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1.  Transitions In and Out of Alcohol Use Disorders: Their Associations with Conditional Changes in Quality of Life Over a 3-Year Follow-Up Interval† 
Aims: The aim of this study was to investigate longitudinal changes in quality of life (QOL) as a function of transitions in alcohol use disorders (AUD) over a 3-year follow-up of a general US population sample. Methods: The analysis is based on individuals who drank alcohol in the year preceding the Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions and were reinterviewed at Wave 2 (n = 22,245). Using multiple linear regression models, changes in SF-12 QOL were estimated as a function of DSM-IV AUD transitions, controlling for baseline QOL and multiple potential confounders. Results: Onset and offset of AUD were strongly associated with changes in mental/psychological functioning, with significant decreases in mental component summary (NBMCS) scores among individuals who developed dependence and significant increases among those who achieved full and partial remission from dependence. The increases in overall NBMCS and its social functioning, role emotional and mental health components were equally great for abstinent and nonabstinent remission from dependence, but improvements in bodily pain and general health were associated with nonabstinent remission only. Onset of abuse was unrelated to changes in QOL, and the increase in NBMCS associated with nonabstinent remission from abuse only was slight. Individuals with abuse only or no AUD who stopped drinking had significant declines in QOL. Conclusions: These results suggest the possible importance of preventing and treating AUD for maintaining and/or improving QOL. They are also consistent with the sick quitter hypothesis and suggest that abuse is less a mental disorder than a maladaptive pattern of behavior.
PMCID: PMC2605522  PMID: 19042925
2.  Transitions In and Out of Alcohol Use Disorders: Their Associations with Conditional Changes in Quality of Life Over a 3-Year Follow-Up Interval 
To investigate longitudinal changes in quality of life (QOL) as a function of transitions in alcohol use disorders (AUD) over a 3-year follow-up of a general U.S. population sample.
The analysis is based on individuals who drank alcohol in the year preceding the Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions and were reinterviewed at Wave 2 (n=22,245). Using multiple linear regression models, changes in SF-12 QOL were estimated as a function of DSM-IV AUD transitions, controlling for baseline QOL and multiple potential confounders.
Onset and offset of AUD were strongly associated with changes in mental/psychological functioning, with significant decreases in mental component summary (NBMCS) scores among individuals who developed dependence and significant increases among those who achieved full and partial remission from dependence. The increases in overall NBMCS and its social functioning, role emotional and mental health components were equally great for abstinent and nonabstinent remission from dependence, but improvements in bodily pain and general health were associated with nonabstinent remission only. Onset of abuse was unrelated to changes in QOL, and the increase in NBMCS associated with nonabstinent remission from abuse only was slight. Individuals with abuse only or no AUD who stopped drinking had significant declines in QOL.
These results suggest the possible importance of preventing and treating AUD for maintaining and/or improving QOL. They are also consistent with the sick quitter hypothesis and suggest that abuse is less a mental disorder than a maladaptive pattern of behavior.
PMCID: PMC2605522  PMID: 19042925
quality of life; QOL; HRQOL; alcohol use disorders; remission; transitions
3.  Alcohol, Moods and Male–Female Differences: Daily Interactive Voice Response over 6 Months 
Aims: The goal of this study was to better understand the predictive relationship in both directions between negative (anger, sadness) and positive (happiness) moods and alcohol consumption using daily process data among heavy drinkers. Methods: Longitudinal daily reports of moods, alcohol use and other covariates such as level of stress were assessed over 180 days using interactive voice response telephone technology. Participants were heavy drinkers (majority meeting criteria for alcohol dependence at baseline) recruited through their primary care provider. The sample included 246 (166 men, 80 women) mostly Caucasian adults. Longitudinal statistical models were used to explore the varying associations between number of alcoholic drinks and mood scores the next day and vice versa with gender as a moderator. Results: Increased alcohol use significantly predicted decreased happiness the next day (P < 0.005), more strongly for females than males. Increased anger predicted higher average alcohol use the next day for males only (P < 0.005). Conclusion: This daily process study challenges the notion that alcohol use enhances positive mood for both males and females. Our findings also suggest a strong association between anger and alcohol use that is specific to males. Thus, discussions about the effects of drinking on one's feeling of happiness may be beneficial for males and females as well as anger interventions may be especially beneficial for heavy-drinking males.
PMCID: PMC3865813  PMID: 23847021
4.  The Relationship Between Midlife and Late Life Alcohol Consumption, APOE e4 and the Decline in Learning and Memory Among Older Adults 
Aims: The aim of the study was to determine whether the trajectory of learning and memory is modified according to an interaction between midlife or late life alcohol consumption status and the presence of one or more APOE e4 alleles. Methods: This was a secondary analysis of cognitive, genetic and alcohol consumption data collected from members of the Framingham Heart Study Offspring Cohort. Results: Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory. Conclusion: Light to moderate alcohol consumption during late life may protect against a decline in learning and memory for non-APOE e4 allele carriers, but not for older adults who carry one or more APOE e4 alleles.
PMCID: PMC3865814  PMID: 24049153
5.  A GABRA2 Variant Is Associated with Increased Stimulation and ‘High’ Following Alcohol Administration 
Aims: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. Methods: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. Results: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items ‘feel the alcohol effect’ (P < 0.001), ‘like the alcohol effect’ (P < 0.001) and feel ‘high’ (P < 0.001). Conclusion: We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD.
PMCID: PMC3865816  PMID: 24166645
This paper describes adolescents’ exposure to alcohol advertising in stores and to alcohol-branded promotional items and their association with self-reported drinking.
A cross-sectional survey was administered in non-tracked required courses to sixth, seventh, and eighth graders (n = 2125) in three California middle schools. Logistic regressions compared the odds of ever (vs. never) drinking and current (vs. ever) drinking after controlling for psychosocial and other risk factors for adolescent alcohol use.
Two-thirds of middle school students reported at least weekly visits to liquor, convenience, or small grocery stores where alcohol advertising is widespread. Such exposure was associated with higher odds of ever drinking, but was not associated with current drinking. One-fifth of students reported owning at least one alcohol promotional item. These students were three times more likely to have ever tried drinking and 1.5 times more likely to report current drinking than students without such items.
This study provides clear evidence of an association of adolescent drinking with weekly exposure to alcohol advertising in stores and with ownership of alcohol promotional items. Given their potential influence on adolescent drinking behaviour, retail ads, and promotional items for alcohol deserve further study.
PMCID: PMC4238906  PMID: 17218364
7.  Time Course of SERCA 2b and Calreticulin Expression in Purkinje Neurons of Ethanol-Fed Rats with Behavioral Correlates 
Chronic ethanol consumption for 40 weeks in adult rats results in dilation of the extensive smooth endoplasmic reticulum (SER), a major component of the calcium homeostatic system within Purkinje neuron (PN) dendrites. Aims: The aim of the present study was to determine whether chronic ethanol consumption results in alterations of the sarco/endoplasmic reticulum Ca2+ ATPase pump (SERCA) on the SER membrane of PN dendrites. The density of calreticulin, a calcium chaperone, was also investigated in the PN along with balancing ability. Methods: Ninety 8-month-old rats were exposed to rat chow, the AIN-93 M liquid control or ethanol diets (30/diet) for a duration of 10, 20 or 40 weeks (30/duration). Age changes relative to the rat chow controls were assessed with 3-month-old control rats (n = 10). Balance was assessed prior to euthanasia. Quantitative immunocytochemistry was used to determine the density of SERCA 2b + dendrites and calreticulin + PN soma and nuclei. Molecular layer volumes were also determined. Results: Following 40 weeks of ethanol treatment, there were ethanol-induced decreases in SERCA 2b densities within the dendritic arbor and decreased balancing ability on the more difficult round rod balance test. There were no ethanol-induced changes in calreticulin densities. Conclusion: It can be concluded that ethanol-induced decreases in the SERCA pump accompany SER dilation and contribute to previously reported ethanol-induced dendritic regression in PN. Ethanol-induced changes in balance also occurred. Chronic ethanol consumption does not alter calreticulin expression in PN.
PMCID: PMC3799558  PMID: 23884168
8.  A Cross-Sectional Study of Attitudes About the Use of Genetic Testing for Clinical Care Among Patients with an Alcohol Use Disorder 
Aim: Modification and individualization of medical treatments due to genetic testing has the potential to revolutionize healthcare delivery. As evidence mounts that genetic testing may improve treatment decisions for patients with alcohol use disorder (AUD), we explored patient concerns and attitudes toward genetic testing. Methods: Subjects of two USA cross-sectional AUD studies were surveyed regarding their attitudes regarding the use of genetic testing for AUD treatment. Results: Four hundred and fifty-seven participants were surveyed. Overall, subjects showed a high degree of willingness to provide DNA for clinical use and recognized genetics as important to the pathophysiology of a number of disorders including AUD. There were, however, significant concerns expressed related to insurance denial or employment problems. Conclusion: We found that patients enrolled in AUD studies had some concerns about use of genetic testing. The patients in these two samples were, however, willing and knowledgeable about providing DNA samples.
PMCID: PMC3799560  PMID: 23926212
9.  Use of Novel Technology-Based Techniques to Improve Alcohol-Related Outcomes in Clinical Trials 
With a better understanding of the biologic basis of alcohol dependence and the considerable financial burden of alcohol abuse and dependence, the number of alcohol-related clinical pharmacotherapy trials has been on the rise. Subsequently, the potential to find efficacious treatments is more promising. Unfortunately, alcohol-related trials face a number of challenges, as a result of the difficulties that arise from traditional and outdated methods to collect data and ensure medication adherence. Novel technology-based assessments, such as ecological momentary assessment, interactive voice response, transdermal sensor and medication-event monitoring system provide a prospective solution—albeit not without possible concerns—to the difficulties faced in alcohol-related clinical trials. Clinical trials are meant to define the efficacy of the treatment and to determine an effective and safe dosage. However, due to lack of adherence a drug could inappropriately or mistakenly be judged as ineffective for treating a specific disorder. The described technologies may be important tools to prevent false negatives in validating drug efficacy, to provide consistency in clinical trials and to improve available data regarding the study of pharmacotherapies for alcohol dependence.
PMCID: PMC3816323  PMID: 23955872
10.  Examining Alcohol's Contribution to the US African-American/White Cirrhosis Mortality Differential from 1950 to 2002 
Aims: The aim of this study was to estimate the overall impact of alcohol on US race- and sex-specific age-adjusted cirrhosis mortality rates and to consider beverage-specific effects that represent changes in drinking patterns over time, comparing states with large and small African-American/White cirrhosis mortality differentials. Methods: Using series data from 1950 to 2002, the effects of per capita alcohol consumption on cirrhosis mortality for African American and White men and women were estimated using generalized least squares panel models on first-differenced data. Granger causality tests explored geographic patterning of racial differences in cirrhosis mortality. Results: Cirrhosis mortality was significantly positively related to apparent consumption of alcohol, with an overall impact of 8–14%/l of ethanol. This effect was driven by spirits which were more strongly associated with mortality for African-American women and for African-American men in states with larger mortality differentials. This disparity first emerged in New York and spread through the Northeast and into Midwestern states. Conclusion: Differences in the contribution of alcohol to cirrhosis mortality rates suggest variation by race and gender in life-course patterns of heavy consumption, illicit liquor and spirits use, as well as birth cohort effects.
PMCID: PMC3746804  PMID: 23558110
11.  Metabolic Abnormalities in Lobar and Subcortical Brain Regions of Abstinent Polysubstance Users: Magnetic Resonance Spectroscopic Imaging 
Aims: The aim of the study was to explore neurometabolic and associated cognitive characteristics of patients with polysubstance use (PSU) in comparison with patients with predominant alcohol use using proton magnetic resonance spectroscopy. Methods: Brain metabolite concentrations were examined in lobar and subcortical brain regions of three age-matched groups: 1-month-abstinent alcohol-dependent PSU, 1-month-abstinent individuals dependent on alcohol alone (ALC) and light drinking controls (CON). Neuropsychological testing assessed cognitive function. Results: While CON and ALC had similar metabolite levels, persistent metabolic abnormalities (primarily higher myo-inositol) were present in temporal gray matter, cerebellar vermis and lenticular nuclei of PSU. Moreover, lower cortical gray matter concentration of the neuronal marker N-acetylaspartate within PSU correlated with higher cocaine (but not alcohol) use quantities and with a reduced cognitive processing speed. Conclusions: These metabolite group differences reflect cellular/astroglial injury and/or dysfunction in alcohol-dependent PSU. Associations of other metabolite concentrations with neurocognitive performance suggest their functional relevance. The metabolic alterations in PSU may represent polydrug abuse biomarkers and/or potential targets for pharmacological and behavioral PSU-specific treatment.
PMCID: PMC3746806  PMID: 23797281
12.  Breath Alcohol Estimation Training: Behavioral Effects and Predictors of Success 
Aims: Breath alcohol concentration (BrAC) estimation training has been effective in increasing estimation accuracy in social drinkers. Predictors of estimation accuracy may identify populations to target for training, yet potential predictors typically are not evaluated. In addition, the therapeutic efficacy of estimation training as a preventive strategy for problematic drinking is unknown. Methods: Forty-six social drinkers with a recent binge history were randomly assigned to an intervention or control group (n = 23 per group). In each of three sessions (pretraining, training, testing), participants consumed alcohol (0.32, 0.24, 0.16 and 0.08 g/kg, in random order) every 30 min (total dose: 0.8 g/kg). Participants provided five BrAC estimates within 3 h of alcohol administration. The intervention group, but not control group, received internal and external training. During testing, participants provided BrAC estimates, but received no feedback. Participants returned for two follow-up visits to complete self-report measures. Results: BrAC estimation training improved intervention group estimation accuracy within the laboratory. Together, training, low trait anxiety and low risk expectancy predicted high testing accuracy. There were no significant group differences in subsequent alcohol consumption, behavior under the influence or risk expectancy regarding potentially hazardous behaviors. Conclusion: BrAC estimation training is effective in the laboratory but may not translate into naturalistic settings.
PMCID: PMC3685329  PMID: 23695976
13.  Awareness and Treatment of Alcohol Dependence in Japan: Results from Internet-Based Surveys in Persons, Family, Physicians and Society 
Aims: To understand current awareness of, and views on, treatment of alcohol dependence in Japan. Methods: (a) Nationwide internet-based survey of 520 individuals, consisting of 52 diagnosed alcohol-dependent (AD) persons, 154 potentially alcohol-dependent (ADP) persons, 104 family members and 106 friends/colleagues of AD persons, and 104 general individuals, derived from a consumer panel where the response rate was 64.3%. We enquired into awareness about the treatment of alcohol dependence and patient pathways through the healthcare network. (b) Nationwide internet-based survey of physicians (response rate 10.1% (2395/23,695) to ask 200 physicians about their management of alcohol use disorders). Results: We deduced that 10% of alcohol-dependent Japanese persons had ever been diagnosed with alcohol dependence, with only 3% ever treated. Regarding putative treatment goals, 20–25% of the AD and ADP persons would prefer to attempt to abstain, while 60–75% preferred ‘reduced drinking.’ A half of the responding physicians considered abstinence as the primary treatment goal in alcohol dependence, while 76% considered reduced drinking as an acceptable goal. Conclusion: AD and ADP persons in Japan have low ‘disease awareness’ defined as ‘understanding of signs, symptoms and consequences of alcohol use disorders,’ which is in line with the overseas situation. The Japanese drinking culture and stigma toward alcohol dependence may contribute to such low disease awareness and current challenging treatment environment. While abstinence remains the preferred treatment goal among physicians, reduced drinking seems to be an acceptable alternative treatment goal to many persons and physicians in Japan.
PMCID: PMC4060736  PMID: 24893604
14.  Evaluating the Effects of the Introduction of Off-Sale Alcohol Outlets on Violent Crime 
Aims: To examine the effects on violence of a policy change that ended prohibition of off-sale alcohol outlets in Lubbock, Texas. Methods: Time-series analysis of violent crime data from police records comparing the periods before and after the policy change. Results: The effect of the policy change on both total violent crime and aggregated assault was small and did not approach statistical significance. Conclusions: Increased availability of alcohol through off-sale premises may not influence the type of violence reported to the police in Lubbock, Texas.
PMCID: PMC3633363  PMID: 23455369
15.  Cardiovascular Responses and Differential Changes in Mitogen-Activated Protein Kinases Following Repeated Episodes of Binge Drinking 
Aims: Excessive alcohol use in the form of binge drinking is associated with many adverse medical outcomes. Using an animal model, the primary objective of this study was to determine the effects of repeated episodes of binge drinking on myocardial structure, blood pressure (BP) and activation of mitogen-activated protein kinases (MAPKs). The effects of carvedilol, a beta-adrenergic blocker, were also examined in this animal model of binge drinking. Methods: Rats were randomized into three groups: control, binge and binge + carvedilol (20 mg/kg). Animals received intragastric administration of 5 g ethanol/kg in the morning × 4 days (Monday–Thursday) followed by no ethanol on Friday–Sunday. Animals were maintained on the protocol for 5 weeks. BP was measured using radiotelemetry methods. Animals underwent echocardiography at baseline, 2.5 and 5 weeks. Myocardial MAPKs were analyzed at 5 weeks using western blot techniques. Results: Over the course of 5 weeks, binge drinking was associated with significant transient increases in BP that were greater at 4 and 5 weeks compared with earlier time points. Carvedilol treatment significantly attenuated the binge-induced transient increases in BP at 4 and 5 weeks. No significant changes were found in echocardiographic parameters at any time period; however, binge drinking was associated with increased phosphorylation of p38 MAPK, which was blocked by carvedilol treatment. Conclusion: Repeated episodes of binge drinking result in progressive and transient increases in BP, no change in myocardial structure and differential regulation of MAPK activation.
PMCID: PMC3571203  PMID: 22878590
16.  Direct Central Nervous System Effect of Alcohol Alters Synthesis and Degradation of Skeletal Muscle Protein 
Aims: Alcohol can directly impair protein synthesis in cultured myocytes as well as in in situ perfused skeletal muscle. However, alcohol in the general circulation diffuses rapidly into the central nervous system (CNS). Therefore, this study determined whether localized elevation of alcohol within the CNS is capable of decreasing muscle protein synthesis. Methods: Conscious unstrained male rats received a continuous intracerebroventricular (ICV) infusion of ethanol and skeletal muscle protein synthesis and degradation were assessed. Results: ICV alcohol decreased protein synthesis in the gastrocnemius after 6 and 24 h, compared with the time-matched controls. The reduction was equivalent for both sarcoplasmic and myofibrillar proteins and was reversible. The inhibitory effect of alcohol was not prevented by the catalase inhibitor 3-amino-1,2,4-triazole and was mimicked by ICV-administered t-butanol. The alcohol-induced decrease in muscle protein synthesis was associated with a concomitant reduction in phosphorylation of 4E-binding protein and ribosomal S6 kinase-1, suggesting impaired mammalian target of rapamycin kinase activity. ICV alcohol also impaired the ability of leucine to stimulate protein synthesis. Conversely, ICV alcohol increased muscle proteasome activity and muscle RING-finger protein-1 mRNA content. Altered muscle protein metabolism was not associated with changes in muscle mRNA content for tumor necrosis factor α, interleukin-6 or insulin-like growth factor (IGF)-I or circulating insulin or IGF-I. Conclusion: Selective elevation of alcohol within the CNS is capable of decreasing protein synthesis and increasing protein degradation in muscle in the absence of alcohol in the general circulation, thus revealing a previously unrecognized central neural mechanism, which may account for part of the inhibitory effect of ingested alcohol on muscle protein homeostasis.
PMCID: PMC3571205  PMID: 23079499
17.  Rare ADH Variant Constellations are Specific for Alcohol Dependence 
Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence.
PMCID: PMC3523382  PMID: 23019235
18.  Alcohol Exposure During Late Adolescence Increases Drinking in Adult Wistar Rats, an Effect that is not Reduced by Finasteride 
Aims: We tested whether an exposure to alcohol in late adolescence, an age of rapid increase in neuroactive steroid precursors, would increase voluntary alcohol consumption in adult rats and whether this effect would be modulated by finasteride, an inhibitor of neuroactive steroid synthesis. Methods: In Experiment 1, we exposed male Wistar rats to 8% alcohol during the dark cycle for 1 week during late adolescence [postnatal days (PNDs) 51–58], and then measured voluntary alcohol consumption 1 month later in adulthood (PNDs 91–104). In Experiment 2, finasteride was administered during the forced alcohol exposure in late adolescence and, in Experiment 3, during voluntary alcohol consumption in adulthood. Plasma was collected at the end of each finasteride treatment to confirm the reduction of plasma neuroactive steroid levels. Results: We found that a daily 12-h exposure to alcohol for 7 days in late adolescence significantly increased voluntary alcohol consumption (4-fold) a month later during adulthood. Finasteride administration in late adolescence increased group alcohol intake in late adolescence but did not block the effect of adolescent alcohol exposure on increasing alcohol preference in adulthood. There was no effect of finasteride treatment in adulthood on alcohol preference. Conclusions: A daily 12-h exposure to alcohol for 7 days in late adolescence was sufficient to induce chronically increased alcohol preference in adulthood, indicating that this age may be sensitive to the effects of alcohol.
PMCID: PMC3523383  PMID: 22997410
19.  Insulin Resistance, Ceramide Accumulation and Endoplasmic Reticulum Stress in Experimental Chronic Alcohol-Induced Steatohepatitis 
Aims: Chronic alcohol abuse causes steatohepatitis with insulin resistance, which impairs hepatocellular growth, survival and metabolism. However, growing evidence supports the concept that progressive alcohol-related liver injury may be mediated by concurrent mal-signaling through other networks that promote insulin resistance, e.g. pro-inflammatory, pro-ceramide and endoplasmic reticulum (ER) stress cascades. Methods: Using the Long Evans rat model of chronic ethanol feeding, we characterized the histopathologic and ultrastructural features of steatohepatitis in relation to biochemical and molecular indices of tissue injury, inflammation, insulin resistance, dysregulated lipid metabolism and ER stress. Results: Chronic steatohepatitis with early chicken-wire fibrosis was associated with enlargement of mitochondria and disruption of ER structure by electron microscopy, elevated indices of lipid storage, lipid peroxidation and DNA damage, increased activation of pro-inflammatory cytokines, impaired signaling through the insulin receptor (InR), InR substrate-1, Akt, ribosomal protein S6 kinase and proline-rich Akt substrate 40 kDa, glycogen synthase kinase 3β activation and constitutive up-regulation of ceramide and ER stress-related genes. Liquid chromatography coupled with tandem mass spectrometry demonstrated altered ceramide profiles with higher levels of C14 and C18, and reduced C16 species in ethanol-exposed livers. Conclusion: The histopathologic and ultrastructural abnormalities in chronic alcohol-related steatohepatitis are associated with persistent hepatic insulin resistance and pro-inflammatory cytokine activation, dysregulated lipid metabolism with altered ceramide profiles and both ER and oxidative stress. Corresponding increases in lipid peroxidation, DNA damage and protein carbonylation may have contributed to the chronicity and progression of disease. The findings herein suggest that multi-pronged therapeutic strategies may be needed for effective treatment of chronic alcoholic liver disease in humans.
PMCID: PMC3523384  PMID: 22997409
20.  Hair Ethyl Glucuronide is Highly Sensitive and Specific for Detecting Moderate-to-Heavy Drinking in Patients with Liver Disease 
Aims: Hair ethyl glucuronide (EtG) is a promising biomarker of moderate-to-heavy alcohol consumption and may have utility in detecting and monitoring alcohol use in clinical populations where alcohol use is of particular importance. This study evaluated the relationship between hair EtG and drinking in patients with liver disease. Methods: The subjects (n = 200) were patients with liver disease who presented for care at a university medical center. Alcohol use during the 3 months preceding participation in the study was assessed, and a sample of hair was obtained for EtG testing. Classification of drinking status (any drinking or averaging at least 28 g per day) by hair EtG was evaluated, as well as the effects of liver disease severity and demographic and hair care factors. Results: The area under the receiver operating characteristic curve for detecting an average of 28 g or more per day during the prior 90 days was 0.93. The corresponding sensitivity and specificity of hair EtG ≥8 pg/mg for averaging at least 28 g of ethanol per day were 92 and 87%, respectively. Cirrhosis and gender may have a modest influence on the relationship between drinking and hair EtG. Conclusion: Hair EtG was highly accurate in differentiating subjects with liver disease averaging at least 28 g of ethanol per day from abstainers and lighter drinkers.
PMCID: PMC3523385  PMID: 23015609
21.  How Might the Alcohol Minimum Unit Pricing (MUP) Impact upon Local Off-Sales Shops and the Communities Which They Serve? 
Aims: The aim of the study was to assess the likely impact of the Scottish Government's proposed alcohol minimum unit pricing (MUP) policy on community off-sales outlets (convenience stores or corner shops), and, in turn, on the local people who purchase drinks at such premises. This research adds to our knowledge by linking sales of alcohol products which will be affected by MUP (e.g. at the proposed 50 ppu) to the types of communities where these are the ‘drinks-of-choice’. Methods: A survey of independent community off-sales operating within the city of Glasgow, Scotland (n = 271) returned 144 completed questionnaires enquiring about each shop's customer base, best-selling alcohol products and participating shopkeepers' views on MUP. Responses were measured against current alcohol product prices (i.e. whether potentially affected by MUP) and local levels of socio-economic deprivation. Results: Participating shopkeepers were divided in their support for MUP, although more were in favour than against. Support for MUP tended to be rooted in business concerns. A majority reported having at least one best-selling alcohol product which will be affected by the proposed MUP policy at current prices, with the beverages that would be most affected (e.g. white cider) tending to be best-sellers at shops serving deprived communities. Conclusion: MUP is likely to impact most in socio-economically deprived communities. This is also where alcohol-related health and other inequalities are currently greatest.
PMCID: PMC3865818  PMID: 24293505
22.  Exposure of Children and Adolescents to Alcohol Marketing on Social Media Websites 
Aims: In 2011, online marketing became the largest marketing channel in the UK, overtaking television for the first time. This study aimed to describe the exposure of children and young adults to alcohol marketing on social media websites in the UK. Methods: We used commercially available data on the three most used social media websites among young people in the UK, from December 2010 to May 2011. We analysed by age (6–14 years; 15–24 years) and gender the reach (proportion of internet users who used the site in each month) and impressions (number of individual pages viewed on the site in each month) for Facebook, YouTube and Twitter. We further analysed case studies of five alcohol brands to assess the marketer-generated brand content available on Facebook, YouTube and Twitter in February and March 2012. Results: Facebook was the social media site with the highest reach, with an average monthly reach of 89% of males and 91% of females aged 15–24. YouTube had a similar average monthly reach while Twitter had a considerably lower usage in the age groups studied. All five of the alcohol brands studied maintained a Facebook page, Twitter page and YouTube channel, with varying levels of user engagement. Facebook pages could not be accessed by an under-18 user, but in most cases YouTube content and Twitter content could be accessed by those of all ages. Conclusion: The rise in online marketing of alcohol and the high use of social media websites by young people suggests that this is an area requiring further monitoring and regulation.
PMCID: PMC3932831  PMID: 24293506
23.  The Impact of Brief Alcohol Interventions in Primary Healthcare: A Systematic Review of Reviews 
Aims: The aim of the study was to assess the cumulative evidence on the effectiveness of brief alcohol interventions in primary healthcare in order to highlight key knowledge gaps for further research. Methods: An overview of systematic reviews and meta-analyses of the effectiveness of brief alcohol intervention in primary healthcare published between 2002 and 2012. Findings: Twenty-four systematic reviews met the eligibility criteria (covering a total of 56 randomized controlled trials reported across 80 papers). Across the included studies, it was consistently reported that brief intervention was effective for addressing hazardous and harmful drinking in primary healthcare, particularly in middle-aged, male drinkers. Evidence gaps included: brief intervention effectiveness in key groups (women, older and younger drinkers, minority ethnic groups, dependent/co-morbid drinkers and those living in transitional and developing countries); and the optimum brief intervention length and frequency to maintain longer-term effectiveness. Conclusion: This overview highlights the large volume of primarily positive evidence supporting brief alcohol intervention effects as well as some unanswered questions with regards to the effectiveness of brief alcohol intervention across different cultural settings and in specific population groups, and in respect of the optimum content of brief interventions that might benefit from further research.
PMCID: PMC3865817  PMID: 24232177
24.  Alcohol Screening and Brief Intervention for Adolescents: The How, What and Where of Reducing Alcohol Consumption and Related Harm Among Young People 
Aim: The aim of the study was to explore the evidence base on alcohol screening and brief intervention for adolescents to determine age appropriate screening tools, effective brief interventions and appropriate locations to undertake these activities. Methods: A review of existing reviews (2003–2013) and a systematic review of recent research not included in earlier reviews. Results: The CRAFFT and AUDIT tools are recommended for identification of ‘at risk’ adolescents. Motivational interventions delivered over one or more sessions and based in health care or educational settings are effective at reducing levels of consumption and alcohol-related harm. Conclusion: Further research to develop age appropriate screening tools needs to be undertaken. Screening and brief intervention activity should be undertaken in settings where young people are likely to present; further assessment at such venues as paediatric emergency departments, sexual health clinics and youth offending teams should be evaluated. The use of electronic (web/smart-phone based) screening and intervention shows promise and should also be the focus of future research.
PMCID: PMC3932830  PMID: 24232178
25.  Advanced Gestational Age Increases Serum Carbohydrate-Deficient Transferrin Levels in Abstinent Pregnant Women 
Aims: Carbohydrate-deficient transferrin (%CDT) is a well-established and highly specific biomarker for sustained heavy consumption of alcohol. However, in pregnant women, the specificity of this biomarker might be affected by advanced gestational age, even after accounting for increased transferrin concentrations in pregnancy. The goal of this prospective study was to assess the variability in %CDT during pregnancy among alcohol-abstaining patients. Methods: Patients were recruited during one of the first prenatal care visits and followed-up to term. Abstinence was confirmed by maternal self-report and by alcohol biomarkers. Biomarkers assessed in the mother included serum gamma-glutamyltranspeptidase, urine ethyl glucuronide and ethyl sulfate, and whole blood phosphatidylethanol (PEth). In addition, PEth was measured in a dry blood spot card obtained from a newborn. For %CDT analysis, serum samples were collected at baseline and at term and analyzed by an internationally validated high-performance liquid chromatography and spectrophotometric detection method. Results: At recruitment (mean gestational age 22.6 ± 7.3 weeks), the mean %CDT concentration was 1.49 ± 0.30%, while at term, it increased to 1.67 ± 0.28% (P = 0.001). Using a conventional cutoff concentration %CDT >1.7%, 22.9 and 45.7% of the sample would be classified as ‘positive’ for this biomarker at recruitment and at term, respectively (P = 0.011 ). Conclusion: These results suggest that a conventional cutoff of 1.7% might be too low for pregnant women and would generate false-positive results. We propose that %CDT >2.0% be used as a cutoff concentration indicative of alcohol exposure in pregnant women. The sensitivity of %CDT at this cutoff for heavy drinking during pregnancy needs to be assessed further.
PMCID: PMC3472616  PMID: 22878591

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