To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.


Saturday, April 9, 2011

Commentaries on " Addiction and dependence in DSM-V " O'Brien (2011)




















    Friday, April 8, 2011

    Addiction and dependence in DSM-V

    As preparations for the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) are under way, this paper focuses upon changes proposed for the substance use disorders section. 

    It briefly outlines the history behind the current nomenclature, and the selection of the term ‘dependence’ over ‘addiction’ in earlier versions of the DSM. 

    The term ‘dependence’, while used in past decades to refer to uncontrolled drug-seeking behavior, has an alternative meaning—the physiological adaptation that occurs when medications acting on the central nervous system are ingested with rebound when the medication is abruptly discontinued. 

    These dual meanings have led to confusion and may have propagated current clinical practices related to under-treatment of pain, as physicians fear creating an ‘addiction’ by prescribing opioids. 

    In part to address this problem, a change proposed for DSM-V is to alter the chapter name to ‘Addiction and Related Disorders’, which will include disordered gambling. 

    The specific substance use disorders may be referred to as ‘alcohol use’ or ‘opioid use’ disorders. The criteria for the disorders are likely to remain similar, with the exception of removal of the ‘committing illegal acts’ criterion and addition of a ‘craving’ criterion. The other major change relates to the elimination of the abuse/dependence dichotomy, given the lack of data supporting an intermediate stage. 

    These changes are anticipated to improve clarification and diagnosis and treatment of substance use and related disorders.

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    Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study

    To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study.

    Combination of prospective cohort study with representative population based data on alcohol exposure.

    Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. 

    109 118 men and 254 870 women, mainly aged 37-70.

    Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcohol consumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer.

    If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (−3 to 38%) for liver, 17% (10 to 25%) and 4% (−1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33 037 of 178 578 alcohol related cancer cases in men and 17 470 of 397 043 alcohol related cases in women. 

    In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer. 

    Read Full Article    (PDF) and Moderation Management: Outcomes of a Randomized Clinical Trial With Non-Dependent Problem Drinkers

    To evaluate the effectiveness of a web-based protocol, (MD; combined with use of the online resources of Moderation Management (MM; as opposed to the use of the online resources of MM alone. 

    We randomly assigned 80 problem drinkers to either the experimental or control group with follow-ups at 3, 6, and 12 months. 

    Seventy-five participants (94%) had outcome data at 1 or more follow-up points, and 59 participants (73%) were assessed at all 3 follow-ups. Comparing baseline measures to the average outcomes at follow-ups indicated a significant overall reduction in both groups in alcohol-related problems and consumption variables. Compared with the control group, the experimental group had better outcomes on percent days abstinent. There was an interaction between intensity of drinking at baseline and treatment in determining outcomes assessing drinking. Less heavy drinkers in the experimental group had better outcomes on log mean blood alcohol content (BAC) per drinking day compared with the control group. Heavier drinkers did not differentially benefit from the MD program on this measure. Mixed model analyses in general corroborated these outcomes. 

    The outcome data provide partial evidence for the effectiveness of the MD web application combined with MM, compared with the effectiveness of the resources available online at MM by themselves.

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    Dissertation - The Experience of Recovery from Alcohol/Drugs (AOD)

    This dissertation contributes to the understanding of the early recovery experience of individuals recovering from alcohol and/or drug abuse by examining the narratives of individuals through their lived experiences. 

    The research model was a qualitative study using the phenomenological approach. The primary research question addressed was: “How do people describe the experience of recovery from alcohol and/or drug addiction
    during early recovery?” 

    The analysis focused on the overall statements participants make about their lived experiences as elicited by an open-ended, guided-question interview.

    The aim was to learn from these experiences what is helpful in recovery and what may be needed and not available. The insight and the knowledge gained from these ‘lived experiences’ will be useful in formulating theoretically grounded models of care.

    The findings concur with the wider literature to a large extent in that the data identified inadequacies with regard to service provision and highlighted the negative impact of issues of exclusion and stigma. 

    A further identified concern was the lack of social support. Just as the
    literature research showed, this research also found it to be desirable and recommends a more
    inclusive, integrated approach for aftercare and recovery management to enhance long-term

    Read  Full  Dissertation   (PDF) 

    Thursday, April 7, 2011

    The Case For Measuring Quality In Mental Health And Substance Abuse Care

    Over the past decade, efforts to measure and improve quality have permeated health policy and health care generally but have barely penetrated mental health and substance abuse care. 

    We review barriers and recent activities in these areas and propose a short list of quality measures to engage the policy and practice community in a discussion about how best to evaluate the care of people with these conditions. 

    Quality measures could include, for example, screening, brief intervention, and referral for alcohol abuse. 

    Because proposing a list is only a first step, we suggest other elements of a broader strategy to bring mental health and substance use care into the mainstream of health care quality improvement. 

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    Most Adults with Alcohol Problems Do Not Recognize Their Need for Treatment

    According to the National Survey on Drug Use and Health, an overwhelming majority of adults aged 21 to 64 in the United States with substantial alcohol problems—those meeting diagnostic criteria for either alcohol abuse disorder or alcohol dependence disorder—do not perceive a need for treatment of their disorder. 

    Read Full Data Spotlight   (PDF)

    Scotland news and updates: AFS release new Manifesto; SNP still seek minimum price; national brief interventions target met

    Alcohol Focus Scotland (AFS) have launched a new Manifesto which calls for the new Scottish Parliament to take decisive steps to reduce the harm caused by alcohol by:
    • Increasing the price and reducing the availability of alcohol
    • Specifically targeting supermarkets for increased regulation
    • Banning alcohol sports sponsorship
    • Reducing drink driving limits to 50mg
    • Awareness raising campaign on the harm alcohol causes to others
    • Improved treatment and support services for people in need
    See here for the full 8 calls to action. The Scottish National Party (SNP) recently announced they would revive their plans for a minimum price if they win the Scottish national elections on May 5th. A senior police officer has also backed the measure.

    NHS Scotland have also recently met the national 3 year target to deliver nearly 150,000 brief interventions by March 2011. See this Alcohol Information Scotland page for previous reports.

    The Impact of Alcohol Outlet Density on the Geographic Clustering of Underage Drinking Behaviors within Census Tracts

    The regulation of alcohol outlet density has been considered as a potential means of reducing alcohol consumption and related harms among underage youth. 

    Whereas prior studies have examined whether alcohol outlet density was associated with an individual’s alcohol consumption and related harms, this study examines whether it is related to the co-occurrence, or clustering, of these behaviors within geographic areas, specifically census tracts.

    The Enforcing Underage Drinking Laws Randomized Community Trial provided cross-sectional telephone survey data in 2006 and 2007 from 10,754 youth aged 14 to 20 from 5 states residing in 1,556 census tracts. The alternating logistic regression approach was used to estimate pairwise odds ratios between responses from youth residing in the same census tract and to model them as a function of alcohol outlet density.

    Riding with a drinking driver, making an alcohol purchase attempt, and making a successful alcohol purchase attempt clustered significantly within census tracts with the highest off-premise alcohol outlet density while frequent drinking clustered within census tracts with the greatest on-premise density. Driving after drinking and experiencing nonviolent alcohol-related consequences clustered marginally within census tracts with the greatest on-premise and off-premise alcohol outlet density, respectively.

    Although youth primarily receive alcohol from social sources, commercial alcohol access is geographically concentrated within census tracts with the greatest off-premise outlet density. A potentially greater concern is the clustering of more frequent drinking and drinking and driving within census tracts with the greatest on-premise outlet density which may necessitate alternative census tract level initiatives to reduce these potentially harmful behaviors.

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    Alterations of Brain-Derived Neurotrophic Factor Serum Levels in Patients with Alcohol Dependence

    Alcohol dependence is a chronic relapsing disorder characterized by repetitive alcohol drinking patterns and a loss of control over alcohol consumption. Recent studies have hypothesized that dysregulations in brain neurotrophic support regulated by neurotrophins may be involved in the vulnerability to dependence and in the brain damage caused by chronic alcohol consumption. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a pivotal role in neurodevelopment and in the maintenance of adult brain homeostasis through the regulation of neurogenesis and neuronal plasticity. The role of BDNF and its signaling in the mechanisms of alcohol dependence has been well documented in studies of animal models, but a few studies have been conducted in human peripheral tissues. 

    On the basis of this rationale, we compared BDNF levels in both serum and plasma in alcohol-dependent patients and healthy volunteers.

    Thirty-seven patients with a principal diagnosis of alcohol dependence were recruited. In parallel, a control group of 37 unrelated volunteers matched for gender and age was enrolled. Serum and plasma BDNF levels were measured by ELISA.

    A significant reduction in BDNF serum levels was observed in the patient group compared to healthy subjects (p = 0.028). On the contrary, no difference in BDNF plasma levels was evident between patients and controls.

    In conclusion, our data show an alteration of BDNF peripheral content in patients with alcohol dependence, suggesting the involvement of this neurotrophin in this psychopathology.

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    Toll-Like Receptor 4 Mediates Alcohol-Induced Steatohepatitis Through Bone Marrow-Derived and Endogenous Liver Cells in Mice

    Excessive alcohol intake causes an increase in intestinal permeability that induces translocation of gut-derived lipopolysaccharide (LPS) to the portal vein. Increased LPS in the portal vein stimulates Kupffer cells through Toll-like receptor (TLR) 4 in the liver. Activated TLR4 signaling in Kupffer cells induces various inflammatory mediators including TNF-α, IL-1β, and reactive oxygen species, resulting in liver injury. Hepatic stellate cells (HSCs) also express TLR4. 

    This study investigates whether TLR4 on bone marrow (BM)-derived cells, including Kupffer cells, or non–BM-derived endogenous liver cells, including HSCs, contributes to the progression of alcohol-induced steatohepatitis and fibrogenesis in mice.

    TLR4 BM chimera (wild-type [WT] mice with TLR4−/− BM or TLR4−/− mice with WT BM) were generated by the combination of liposomal clodronate injection with whole body irradiation and BM transplantation, followed by treatment with intragastric alcohol feeding.

    WT mice transplanted with WT BM exhibited liver injury, steatosis, inflammation, and a fibrogenic response. Conversely, TLR4−/− mice with TLR4−/− BM displayed less steatosis, liver injury, and inflammation. Notably, steatosis, macrophage infiltration, and alanine aminotransferase levels in both TLR4-chimeric mice showed intermediate levels between WT mice transplanted with WT BM and TLR4−/− mice transplanted with TLR4−/− BM. Hepatic mRNA expression of fibrogenic markers (collagen α1(I), TIMP1, TGF-β1) and inflammatory cytokines (IL-1β, IL-6) were markedly increased in WT mice with WT BM, but there was less of an increase in both TLR4-chimeric mice and in TLR4−/− mice transplanted with TLR4−/− BM.

    TLR4 signaling in both BM-derived and non–BM-derived liver cells is required for liver steatosis, inflammation, and a fibrogenic response after chronic alcohol treatment.

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    Acute Ethanol Disrupts Photic and Serotonergic Circadian Clock Phase-Resetting in the Mouse

    Alcohol dependence is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol dependence on the circadian timing system.

    In this study, we extend previous work in C57BL/6J mice to: (i) characterize the suprachiasmatic nucleus (SCN) pharmacokinetics of acute systemic ethanol administration, (ii) explore the effects of acute ethanol on photic and nonphotic phase-resetting, and (iii) determine if the SCN is a direct target for photic effects.

    First, microdialysis was used to characterize the pharmacokinetics of acute intraperitoneal (i.p.) injections of 3 doses of ethanol (0.5, 1.0, and 2.0 g/kg) in the mouse SCN circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase delays and serotonergic ([+]8-OH-DPAT-induced) phase advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized.

    Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20 to 40 minutes postinjection with half-lives for clearance ranging from 0.6 to 1.8 hours. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase delays.

    These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and nonphotic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism.

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    Wednesday, April 6, 2011

    A Time-Series Analysis of Alcohol Tax Policy in Relation to Mortality from Alcohol Attributed Causes in Taiwan

    It is known that taxation on alcohol products may effectively reduce the alcohol consumption. However, whether alcohol taxation may lead to a decrease in alcohol attributed disease mortality (ADM) has been inclusively. 
    We conducted this time-series analysis to assess the effect of alcohol tax policy intervention in 2002 on rate of ADM in Taiwan. 
    Mortality data were retrieved from Taiwan’s Death Registry. We employed the autoregression integrated moving average technique to examine secular patterns of quarterly rate of ADM in residents aged 15 or above between 1991 and 2007, and to determine whether alcohol tax policy intervention, imposed in January 2002, had affected the time trend in rate of ADM in subsequent years. 
    We observed a statistically significant reduction in the rate of ADM following the implementation of alcohol tax policy for all sex- and age-specific segments of population. 
    Further analyses revealed that the effect was most obvious in men aged 15–64 years, who showed an abrupt decline in AMD rate (10.9%) in the first quarter of 2002. 
    For elderly men and women, the tax intervention was followed by a gradually declining trend of ADM, with a magnitude ranging from 0.53% per season (elderly women) to 0.63% per season (elderly men). 
    This study demonstrated that alcohol taxation policy may pose favorite influences on the time trend of ADM rate in Taiwan, and such influence was most noteworthy in young and middle aged men. 
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    News Release - Scientists find gene linked to alcohol consumption

    The researchers say that finding a common genetic variation influencing levels of alcohol consumption may lead to a better understanding of mechanisms underlying alcohol drinking behaviour in the general population.

    The gene, called “autism susceptibility candidate 2”, or AUTS2, has previously been linked to autism and attention deficit hyperactivity disorder, but its function is not known.

    Today’s study, by an international consortium led by scientists at Imperial College London and King’s College London, found that there are two versions of the AUTS2 gene, one three times more common than the other. People with the less common version drink on average five per cent less alcohol than people with the more common version.  > > > >  Read More

    Previous Ethanol Experience Enhances Synaptic Plasticity of NMDA Receptors in the Ventral Tegmental Area

    Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. 

    However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. 

    Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. 

    Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP3) in producing facilitation of action potential-evoked Ca2+ signals, which is critical for LTP induction. This increase in IP3 effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. 

    Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP3 effect in ethanol-treated mice. 

    Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. 

    These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons. 

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    Alcohol involvement as a function of co-occurring alcohol use disorders and major depressive episode: Evidence from the National Epidemiologic Survey on Alcohol and Related Conditions

    Co-occurring alcohol use disorder and major depression (C-ALDP) is a major public health problem. Yet, the available evidence is mixed regarding the implications of C-ALDP for alcohol involvement. The purpose of this research was to examine the associations between past 12-month co-occurring AUDs (abuse and dependence) and major depressive episode (MDE) and alcohol involvement in a representative community sample.
    The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is a national household survey of 43,093 adults ages 18 and older. For the NESARC, the target population is the civilian noninstitutionalized population, 18 years of age and older, living in the United States and the District of Columbia.
    All NESARC interviews were conducted with the Alcohol Use Disorder and Associated Disabilities Interview Schedule – DSM IV Version (AUDADIS-IV; Grant et al., 2003a).

    Prevalence of past 12-month co-occurring AUD (abuse or dependence) and MDE was 1.2%, corresponding to about 2.4 million adults ages 18 and older. Among males with alcohol dependence, comorbid MDE was associated with a greater number of days drinking at home alone. Among females and males with alcohol abuse and dependence, comorbid MDE was associated with higher prevalence of drinking to enhance depressed mood. Comorbid MDE was also associated with lower levels of some drinking behaviors among those with alcohol abuse.

    Co-occurring AUDs and MDE are associated with specific dimensions of alcohol involvement, and this association is more consistent for alcohol dependence than abuse.

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    Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumptio

    Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. 

    We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. 

    SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10−8 to P = 4 × 10−9). 

    We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. 

    Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001).

    Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior. 

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    Empowerment. Advocacy. NGO´s. Vilnius, Lithuania 21. – 23. October 2011.

    How to make efficient alcohol and drug policy?
    What kind of important things NGOs must know before reaching this aim? It is important to get policymakers interested and involved in public health policy. How? With better advocacy?  Mobilizing people? Training and education?
       > > > >    Read More

    2010 Partnership Attitude Tracking Study, sponsored by MetLife Foundation

    The 22nd annual Partnership Attitude Tracking Study (PATS), sponsored by MetLife Foundation, shows that teen drug and alcohol use is headed in the wrong direction, with marked increases in teen use of marijuana and Ecstasy over the past three years. The study confirms a disturbing trend that has emerged among American teens since 2008 and highlights that underage drinking has become more normalized among adolescents.

    Read  Full Key Findings    (PDF)

    Read Full Report   (PDF)

    Press Release - State disburses $6.3 million to reduce alcohol abuse

    Community coalitions statewide are invited to apply for six grants to develop comprehensive prevention programs targeting youth alcohol use, ages 12–20, and adult heavy and binge drinking, ages 21–44. The two age and behavior targets were chosen as those causing Alaskans the most harm, via accidents, homicides, suicides, crime, domestic violence and other categories.
    The state grants are funded by a $10.7 million federal Strategic Prevention Framework State Incentive Grant program awarded in 2009. Some funding will go to building state infrastructure, such as trainers and prevention resources, and evaluation of grantee performance. The Department of Health and Social Services, Division of Behavioral Health, is now accepting proposals from coalitions in both urban and rural areas of Alaska to provide services from July 1, 2011 to June 30, 2014.

    The funding agent, the federal Substance Abuse and Mental Health Services Administration, requires that grantees 1) be part of a community coalition; 2) provide a comprehensive array of promotion, prevention and early intervention strategies; 3) use data-focused, community-designed strategies that have proven effective; and 4) have clearly defined and measurable outcomes.
      > > > >  Read More

    News Release - Three in Ten Americans Drink Alcohol at Least Once a Week

    Maybe it’s a glass of wine. For some, it might be a beer or a gin and tonic. But whatever the choice is, three in ten Americans, 21 and older (29%) say they drink alcohol at least once a week, including 5% who drink daily and 10% who drink several times a week. One in five Americans 21 or older (20%) say they drink alcohol at least once a month and 15% drink it several times a year. One in five Americans (22%) say they never drink alcohol. Men are more frequent drinkers than women are as almost two in five men (38%) say they drink at least once a week compared to 21% of women.  > > > >  Read More

    Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol

    The hippocampus is a key brain region involved in both short- and long-term memory processes and may play critical roles in drug-associated learning and addiction. 

    Using whole genome sequencing of mRNA transcripts (RNA-Seq) and immunoprecipitation-enriched genomic DNA (ChIP-Seq) coupled with histone H3 lysine 4 trimethylation (H3K4me3), we found extensive hippocampal gene expression changes common to both cocaine-addicted and alcoholic individuals that may reflect neuronal adaptations common to both addictions. 

    However, we also observed functional changes that were related only to long-term cocaine exposure, particularly the inhibition of mitochondrial inner membrane functions related to oxidative phosphorylation and energy metabolism, which has also been observed previously in neurodegenerative diseases.

    Cocaine- and alcohol-related histone H3K4me3 changes highly overlapped, but greater effects were detected under cocaine exposure. 

    There was no direct correlation, however, between either cocaine- or alcohol- related histone H3k4me3 and gene expression changes at an individual gene level, indicating that transcriptional regulation as well as drug-related gene expression changes are outcomes of a complex gene-regulatory process that includes multifaceted histone modifications. 

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    Tuesday, April 5, 2011

    Pathway based analysis of genotypes in relation to alcohol dependence

    We introduce a method for detecting variants in several genes of related function with small effect on a phenotype of interest. 

    Our method uses logistic regression to test whether multiple alleles within a functional set have significantly higher than expected predictive value, even though none individually may have strong individual effects. 

    We illustrate this method by testing seven gene sets (including 48 genes), from a study with1350 single nucleotide polymorphisms in 130 addiction candidate genes studied in a sample of 575 alcohol dependence (AD) cases and 530 controls. 

    We conclude that AD is related to variation in genes participating in Glutamate and γ-amino butyric acid signaling, as has been reported elsewhere, and in stress response pathways, but not with genes in several other systems implicated in other drugs of abuse.

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    The Chinese Translations of Alcohol Use Disorders Identification Test (AUDIT) in China: A Systematic Review

    To systematically review the literature on the Chinese translations of the Alcohol Use Disorders Identification Test (AUDIT) and their cross-cultural applicability in Chinese language populations.
    We identified peer-reviewed articles published in English (n = 10) and in Chinese (n = 11) from 1980 to September 2009, with key words China, Chinese and AUDIT among PubMed, EBSCO, PsycInfo, FirstSearch electronic databases and two Chinese databases.

    Five teams from Beijing, Tibet, Taiwan and Hong Kong reported their region-specific translation procedures, cultural adaptations, validity (0.93–0.95 in two versions) and reliability (0.63–0.99).

    These Chinese translations and short versions demonstrated relatively high sensitivity (0.880–0.997) and moderate specificity (0.709–0.934) for hazardous/harmful drinking and alcohol dependence, but low specificity for alcohol dependence among Min-Nan Taiwanese (0.58).

    The AUDIT and its adaptations were most utilized in workplace- and hospital-settings for screening and brief intervention. However, they were under-utilized in population-based surveys, primary care settings, and among women, adolescents, rural-to-urban migrants, the elderly and minorities.
    Among 12 studies from mainland China, four included both women and men, and only one in Tibet was published in English.  

    There is a growing amount of psychometric, epidemiologic and treatment research using Chinese translations of the AUDIT, much of it still unavailable in the English-language literature.

    Given the increase in burden of disease and injury attributable to alcohol use in the Western Pacific region, the use of an internationally comparable instrument (such as the AUDIT) in research with Chinese populations presents a unique opportunity to expand clinical and epidemiologic knowledge about alcohol problem epidemics. 

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    Monday, April 4, 2011

    Surrogate Alcohol Drinking in Estonia

    Surrogate, nonbeverage alcohols, provide a cheap and concentrated source of ethanol for drinking that has been associated with premature mortality.

    The aim of this study was to provide the first estimate of the prevalence of surrogate alcohol consumption in a national population sample of Estonia.

    The Estonian Health Interview Survey conducted in 2006 to 2007 was a nationally representative sample of the population aged 15 to 84 years (N = 6,370). The age-standardized percentage prevalences of ever having drunk surrogates were estimated. The association of age, ethnicity, and education with the prevalence of surrogate drinking was estimated using logistic regression.

    Of all respondents who reported drinking at least once in their lifetime (N = 5,423), 65% had consumed alcohol during the previous 4 weeks. In this group (N = 3,525), the age-standardized prevalence rate of surrogate drinking was 1.4% (2.3% men, 0.3% women). Among men, surrogate drinking was rare under the age of 35 years (0.3%). Ethnicity and education were both related to surrogate drinking: relative to Estonian men, non-Estonians (mainly Russians) had an odds ratio (OR) for surrogate drinking (adjusted for age and education) of 2.58 (95% CI 1.41, 4.72), while relative to those with higher education those with secondary education had an OR (adjusted for age and ethnicity) of 2.28 (0.78, 6.67) and those with basic education an OR of 3.91 (1.29, 11.84).

    Surrogate alcohols are drunk in Estonia, particularly among men. This behavior shows pronounced variation in prevalence by ethnicity and education. Reducing consumption of these substances needs to be part of any strategy to reduce the burden of alcohol-related problems in Estonia today.

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    Ethanol Inhibits Lipid Raft-Mediated TCR Signaling and IL-2 Expression: Potential Mechanism of Alcohol-Induced Immune Suppression

    Alcohol abuse has long-term deleterious effects on the immune system, and results in a depletion and loss of function of CD4+ T lymphocytes, which regulate both innate and adaptive immunity. T-lymphocyte activation via T-cell receptor (TCR) involves the lipid raft colocalization and aggregation of proteins into the immunological signalosome, which triggers a signaling cascade resulting in the production of interleukin-2 (IL-2). IL-2 regulates the proliferation and clonal expansion of activated T cells and is essential for an effective immune response. 

    The present work examines the mechanisms underlying ethanol-induced dysfunction of CD4+ T lymphocytes based on the hypothesis that ethanol downregulates lipid raft-mediated TCR signal transduction and resultant IL-2 production.

    Primary or cultured human T lymphocytes were exposed to ethanol for 24 hours prior to stimulation with anti-CD3/anti-CD28 antibodies or phytohemagglutinin. Effects of ethanol exposure on TCR-signaling (including activation of Lck, ZAP70, LAT, and PLCγ1) and IL-2 gene expression were examined.

    Exposure of both primary and cultured human CD4+ T lymphocytes to physiologically relevant concentrations of ethanol leads to down-regulation of IL-2 mRNA and protein via inhibition of DNA-binding activity of NFAT, the essential transcription factor for IL-2. Ethanol decreases tyrosine phosphorylation and activation of upstream signaling proteins PLCγ1, LAT, ZAP70, and Lck. These effects are prevented by inhibition of metabolism of ethanol. Sucrose density gradient fractionation and confocal microscopy revealed that ethanol inhibited essential upstream lipid raft-mediated TCR-dependent signaling events, namely colocalization of Lck, ZAP70, LAT, and PLCγ1 with plasma membrane lipid rafts.

    Overall, our data demonstrate that ethanol inhibits lipid raft-mediated TCR-signaling in CD4+ T lymphocytes, resulting in suppression of IL-2 production. These findings may represent a novel mechanism underlying alcohol abuse-associated immune suppression and may be particularly relevant in diseases such as HIV/AIDS and hepatitis C virus infection where alcohol abuse is a known comorbidity.

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    A New Model of Interactive Effects of Alcohol and High-Fat Diet on Hepatic Fibrosis

    Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood.

    The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.

    Balb/c mice were randomly allocated into 4 experimental groups receiving (i) standard chow, (ii) an HF diet, (iii) alcohol in drinking water (increasing concentrations up to 5%), or (iv) an HF diet and alcohol ad libitum for 6 weeks.

    An HF diet significantly induced hepatic triglyceride accumulation and expression of proinflammatory genes (p47phox and tumor necrosis factor), while the effects of alcohol alone were less pronounced. However, in combination with HF diet, alcohol significantly enhanced proinflammatory gene expression compared to the HF diet alone. Furthermore, alcohol as well as HF diet led to a marked increase in profibrogenic genes (collagen type I and transforming growth factor-β), activation of hepatic stellate cells, and extracellular matrix deposition in the liver tissue, and noteworthy, the combination of both alcohol and HF diet led to a further marked induction of hepatic fibrosis. Moreover, endotoxin levels in the portal circulation were significantly elevated in mice that received alcohol or HF diet and were further significantly increased in those receiving both. Furthermore and surprisingly, HF diet alone and in combination with alcohol led to a markedly increased hepatic expression of the endotoxin receptor Toll-like receptor 4 (TLR4), which is known to play a crucial role in hepatic fibrosis.

    In summary, this new model allows the investigation of isolated or joint effects of alcohol and HF diet on hepatic injury, where alcohol and HF diet appear to act synergistically on the development of hepatic fibrosis, potentially via enhanced TLR4 signaling.

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    A Longitudinal Twin Study of Effects of Adolescent Alcohol Abuse on the Neurophysiology of Attention and Orienting

    Long-term functional brain effects of adolescent alcohol abuse remain uncertain, partially because of difficulties in distinguishing inherited deficits from neuronal effects of ethanol and by confounds associated with alcohol abuse, especially nicotine exposure.

    We conducted a longitudinal twin study to determine neurocognitive effects of adolescent alcohol abuse, as measured with the auditory event-related potential (ERP) component P3, a putative marker of genetic vulnerability to alcoholism.

    Twin pairs (= 177; 150 selected for intrapair concordance/discordance for alcohol-related problems at age 18½) were recruited from ongoing studies of twins born 1975–1979 in Finland. Alcohol and tobacco use were assessed with questionnaires at ages 16, 17, 18½, and ∼25, and by a structured psychiatric interview concurrent with the ERP testing at mean age 25.8. During ERP recordings, subjects were instructed to detect target tones within a train of frequent “standards” and to ignore occasional “novel” sounds. To distinguish familial factors from ethanol effects, ERP and self-reported alcohol use measures were incorporated into hierarchical multiple regression (HMR) analysis, and intrapair differences in ERP were associated with intra-pair differences in alcohol variables.

    Novel-sound P3 amplitude correlated negatively with self-reported alcohol use in both between- and within-family analyses. No similar effect was observed for target-tone P3. HMR results suggest that twins’ similarity for novel-sound P3 amplitude is modulated by their alcohol use, and this effect of alcohol use is influenced by genetic factors.

    Our results, from a large sample of twins selected from a population-based registry for pairwise concordance/discordance for alcohol problems at 18½, demonstrate that adolescent alcohol abuse is associated with subtle neurophysiological changes in attention and orienting. The changes are reflected in decreased novel-sound P3 amplitude and may be modified by genetic factors.

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    Role of Intestinal Circadian Genes in Alcohol-Induced Gut Leakiness

    Several studies have indicated that endotoxemia is the required co-factor for alcoholic steatohepatitis (ASH) that is seen in only about 30% of alcoholics. Recent studies have shown that gut leakiness that occurs in a subset of alcoholics is the primary cause of endotoxemia in ASH. The reasons for this differential susceptibility are not known. Since disruption of circadian rhythms occurs in some alcoholics and circadian genes control the expression of several genes that are involved in regulation of intestinal permeability, we hypothesized that alcohol induces intestinal hyperpermeability by stimulating expression of circadian clock gene proteins in the intestinal epithelial cells.

    We used Caco-2 monolayers grown on culture inserts as an in vitro model of intestinal permeability and performed Western blotting, permeability, and siRNA inhibition studies to examine the role of Clock and Per2 circadian genes in alcohol-induced hyperpermeability. We also measured PER2 protein levels in intestinal mucosa of alcohol-fed rats with intestinal hyperpermeability.

    Alcohol, as low as 0.2%, induced time dependent increases in both Caco-2 cell monolayer permeability and in CLOCK and PER2 proteins. SiRNA specific inhibition of either Clock or Per2 significantly inhibited alcohol-induced monolayer hyperpermeability. Alcohol-fed rats with increased total gut permeability, assessed by urinary sucralose, also had significantly higher levels of PER2 protein in their duodenum and proximal colon than control rats.

    Our studies: (i) demonstrate a novel mechanism for alcohol-induced intestinal hyperpermeability through stimulation of intestinal circadian clock gene expression, and (ii) provide direct evidence for a central role of circadian genes in regulation of intestinal permeability.

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