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CORK Bibliography: Biochemical Markers of Substance Use

47 citations. January 2009 to present

Prepared: March 2011

Achur RN; Freeman WM; Vrana KE. Circulating cytokines as biomarkers of alcohol abuse and alcoholism. (review). Journal of Neuroimmune Pharmacology 5(1): 83-91, 2010. (72 refs.)

There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long-term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: tumor necrosis factor-alpha, interleukin (IL)-1-alpha, IL-1-beta, IL-6, IL-8, IL-12, and monocyte chemoattractant protein-1. This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels, and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake.

Alonso M; Castellanos M; Sanchez JM. Evaluation of potential breath biomarkers for active smoking: Assessment of smoking habits. Analytical and Bioanalytical Chemistry 396(8): 2987-2995, 2010. (31 refs.)

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography-mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2, 5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short-and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure.

Aranda JV; Beharry K; Valencia GB; Natarajan G; Davis J. Caffeine impact on neonatal morbidities. Journal of Maternal-Fetal & Neonatal Medicine 23(Supplement 3): 20-23, 2010. (30 refs.)

Caffeine is a silver bullet in neonatology. This ubiquitous trimethylxanthine, pervasively used in the human diet and beverages, significantly impacts on major acute neonatal morbidities including apnea of prematurity, bronchopulmonary dysplasia, patent ductus arteriousus with or without surgical ligation and post-operative apnea. Potential uses in respiratory distress syndrome as suggested by improved lung function in primate models is supported by the decreased time on mechanical ventilation and need for oxygen therapy. Improved later outcomes at 18 to 22 months include clinically significant decreases in cerebral palsy, cognitive impairment, and severe retinopathy of prematurity in those babies who received caffeine during the neonatal period compared to non-caffeine treated placebo neonates. Ongoing and future research studies focus on optimizing current dose regimens to determine whether benefits can be maximized while maintaining an impressive safety profile. Molecular pharmacologic studies focused on the molecular and the biochemical mechanisms underlying the protective effects of caffeine are also being done to optimize treatment regimes and to target potential molecular pathways leading to further decreases in acute and long term neonatal morbidities. Since its use in newborns three decades ago, caffeine is now one of the safest, most cost-beneficial and effective therapies in the newborn.

Bearer CF; Bailey SM; Hoek JB. Advancing alcohol biomarkers research. Alcoholism: Clinical and Experimental Research 34(6): 941-945, 2010. (14 refs.)

Biomarkers to detect past alcohol use and identify alcohol-related diseases have long been pursued as important tools for research into alcohol use disorders as well as for clinical and treatment applications and other settings. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a workshop titled "Workshop on Biomarkers for Alcohol-Induced Disorders" in June 2008. The intent of this workshop was to review and discuss recent progress in the development and implementation of biomarkers for alcohol use and alcohol-related disorders with a goal to formulate a set of recommendations to use to stimulate and advance research progress in this critical area of alcoholism research. Presentations at this workshop reviewed the current status of alcohol biomarkers, providing a summary of the history of biomarkers and the major goals of alcohol biomarker research. Moreover, presentations provided a comprehensive overview of the current status of several well-recognized biomarkers of alcohol use, a summary of recent studies to characterize novel biomarkers and their validation, along with perspectives and experiences from other NIH institutes and from other federal agencies and industry, related to regulatory issues. Following these presentations, a panel discussion focused on a set of issues presented by the organizers of this workshop. These discussion points addressed: (i) issues related to strategies to be adopted to stimulate biomarker discovery and application, (ii) the relevance of animal studies in biomarker development and the status of biomarkers in basic science studies, and (iii) issues related to the opportunities for clinical and commercial applications. This article summarizes these perspectives and highlights topics that constituted the basis for recommendations to enhance alcohol biomarker research.

Benowitz NL; Dains KM; Dempsey D; Yu LS; Jacob P. Estimation of nicotine dose after low-level exposure using plasma and urine nicotine metabolites. Cancer Epidemiology, Biomarkers & Prevention 19(5): 1160-1166, 2010. (11 refs.)

Background: We sought to determine the optimal plasma and urine nicotine metabolites, alone or in combination, to estimate the systemic dose of nicotine after low-level exposure. Methods: We dosed 36 nonsmokers with 100, 200, or 400 mu g p.o. of deuterium-labeled nicotine (doses similar to exposure to secondhand smoke) daily for 5 days and then measured plasma and urine nicotine metabolites at various intervals over 24 hours. Results: The strongest correlations with nicotine dose were seen for the sum of four (cotinine + cotinine-glucuronide + trans-3'-hydroxycotinine + 3HC-glucuronide) or six (including also nicotine + nicotine-glucuronide) of the major nicotine metabolites in 24-hour urine collection (r = 0.96), with lesser correlations for these metabolites using spot urines corrected for creatinine at various times of day (r = 0.72-0.80). The sum of plasma cotinine + trans-3'-hydroxycotine was more highly correlated with nicotine dose than plasma cotinine alone (r = 0.82 versus 0.75). Conclusions: Our results provide guidance for the selection of biomarkers to estimate the dose of nicotine taken in low-level (secondhand smoke) tobacco exposure. Impact: This is probably relevant to active smoking as well.

Bonevski B; Campbell E; Sanson-Fisher RW. The validity and reliability of an interactive computer tobacco and alcohol use survey in general practice. Addictive Behaviors 35(5): 492-498, 2010. (42 refs.)

Background: Uncertainty regarding the accuracy of the computer as a data collection or patient screening tool persists. Previous research evaluating the validity of computer health surveys have tended to compare those responses to that of paper survey or clinical interview (as the gold standard). This approach is limited as it assumes that the paper version of the self-report survey is valid and an appropriate gold standard. Objectives: First, to compare the accuracy of computer and paper methods of assessing self-reported smoking and alcohol use in general practice with biochemical measures as gold standard. Second, to compare the test re-test reliability of computer administration, paper administration and mixed methods of assessing self-reported smoking status and alcohol use in general practice. Methods: A randomised cross-over design was used. Consenting patients were randomly assigned to one of four groups; Group I. C-C : completing a computer survey at the time of that consultation (Time 1) and a computer survey 4-7 days later (Time 2); Group 2. C-P: completing a computer survey at Time 1 and a paper survey at Time 2; Group 3. P-C: completing a paper survey at Time I and a computer survey at Time 2: and Group 4. P-P: completing a paper survey at Time 1 and 2. At Time I all participants also completed biochemical measures to validate self-reported smoking status (expired air carbon monoxide breath test) and alcohol consumption (ethyl alcohol urine assay). Results: Of the 618 who were eligible, 575 (93%) consented to completing the Time 1 surveys. Of these, 71% (N = 411) completed Time 2 surveys. Compared to CO, the computer smoking self-report survey demonstrated 91% sensitivity, 94% specificity, 75% positive predictive value (PPV) and 98% negative predictive value (NPV). The equivalent paper survey demonstrated 86% sensitivity, 95% specificity, 80% PPV, and 96% NPV. Compared to urine assay, the computer alcohol use self-report survey demonstrated 92% sensitivity, 50% specificity, 10% PPV and 99% NPV. The equivalent paper survey demonstrated 75% sensitivity, 57% specificity, 6% PPV, and 98% NPV. Level of agreement of smoking self-reports at Time 1 and Time 2 revealed kappa coefficients ranging from 0.95 to 0.98 in each group and hazardous alcohol use self-reports at Time 1 and Time 2 revealed kappa coefficients ranging from 0.90 to 0.96 in each group. Conclusion: The collection of self-reported health risk information is equally accurate and reliable using computer interface in the general practice setting as traditional paper survey. Computer survey appears highly reliable and accurate for the measurement of smoking status. Further research is needed to confirm the adequacy of the quantity/frequency measure in detecting those who drink alcohol. Interactive computer administered health surveys offer a number of advantages to researchers and clinicians and further research is warranted.

Bright RP. Denial of hepatic transplantation on the basis of smoking: Is it ethical? (review). Current Opinion in Organ Transplantation 15(2): 249-253, 2010. (29 refs.)

Purpose of review: There is disagreement and inconsistency between liver transplant programs regarding the acceptance or rejection of smokers as candidates for transplantation. This article reviews the outcome data for transplanted smokers, the rate of maintained abstinence from cigarettes by smokers who have quit and the ethics of using tobacco use as a transplant selection criterion. Recent findings Consistent with earlier studies, recently published articles continue to demonstrate an increased risk of noncutaneous malignancies, higher rates of graft arterial thrombosis and a higher mortality rate in liver transplant patients who smoke as compared with nonsmokers. There is a significant rate of relapse to smoking after transplantation, and the rates are higher among patients with alcoholic liver disease. Recent studies have shown that 10-16% of patients with biochemical verification of active smoking deny their tobacco use when interviewed for transplant consideration. Although extensively, if not universally, used to exclude transplant candidates, a recent study of marijuana use showed no difference in mortality outcomes as compared with nonusers. Summary: With the exception of one recent study, there is substantial literature to support increased morbidity and mortality among posthepatic transplant smokers.

Coleman T; Chamberlain C; Cooper S; Leonardi-Bee J. Efficacy and safety of nicotine replacement therapy for smoking cessation in pregnancy: Systematic review and meta-analysis. (review). Addiction 106(1): 52-61, 2011. (34 refs.)

Aims: To determine the efficacy and safety of nicotine replacement therapy (NRT) with or without behavioural support when used to support smoking cessation in pregnancy. Design, Setting and Participants: A systematic review of randomized controlled trials (RCTs) in which NRT was used with or without behavioural support to promote smoking cessation; trials providing unequal behavioural support to different trial groups were excluded. Measurements: Efficacy: self-reported smoking cessation in later pregnancy, validated where possible by biochemical measures with appropriate cut-points; infants' safety: mean and low birth weights (LBW), preterm birth, fetal demise and neonatal intensive care unit (NICU) admissions. Findings: Five trials, enrolling 695 pregnant, regular smokers were included in the review. The pooled risk ratio (RR) and 95% confidence Interval (CI) for smoking cessation in later pregnancy after using NRT was 1.63 (0.85, 3.14). Subgroup analysis comparing studies at lower risk of bias (placebo-RCTs) with those at higher risk of bias (non-placebo-RCTs) found that efficacy estimates varied with trial design [RR (95% CI) for cessation in placebo-RCTs 1.17 (0.83, 1.65) versus 7.81 (1.51, 40.35) for non-placebo-RCTs]. Five of the seven safety outcomes were more positive among infants born to women who had used NRT, but none of the observed differences between trial groups reached statistical significance. Conclusions: There is currently insufficient evidence to determine whether or not nicotine replacement therapy is effective or safe when used in pregnancy for smoking cessation; further research and, in particular, placebo-randomized controlled trials are required.

Comandini A; Marzano V; Curradi G; Federici G; Urbani A; Saltini C. Markers of anti-oxidant response in tobacco smoke exposed subjects: A data-mining review. (review). Pulmonary Pharmacology & Therapeutics 23(6, Special Issue): 482-492, 2010. (57 refs.)

Tobacco smoke exposure is the cause of exaggerated inflammatory responses and tissue destruction leading to chronic bronchitis and emphysema. A number of studies have used biochemical and immunological technologies to identify biomarkers of severity, risk and pharmacological target of disease. Recently, genomic and proteomic studies have been carried out to explore tobacco smoke-induced lung damage mechanisms. Eight of these studies, including 81 healthy non-smokers, 138 healthy smokers and 24 smokers with COPD, had open platform generated data available online and were reviewed in order to identify markers of smoke-induced damage by analyzing differential gene and protein expression in healthy individuals exposed to tobacco smoke in comparison with chronic obstructive pulmonary disease (COPD) smokers and healthy non-smokers. To this end the Ingenuity Pathways Analysis, a web-based application enables identifying the main biological functions and pathways, was used. The pathway most significantly associated with healthy smokers was the Nrf2-mediated Oxidative Stress Response (p-value < 0.01): out of the 22 genes/proteins identified in healthy smokers, 19 were up-regulated and three down-regulated, compared to non-smokers. Interestingly, four genes/proteins of the same pathway were differentially regulated in COPD, one up-regulated and three down-regulated, compared to healthy smokers. Moreover, in the comparison between COPD and healthy smokers, our analysis showed that the most relevant pathway was the Mitochondrial Dysfunction (p-value < 0.01) with 12 differentially regulated genes/proteins. This data-mining review supports the notion that Nrf2-regulated anti-oxidant genes play a central role in protection against tobacco smoke toxic effects and may be amenable to use as COPD risk biomarkers. Furthermore, this review suggests that mitochondrial dysfunction may be involved in the development of COPD.

Cylwik B; Chrostek L; Krawiec A; Supronowicz Z; Koput A; Szmitkowski M. Lipid-bound sialic acid in alcoholics participates in increased level of total sialic acid. Alcohol 44(5): 457-462, 2010. (20 refs.)

Serum total sialic acid (TSA) concentration is a sensitive marker of excessive alcohol consumption and is the sum of protein-bound sialic acid, lipid-bound sialic acid (LSA), and free sialic acid. The LSA is the fraction of SA attached to gangliosides that are transported in the blood by the lipoproteins. In this article, the effect of chronic alcohol consumption on the serum levels of LSA was evaluated. The objective of the study was to understand the mechanism of elevated serum TSA concentration during alcohol abuse. Additionally, the association of LSA with serum lipid profile was tested. For this purpose, the levels of LSA, TSA, lipids, lipoproteins, and apolipoproteins (apos) in the sera of 106 alcoholics were measured. The serum level of LSA in alcohol abusers was significantly elevated. This increase was because of the elevated level of LSA in patients drinking alcohol up to 2 days before sampling. The elevated level of LSA positively correlated with TSA, and also with biochemical indices of hepatocellular injury such as aspartate aminotransferase and gamma-glutamyltransferase, but did not correlate with any lipids, apos, and lipoproteins. The increase in LSA level is not related with the status of serum lipid profile but is related to the liver status estimated by the biochemical markers of liver cell damage. On the basis of our results, we conclude that the elevated level of LSA in alcohol abusers contributes to an increase in the serum concentration of TSA, and contrary to TSA, is affected by the status of liver cells.

Dietz PM; Homa D; England LJ; Burley K; Tong VT; Dube SR et al. Estimates of nondisclosure of cigarette smoking among pregnant and nonpregnant women of reproductive age in the United States. American Journal of Epidemiology 173(3): 355-359, 2011. (14 refs.)

Although clinic-based studies have used biochemical validation to estimate the percentage of pregnant women who deny smoking but are actually smokers, a population-based estimate of nondisclosure of smoking status in US pregnant women has not been calculated. The authors analyzed data from the 1999-2006 National Health and Nutrition Examination Survey and estimated the percentage of 994 pregnant and 3,203 nonpregnant women 20-44 years of age who did not report smoking but had serum cotinine levels that exceeded the defined cut point for active smoking (nondisclosure). Active smoking was defined as self-reporting smoking or having a serum cotinine concentration that exceeded the cut point for active smoking. Overall, 13.0% (95% confidence interval (CI): 8.8, 17.1) of pregnant women and 29.7% (95% CI: 27.3, 32.1) of nonpregnant women were active smokers. Nondisclosure was higher among pregnant active smokers (22.9%, 95% CI: 11.8, 34.6) than among nonpregnant smokers (9.2%, 95% CI: 7.1, 11.2). Among pregnant active smokers, nondisclosure was associated with younger age (20-24 years). Among nonpregnant active smokers, nondisclosure was associated with Mexican-American and non-Hispanic black race/ethnicity. Studies and surveillance systems that rely on self-reported smoking status are subject to underestimation of smoking prevalence, especially among pregnant women, and underreporting may vary by demographic characteristics.

Dunn KE; Saulsgiver KA; Sigmon SC. Contingency management for behavior change: Applications to promote brief smoking cessation among opioid-maintained patients. Experimental and Clinical Psychopharmacology 19(1): 20-30, 2011. (86 refs.)

Cigarette smoking is highly prevalent among patients who are being treated for opioid-dependence, yet there have been limited scientific efforts to promote smoking cessation in this population. Contingency management (CM) is a behavioral treatment that provides monetary incentives contingent upon biochemical evidence of drug abstinence. This paper discusses the results of two studies that utilized CM to promote brief smoking cessation among opioid-maintained patients. Participants in a pilot study were randomly assigned for a 2-week period to a Contingent group that earned monetary vouchers for providing biochemical samples that met criteria for smoking abstinence, or a Noncontingent group that earned monetary vouchers independent of smoking status (Dunn et al, 2008). Results showed Contingent participants provided significantly more smoking-negative samples than Noncontingent participants (55% vs. 5%, respectively). A second randomized trial that utilized the same 2-week intervention and provided access to the smoking cessation pharmacotherapy bupropion replicated the results of the pilot study (55% and 17% abstinence in Contingent and Noncontingent groups, respectively; Dunn et al, 2010). Relapse to illicit drug use was also evaluated prospectively and no association between smoking abstinence and relapse to illicit drug use was observed (Dunn et al, 2009). It will be important for future studies to evaluate participant characteristics that might predict better treatment outcome, to assess the contribution that pharmacotherapies might have alone or in combination with a CM intervention on smoking cessation and to evaluate methods for maintaining the abstinence that is achieved during this brief intervention for longer periods of time.

Durazzo TC; Meyerhoff DJ; Nixon SJ. Chronic cigarette smoking: Implications for neurocognition and brain neurobiology. International Journal of Environmental Research and Public Health 7(10): 3760-3791, 2010. (196 refs.)

Compared to the substantial volume of research on the general health consequences associated with chronic smoking, little research has been specifically devoted to the investigation of its effects on human neurobiology and neurocognition. This review summarizes the peer-reviewed literature on the neurocognitive and neurobiological implications of chronic cigarette smoking in cohorts that were not seeking treatment for substance use or psychiatric disorders. Studies that specifically assessed the neurocognitive or neurobiological (with emphasis on computed tomography and magnetic resonance-based neuroimaging studies) consequences of chronic smoking are highlighted. Chronic cigarette smoking appears to be associated with deficiencies in executive functions, cognitive flexibility, general intellectual abilities, learning and/or memory processing speed, and working memory. Chronic smoking is related to global brain atrophy and to structural and biochemical abnormalities in anterior frontal regions, subcortical nuclei and commissural white matter. Chronic smoking may also be associated with an increased risk for various forms of neurodegenerative diseases. The existing literature is limited by inconsistent accounting for potentially confounding biomedical and psychiatric conditions, focus on cross-sectional studies with middle aged and older adults and the absence of studies concurrently assessing neurocognitive, neurobiological and genetic factors in the same cohort. Consequently, the mechanisms promoting the neurocognitive and neurobiological abnormalities reported in chronic smokers are unclear. Longitudinal studies are needed to determine if the smoking-related neurobiological and neurocognitive abnormalities increase over time and/or show recovery with sustained smoking cessation.

Freeman WM; Salzberg AC; Gonzales SW; Grant KA; Vrana KE. Classification of alcohol abuse by plasma protein biomarkers. Biological Psychiatry 68(3): 219-222, 2010. (20 refs.)

Background: Biochemical diagnostics of ethanol intake would improve alcohol abuse treatment and have applications in clinical trial and public safety settings. Self-reporting of alcohol use has clinical utility but lacks the desired reliability. Previously, proposed single-analyte biochemical tests of alcohol intake suffer from low sensitivity and specificity or examine only acute drinking and have therefore seen limited clinical use. Methods: To address this unmet need, plasma protein biomarker discovery and validation were performed with an alcohol self-administering nonhuman primate model system to develop a diagnostic that accurately classifies subjects into nondrinking, nonabusive drinking, and abusive drinking categories. Results: A 17-plasma protein panel was determined that correctly classifies abusive drinking with 100% sensitivity and also differentiates any level of drinking from alcohol abstinence with 88% accuracy. Conclusions: The biomarker panel reflects changes in multiple organ systems and suggests robust changes in the plasma proteome with drinking that might serve as a sensitive and specific diagnostic test. The specific plasma proteins altered with alcohol self-administration might represent indicators of alcohol-induced stress on a variety of organ systems.

Freeman WM; Vrana KE. Future prospects for biomarkers of alcohol consumption and alcohol-induced disorders. Alcoholism: Clinical and Experimental Research 34(6): 946-954, 2010. (55 refs.)

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis, treatment, and research of alcohol abuse and alcoholism. Successful development of a biomarker that allows for accurate assessment of alcohol intake and drinking patterns would not only be a major advance in clinical care but also a valuable research tool. A number of advances have been made in testing the validity of proposed biomarkers as well as in identifying potential new biomarkers through systems biology approaches. This commentary will examine the definition of a biomarker of heavy drinking, the types of potential biomarkers, the steps in biomarker development, the current state of biomarker development, and critical obstacles for the field. The challenges in developing biomarkers for alcohol treatment and research are similar to those found in other fields. However, the alcohol research field must reach a competitive level of rigor and organization. We recommend that NIAAA consider taking a leadership role in organizing investigators in the field and providing a common set of clinical specimens for biomarker validation studies.

Gilligan C; Sanson-Fisher R; Eades S; Wenitong M; Panaretto K; D'este C. Assessing the accuracy of self-reported smoking status and impact of passive smoke exposure among pregnant Aboriginal and Torres Strait Islander women using cotinine biochemical validation. Drug and Alcohol Review 29(1): 35-40, 2010. (27 refs.)

Introduction and Aims. A significant level of misreport or error occurs during questionnaire-based assessment of smoking behaviour. Failure to measure environmental tobacco smoke, and participant's inclination to under-report their smoking raise questions as to the accuracy of assessment. In order to establish an estimation of the possible error associated with such assessment, the accuracy of self-reported smoking status among a group of pregnant Aboriginal and Torres Strait Islander women was examined. Design and Methods. Women attending two Aboriginal Medical services in Far North Queensland for antenatal care were invited to participate. Women completed an interviewer assisted questionnaire relating to their smoking status and a 24 h diary of their exposure to nicotine and consumption of alcohol. Urine samples were analysed for cotinine using an Enzyme Linked Immunosorbent Assay. Results. Cotinine analysis indicated that 17% of women who reported that they were non-smokers were likely to have misreported this status, or be exposed to high levels of passive smoke. The only significant predictors of cotinine level were self-reported nicotine exposure (including passive smoke) and number of cigarettes smoked in the previous 24 h. Other individual and environmental variables had no significant influence on cotinine level using this analysis technique. Discussion and Conclusions. The level of potential error in smoking assessment among this group was substantial. Exposure to environmental tobacco smoke might explain part of this error, but the reasons for misreport can only be speculated. This rate of misclassification should be taken into consideration in routine screening of antenatal women in primary health care.

Gray TR; Eiden RD; Leonard KE; Connors G; Shisler S; Huestis MA. Nicotine and metabolites in meconium as evidence of maternal cigarette smoking during pregnancy and predictors of neonatal growth deficits. Nicotine & Tobacco Research 12(6): 658-664, 2010. (29 refs.)

Many women continue tobacco use during pregnancy despite known adverse consequences on neonatal growth and development. Testing meconium, the first neonatal feces, for tobacco biomarkers offers objective evidence of prenatal tobacco exposure. However, relationships between the amount, frequency, and timing of cigarette smoking during gestation and tobacco biomarker meconium concentrations and neonatal outcomes are unclear. Eighty-seven pregnant women provided detailed self-reports of daily tobacco consumption throughout pregnancy. Nicotine, cotinine, and trans-3'-hydroxycotinine were quantified in neonatal meconium by liquid chromatography-tandem mass spectrometry. Among nonsmokers, all meconium specimens were negative, whereas nearly all meconium specimens were positive if the mother self-reported tobacco use into the third trimester. Tobacco biomarker concentrations were significantly albeit weakly correlated with mean cigarettes per day in the third trimester. Reduced birth weight, gestational age, or head circumference were observed if meconium contained one or more tobacco biomarkers, but deficits did not correlate with biomarker concentrations. While previously thought to reflect second and third trimester drug exposure, meconium appears to reliably identify only third trimester drug use. While a 10 ng/g nicotine, cotinine, or trans-3'-hydroxycotinine cutoff in meconium was previously proposed to differentiate tobacco-exposed from nonexposed or passively exposed neonates, improved maternal self-reporting techniques in this cohort suggest that a lower cutoff, equivalent to the analytic limits of quantification, is more appropriate.

Grey A; Rix-Trott K; Horne A; Gamble G; Bolland M; Reid IR. Decreased bone density in men on methadone maintenance therapy. Addiction 106(2): 349-354, 2011. (30 refs.)

Aims: Opioid use may impact adversely upon skeletal health. Participants in methadone maintenance programmes commonly have prolonged exposure to opioids. We sought to determine whether participants in a methadone maintenance programme have evidence of altered bone mineral density (BMD) and bone turnover. Design: Cross-sectional study of people taking methadone maintenance therapy (MMT). Setting: Clinical research centre. Participants: Eighty-three people (48 men, 35 women) who had taken MMT for a median (interquartile range) of 11 (6-16) years. Comparison data were from both a normative database and control subjects recruited and assessed at the same location as the participants taking MMT. Measurements: BMD at lumbar spine, total hip and total body; biochemical markers of bone turnover. Findings: In men taking MMT, BMD was lower than normal at each skeletal site [mean, 95% confidence interval Z-score -1.1 (-1.6 to -0.7) at the lumbar spine, -1.0 (-1.3 to -0.7) at the total hip, and -1.1 (-1.4 to -0.8) at the total body, P < 0.001 at each site]. BMD in the women taking MMT was not different from control values. Bone turnover was within the normal range in both genders. Serum testosterone was lower in the men taking MMT than in controls. Conclusions: BMD is lower than normal throughout the skeleton in men, but not women, taking MMT. Assessment of skeletal health, including estimation of absolute fracture risk, should be undertaken in men participating in methadone maintenance programmes.

Hamer M; Stamatakis E; Batty GD. Objectively assessed secondhand smoke exposure and mental health in adults: Cross-sectional and prospective evidence from the Scottish Health Survey. Archives of General Psychiatry 67(8): 850-855, 2010. (29 refs.)

Context: Secondhand smoke (SHS) exposure has been related to various somatic health outcomes, although very little is known about the association between SHS exposure and mental health. Objective: To assess the associations between mental health and SHS exposure, which was objectively measured using the salivary cotinine level as a circulating biochemical marker. Design, Setting, and Participants: In a cross-sectional and longitudinal study, a representative sample of 5560 nonsmoking adults (mean [SD] age, 49.8 [15.4] years; 45.5% men) and 2595 smokers (mean [SD] age, 44.8 [14.8] years; 50.2% men) without history of mental illness was drawn from the 1998 and 2003 Scottish Health Survey. A priori, study participants with cotinine values of 15.00 mu g/L or higher (to convert to nano-moles per liter, multiply by 5.675) were assumed to be smokers and recategorized as such in all analyses. Main Outcome Measures: A score greater than 3 on the 12-item General Health Questionnaire was used as an indicator of psychological distress. Incident psychiatric hospital admissions over 6 years of follow-up were also recorded. Results: Psychological distress was apparent in 14.5% of the sample. In logistic regression analyses of the cross-sectional data, after adjustments for a range of covariates, high SHS exposure among nonsmokers (cotinine level >0.70 and <15.00 mu g/L) was associated with higher odds of psychological distress (odds ratio=1.49; 95% confidence interval, 1.13-1.97) in comparison with participants with cotinine levels below the limit of detection (<= 0.05 mu g/L). In prospective analyses, risk of a psychiatric hospital admission was related to high SHS exposure (multivariate adjusted hazard ratio=2.84; 95% confidence interval, 1.07-7.59) and active smoking (multivariate adjusted hazard ratio=3.74; 95% confidence interval, 1.55-8.98). Conclusions: Exposure to SHS is associated with psychological distress and risk of future psychiatric illness in healthy adults. These concordant findings using 2 different research designs emphasize the importance of reducing SHS exposure at a population level not only for physical health but also for mental health.

Hsieh SJ; Ware LB; Eisner MD; Yu L; Jacob P; Havel C et al. Biomarkers increase detection of active smoking and secondhand smoke exposure in critically ill patients. Critical Care Medicine 39(1): 40-45, 2011. (31 refs.)

Objectives: The association between tobacco smoke exposure and critical illness is not well studied, largely because obtaining an accurate smoking history from critically ill patients is difficult. Biomarkers can provide quantitative data on active and secondhand cigarette smoke exposure. We sought to compare cigarette smoke exposure as measured by biomarkers to exposure by self-report in a cohort of critically ill patients and to determine how well biomarkers of cigarette smoke exposure correlate with each other in this population. Design, Setting, and Patients: Serum and urine cotinine and trans-3'-hydroxycotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and hair and nail nicotine levels were measured in 60 subjects enrolled in an observational cohort of critically ill subjects at a tertiary academic medical center in Tennessee. Smoking history was obtained from patients, their surrogates, or the medical chart. Cigarette smoke exposure as measured by biomarkers was compared to exposure by history. Measurements and Main Results: By smoking history, 29 subjects were identified as smokers, 28 were identified as nonsmokers, and 3 were identified as unknown. The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified 27 of the 28 nonsmokers by history either as active smokers (n = 6, 21%) or as exposed to secondhand smoke (n = 21, 75%). All biomarker levels were strongly correlated with each other (r = .69-.95, p < .0001). Conclusions: The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified considerably more active smokers than did smoking history and detected a high prevalence of secondhand smoke exposure in a critically ill population. These markers will be important for future studies investigating the relationship between active smoking and secondhand smoke exposure and critical illness.

Kouros D; Tahereh H; Mohammadreza A; Minoo MZ. Opium and heroin alter biochemical parameters of human's serum. American Journal of Drug and Alcohol Abuse 36(3): 135-139, 2010. (43 refs.)

Background: Iran is a significant consumer of opium, and, generally, of opioids, in the world. Addiction is one of the important issues of the 21st century and is an imperative issue in Iran. Longterm consumption of opioids affects homeostasis. Objective: To determine the effects of opium and heroin consumption on serum biochemical parameters. Methods: In a cross-sectional study, subjects who had consumed heroin (n = 35) or opium (n = 42) for more than two years and 35 nonaddict volunteers as the control group were compared in regard to various biochemical parameters such as fasting blood sugar (FBS), Na+, K+, Ca2+, blood urea nitrogen (BUN), uric acid (UA), triglyceride (TG), cholesterol, creatinine, and total protein. Chromatography was used to confirm opioid consumption, and the concentration of biochemical parameters was determined by laboratory diagnostic tests on serum. Results: No significant differences were found in Na+, Ca2+, BUN, UA, TG, creatinine, and total protein concentrations among the three groups. FBS, K+, and UA levels were significantly lower in opium addicts compared to the control group. Serum Ca2+ concentration of heroin addicts showed a significant decrease compared to that of the control group. Both addict groups showed a significant decrease in serum cholesterol levels. Conclusion: Chronic use of opium and heroin can change serum FBS, K+, Ca2+, UA, and cholesterol. Scientific Significance: This study, one of few on the effects of opium on serum biochemical parameters in human subjects, has the potential to contribute to the investigation of new approaches for further basic studies.

Kravos M; Malesic I. Glutamate dehydrogenase as a marker of alcohol dependence. Alcohol and Alcoholism 45(1): 39-44, 2010. (35 refs.)

Aims: The aim of this study was to examine glutamate dehydrogenase (GLDH) in the diagnostic combinations as a result of new findings. Methods: GLDH, gama-glutamyltransferase (GGT), aspartate-aminotranferase (AST), alanine-aminotransferase (ALT) and erythrocyte mean cell volume (MCV) were assessed three times in 238 alcoholics admitted to hospital: on admission, after 24 h and after 7 days. Results: All the values were significantly higher than those in healthy persons. The fastest activity decrease was seen in GLDH. The kinetics of GLDH and AST were more applicable than GGT kinetics after a week, but GLDH kinetics were most reliable. GLDH was the most specific laboratory marker with almost 90% specificity. The sensitivity of combination MCV and GLDH kinetics after 1 week of abstinence was pathognomonic by 97.2%. This decision tree gave us a model with 84.5% accuracy. Conclusions: GLDH is an equally accurate marker of alcoholism in comparison to others, if its significantly faster decrease is taken into consideration. We strongly believe that watching changes in the activity of laboratory markers of alcoholism is an effective yet overlooked aid.

Kuhar MJ. Contributions of basic science to understanding addiction. BioSocieties 5(1, special issue): 25-35, 2010. (35 refs.)

Discoveries in basic science have helped us understand the drug abuse/dependence/addiction brain disorder. One can view this brain disorder as a long-lasting, relapsing pattern of drug seeking and taking with adverse consequences. Drug self-administration studies in animals have revealed brain circuits and neurotransmitters that underlie drug-induced reward and reinforcement. Moreover, studies of effects of drugs on receptors have shown us how drugs can change gene expression and how drugs can change the biochemical makeup of the brain. Drug-induced changes in the brain are very long lasting, which presumably can explain why drug addiction is a chronic and relapsing disease. Also, drugs exert their actions at least partly through evolved brain circuits that serve functions critical for survival such as feeding and sex. Thus, drugs can harness our strongest instincts and the desire to use them can become very powerful. These findings should influence research, treatment and policy towards the disorder of drug addiction and abuse.

Kulaga V; Gareri J; Fulga N; Koren G. Agreement between the fatty acid ethyl ester hair test for alcohol and social workers' reports. Therapeutic Drug Monitoring 32(3): 294-299, 2010. (59 refs.)

The purpose of this study was to examine the relationship between social worker reports and the fatty acid ethyl ester (FAEE) test as a biomarker for heavy alcohol use. In 2005, a diagnostic program to detect excessive alcohol use by FAEE hair analysis in parents at high risk of having children with fetal alcohol spectrum disorders was established. All cases submitted by Child Protective Services between May and December of 2007 (n = 172) were included comparing social worker reports with FAEE test outcome by odds ratio analysis. A subanalysis of mothers (n = 119), excluding fathers, was also performed. Factors associated with testing positive for hair FAEE in parents, and mothers alone, were: knowledge of a specific instance of problem drinking within the past 6 months (odds ratio [OR] = 5.11, 2.57-10.16 and OR = 8.51, 3.59-20.18, respectively) and third party reports alleging alcohol abuse (OR = 3.31, 1.69-6.46 and OR = 3.30, 1.45-7.50, respectively). Mothers who admitted to heavy drinking were also seven times more likely to test positive for hair FAEE (OR = 6.74, 1.50-30.38) than those who did not. Factors negatively associated with testing positive for hair FAEE in parents, and mothers alone, were: social workers testing for FAEE without the suspicion of alcohol use but rather as a measure to "cover all bases'' (OR = 0.09, 0.02-0.40 and (OR = 0.13, 0.03-0.58, respectively) or because of a history/suspicion of illicit drug use (OR = 0.2, 0.07-0.55 and OR = 0.26, 0.08-0.80, respectively). Eleven of 15 reports, indicating levels of consumption, were also in clinical agreement with FAEE test outcome. The FAEE hair test is being applied for the first time in the present context. Our results show the test corroborates well with social workers' suspicion of alcohol use. Reported factors directly related to alcohol use were significantly associated with testing positive for excessive alcohol use, whereas factors not directly related to alcohol use were negatively associated with testing positive.

Li LH; Everhart T; Jacob P; Jones R; Mendelson J. Stereoselectivity in the human metabolism of methamphetamine. British Journal of Clinical Pharmacology 69(2): 187-192, 2010. (17 refs.)

AIM: To characterize the formation and urinary elimination of metabolites of S-(+) and R-(-) methamphetamine (MA) in humans. METHODS: In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg(-1), R-(-)-MA 0.25 and 0.5 mg kg(-1), racemic MA 0.5 mg kg(-1), or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS: An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(-)-AMP (P < 0.001). Furthermore, less R-(-)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P = 0.02). Correspondingly, S-(+)-MA excretion was less than R-(-)-MA (42% vs. 52%; P = 0.005). CONCLUSIONS: The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8-11%) than AMP (2-7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism.

Li LH; Lopez JC; Galloway GP; Baggott MJ; Everhart T; Mendelson J. Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled r-methamphetamine: Selection of the r-methamphetamine dose. Therapeutic Drug Monitoring 32(4): 504-507, 2010. (9 refs.)

All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), we have developed a method to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from our study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction.

Lippi G; Franchini M; Favaloro EJ; Targher G. Moderate red wine consumption and cardiovascular disease risk: Beyond the "French Paradox". Seminars in Thrombosis and Hemostasis 36(1): 59-70, 2010. (85 refs.)

The term French paradox was coined in 1992 to describe the relatively low incidence of cardiovascular disease in the French population, despite a relatively high dietary intake of saturated fats, and potentially attributable to the consumption of red wine. After nearly 20 years, several studies have investigated the fascinating, overwhelmingly positive biological and clinical associations of red wine consumption with cardiovascular disease and mortality. Light to moderate intake of red wine produces a kaleidoscope of potentially beneficial effects that target all phases of the atherosclerotic process, from atherogenesis (early plaque development and growth) to vessel occlusion (flow-mediated dilatation, thrombosis). Such beneficial effects involve cellular signaling mechanisms, interactions at the genomic level, and biochemical modifications of cellular and plasma components. Red wine components, especially alcohol, resveratrol, and other polyphenolic compounds, may decrease oxidative stress, enhance cholesterol efflux from vessel walls (mainly by increasing levels of high-density lipoprotein cholesterol), and inhibit lipoproteins oxidation, macrophage cholesterol accumulation, and foam-cell formation. These components may also increase nitric oxide bioavailability, thereby antagonizing the development of endothelial dysfunction, decrease blood viscosity, improve insulin sensitivity, counteract platelet hyperactivity, inhibit platelet adhesion to fibrinogen-coated surfaces, and decrease plasma levels of von Willebrand factor, fibrinogen, and coagulation factor VII. Light to moderate red wine consumption is also associated with a favorable genetic modulation of fibrinolytic proteins, ultimately increasing the surface-localized endothelial cell fibrinolysis. Overall, therefore, the "French paradox'' may have its basis within a milieu containing several key molecules, so that favorable cardiovascular benefits might be primarily attributable to combined, additive, or perhaps synergistic effects of alcohol and other wine components on atherogenesis, coagulation, and fibrinolysis. Conversely, chronic heavy alcohol consumption and binge drinking are associated with increased risk of cardiovascular events. In conclusion, although mounting evidence strongly supports beneficial cardiovascular effects of moderate red wine consumption (one to two drinks per day; 10-30 g alcohol) in most populations, clinical advice to abstainers to initiate daily alcohol consumption has not yet been substantiated in the literature and must be considered with caution on an individual basis.

Maldonado R; Berrendero F. Endogenous cannabinoid and opioid systems and their role in nicotine addiction. (review). Current Drug Targets 11(4): 440-449, 2010. (117 refs.)

Nicotine addiction is a complex behavioural alteration, in which many neuronal pathways and neurotransmitters are involved. For a long time, dopamine has been considered one of the most important neurotransmitters in mediating the rewarding effects of nicotine. In addition, a great amount of research suggests that the endogenous cannabinoid and opioid systems play an overall modulatory effect on the reward circuitry and participate in the addictive properties of most of the prototypical drugs of abuse. This review focuses on recent behavioural and biochemical data involving these systems in the different processes that contribute to tobacco addiction. A possible role for the endogenous cannabinoid and opioid systems in the rewarding properties of nicotine as well as in the development of nicotine physical dependence and relapse to nicotine-seeking behaviour will be examined. According to preclinical studies, clinical trials suggest that the manipulation of these systems with cannabinoid or opioid antagonists could be a potential therapeutical strategy for treating nicotine addiction.

Marques P; Tippetts S; Allen J; Javors M; Alling C; Yegles M et al. Estimating driver risk using alcohol biomarkers, interlock blood alcohol concentration tests and psychometric assessments: Initial descriptives. Addiction 105(2): 226-239, 2010. (48 refs.)

Aim: To identify alcohol biomarker and psychometric measures that relate to drivers' blood alcohol concentration (BAC) patterns from ignition interlock devices (IIDs). Design, setting, participants, measurements In Alberta, Canada, 534 drivers, convicted of driving under the influence of alcohol (DUI), installed IIDs and agreed to participate in a research study. IID BAC tests are an established proxy for predicting future DUI convictions. Three risk groups were defined by rates of failed BAC tests. Program entry and follow-up blood samples (n = 302, 171) were used to measure phosphatidyl ethanol (PETH), carbohydrate deficient transferrin (%CDT), gamma glutamyltransferase (GGT) and other biomarkers. Program entry urine (n = 130) was analyzed for ethyl glucuronide (ETG) and ethyl sulphate (ETS). Entry hair samples were tested for fatty acid ethyl esters (FAEE) (n = 92) and ETG (n = 146). Psychometric measures included the DSM-4 Diagnostic Interview Schedule Alcohol Module, Alcohol Use Disorders Identification Test (AUDIT), the time-line follow-back (TLFB), the Drinker Inventory of Consequences (DRINC) and the Temptation and Restraint Inventory (TRI). Findings: Except for FAEE, all alcohol biomarkers were related significantly to the interlock BAC test profiles; higher marker levels predicted higher rates of interlock BAC test failures. PETH, the strongest with an overall analysis of variance F ratio of 35.5, had significant correlations with all nine of the other alcohol biomarkers and with 16 of 19 psychometric variables. Urine ETG and ETS were correlated strongly with the IID BAC tests. Conclusions The findings suggest that several alcohol biomarkers and assessments could play an important role in the prediction and control of driver alcohol risk when re-licensing.

Miller EI; Norris HRK; Rollins DE; Tiffany ST; Moore CM; Vincent MJ et al. Identification and quantification of nicotine biomarkers in human oral fluid from individuals receiving low-dose transdermal nicotine: A preliminary study. Journal of Analytical Toxicology 34(7): 357-366, 2010. (39 refs.)

The objective of this preliminary study was to identify and quantify potential nicotine (NIC) biomarkers in post-exposure oral fluid samples collected from 10 NIC-abstinent human participants administered 7 mg transdermal NIC using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Oral fluid samples were collected prior to NIC patch application and at 0.5 and 0.75 h after patch removal using the Quantisal(tm) oral fluid collection device. The validated LC-MS-MS analyte panel included nicotine-N?-D-glucuronide, cotinine-N-oxide, trans-3-hydroxycotinine, norcotinine, trans-nicotine-1?-N-oxide, cotinine (COT), nornicotine, NIC, anatabine, anabasine, and cotinine-N-?-D-glucuronide. Analytes and corresponding deuterated internal standards were extracted by solid-phase extraction. NIC and COT concentrations were quantifiable in oral fluid samples collected from 6 of the 10 participants 0.5 h after patch removal and in oral fluid samples collected from 7 of the 10 participants 0.75 h after patch removal. Based on the mean NIC and COT concentrations in oral fluid and plasma for the participants with both quantifiable NIC and COT at the 0.5 and 0.75 h collection times, the oral fluid-plasma ratio was 6.4 for NIC and 3.3 for COT. An ELISA procedure was also validated and successfully applied as a screening tool for these oral fluid samples in conjunction with LC-MS-MS confirmation. An ELISA cut-off concentration of 5.0 ng/mL provided excellent sensitivity for discrimination of COT-positive post-exposure oral fluid samples collected after low-level transdermal NIC exposure and oral fluid samples collected prior to patch application.

Miranda RC; Pietrzykowski AZ; Tang YM; Sathyan P; Mayfield D; Keshavarzian A. MicroRNAs: Master regulators of ethanol abuse and toxicity? (review). Alcoholism: Clinical and Experimental Research 34(4): 575-587, 2010. (119 refs.)

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

Monte R; Rabunal R; Casariego E; Lopez-Agreda H; Mateos A; Pertega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol and Alcoholism 45(2): 151-158, 2010. (35 refs.)

Aim: To investigate the clinical variables associated with the risk of dying and the causes of death during the course of alcoholic withdrawal syndrome (AWS) in a general hospital. Methods: Cohort study of AWS patients admitted to Xeral Hospital in Lugo, Spain between 1987 and 2003. The characteristics of patients who died were contrasted with those who survived. The different clinical, epidemiological and biochemical variables reflective of alcohol consumption habits, basal health status and presentation features of the syndrome and its complications were all recorded. Results: There were 539 episodes of hospitalization for AWS in 436 patients (mean age 45.0, SD 12.0, 91.3% males), 71.1% of whom presented with delirium tremens. A total of 29 patients died, yielding a 6.6% mortality rate (95% confidence interval, CI: 4.2-9.1%). Eighteen patients (62%) died after being admitted to the intensive care unit (ICU). The following independent variables were associated with the risk of dying in a multivariate logistic regression model: cirrhosis [odds ratio (OR) 4.8 (95% CI 1.5-14.6), P = 0.006]; presenting with delirium tremens at diagnosis [OR 3.5 (95% CI 1.3-8.9), P = 0.008]; the existence of an underlying chronic pathology other than liver disease [OR 2.5 (95% CI 1-6.1), P = 0.01]; and the need for orotracheal intubation [OR 2.9 (95% CI 1.1-7.9), P = 0.03], especially if pneumonia requiring ICU is added [OR 8 (95% CI 3-21.3), P < 0.001]. Receiver operating characteristic analysis revealed an area under the curve of 0.818 (95% CI 0.742-0.894). Conclusions: The factors determining survival after admission to a general hospital for alcoholic withdrawal syndrome depend on the intensity of clinical manifestations (delirium tremens, ICU, orotracheal intubation) and the presence of associated comorbidity.

Ortells MO; Arias HR. Neuronal networks of nicotine addiction. International Journal of Biochemistry & Cell Biology 42(12): 1931-1935, 2010. (30 refs.)

Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors. The main effects of nicotine associated with smoking are nicotinic receptor activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction.

Poulsen PB; Dollerup J; Moller AM. Is a percentage a percentage? Systematic review of the effectiveness of Scandinavian behavioural modification smoking cessation programmes. (review). Clinical Respiratory Journal 4(1): 3-12, 2010. (46 refs.)

Introduction: Tobacco smoke is the leading preventable cause of death in the world. A total of 50% of all smokers will die from a smoking-related disease with a major impact upon quality of life and health-care costs. Tobacco-controlling policies, including smoking cessation, have increasingly been implemented across European countries. Reported effectiveness data on smoking cessation interventions are important for decision making. Objective: This study aimed to conduct a literature review on how the effectiveness (quit rates) of behavioural modification smoking cessation programmes (BMSCPs) - counselling, quitlines and quit-and-win contests - were analysed in Denmark, Sweden and Norway. Methods: A systematic review was carried out by using the search engines Medline (U.S. National Library of Medicine, Bethesda, MD, USA), Cinahl (CINAHL Information Systems, EBSCO Industries, Ipswich, MA, USA), Embase (Elsevier, New York, NY, USA) and the grey literature. Following the Russell Standards, studies were selected according to design, analysis of data [intention-to-treat (ITT)/per protocol (PP)], documentation of abstinence and length of follow-up. Cochrane reviews of pharmacological studies were used as the benchmark. Results: Although ITT analysis is the standard scientific approach advocated, most studies of BMSCPs reviewed were analysed by using the PP approach and were based on self-reported point prevalence estimates. This resulted in the reported 1-year quit rates between 16%-45% (PP) and 9%-23% (ITT). In contrast, pharmacological studies are conservative, as they are randomised, use ITT analysis and have continuous quit rates with biochemical verification of abstinence. Conclusion: This literature review reveals that quit rates of smoking cessation interventions are not always comparable. Scandinavian BMSCPs reported optimistic quit rates, confirmed by Cochrane literature review criteria. Care should be exercised when comparing smoking cessation interventions.

Rosenbloom MJ; Sullivan EV; Pfefferbaum A. Focus on the brain: HIV infection and alcoholism comorbidity effects on brain structure and function. Alcohol Research & Health 33(3): 247-257, 2010. (53 refs.)

Both HIV infection and alcohol abuse have negative effects on the brain, with some unique to each condition and others shared by both conditions. Investigators have used magnetic resonance imaging to study the size and integrity of various brain structures in participants with alcoholism, HIV infection, or both conditions and in healthy control subjects. In these studies, alcoholics exhibited enlarged cerebrospinal fluid-filled spaces (i.e., ventricles) as well as tissue shrinkage in various brain regions (e.g., the corpus callosum and frontal cortex), whereas study participants with asymptomatic HIV infection showed few abnormalities. Those with both HIV infection and alcoholism also had these volume abnormalities, particularly if they had experienced an AIDS-defining event. Diffusion tensor imaging, which measures the integrity of white matter fibers, has identified abnormalities of constituents of these fibers in both diseases. Again, people with HIV infection plus alcoholism show the greatest abnormalities, particularly those with a history of an AIDS-defining event. Magnetic resonance spectroscopy, which assesses the levels of brain metabolites and selective neurotransmitters, has revealed different patterns of deficits in biochemical markers of brain integrity in individuals singly affected and a compounding of effects in individuals with both HIV infection and alcoholism. Finally, neuropsychological studies have revealed impairment in selective functions involving working memory, visuospatial abilities, and movement speed that are especially likely to occur in people with comorbid HIV infection and alcoholism. Thus, alcoholism is a major risk factor for development of neuropathology and its functional sequelae in HIV-infected people.

Schane RE; Ling PM; Glantz SA. Health effects of light and intermittent smoking: A review. Circulation 121(13): 1518-1522, 2010. (61 refs.)

There is a widespread belief, based in part on truth (ie, the dose-response relationship between smoking intensity and some diseases, including cancer) and in part on successful tobacco industry marketing to "health-conscious smokers," that light and intermittent smoking are safer than heavier smoking. The fact remains, however, that even stable light smoking carries substantial health risks. Although a reduction in cigarette consumption can be an intermediate stage before a total stop and may increase the motivation of daily, heavier smokers without intention to quit to achieve eventual cessation, chronic light and intermittent smoking should not be presented to patients as a healthy long-term choice. Complete cessation is 1 of the most cost-effective interventions and provides a benefit nearly as large as, if not greater than, other widely used forms of treatment for the secondary prevention of cardiovascular disease. Cessation is the only known primary therapy that can significantly reduce the risk of cancer and obstructive lung disease. Light and intermittent smokers often go undetected because many of them do not view themselves as smokers and will deny their habit when asked by family, friends, and healthcare providers. Clinical screening for light and intermittent smoking should be improved. Specifically, questions that rely on self-labeling such as "Are you a smoker?" should be abandoned in favor of questions that focus on smoking behavior such as "Do you use any tobacco products on a daily, weekly, or social basis?" Although this question has not been the subject of a formal clinical trial, it is more specific and recognizes behavioral triggers that are not normally assessed with the existing screening tools. Consequently, healthcare providers may capture many tobacco users who otherwise may not consider themselves smokers. Relying only on the current healthcare screening question of "Are you a smoker?" runs the risk of missing light and intermittent consumers who do not consider themselves tobacco users. Furthermore, biochemical markers, such as cotinine, may also serve as screening tools.

Seger D. Cocaine, metamfetamine, and MDMA abuse: The role and clinical importance of neuroadaptation. (review). Clinical Toxicology 48(7): 695-708, 2010. (152 refs.)

Introduction. This article reviews the role and clinical importance of specific neuroadaptations that may occur following use of cocaine, metamfetamine, and 3,4, methylenedioxymetamfetamine (MDMA). Methods. A literature search was performed using OVID MEDLINE and PubMed for all years to the present date, which identified 250 papers of which 154 were considered relevant. Mechanisms of action of cocaine and metamfetamine. Cocaine and metamfetamine increase central nervous system synaptic dopamine primarily by increasing the release of dopamine into the synapse and binding to the dopamine reuptake transporter, which prevents the reuptake of dopamine from the synapse back into the nerve cell. Synaptic dopamine then stimulates post synaptic receptors. The continued release of dopamine and prevention of reuptake results in a supraphysiological concentration of dopamine, which causes euphoria or a "high." The greater the concentration of dopamine, the greater the high. Continued supraphysiological concentrations of dopamine and postsynaptic receptor stimulation may cause physiological and anatomical changes (neuroadaptations) in the central nervous system (CNS) synapse that attempt to maintain homeostasis. An example of a dopaminergic neuroadaptation is the decrease in number of post synaptic D2 receptors that occurs when synaptic dopamine concentrations remain supraphysiological. This neuroadaptation attempts to maintain homeostasis, that is, the decreased number of D2 receptors provides fewer receptors to be constantly stimulated by increased synaptic dopamine. Although metamfetamine also increases synaptic dopamine similarly to cocaine, metamfetamine also increases cytoplasmic dopamine, which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. Mechanisms of action of MDMA. MDMA increases concentrations of synaptic serotonin by increasing the release of serotonin and binding to the serotonin reuptake transporter, preventing the reuptake of serotonin from the synapse back into the nerve cell. An example of a serotonergic neuroadaptation is a decrease in the number of serotonin presynaptic autoreceptors (one of the regulators of synaptic serotonin concentration) to maintain homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation, but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Pharmacogenomics may play a role in the varied response of the individual to MDMA. Conclusions. Neuroadaptations may be transient or permanent. The duration of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age at the initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations that occur will allow clinicians to better understand the interindividual variability in response to drugs of abuse.

Stewart SH; Law TL; Randall PK; Newman R. Phosphatidylethanol and alcohol consumption in reproductive age women. Alcoholism: Clinical and Experimental Research 34(3): 488-492, 2010. (24 refs.)

Background: Fetal alcohol disorders are preventable, but self-reported alcohol consumption can be misleading and impede effective treatment. Biomarkers represent an alternative method for assessing alcohol use, and this study evaluated the relationship between blood phosphatidylethanol (PEth) and alcohol use in a sample of reproductive age women. Methods: Alcohol use was estimated by validated self-report methods in 80 nonpregnant women ages 18 to 35. PEth was measured by a contracted laboratory using a liquid chromatography-tandem mass spectrometry assay. Regression methods appropriate for the distribution of PEth were used to define its relationship to alcohol consumption during the prior 2 weeks and explore the effects of drinking patterns on this association. Receiver operating characteristic analysis was used to estimate the sensitivity of PEth for various drinking levels at 95% specific cutoffs. Results: PEth had a positive linear association with grams of alcohol consumed (p < 0.001), and was detectable in 93% of subjects consuming an average of 2 or more drinks per day. The relationship between total alcohol consumption and PEth may be stronger in women with recent heavy drinking days. The relationship between drinking and PEth varied considerably between individuals, and sensitivity for a certain amount of drinking was low at a highly specific cutoff concentration. Conclusions: PEth is a highly sensitive indicator of moderate and heavy alcohol consumption in reproductive age women and may complement the use of self-report alcohol screens when additional objective markers of alcohol use are desirable. However, choosing a highly valid cutoff concentration for PEth to differentiate various levels of alcohol

Swamy GK; Reddick KLB; Brouwer RJN; Pollak KI; Myers ER. Smoking prevalence in early pregnancy: Comparison of self-report and anonymous urine cotinine testing. Journal of Maternal-Fetal & Neonatal Medicine 24(1): 86-90, 2011. (28 refs.)

Objective. Societal pressures against smoking during pregnancy may lead to a reduction in disclosure of smoking status. The objective of this study was to compare prevalence of smoking at prenatal intake by self-report with anonymous biochemical validation. Methods. Women receiving care at the Duke Obstetrics Clinic from February 2005 through January 2006 were eligible for evaluation. Self-reported smoking and urine samples were obtained anonymously at prenatal intake. The NicCheck (TM) I semi-quantitative dipstick was used to detect urinary nicotine, cotinine, and 3-hydroxycotinine. The difference, with 95% confidence interval, between the proportions of smokers by self-report and urine testing was calculated for (1) high-positive vs. low-positive and negative results combined and (2) any positive vs. negative results. Results. Among 297 subjects, self-reported smoking was 18.2 vs. 14.8% for low-positive and negative results combined with an absolute difference of 3.4%, [-2.9%, 9.6%]. When comparing self-report with any positive result (43.1%), the absolute difference was 24.9%, [17.4%, 32.1%]. Conclusions. Our findings suggest that most pregnant women disclose their smoking and many nonsmokers may have significant second-hand exposure. Universal urinary cotinine screening of pregnant women could aid in appropriately counseling women about second-hand exposure as well as monitoring women at high risk for adverse pregnancy outcomes.

Tamaki J; Iki M; Fujita Y; Kouda K; Yura A; Kadowaki E et al. Impact of smoking on bone mineral density and bone metabolism in elderly men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study. Osteoporosis International 22(1): 133-141, 2011. (40 refs.)

Our cross-sectional analysis of 1,576 men aged a parts per thousand yen65 years examined smoking effects on bone status. Number of smoking years was associated with decreased bone mineral density (BMD), after adjusting for age, height, weight, and number of cigarettes smoked daily. Smoking did not affect biochemical marker serum values for bone turnover. The impact of smoking on bone status in men has not been conclusively established. We examined how smoking and its cessation influence bone status and metabolism in men. We analyzed 1,576 men among a baseline survey of Japanese men aged a parts per thousand yen65 years, the Fujiwara-kyo Osteoporosis Risk in Men study, conducted during 2007-2008. Lumbar spine (LS) BMD values among never, former, and current smokers were 1.045 +/- 0.194, 1.030 +/- 0.189, and 1.001 +/- 0.182 g/cm(2) (P = 0.005), respectively, while total hip (TH) BMD values were 0.888 +/- 0.120, 0.885 +/- 0.127, and 0.870 +/- 0.124 (P = 0.078), respectively. The significant trend for LS BMD remained after adjusting for the covariates; age, height, weight, physical activity, milk consumption, and drinking habit (P = 0.036). Among never and ever (current and former) smokers, LS and TH BMD decreased with the number of pack years or the number of smoking years, respectively, adjusted for those covariates. Among ever smokers, LS and TH BMD decreased with the number of smoking years after adjusting for age, height, weight, and number of cigarettes smoked daily. Smoking did not reveal significant effect for serum osteocalcin or tartrate resistant acid phosphatase isoenzyme 5b. The impact of smoking on bone status is mainly associated with the number of smoking years in elderly men.

Umhau JC; Momenan R; Schwandt ML; Singley E; Lifshitz M; Doty L et al. Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: A randomized controlled experimental medicine study. Archives of General Psychiatry 67(10): 1069-1077, 2010. (45 refs.)

Context: Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking. Objective: To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (H-1-MRS). Design: A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with H-1-MRS measures obtained on days 4 and 25. Setting: An inpatient research unit at the NIH Clinical Center. Patients: Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use. Intervention: Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or 'matched placebo, initiated at the time of admission. Main Outcome Measures: The glutamate to creatine ratio as determined using single-voxel H-1-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures. Results: There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time X treatment interaction: F-1,F-29= 13.5, P<.001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelatecl with the MRS measures and unaffected by treatment but were strongly correlated (R-2=0.48, P<.001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate. Conclusion: The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence.

Varenbut M; Plater-Zyberk C; Worster A; Daiter J. Does low urine creatinine level indicate the presence of urine alcohol in methadone maintenance treatment patients? American Journal of Drug and Alcohol Abuse 36(4): 199-201, 2010. (19 refs.)

Objective: We sought to test the assumption that a low urine creatinine level is indicative of the presence of alcohol in the urine of patients prescribed methadone. Methods: This is a medical record review of 261,055 urine samples from approximately 6,000 patients prescribed methadone during a one-year period and for whom both urine creatinine and ethanol levels were simultaneously measured. We defined a creatinine level of less than 2.26 mmol/L as 'low' used a urine ethanol level of greater than 2.0 mmol/L as the reference standard for alcohol consumption. Results: The sensitivity and specificity of low urine creatinine as a marker for the detection of urine ethanol are 11.9% (95% CI: 11.3, 12.5%) and 96.7% (95% CI: 96.7, 96.7%), respectively. In this patient population with a low (3.6%) prevalence of alcohol in the urine, the results correspond to a positive predictive value of 11.9% (95% CI: 11.3, 12.6%) and a negative predictive value of 96.7% (95% CI: 96.7, 96.7%), respectively. Conclusions: Low urine creatinine is a poor screening test for detecting alcohol consumption among patients on methadone. However, a normal creatinine level has a 96.7% probability of no alcohol urine present in the urine.

Wallstrom M; Bolinder G; Hasseus B; Hirsch JM. A cessation program for snuff-dippers with long-term, extensive exposure to Swedish moist snuff: A 1-year follow-up study. Acta Odontologica Scandinavica 68(6): 377-384, 2010. (47 refs.)

Objective. Smokeless tobacco (Swedish moist 'snus') users are often strongly addicted to nicotine. Compared to the large number of smoking-cessation studies, there have been few evaluated clinical cessation programs in conjunction with nicotine replacement therapy (NRT). The aim of this study was to evaluate a cessation program for snus users with a weekly use of >2 cans/week for >10 years. Material and methods. A prospective, open, non-randomized intervention trial was undertaken including baseline oral examination and soft tissue biopsy, minor physical examination, brief cessation advice, NRT recommendations and five prospective follow-up visits within 12 months. Individual cessation counseling was given, together with oral examination in the dental office. Fifty snus users with a minimum consumption of 100 g/week who were actively seeking cessation treatment were recruited through advertising. Self-reported abstaining, including random-sample biochemical verification, and NRT use were evaluated at 6 weeks and 3, 6 and 12 months. Results. At the 3-, 6- and 12-month visits, 58%, 46% and 30% of subjects, respectively were tobacco-abstinent. All nicotine abstinence was randomly controlled during the study except at 12 months, where all subjects claiming abstinence were confirmed biochemically and clinically. Conclusion. Smokeless tobacco cessation achieved together with suitable NRT seems a promising way to improve a persistent tobacco-free condition.

Waszkiewicz N; Konarzewska B; Waszkiewicz M; Poplawska R; Szajda SD; Zalewska A et al. Biomarkers of alcohol abuse. Part I. Traditional biomarkers and their interpretation. Psychiatria Polska 44(1): 127-136, 2010. (35 refs.)

Approximately 15% of the Polish population abuse alcohol. Early detection of alcohol problems may prevent their further development and progression. The study reviews traditional biomarkers associated with alcohol abuse. The nature of biomarkers, their practical application and limitations in alcohol abuse detection, in assessment and monitoring of drinking, are reviewed. Despite the limited sensitivity and specificity in alcohol abuse detection, traditional biomarkers remain useful in alcohol abuse detection. They are widely available and relatively inexpensive, providing valuable data on complications of drinking and prognosis as well as on concurrent conditions affected by drinking.

Waszkiewicz N; Poplawska R; Konarzewska B; Szajda SD; Galinska B; Rutkowski P et al. Biomarkers of alcohol abuse. Part II. New biomarkers and their interpretation. Psychiatria Polska 44(1): 137-146, 2010. (34 refs.)

An increasing number of new biomarkers of alcohol abuse appear in the literature. The most commonly used biomarkers (5-hydroxytryptophol, fatty acid ethyl esters, ethyl glucuronide, phosphatidyl ethanol, ethyl sulphate, mitochondrial aspartate aminotransferase, carbohydrate deficient transferrin, acetaldehyde adducts, beta-hexosaminidase, and sialic acid) were described. Then other known and less known biomarkers associated with alcohol abuse were described in brief (e.g. acetaldehyde, acetate, methanol, alpha-amino-n-butyric acid, dolichol, proteomics). Their sensitivity and specificity is generally higher than that of traditional biomarkers. The time of detection in biological fluids occur from one day to few months after alcohol consumption. Hence, their usefulness in clinical practice as well as in experimental studies is increasing.

Windle M. A multilevel developmental contextual approach to substance use and addiction. BioSocieties 5(1, special issue): 124-136, 2010. (36 refs.)

Emerging technological advances in genetics and neuroscience have spawned innovative or elaborated conceptual models in the field of addiction science, as well as contributed to the mushrooming of new knowledge. By addictions, reference is made to chronic, often relapsing disorders typified by obsession, compulsion or physical or psychological dependence. In this article it is proposed that a multilevel developmental contextual approach to substance use and addictions provides a useful framework for integrating existing studies across disciplines and serving as a generative guide to intriguing novel research questions. The multilevel developmental contextual approach emphasizes multiple-factor influences on substance use and addiction, the conjoint influence of variables from different levels of analysis (for example, genetic, biochemical, physiological, cognitive, social, neighborhood, societal), and dynamic, probabilistic behavior-outcome relations (that is, the occurrence as well as the nature of expression of substance problems and addiction depend on a range of emerging, interactive factors that may vary across individuals and over time). The approach is illustrated with a long-term prospective study of predictors of binge drinking from adolescence to young adulthood and a description of the role of brain processes and mechanisms involved in the development and expression of alcohol use during adolescence.

Yamamoto R; Nagasawa Y; Shoji T; Iwatani H; Hamano T; Kawada N et al. Cigarette smoking and progression of IgA nephropathy. American Journal of Kidney Diseases 56(2): 313-324, 2010. (47 refs.)

Background: Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy. Study Design: Retrospective cohort study. Setting & Participants: 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN). Predictors: Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching. Outcomes: 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes. Results: During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.391 per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates. Limitation: Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable. Conclusions: Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.
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