Alcohol consumption among patients with hepatitis B infection in northern Portugal considering gender and hepatitis B virus genotype differences

Alcohol abuse is an important public health problem. In Portugal with a population of 10 millions of inhabitants, there are around 10% of alcoholics or excessive alcohol drinkers and 1% of chronically infected patients with hepatitis B virus (HBV).

To examine the characteristics of patients with higher levels of alcohol consumption and to investigate the association between alcohol consumption and liver damage a total of 298 chronically infected individuals, with HBV genotyped and submitted to liver biopsy, were classified with Child's grading and separated by habits of alcohol intake, less and greater than 20g/day.

No significant differences were observed about genotype but genotypes A and D were predominant in both of them. A higher percentage of males (P.001) were observed in the group with alcohol intake above 20g/day, as well a lower proportion of patients with HBeAg negativity (P≤.035). In this group, biochemistry parameters, such as alanine aminotransferase (P=.006), aspartate aminotransferase (P=.001), gamma-glutamyl transferase (P.001) were elevated in a significantly higher proportion than in the other group.

The analysis of hematological parameters showed significantly lower values of platelets (P=.042) and mean corpuscular volume (P.001) and significantly higher values of prothrombin time (P.001) in the group with higher levels of alcohol consumption.

The characteristics of biopsy (P.001) and Child–Phug's classification (P=.002) revealed more severe results in this group.

Logistic regression showed a positive association between liver damage and alcohol intake, increasing with age. In female patients, a strong positive association between alcohol intake and liver damage was also found (odds ratio: 9.379; 95% confidence interval: 0.859–468.422; P = .037); however, the most severe cases were only observed in women older than 45 years.

In patients with HBV infection, alcohol is associated with a more severe liver disease.

No evidence was found concerning association with HBV genotype.
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Request Reprint E-Mail: mcard@icbas.up.pt
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Breast pumping and lactational state exert differential effects on ethanol pharmacokinetics

Prior research revealed that breast stimulation altered the way the lactating body handles alcohol. Its effects depended upon when it occurred relative to drinking.

The goal of the present study was to determine whether breast pumping works independently of the physiological and metabolic changes that accompany lactation.

To this end, we tested 12 women when they were exclusively breastfeeding 3–5-month-old infants and then again several months after lactation had ceased. Subjects were randomly assigned to one of two groups that differed in the timing of breast pumping relative to drinking a 0.4g/kg dose of alcohol: one group breast pumped 0.6h after drinking (pumped after group) and the other pumped 1h before drinking (pumped before group). For each reproductive stage, subjects were tested on 2 separate days, consuming a standardized meal 1 h before drinking during 1 test day and remaining fasted during the other. Breath alcohol concentrations (BrAC) and temperature readings were obtained before and at fixed intervals after drinking.

Pumping before drinking significantly decreased BrAC during both reproductive stages, whereas pumping after drinking resulted in different BrAC time curves during lactation when compared with after lactation. That is, levels were significantly lower during the descending phase of the time curve during than after lactation. The interactions between pumping and reproductive stage were most apparent during fed condition. Furthermore, women were more sensitive to hypothermic effects of both fasting and drinking alcohol during lactation.

These findings add to the growing literature that lactating women metabolize alcohol differently, in part, due to the frequent breast stimulation during breastfeeding and the pronounced physiological changes that accompany one of the most energetically costly mammalian activities.

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Request Reprint E-Mail: mennella@monell.org
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Behind Bars II: Substance Abuse and America’s Prison Population

Of the 2.3 million inmates crowding our nations prisons and jails, 1.5 million meet the DSM IV medical criteria for substance abuse or addiction, and another 458,000, while not meeting the strict DSM IV criteria, had histories of substance abuse; were under the influence of alcohol or other drugs at the time of their crime; committed their offense to get money to buy drugs; were incarcerated for an alcohol or drug law violation; or shared some combination of these characteristics, according to "Behind Bars II: Substance Abuse and America’s Prison Population".

Combined these two groups constitute 85 percent of the U.S. prison population.

The new 144-page report released by The National Center on Addiction and Substance Abuse (CASA) at Columbia University also reveals that alcohol and other drugs are significant factors in all crime.

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The UN tackles road safety

WHO welcomes the proclamation by the UN General Assembly of the first "Decade of Action for Road Safety 2011-2020" which seeks to halt the increasing trends in road traffic deaths and injuries worldwide.

"This Decade of Action for Road Safety is long overdue," says WHO Assistant Director-General Dr Ala Alwan. "It will help us increase action to address what will otherwise become the fifth leading cause of death by 2030."

Road traffic injuries are a major public health problem, killing nearly 1.3 million people each year and injuring as many as 50 million. They are the leading cause of death for children and young people aged 5–29 years. Almost half of the world's road traffic fatalities are among pedestrians, cyclists and motorcyclists and more than 90% occur in developing countries.

While road traffic death rates in many high-income countries have stabilized or declined in recent decades, research suggests road deaths are increasing in most regions of the world. If trends continue unabated deaths will rise to an estimated 2.4 million a year by 2030. . . . . .

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Long-Evans Rats Acquire Operant Self-Administration of 20% Ethanol Without Sucrose Fading

A major obstacle in the development of new medications for the treatment of alcohol use disorders (AUDs) has been the lack of preclinical, oral ethanol consumption paradigms that elicit high consumption.

We have previously shown that rats exposed to 20 ethanol intermittently in a two-bottle choice paradigm will consume two times more ethanol than those given continuous access without the use of water deprivation or sucrose fading (5–6% g/kg every 24 h vs 2–3 g/kg every 24 h, respectively).

In this study, we have adapted the model to an operant self-administration paradigm. Long-Evans rats were given access to 20% ethanol in overnight sessions on one of two schedules: (1) intermittent (Monday, Wednesday, and Friday) or (2) daily (Monday through Friday).

With the progression of the overnight sessions, both groups showed a steady escalation in drinking (3–6 g/kg every 14 h) without the use of a sucrose-fading procedure.

Following the acquisition phase, the 20% ethanol groups consumed significantly more ethanol than did animals trained to consume 10% ethanol with a sucrose fade (1.5 vs 0.7 g/kg every 30 min) and reached significantly higher blood ethanol concentrations.

In addition, training history (20% ethanol vs 10% ethanol with sucrose fade) had a significant effect on the subsequent self-administration of higher concentrations of ethanol.

Administration of the pharmacological stressor yohimbine following extinction caused a significant reinstatement of ethanol-seeking behavior.

Both 20% ethanol models show promise and are amenable to the study of maintenance, motivation, and reinstatement. Furthermore, training animals to lever press for ethanol without the use of sucrose fading removes a potential confound from self-administration studies.

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Request Reprint E-Mail: selenab@gallo.ucsf.edu
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Early onset alcohol dependence with high density of family history is not "male limited".

Based on classical adoption studies, early onset type II alcoholism was originally described as “male limited.”

We examined the possible expression of this subtype in present day alcohol-dependent women. Detailed systematic assessment was obtained from 200 treatment-seeking alcohol-dependent women and 189 healthy population controls.

Women fulfilling type II alcoholism criteria had higher alcoholism severity as measured by The Alcohol Use Disorders Identification Test and markedly higher use of illicit drugs.

Both alcoholism subtypes scored higher than normal on anxiety and impulsivity traits, but type II women scored markedly higher on aggression subscales than either of the other groups. Importantly, density of family history was markedly higher in type II women, suggesting a higher heritability.

Despite its original description as male limited, early onset alcoholism with high density of family history is likely to be a valid construct in women. Its recognition has important implications for diagnosis, treatment, and research.

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Request Reprint E-Mail: markus.heilig@mail.nih.gov
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Analysis of the alcohol biomarker phosphatidylethanol by NACE with on-line ESI-MS

Phosphatidylethanol (Peth), a group of aberrant phospholipids formed in cell membranes in the presence of ethanol, has been recently proposed as biomarker of chronic alcohol abuse.

The aim of this study was to develop a new analytical method, based on NACE online coupled with a mass spectrometer for the analysis of Peth in blood.

For this purpose an ion-trap mass spectrometer equipped with an orthogonal ESI source operating in negative ion mode was used. An alkaline solution of ammonium acetate 5 mM (pH 9) in water/methanol (MeOH) (80:20 v/v) was delivered as coaxial sheath liquid. All experiments were performed using an uncoated fused-silica capillary (90 cm×75 m id).

The effects of variable percentages of ACN, MeOH, 2-propanol, dichloromethane, along with variable concentrations of ammonium acetate were investigated for the separation of Peth. Collectively, a separation medium composed of ACN (45% v/v), 2-propanol (20% v/v), dichloromethane (20% v/v), MeOH (10% v/v), water (5% v/v), and ammonium acetate (25 mM) was chosen.

The estimated LOD was 0.1 M, while LOQ was 0.4 M. Within-run (intra-day) and between-run (inter-day) precision was always lower than 15%.

The method proved to be robust and reliable. The MS detector allowed the simultaneous identification of several Peth homologues, and the use of an internal standard (phosphatidylbutanol) with similar electrophoretic properties of that of Peth increased quantitation effectiveness.

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Request Reprint E-Mail: santodavide.ferrara@unipd.it
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Effects of the mGlu2/3 Agonist LY379268 and the mGlu5 Antagonist MTEP on Ethanol Seeking and Reinforcement Are Differentially Altered in Rats with a H

Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol seeking in rats with a history of ethanol dependence.

LY379268 and MTEP dose-dependently reduced both ethanol self-administration and reinstatement of ethanol seeking induced by footshock stress. Additionally, LY379268 was more effective than MTEP in inhibiting both behaviors in postdependent than in nondependent animals.

These findings suggest that neuroadaptation associated with chronic ethanol exposure or withdrawal alters the sensitivity of mGlu2/3 receptors, with implications for the understanding of the neural basis of alcohol dependence and the treatment target potential of these receptors.

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Request Reprint E-Mail: nsidhp@scripps.edu

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Effects of a community intervention to reduce the serving of alcohol to intoxicated patrons

To assess the effects of an alcohol prevention programme to reduce the serving of alcoholic beverages to intoxicated clients on licensed premises.

A community-based programme combining law enforcement, responsible beverage service training, information campaigns and policy initiatives in one Finnish town (Jyväskylä).

A male actor pretended to be clearly under the influence of alcohol and tried to buy a pint of beer at licensed premises. For the baseline measurement, every bar and nightclub was visited in the intervention and the control areas (94 licensed premises in total). Post-intervention data were gathered with the same principles (100 licensed premises in total). A researcher observed every visit and documented the results.

In the post-intervention study there was a statistically significant increase in refusals to serve denials alcohol to the actor in the intervention area (from 23% to 42% of the licensed premises) compared to refusals in the control area (from 36% to 27% of the licensed premises).

Previous research has documented that multi-component community-based interventions can have a significant impact on over-serving of alcohol when training and house policies are combined with effective law enforcement.

The present findings also demonstrate that comprehensive Responsible Beverage Service (RBS) interventions applied at a local community level can be effective in decreasing service to intoxicated clients in a Nordic context.

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Request Reprint E-Mail: katariina.warpenius@thl.fi

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ADH1B*2 allele is protective against alcoholism but not chronic liver disease in the Hungarian population

Standardized death rates from chronic liver diseases (CLDs) in Hungary are much higher than the European Union average. Carrying the alcohol dehydrogenase 1B 48His allele (rs1229984 or ADH1B*2) could decrease the risk of alcoholism, but with persistent drinking may confer a greater risk of CLDs.

The aim of this study was to assess the prevalence of this polymorphism in the Hungarian population and its association with alcohol consumption and with CLDs.

A total of 278 cases with diagnosed CLDs and 752 controls without any alterations in liver function, all males aged 45–64, were screened for ADH1B Arg48His polymorphism. ADH1B*2 allele frequencies in controls and cases were 8.31% and 4.50%, respectively (χ² = 9.2; P = 0.01).

Carrying the ADH1B*2 allele was associated with significantly lower odds ratio (OR) for drinking frequency (OR = 0.63; P = 0.003), the number of positive answers on CAGE (Cut-down, Annoyed, Guilt, Eye-opener) assessment (OR = 0.58; P = 0.005) and a positive CAGE status (OR = 0.55; P = 0.007). There was a significant association between ADH1B*2 and CLDs (OR = 0.50; P = 0.003), but it disappeared after adjusting for CAGE status and scores (OR = 0.67 P = 0.134; OR = 0.67 P = 0.148, respectively) and weakened after adjusting for drinking frequency (OR = 0.61; P = 0.045).

Among heavy drinkers the presence of ADH1B*2 did not increase the risk of cirrhosis but there was a significant interaction between genotype and CAGE status (P = 0.003, P = 0.042), with ADH1B*2 conferring reduced risk of CLDs in CAGE negatives.

In Hungarians, the ADH1B 48His allele reduces the risk of alcoholism, but not the risk of chronic liver disease among heavy drinkers.

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Request Reprint E-Mail: adany@dote.hu

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Corticotropin-releasing factor mediates the dysphoria-like state associated with alcohol withdrawal in rats

This study investigated the role of CRF in the dysphoria-like state associated with alcohol withdrawal in rats. The intracranial self-stimulation procedure was used to assess brain reward thresholds.

Cessation of chronic alcohol administration lead to an elevation in brain reward thresholds in the alcohol dependent rats.

The CRF receptor antagonist D-Phe CRF_(12-41) dose-dependently prevented the elevations in brain reward thresholds associated with alcohol withdrawal.

This indicates that the dysphoria associated with alcohol withdrawal is at least partly mediated by the activation of central CRF receptors.

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Request Reprint E-Mail: awbruijn@ufl.edu
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Association between alcohol intake amount and prevalence of metabolic syndrome in Korean rural male population

Moderate alcohol consumption is known to be associated with a reduced risk of cardiovascular disease and mortality. However, few studies reported that long-term alcohol drinking may increase the prevalence of central obesity, and cardiovascular disease.

We examined the association between metabolic syndrome, nutritional factors and alcohol intake amount in Korean male rural population.

We performed a cross-sectional analysis on data from Korean Rural Genomic Cohort (KRGC) study. We used multiple logistic regression analysis to estimate the adjusted odds ratio of metabolic syndrome according to alcohol intake amount categories (never, 0–16 g/day, 16–40 g/day, and >40 g/day).

The age adjusted odds ratio for the prevalence of metabolic syndrome was significantly increased in the quartile with the highest alcohol consumption compared to the non-alcohol drinking group (1.33; C.I., 1.11–1.59). These results were similar in the high energy intake group, but not in the low energy intake group. Waist circumference, blood pressure, and serum triglyceride levels were significantly higher in the quartile with the highest alcohol consumption compared to the non-alcohol drinking group.

These results suggest that large alcohol consumption is associated with metabolic syndrome and may be a modifiable risk factor of metabolic syndrome especially in subjects with high calorie intake.

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Request Reprint E-Mail: kohhj@yonsei.ac.kr

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DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence

Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has been implicated in the pathogenesis of addictive behaviour and especially in alcohol craving.

The pro-opiomelanocortin gene (POMC), encoding a 241 amino acids stretching polypeptide hormone precursor, plays an important role in the regulation of the HPA, and is prone to epigenetic regulation due to promoter-related DNA methylation.

Aim of the present study therefore was to investigate possible differences in promoter-related DNA methylation in patients suffering from alcohol dependence compared to healthy controls.

We analysed the DNA methylation of the 5′ promoter of the POMC gene that is embedded in a CpG island using bisulfite sequencing in 145 alcohol-dependent patients and 37 healthy controls taken from the Franconian Alcoholism Research Studies.

We found only marginal, hence significant differences at single CpG sites between patients and controls. We identified a cluster of CpGs showing a significant association with alcohol craving in the patients group.

These results implicate that epigenetic changes possibly due to alcohol intake may contribute to craving via promoting HPA-axis dysfunction. Further studies should more closely investigate the impact of these changes on the several derivatives of the POMC gene.

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Request Reprint E-Mail: muschler.marc@mh-hannover.de


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Cause for Concern: National Study Shows Reverse in Decade-Long Declines in Teen Abuse of Drugs and Alcohol

After a decade of consistent declines in teen drug abuse, a new national study released today by the Partnership for a Drug-Free America® and MetLife Foundation points to marked upswings in use of drugs that teens are likely to encounter at parties and in other social situations.

According to the 2009 Partnership Attitude Tracking Study, sponsored by MetLife Foundation, the number of teens in grades 9-12 that used alcohol in the past month has grown by 11 percent, (from 35 percent in 2008 to 39 percent in 2009), past year Ecstasy use shows a 67 percent increase (from 6 percent in 2008 to 10 percent in 2009) and past year marijuana use shows a 19 percent increase (from 32 percent in 2008 to 38 percent in 2009). The PATS data mark a reverse in the remarkable, sustained declines in several drugs of abuse among teens: methamphetamine (meth) was down by over 60 percent and past month alcohol and marijuana use had decreased a full 30 percent over the past decade from 1998-2008.

Underlying these increases are negative shifts in teen attitudes, particularly a growing belief in the benefits and acceptability of drug use and drinking. The percentage of teens agreeing that “being high feels good” increased significantly from 45 percent in 2008 to 51 percent in 2009, while those saying that “friends usually get high at parties” increased from 69 percent to 75 percent over the same time period. The Partnership/ MetLife Foundation Attitude Tracking Study (PATS) also found a significant drop in the number of teens agreeing strongly that they “don’t want to hang around drug users” – from 35 percent in 2008 to 30 percent in 2009. . . . . .

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2009 PATS Full Report (PDF) ______________________________________

Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment

Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined.

The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.

During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.

Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.

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Request Reprint E-Mail: mostacher@partners.org

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It's not too late to save 'normal'

As chairman of the task force that created the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), which came out in 1994, I learned from painful experience how small changes in the definition of mental disorders can create huge, unintended consequences.

Our panel tried hard to be conservative and careful but inadvertently contributed to three false "epidemics" -- attention deficit disorder, autism and childhood bipolar disorder. Clearly, our net was cast too wide and captured many "patients" who might have been far better off never entering the mental health system.

The first draft of the next edition of the DSM, posted for comment with much fanfare last month, is filled with suggestions that would multiply our mistakes and extend the reach of psychiatry dramatically deeper into the ever-shrinking domain of the normal. This wholesale medical imperialization of normality could potentially create tens of millions of innocent bystanders who would be mislabeled as having a mental disorder. The pharmaceutical industry would have a field day -- despite the lack of solid evidence of any effective treatments for these newly proposed diagnoses. . . . .

Read Full Article ________________________________________

Reduce demand for alcohol as well as supply

In our testimony to the Scottish Parliament's Health Committee, Children in Scotland supported the Alcohol Bill's direction of travel. However, we argued that such measures as increasing the price of alcohol must be accompanied by an equal effort to combat the reasons why young people and adults drink unhealthily.

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Foetal alcohol harm

In our evidence to the House of Commons Alcohol Inquiry, we noted the seven basics of foetal alcohol harm:

1. It is potentially 100% preventable

2. It is incurable

3. It is unpredictable

4. It can be difficult to diagnose

5. It is under-diagnosed (or misdiagnosed) and under-reported

6. It has wide-ranging, serious consequences for individuals, communities and society

7. Its ill effects can be lessened by proper diagnosis and proper treatment/support

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The NY Salon in association with The Albert Ellis Institute presents “Hardwired for Life?”

Tuesday, March 9, 2010, 6.30pm to 8.30pm
Please RSVP to jean@nysalon.org

Venue: The Albert Ellis Institute

Researchers in the field of behavioral genetics have asserted claims for a genetic basis to numerous behaviors, including homosexuality, aggression, alcoholism, and nurturing. Furthermore, a growing scientific and popular focus on genes and behavior has contributed to a resurgence of behavioral genetic determinism - the belief that genetics is the major factor in determining behavior. Just recently commentators have blamed the international economic crisis on the innate greed of our consumer “have it all now” society.

Are behaviors inbred, written indelibly in our genes as immutable biological imperatives, or is the environment more important in shaping our thoughts and actions? What are the social consequences of genetic diagnoses of such traits as intelligence, criminality, or homosexuality? How much of our behavior can be attributed to our hardwiring? . . . . .

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Press Release - Genome-wide study of alcohol dependence points to chromosome 11

• Genome-wide study of alcohol dependence points to chromosome 11

• Both genetic and environmental factors affect susceptibility to alcohol dependence (AD).

• To date, researchers have identified several genes associated with AD.
  
  
• Findings from a new genome-wide association study support an association between AD and a cluster of genes on chromosome 11.

Alcohol dependence (AD) is a complex disease for which both genetic and environmental factors affect susceptibility. Previous research had identified several genes associated with AD through linkage analysis or candidate-gene approaches. Findings from a genome-wide association study (GWAS) support an association between AD and a cluster of genes on chromosome 11.

Results will be published in the May 2010 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View. . . . . .

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MAOA Alters the Effects of Heavy Drinking and Childhood Physical Abuse on Risk for Severe Impulsive Acts of Violence Among Alcoholic Violent Offenders

A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency.

Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both.

We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes.

Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA-H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L).

Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA.

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Request Reprint E-Mail: roope.tikkanen@helsinki.fi

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Assessing the Severity of Hazardous Drinking and Related Consequences Among Incarcerated Women

Recent epidemiological efforts have demonstrated the utility of measuring individual differences in the severity of alcohol use along a single severity continuum marked by alcohol-related problems, symptoms of alcohol dependence, and the social consequences of drinking. Translation of this utility to specialized clinical populations is not assured. The expected inter-relationships among problems, symptoms and consequences, and enhanced sensitivity of combined assessments require confirmation in applied clinical settings.

Analyses suggested that the 6 problems of alcohol abuse, 7 symptoms for alcohol dependence, and 14 alcohol-related social consequences loaded to a single factor (0.38 to 0.85) that formed a continuum of alcohol severity. Contrary to epidemiological studies, physical fights and being arrested were the most prevalent consequences and were associated with lower alcohol severity in this population. Three of the five items that discriminated best between higher and lower alcohol severity were related to familial and relationship consequences.

Consistent with epidemiological studies, alcohol severity can be measured among incarcerated hazardously drinking women on a single continuum that includes alcohol problems, symptoms, and social consequences. Replication of the expected alignment of problems and symptoms supports the construct validity of the continuum and further challenges the proposed hierarchical structure of abuse/dependence distinction.

Large differences in rates of specific consequences and observed effectiveness of tailored social consequence items suggest the benefits of cross-sample validation to improve evaluation of clinical outcomes.

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Request Reprint E-Mail: david_strong@brown.edu

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Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders

Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations.

In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells.

Findings from these studies demonstrated that ethanol exposure reduced the expression of RARα/γ while it increased the expression of RXRα/γ in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure.

For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells.

Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.

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Request Reprint E-Mail: Ugra.Singh@uscmed.sc.edu

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Ethanol Enhances the Interaction of Breast Cancer Cells Over-Expressing ErbB2 With Fibronectin

Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Amplification of ErbB2 or HER2, a receptor tyrosine kinase of the ErbB family, is found in 20 to 30% of patients with breast cancer. We have previously demonstrated that the effect of ethanol on the migration/invasion of breast cancer cells positively correlated with the expression levels of ErbB2. Adhesion to the extracellular matrix (ECM) is an important initial step for cancer cell invasion and metastasis.

In this study, we investigated the effects of ethanol on the adhesion of MCF7 breast cancer cells over-expressing ErbB2 (MCF7^ErbB2) to human plasma fibronectin.

To test the hypothesis that ethanol may enhance the attachment of human breast cancer cells to fibronectin, an important component of the ECM, we evaluated the effect of ethanol on the expression of focal adhesions, cell attachment, and ErbB2 signaling in cultured MCF7^ErbB2 cells.

Exposure to ethanol drastically enhanced the adhesion of MCF^ErbB2 cells to fibronectin and increased the expression of focal adhesions. Ethanol induced phosphorylation of ErbB2 at Tyr1248, FAK at Tyr861, and cSrc at Try216. Ethanol promoted the interaction among ErbB2, FAK, and cSrc, and the formation of a focal complex. AG825, a selective ErbB2 inhibitor, attenuated the ethanol-induced phosphorylation of ErbB2 and its association with FAK. Furthermore, AG825 blocked ethanol-promoted cell/fibronectin adhesion as well as the expression of focal adhesions.

Our results suggest that ethanol enhances the adhesion of breast cancer cells to fibronectin in an ErbB2-dependent manner, and the FAK pathway plays an important role in ethanol-induced formation of a focal complex.

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Request Reprint E-Mail: jialuo888@uky.edu

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Influence of Dissolved Oxygen Concentration on the Pharmacokinetics of Alcohol in Humans

Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation.

We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5%v/v).

The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p <>inf and K_el of the high oxygen groups were lower than in the normal oxygen group, while C_max and T_max were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC_inf and t_1/2 was expected to be reduced in the high oxygen group compared to the normal oxygen group.

In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol.

Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents.

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Request Reprint E-Mail: kwon@cnu.ac.kr

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Genome-Wide Association Study of Alcohol Dependence Implicates a Region on Chromosome 11

Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk.

We carried out a genome-wide association study (GWAS) on a case–control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p ≤ 2.1 × 10⁻⁴) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells.

Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case–control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3.

We have identified several promising associations that warrant further examination in independent samples.

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Request Reprint E-Mail: edenberg@iupui.edu

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Increased Activation of the ACC During a Spatial Working Memory Task in Alcohol-Dependence Versus Heavy Social Drinking

Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults.

During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive–Compulsive Drinking Scale—OCDS), alcohol use of the last 90 days, and general intelligence.

Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants.

Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing.

Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts.

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Request Reprint E-Mail: s.vollstaedt-klein@zi-mannheim.de

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Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling Genes

Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs.

A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected.

The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population.

These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response.

Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects.

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Request Reprint E-Mail: mailto:gjoslyn@gallo.ucsf.edu

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News Release - Over 1 in 5 blame peer pressure for drinking more

But pressure to drink could be all in the mind

Peer pressure to drink to excess could be all in our minds according to a survey published for the Department of Health today.

A YouGov poll of more than 2,000 English adults suggests over one in five (22 percent) people who have ended up drinking more than planned put it down to peer pressure, while 39 percent of drinkers feel the need to make up an excuse or lie to justify refusing a drink.

However, the survey for the Department of Health’s ‘Alcohol Effects’ campaign shows this is unnecessary as it appears peer pressure hardly exists. . . . . .

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