MMA(III) spiked into treated urine samples actually showed lower stability than in untreated samples. In 643 urine samples from a highly exposed population from the Matlab district in Bangladesh stored for 3-6 months at ≤-70 °C, MMA(III) was detected in 41 samples, with an estimated median value of 0.3 µg/l, and levels of MMA(III) above 1 µg/l in only two samples. The low urinary concentrations in highly exposed individuals and known difficulties in preserving sample oxidation state indicate that urinary MMA(III) is not suitable for use as an epidemiological biomarker.

Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile.

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., <200µg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99-3.67), and 3.26 (1.76-6.04) (p-trend <0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06-3.11), and 2.02 (1.15-3.54) (p-trend <0.001). In analyses confined to subjects only with arsenic water concentrations <200µg/L (median=60µg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08-5.68) and 2.37 (1.01-5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations.

Smoking among individuals with schizophrenia in Korea: gender differences.

OBJECTIVE: This study examined gender differences in smoking and quitting among individuals diagnosed with schizophrenia in Korea. In addition, the study investigated differences in caffeine use by gender and smoking status. METHOD: An anonymous self-report survey was conducted with psychiatric inpatients. RESULTS: Compared to males, females were less likely to be current smokers (P<.001) and more likely to be former smokers (P<.01). Females were also less likely to be daily caffeine users (P<.001). Having more years of education (P<.05) and higher nicotine dependence scores (P<.05) were associated with decreased odds of intending to quit smoking, whereas having more previous quit attempts (P<.01) was associated with increased odds. These findings were significant even after adjusting for gender. Smokers were more likely to be daily caffeine users (P<.001) than their non-smoking counterparts. CONCLUSION: Nurses in Korea should play an active role in tobacco control for patients with schizophrenia by providing cessation counseling and educating the effect of caffeine use on cigarette consumption, while tailoring the service to gender differences found in this study.

Chronic respiratory symptoms in children following in utero and early life exposure to arsenic in drinking water in Bangladesh.

BACKGROUND: Arsenic exposure via drinking water increases the risk of chronic respiratory disease in adults. However, information on pulmonary health effects in children after early life exposure is limited. METHODS: This population-based cohort study set in rural Matlab, Bangladesh, assessed lung function and respiratory symptoms of 650 children aged 7-17 years. Children with in utero and early life arsenic exposure were compared with children exposed to less than 10 µg/l in utero and throughout childhood. Because most children drank the same water as their mother had drunk during pregnancy, we could not assess only in utero or only childhood exposure. RESULTS: Children exposed in utero to more than 500 µg/l of arsenic were more than eight times more likely to report wheezing when not having a cold [odds ratio (OR) = 8.41, 95% confidence interval (CI): 1.66-42.6, P < 0.01] and more than three times more likely to report shortness of breath when walking on level ground (OR = 3.86, 95% CI: 1.09-13.7, P = 0.02) and when walking fast or climbing (OR = 3.19, 95% CI: 1.22-8.32, P < 0.01]. However, there was little evidence of reduced lung function in either exposure category. CONCLUSIONS: Children with high in utero and early life arsenic exposure had marked increases in several chronic respiratory symptoms, which could be due to in utero exposure or to early life exposure, or to both. Our findings suggest that arsenic in water has early pulmonary effects and that respiratory symptoms are a better marker of early life arsenic toxicity than changes in lung function measured by spirometry.

Telephone care coordination for smokers in VA mental health clinics: protocol for a hybrid type-2 effectiveness-implementation trial.

BACKGROUND: This paper describes an innovative protocol for a type-II hybrid effectiveness-implementation trial that is evaluating a smoking cessation telephone care coordination program for Veterans Health Administration (VA) mental-health clinic patients. As a hybrid trial, the protocol combines implementation science and clinical trial methods and outcomes that can inform future cessation studies and the implementation of tobacco cessation programs into routine care. The primary objectives of the trial are (1) to evaluate the process of adapting, implementing, and sustaining a smoking cessation telephone care coordination program in VA mental health clinics, (2) to determine the effectiveness of the program in promoting long-term abstinence from smoking among mental health patients, and (3) to compare the effectiveness of telephone counseling delivered by VA staff with that delivered by state quitlines. METHODS/DESIGN: The care coordination program is being implemented at six VA facilities. VA mental health providers refer patients to the program via an electronic medical record consult. Program staff call referred patients to offer enrollment. All patients who enroll receive a self-help booklet, mailed smoking cessation medications, and proactive multi-call telephone counseling. Participants are randomized to receive this counseling from VA staff or their state's quitline. Four primary implementation strategies are being used to optimize program implementation and sustainability: blended facilitation, provider training, informatics support, and provider feedback. A three-phase formative evaluation is being conducted to identify barriers to, and facilitators for, program implementation and sustainability. A mixed-methods approach is being used to collect quantitative clinical effectiveness data (e.g., self-reported abstinence at six months) and both quantitative and qualitative implementation data (e.g., provider referral rates, coded interviews with providers). Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. DISCUSSION: This paper describes the rationale and methods of a trial designed to simultaneously study the clinical effectiveness and implementation of a telephone smoking cessation program for smokers using VA mental health clinics. Such hybrid designs are an important methodological design that can shorten the time between the development of an intervention and its translation into routine clinical care.

Predictors of relapse in a bupropion trial for smoking cessation in recently-abstinent alcoholics: preliminary results using an aggregate genetic risk score.

INTRODUCTION: Rates of smoking in the US population have decreased overall, but rates in some groups, including alcoholic smokers, remain high. Many newly sober alcoholics are concerned about their smoking and some attempt to quit. However, quit rates in this population are low. Prior studies suggest risk for relapse in this population may be genetically influenced and that genetic factors may moderate response to treatment. METHODS: IN THIS EXPLORATORY STUDY, WE HAD TWO SPECIFIC AIMS: (1) to investigate associations between genetic risk and outcome; (2) to investigate whether genetic risk moderates the efficacy of a medication intervention. Data are from a subsample of 90 participants from a clinical trial of smoking cessation treatment for smokers with between 2 and 12 months of alcohol abstinence. Subjects were randomly assigned to bupropion or placebo. All subjects received counseling and nicotine patches. To examine the possibility that bupropion may have been efficacious in participants with a specific genetic profile (ie, a pharmacogenetic approach), an aggregate genetic risk score was created by combining risk genotypes previously identified in bupropion treatment studies. RESULTS: Although medication efficacy was not moderated by the aggregate genetic risk score, there was an interaction between nicotine dependence and genetic risk in predicting smoking abstinence rates at the end of treatment (10 weeks). CONCLUSIONS: Results suggest an aggregate genetic risk score approach may have utility in treatment trials of alcoholics who smoke. Additionally, these findings suggest a strategy for understanding and interpreting conflicting results for single genetic markers examined as moderators of smoking cessation treatment.

A brief treatment engagement intervention for individuals with co-occurring mental illness and substance use disorders: results of a randomized clinical trial.

Study objectives were to evaluate a brief intervention designed to facilitate outpatient engagement following an inpatient psychiatric stay for individuals with mental illness and substance use. A total of 102 veterans were randomly assigned to one of two conditions: (1) Time Limited Care-Coordination (TLC), an eight-week co-occurring disorders intervention or (2) a matched attention (MA) control condition in the form of health education sessions. Both groups also received treatment as usual in inpatient and outpatient settings. Sixty-nine percent of TLC participants attended an outpatient appointment within 14 days of discharge, compared to only 33% of MA participants (P < 0.01). TLC participants were also more likely to be engaged in outpatient services at the end of the intervention period (44 vs. 22%, P < 0.01). This study provided evidence that an eight-week intervention could improve treatment engagement. Research is currently underway to examine impact of TLC intervention beyond the 8 week study period.

Front-loaded versus weekly counseling for treatment of tobacco addiction.

INTRODUCTION: Approximately 60%-70% of cigarette smokers who try to quit relapse by 2 weeks postcessation. We tested the efficacy of a front-loaded (FL) counseling intervention whose goal was to increase the likelihood of successful early abstinence and subsequent long-term abstinence. METHODS: We randomized 278 adult smokers to an FL or weekly behavioral smoking cessation counseling schedule. The total number of sessions across treatment was the same for both groups. However, those assigned to the FL schedule received 6 counseling sessions in the first 2 weeks postcessation, while those in the weekly condition received 2 sessions. Participants in both groups also received standard nicotine patch treatment. RESULTS: At 1 year postcessation, FL participants were significantly less likely to have relapsed when continuous abstinence was used as the definition of abstinence/relapse (11.7% abstinent vs. 6.3%, hazard ratio [HR] = 0.69, p = .007); and there were nonsignificant trends for FL subjects to have better outcomes when abstinence was defined as never smoking for 7 or more consecutive days nor for 7 or more consecutive episodes (18.4% abstinent vs. 14.8%, HR = 0.83, p = .20) and as point prevalence abstinence (15.6% abstinent vs. 12.9%, p = .11). The relationship between FL counseling treatment and continuous abstinence was partially mediated by higher postcessation levels of social support perceived from counseling and greater use of cessation-related coping strategies. CONCLUSIONS: We conclude that FL counseling is a promising treatment model that should be evaluated further, perhaps using modifications of the FL schedule used in this study.

Creatinine, diet, micronutrients, and arsenic methylation in West Bengal, India.

BACKGROUND: Ingested inorganic arsenic (InAs) is methylated to monomethylated (MMA) and dimethylated metabolites (DMA). Methylation may have an important role in arsenic toxicity, because the monomethylated trivalent metabolite [MMA(III)] is highly toxic. OBJECTIVES: We assessed the relationship of creatinine and nutrition--using dietary intake and blood concentrations of micronutrients--with arsenic metabolism, as reflected in the proportions of InAS, MMA, and DMA in urine, in the first study that incorporated both dietary and micronutrient data. METHODS: We studied methylation patterns and nutritional factors in 405 persons who were selected from a cross-sectional survey of 7,638 people in an arsenic-exposed population in West Bengal, India. We assessed associations of urine creatinine and nutritional factors (19 dietary intake variables and 16 blood micronutrients) with arsenic metabolites in urine. RESULTS: Urinary creatinine had the strongest relationship with overall arsenic methylation to DMA. Those with the highest urinary creatinine concentrations had 7.2% more arsenic as DMA compared with those with low creatinine (p < 0.001). Animal fat intake had the strongest relationship with MMA% (highest tertile animal fat intake had 2.3% more arsenic as MMA, p < 0.001). Low serum selenium and low folate were also associated with increased MMA%. CONCLUSIONS: Urine creatinine concentration was the strongest biological marker of arsenic methylation efficiency, and therefore should not be used to adjust for urine concentration in arsenic studies. The new finding that animal fat intake has a positive relationship with MMA% warrants further assessment in other studies. Increased MMA% was also associated, to a lesser extent, with low serum selenium and folate.

Incremental efficacy of adding bupropion to the nicotine patch for smoking cessation in smokers with a recent history of alcohol dependence: results from a randomized, double-blind, placebo-controlled study.

AIMS: The primary aim of this study was to compare the efficacy of smoking cessation treatment using a combination of nicotine patch and bupropion vs. nicotine patch and placebo bupropion. A secondary aim was to investigate whether the efficacy of bupropion is moderated by belief about whether one is receiving active or placebo medication. METHODS: Participants were recruited from a residential substance abuse treatment program and the community. We randomly assigned 148 smokers with between 2 and 12 months of alcohol abstinence to nicotine patch plus bupropion or nicotine patch plus placebo. All participants also received seven counseling sessions. RESULTS: At follow up, differences between medication conditions were not significant. Seven-day point prevalence quit rates in the patch plus bupropion vs. patch plus placebo conditions at week 24 were 6% and 11%, respectively. Differences between groups on prolonged abstinence and time to first smoking lapse were also not significant. However, among participants who received bupropion, those who accurately "guessed" that they were receiving bupropion were more likely to remain abstinent than those who incorrectly believed they were receiving placebo. CONCLUSIONS: Findings do not support combining nicotine patch and bupropion for smoking cessation in this population. However, findings support previous studies suggesting the importance of assessing the blind in smoking cessation studies and its possible moderating effect on medication efficacy. Future directions for enhancing smoking cessation outcome in these smokers include investigations of intensive behavioral and pharmacological interventions, including studies of potential interactions between individual genetic differences and medication efficacy.

Involvement of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) in arsenic biomethylation and its role in arsenic-induced toxicity.

BACKGROUND: In humans, inorganic arsenic (iAs) is metabolized to methylated arsenical species in a multistep process mainly mediated by arsenic (+3 oxidation state) methyltransferase (AS3MT). Among these metabolites is monomethylarsonous acid (MMAIII), the most toxic arsenic species. A recent study in As3mt-knockout mice suggests that unidentified methyltransferases could be involved in alternative iAs methylation pathways. We found that yeast deletion mutants lacking MTQ2 were highly resistant to iAs exposure. The human ortholog of the yeast MTQ2 is N-6 adenine-specific DNA methyltransferase 1 (N6AMT1), encoding a putative methyltransferase. OBJECTIVE: We investigated the potential role of N6AMT1 in arsenic-induced toxicity. METHODS: We measured and compared the cytotoxicity induced by arsenicals and their metabolic profiles using inductively coupled plasma-mass spectrometry in UROtsa human urothelial cells with enhanced N6AMT1 expression and UROtsa vector control cells treated with different concentrations of either iAsIII or MMAIII. RESULTS: N6AMT1 was able to convert MMAIII to the less toxic dimethylarsonic acid (DMA) when overexpressed in UROtsa cells. The enhanced expression of N6AMT1 in UROtsa cells decreased cytotoxicity of both iAsIII and MMAIII. Moreover, N6AMT1 is expressed in many human tissues at variable levels, although at levels lower than those of AS3MT, supporting a potential participation in arsenic metabolism in vivo. CONCLUSIONS: Considering that MMAIII is the most toxic arsenical, our data suggest that N6AMT1 has a significant role in determining susceptibility to arsenic toxicity and carcinogenicity because of its specific activity in methylating MMAIII to DMA and other unknown mechanisms.

Association of genetic variation in cystathionine-beta-synthase and arsenic metabolism.

Variation in individual susceptibility to arsenic-induced disease may be partially explained by genetic differences in arsenic metabolism. Mounting epidemiological evidence and in vitro studies suggest that methylated arsenic metabolites, particularly monomethylarsonic (MMA3), are more acutely toxic than inorganic arsenic; thus, MMA3 may be the primary toxic arsenic species. To test the role of genetic variation in arsenic metabolism, polymorphisms in genes involved in one-carbon metabolism [methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), cystathionine-beta-synthase (CBS), thymidylate synthase (TYMS), dihydrofolate reductase (DHFR), serine hydroxymethyltransferase 1 (SHMT1)] and glutathione biosynthesis [glutathione-S-transferase omega 1 (GSTO1)] were examined in an arsenic-exposed population to determine their influence in urinary arsenic metabolite patterns. In 142 subjects in Cordoba Province, Argentina, variant genotypes for CBS rs234709 and rs4920037 SNPs compared with wild-type homozygotes were associated with 24% and 26% increases, respectively, in the mean proportion of arsenic excreted as monomethylarsonic acid (%MMA). This difference is within the range of differences in %MMA seen between people with arsenic-related disease and those without such disease in other studies. Small inverse associations with CBS rs234709 and rs4920037 variants were also found for the mean levels of the proportion of arsenic excreted as dimethylarsinous acid (%DMA). No other genetic associations were found. These findings are the first to suggest that CBS polymorphisms may influence arsenic metabolism in humans and susceptibility to arsenic-related disease.

Effects of bupropion on simulated demand for cigarettes and the subjective effects of smoking.

INTRODUCTION: The biobehavioral mechanism(s) mediating bupropion's efficacy are not well understood. Behavioral economic measures such as demand curves have proven useful in investigations of the reinforcing effects of drugs of abuse. Behavioral economic measures may also be used to measure the effect of pharmacotherapies on the reinforcing effects of drugs of abuse. METHODS: The effects of bupropion on simulated demand for cigarettes were investigated in a placebo-controlled double-blind clinical trial. Participants reported the number of cigarettes they would purchase and consume in a single day at a range of prices. The effects of medication on the subjective effects of smoking were also explored. RESULTS: Demand for cigarettes was well described by an exponential demand equation. Bupropion did not significantly decrease the maximum number of cigarettes that participants said they would smoke in a single day nor did it significantly alter the relation between price per cigarette and demand. Baseline demand elasticity did not predict smoking cessation, but changes in elasticity following 1 week of treatment did. Medication group had no effect on any subjective effects of smoking. DISCUSSION: Bupropion had no significant effects on demand for cigarettes. The exponential demand equation, recently introduced in behavioral economics, proved amenable to human simulated demand and might be usefully employed in other pharmacotherapy studies as it provides a potentially useful measure of changes in the essential value of the drug as a reinforcer. Such changes may be useful in predicting the efficacy of medications designed to reduce drug consumption.

Addressing tobacco use disorder in smokers in early remission from alcohol dependence: the case for integrating smoking cessation services in substance use disorder treatment programs.

Despite the declining overall rate of cigarette smoking in the general population in the United States, the prevalence of smoking is estimated to be as high as 80% among treatment-seeking alcoholics. The serious adverse health effects of tobacco and heavy alcohol use are synergistic and recent evidence suggests that smoking slows the process of cognitive recovery following alcohol abstinence. In addition, substantial evidence shows that treatment for tobacco dependence does not jeopardize alcohol abstinence. In this paper, we focus on the impact and treatment implications of tobacco dependence among treatment-seeking alcoholics through a review of five areas of research. We begin with brief reviews of two areas of research: studies investigating the genetic and neurobiological vulnerability of comorbid tobacco and alcohol dependence and studies investigating the consequences of comorbid dependence on neurobiological and cognitive functioning. We then review literature on the effects of smoking cessation on drinking urges and alcohol use and the effectiveness of smoking cessation interventions with alcoholic smokers. Finally, we offer recommendations for research with an emphasis on clinical research for enhancing smoking cessation outcomes in this population.

A prospective study of persistence in the prediction of smoking cessation outcome: results from a randomized clinical trial.

Research has had mixed success in identifying pretreatment variables which can be used to guide treatment and enhance outcome. A critical first step in the process is to identify variables that reliably predict outcome. Some recent studies, largely retrospective, have found mixed evidence on the relationship between task persistence and smoking outcome measures. In the present study, we use data from a randomized clinical trial (N=241) to prospectively investigate the ability of persistence to predict outcome. Findings from multivariate analyses did not support our hypotheses: persistence did not predict outcome. We discuss these findings in relation to previous studies by focusing on theoretical and measurement issues related to the study of persistence in smoking cessation research. We conclude by recommending directions for future research, including conceptual clarification of the relationship between persistence and theoretically related constructs and investigations of variables that may moderate relationships between these constructs and cessation outcome.