Workplace Alcohol Testing Program by Combined Use of Ethyl Glucuronide and Fatty Acid Ethyl Esters in Hair

The applicability of fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG) in hair in a workplace alcohol testing program was investigated.

A total of 78 hair samples from employees in jobs with a high endangering potential were tested for EtG and FAEEs. In most cases excessive drinking was suspected. For 59 of these cases additional data of the traditional alcohol markers aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase and of the mean corpuscular volume of the erythrocytes (58 cases) were available.

By application of the cut-offs of the Consensus of the Society of Hair Testing and of a gradual system for combined interpretation of FAEEs and EtG in hair no indications of alcohol abuse were obtained in 50 cases (64%), slight indications were seen in 13 cases (17%) and clear indications in 11 cases (14%). In four cases, the results were inconclusive with strongly conflicting results of both markers, the reason for which could not be cleared. The traditional markers confirmed the hair results only partly and displayed altogether a lower portion of positive results.

EtG and FAEEs in hair, especially when interpreted in combination, are suitable for application in workplace alcohol testing programs. Nevertheless, the results obtained by hair analysis for alcohol markers can only be one part of a proper assessment aiming at the question whether an employee is addicted to alcohol or not.



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Request Reprint E-Mail: martin.hastedt@charite.de

Role of Novelty and Ethanol History in Locomotor Stimulation Induced by Binge-Like Ethanol Intake

The acute locomotor effects of voluntary ethanol (EtOH) intake in mice (stimulation/sedation) might be important behavioral indicators of an animals’ propensity to engage in EtOH consumption and/or EtOH seeking behaviors. Using a binge-like EtOH intake model dubbed “Drinking-in-the-Dark (DID),” we recently observed home cage locomotor stimulation in C57BL/6J mice during an acute EtOH intake session, but acute home cage locomotor sedation following repeated EtOH exposures. To determine the role of novelty and/or EtOH history on these previously described locomotor effects, and to determine the relationship between these variables on locomotor activity immediately following DID intake, we conducted 2 separate experiments.

In experiment 1, mice were given access to either EtOH or water, and locomotor activity was monitored immediately afterwards. In experiment 2, mice were given 13 days access to EtOH or water solution while home cage locomotor activity was monitored. On the 14th day, half of the water consuming animals received EtOH access for the first time. On the 15th day, all animals received EtOH access, and locomotion was assessed afterwards in locomotor activity testing chambers.

In experiment 1, locomotor activity following DID was positively associated with EtOH intake and blood EtOH concentrations (BECs). In experiment 2, the group that received EtOH for the first time on the 14th day did not display locomotor stimulation. Locomotor activity following DID EtOH intake was positively associated with BECs in all groups regardless of EtOH history.

These results suggest that (i) DID-induced locomotor stimulation in the home cage may involve relative familiarity with the DID procedures, and (ii) locomotor stimulation immediately following DID is directly related to the relative concentration of EtOH in blood; an effect that is not altered by prior EtOH history. These data add new evidence of the pharmacological actions of binge-like EtOH intake, and provide a basis by which we may explore the motivation and consequences of such binge consumption.

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Request Reprint E-Mail: dlinsenb@iupui.edu

Ethanol Affects Differentiation-Related Pathways and Suppresses Wnt Signaling Protein Expression in Human Neural Stem Cells

Prenatal exposure of the fetus to ethanol (EtOH) can be teratogenic. We previously showed that EtOH alters the cell fate of human neural stem cells (NSC). As Wnt signaling plays an important role in fetal brain development, we hypothesized that EtOH suppresses Wnt signaling protein expression in differentiating NSC and thereby contributes to fetal alcohol spectrum disorder.

NSC isolated from fetal human brains were cultured in mitogenic media to induce neurospheres, which were dissociated into single-cell suspensions and used for all experiments. Equal numbers of NSC were cultured on lysine/laminin-coated plates for 96 hours in differentiating media containing 0, 20, or 100 mM EtOH. Total mRNA was isolated from samples containing 0 or 100 mM EtOH and changes in expression of 263 genes associated with neurogenesis and NSC differentiation were determined by Oligo GEArray technology. The biological impact of gene changes was estimated using a systems biology approach with pathway express software and KEGG database. Based on the pathways identified, expression of Wnt proteins (Wnt3a and Wnt5a), Wnt-receptor complex proteins (p-LRP6, LRP6, DVL2, and DVL3), Wnt antagonist Naked-2 (NKD-2), and downstream Wnt proteins (β-catenin, Tyr-p-GSK3β, Ser-p-GSK3β) were analyzed by Western blot.

Of the 263 genes examined, the expressions of 22 genes in differentiating NSC were either upwardly or downwardly affected by EtOH. These genes are associated with 5 pathways/cellular processes: axon guidance; hedgehog signaling; TGF-β signaling; cell adhesion molecules; and Wnt signaling. When compared to controls, EtOH, at both 20 and 100 mM concentrations, suppressed the expression of Wnt3a and Wnt5a, receptor complex proteins p-LRP6, LRP6 and DVL2, and cytoplasmic proteins Ser-p-GSK3β and β-catenin. Expression of NKD-2 and DVL3 remained unchanged and the expression of active Tyr-p-GSK3β increased significantly.

EtOH can significantly alter neural differentiation pathway-related gene expression and suppress Wnt signaling proteins in differentiating human NSC

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Request Reprint E-Mail: svangipuram@med.wayne.edu

ADH1B Polymorphism, Alcohol Consumption, and Binge Drinking in Slavic Caucasians: Results from the Czech HAPIEE Study

Several genetic polymorphisms influence the risk of heavy alcohol consumption but it is not well understood whether the genetic effects are similar in different populations and drinking cultures, nor whether the genetic influences on binge drinking are similar to those seen for alcoholism.

We have analyzed the effect of the Arg47His (rs1229984) variant within the alcohol dehydrogenase (ADH1B) gene on a range of drinking related variables in a large Eastern European Slavic population (Czech HAPIEE study), which recruited random samples of men and women aged 45–69 years in 7 Czech towns (3,016 males and 3,481 females with complete data). Drinking frequency, annual alcohol intake, prevalence of binge drinking (≥100 g in men and ≥60 g in women at least once a month) and the mean dose of alcohol per occasion were measured by the graduated frequency questionnaire. Alcohol intake in a typical week was used to define heavy drinking (≥350 g/wk in men and ≥210 g in women). Problem drinking (≥2 positive answers on CAGE) and negative consequences of drinking on different aspects of life were also measured.

The frequency of the His47 allele carriers was 11%. Homozygotes in the common allele (Arg47Arg), among both males and females, had significantly higher drinking frequency, and annual and weekly intake of alcohol than His47 carriers. The odds ratio of heavy drinking in Arg47Arg homozygotes versus His47 carriers was 2.1 (95% confidence intervals 1.1–3.2) in men and 2.2 (1.0–4.7) in women. In females, but not in males, Arg47Arg homozygotes had marginally significantly higher prevalence of binge drinking and mean alcohol dose per drinking session. There was no consistent association with problem drinking and negative consequences of drinking.

The ADH1B genotype was associated with the frequency and volume of drinking but its associations with binge drinking and problem drinking were less consistent.

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Request Reprint E-Mail: m.bobak@ucl.ac.uk

Callosal Thickness Reductions Relate to Facial Dysmorphology in Fetal Alcohol Spectrum Disorders

Structural abnormalities of the corpus callosum (CC), such as reduced size and increased shape variability, have been documented in individuals with fetal alcohol spectrum disorders (FASD). However, the regional specificity of altered CC structure, which may point to the timing of neurodevelopmental disturbances and/or relate to specific functional impairments, remains unclear. Furthermore, associations between facial dysmorphology and callosal structure remain undetermined.

One hundred and fifty-three participants (age range 8 to 16) including 82 subjects with FASD and 71 nonexposed controls were included in this study. The structural magnetic resonance imaging data of these subjects was collected at 3 sites (Los Angeles and San Diego, California, and Cape Town, South Africa) and analyzed using classical parcellation schemes, as well as more refined surface-based geometrical modeling methods, to identify callosal morphological alterations in FASD at high spatial resolution.

Reductions in callosal thickness and area, specifically in the anterior third and the splenium, were observed in FASD compared with nonexposed controls. In addition, reduced CC thickness and area significantly correlated with reduced palpebral fissure length.

Consistent with previous reports, findings suggest an adverse effect of prenatal alcohol exposure on callosal growth and further indicate that fiber pathways connecting frontal and parieto-occipital regions in each hemisphere may be particularly affected. Significant associations between callosal and facial dysmorphology provide evidence for a concurrent insult to midline facial and brain structural development in FASD.

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Request Reprint E-Mail: esowell@chla.usc.edu

A Dynamic Flux in Natural Killer Cell Subsets as a Function of the Duration of Alcohol Ingestion

Chronic ethanol (EtOH) consumption is associated with a wide variety of immune abnormalities including changes in T cells, B cells, dendritic cells, and natural killer (NK) cells. However, there is conflicting information as to the direction of such immune changes. The hypothesis that was tested in this report is that, for NK cells, the changes can vary as a function of the duration of alcohol ingestion.

Using the Meadows–Cook murine model of chronic alcohol ingestion, the changes in NK cell function and subset distribution were examined as a function of the duration of alcohol ingestion.

Acute alcohol ingestion resulted in decreased number and cytotoxic function of NK cells with no effect on intracellular interferon gamma expression. These abnormalities normalized after 12 to 14 days of alcohol ingestion and there was an increase of NK cell number and cytotoxicity after 8 weeks of continued EtOH ingestion. Ten weeks of continued alcohol consumption results in a significant decrease in the Ly49H+ CD11b+ CD27− splenic NK cell subset; this difference continued to be significant at 30 weeks.

This report may explain some of the conflicting data in the literature that examined NK cell activity in alcoholic patients. It is apparent that various abnormalities can be seen in NK cell activity and subset distribution with the flux being a function of the duration of alcohol ingestion. The demonstration of a decrease in the Ly49H+ subset (which is known to be involved in resisting murine cytomegalovirus infection) may explain the reported increase in susceptibility to some viral infections in chronic alcohol abuse. Another novel finding is that changes of some subsets of NK cells are not evident until at least 10 weeks of continued EtOH consumption.

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Request Reprint E-Mail: ballasz@uiowa.edu

Chronic Alcohol Exposure Alters Gene Expression in HepG2 Cells

The liver is the primary site of alcohol metabolism and is highly vulnerable to injuries due to chronic alcohol abuse. Several molecular mechanisms, including oxidative stress and altered cellular metabolism, have been implicated in the development and progression of alcoholic liver disease. We sought to gain further insight into the molecular pathogenesis by studying the effects of ethanol exposure on the global gene expression in HepG2 cells.

HepG2 cells were cultured in the presence or absence of 75 mM ethanol for 9 days, with fresh media daily. Global gene expression changes were studied using Affymetrix GeneChip^® Human Exon 1.0 ST Arrays. Gene expression differences were validated for 13 genes by quantitative real-time RT-PCR. To identify biological pathways affected by ethanol treatment, differentially expressed genes were analyzed by Ingenuity Pathway Analysis software.

Long-term ethanol exposure altered the expression of 1,093 genes (false discovery rate ≤ 3%); many of these changes were modest. Long-term ethanol exposure affected several pathways, including acute phase response, amino acid metabolism, carbohydrate metabolism, and lipid metabolism.

Global measurements of gene expression show that a large number of genes are affected by chronic ethanol, although most show modest effect. These data provide insight into the molecular pathology resulting from extended alcohol exposure.

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Request Reprint E-Mail: edenberg@iupui.edu

The Type of Dietary Fat Modulates Intestinal Tight Junction Integrity, Gut Permeability, and Hepatic Toll-Like Receptor Expression in a Mouse Model of

Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD.

C57BL/6N mice were fed Lieber–DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated.

After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups.

Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.

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Request Reprint E-Mail: craig.mcclain@louisville.edu

Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rat

Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats.

Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment.

DOV (6.25 to 50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose-dependently reduced immobility of P rats in the FST.

DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.

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Request Reprint E-Mail: harry.June@howard.edu

Phosphatidylethanol (PEth) as a Biomarker of Alcohol Consumption in HIV-Positive Patients in Sub-Saharan Africa

Alcohol is heavily consumed in sub-Saharan Africa and affects HIV transmission and treatment and is difficult to measure. Our goal was to examine the test characteristics of a direct metabolite of alcohol consumption, phosphatidylethanol (PEth).

Persons infected with HIV were recruited from a large HIV clinic in southwestern Uganda. We conducted surveys and breath alcohol concentration (BRAC) testing at 21 daily home or drinking establishment visits, and blood was collected on day 21 (n = 77). PEth in whole blood was compared with prior 7-, 14-, and 21-day alcohol consumption.

(i) The receiver operator characteristic area under the curve (ROC-AUC) was highest for PEth versus any consumption over the prior 21 days (0.92; 95% confidence interval [CI]: 0.86 to 0.97). The sensitivity for any detectable PEth was 88.0% (95% CI: 76.0 to 95.6) and the specificity was 88.5% (95% CI: 69.8 to 97.6). (ii) The ROC-AUC of PEth versus any 21-day alcohol consumption did not vary with age, body mass index, CD4 cell count, hepatitis B virus infection, and antiretroviral therapy status, but was higher for men compared with women (p = 0.03). (iii) PEth measurements were correlated with several measures of alcohol consumption, including number of drinking days in the prior 21 days (Spearman r = 0.74, p < 0.001) and BRAC (r = 0.75, p < 0.001).

The data add support to the body of evidence for PEth as a useful marker of alcohol consumption with high ROC-AUC, sensitivity, and specificity. Future studies should further address the period and level of alcohol consumption for which PEth is detectable.

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Request Reprint E-Mail: judy.hahn@ucsf.edu

Questionable tactics in marketing

A new report studying marketing practices for alcohol in seven developing countries will be presented at the GAPC conference in Bangkok early next year. The study has been conducted by Tom Farrell, senior lecturer at Oxford Brookes University in England and Dr. Ross Gordon, research fellow at the University of Wollongong in Australia. They have analyzed a sample of 15 alcohol promotions against the regulatory codes governing such marketing in the UK, often cited as a ‘gold standard system’ according to the researchers. > > > > Read More

News Release - Study Underlines Potential of Anti-Stress Peptide to Block Alcohol Dependence

New research by scientists at The Scripps Research Institute has underlined the power of an endogenous anti-stress peptide in the brain to prevent and even reverse some of the cellular effects of acute alcohol and alcohol dependence in animal models. The work could lead to the development of novel drugs to treat alcoholism.

The new study, led by Scripps Research Associate Professor Marisa Roberto and published online ahead of print by the journal Biological Psychiatry, illuminates the cellular mechanisms that govern the transition from alcohol use to alcohol dependence. Specifically, the study examined the interaction between two competing agents—one a stress peptide that promotes excessive alcohol drinking, the other an anti-stress peptide that opposes it. The results confirm that drugs derived from the anti-stress peptide nociceptin could play an important role in treating a complex and multi-faceted disease.

"Alcohol affects a lot of systems in the brain, and there won't be a single pill that will cure the multiple and complex aspects of this disease," Roberto said. Instead, scientists are seeking to attack the disease from a variety of angles, and are investigating the many different areas of the brain that appear to play a role in the use and abuse of alcohol. > > > > Read More

Nociceptin/Orphanin FQ Blockade of Corticotropin-Releasing Factor-Induced Gamma-Aminobutyric Acid Release in Central Amygdala Is Enhanced After Chroni

The central nucleus of the amygdala (CeA) mediates stress- and addiction-related processes. Corticotropin-releasing factor (CRF) and nociceptin/orphanin FQ (nociceptin) regulate ethanol intake and anxiety-like behavior. In the rat, CRF and ethanol significantly augment CeA gamma-aminobutyric acid (GABA) release, whereas nociceptin diminishes it.

Using electrophysiologic techniques in an in vitro slice preparation, we investigated the interaction of nociceptin and CRF on evoked and spontaneous GABAergic transmission in CeA slices of naive and ethanol-dependent rats and the mechanistic role of protein kinase A.

In neurons from naive animals, nociceptin dose-dependently diminished basal-evoked GABA_A receptor-mediated inhibitory postsynaptic potentials (IPSPs) by decreasing GABA release and prevented, as well as reversed, CRF-induced augmentation of IPSPs, actions that required PKA signaling. In neurons from ethanol-dependent animals, nociceptin decreased basal GABAergic transmission and blocked the CRF-induced increase in GABA release to a greater extent than in naive controls.

These data provide new evidence for an interaction between the nociceptin and CRF systems in the CeA. Nociceptin opposes CRF effects on CeA GABAergic transmission with sensitization of this effect in dependent animals. These properties of nociceptin may underlie its anti-alcohol and anxiolytic properties and identify the nociceptin receptor as a useful therapeutic target for alcoholism.

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Request Reprint E-Mail: mroberto@scripps.edu

SIPS brief interventions findings conference: 5th March 2012, King's College London

Results from the UK's largest brief intervention study, the SIPS trial, will be officialy released at a conference on Monday 5th March 2012, Institute of Psychiatry, King's College London.

Download the flyer for Alcohol Screening and Brief Interventions: From Research into Practice [pdf]. The event is a one day conference including the launch of SIPS Junior, a new trial into brief interventions for adolescents. > > > > Read More

News Release - Early Intervention Program Reduces Youth Substance Abuse in WV

A pilot program in Logan and Mercer counties is cutting down on youth substance abuse in the Mountain State. WV’s Substance Abuse Early Intervention Program (EIP) targets youth ages 12-18 who have just begun to use alcohol, tobacco, or other substances and/or are engaging in delinquent behavior often associated with substance use. Since its inception in 2010, 65 youth have completed the program, which enhances accurate understanding of the risks of alcohol, tobacco, & other drug (ATOD) use and develops ATOD refusal skills. The program also provides an alternative option for youth who may be on their way into the juvenile justice system. > > > > Read More

Differential Effects of Single Versus Repeated Alcohol Withdrawal on the Expression of Endocannabinoid System-Related Genes in the Rat Amygdala

Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) exert important regulatory influences on neuronal signaling, participate in short- and long-term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity, and affective control.

The consequence of long-term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT-PCR analyses of amygdala tissue. Two groups of ethanol (EtOH)-exposed rats were generated by maintenance on an EtOH liquid diet (10%): the first group received continuous access to EtOH for 15 days, whereas the second group was given intermittent access to the EtOH diet (5 d/wk for 3 weeks). Control subjects were maintained on an isocaloric EtOH-free liquid diet. To provide an initial profile of acute withdrawal, amygdala tissue was harvested following either 6 or 24 hours of EtOH withdrawal.

Acute EtOH withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) were evident, as were reductions in mRNA expression for CB₁, CB₂, and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent EtOH exposure, alterations in MAGL and cannabinoid receptor-related mRNA (e.g., CB₁, CB₂, GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal-associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in 2-AG biosynthesis (e.g., diacylglicerol lipase-α/β) were found in any condition.

These findings suggest that EtOH dependence and withdrawal are associated with dysregulated endocannabinoid signaling in the amygdala. These alterations may contribute to withdrawal-related dysregulation of amygdalar neurotransmission.

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Request Reprint E-Mail: lparsons@scripps.edu

A Longitudinal Analysis of Circulating Stress-Related Proteins and Chronic Ethanol Self-Administration in Cynomolgus Macaques

Alcoholics have alterations in endocrine and immune functions and increased susceptibility to stress-related disorders. A longitudinal analysis of chronic ethanol intake on homeostatic mechanisms is, however, incompletely characterized in primates.

Plasma proteins (n = 60; Luminex) and hormones (adrenocorticotropic hormone [ACTH]; cortisol) were repeatedly measured in adult male cynomolgus monkeys (Macaca fascicularis, n = 10) during a 32-month experimental protocol at baseline, during induction of water and ethanol (4% w/v in water) self-administration, after 4 months, and after 12 months of 22-hour daily concurrent access to ethanol and water.

Significant changes were observed in ACTH, cortisol, and 45/60 plasma proteins: a majority (28/45) were suppressed as a function of ethanol self-administration, 8 proteins were elevated, and 9 showed biphasic changes. Cortisol and ACTH were greatest during induction, and correlations between these hormones and plasma proteins varied across the experiment. Pathway analyses implicated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) as possible mediators of ethanol-induced effects on immune-related proteins in primates.

Chronic ethanol consumption in primates leads to an allostatic state of physiological compromise with respect to circulating immune- and stress-related proteins in NF-κB- and STAT/JAK-related pathways in correlation with altered endocrine activity.

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Request Reprint E-Mail: helmsc@ohsu.edu

Early Growth Response-1 Contributes to Steatosis Development After Acute Ethanol Administration

Previous work demonstrated that the transcription factor, early growth response-1 (Egr-1), participates in the development of steatosis (fatty liver) after chronic ethanol (EtOH) administration. Here, we determined the extent to which Egr-1 is involved in fatty liver development in mice subjected to acute EtOH administration.

In acute studies, we treated both wild-type and Egr-1 null mice with either EtOH or phosphate-buffered saline (PBS) by gastric intubation. At various times after treatment, we harvested sera and livers and quantified endotoxin, indices of liver injury, steatosis, and hepatic Egr-1 content. In chronic studies, groups of mice were fed liquid diets containing either EtOH or isocaloric maltose-dextrin for 7 to 8 weeks.

Compared with controls, acute EtOH-treated mice showed a rapid, transient elevation in serum endotoxin beginning 30 minutes after treatment. One hour postgavage, livers from EtOH-treated mice exhibited a robust elevation of both Egr-1 mRNA and protein. By 3 hours postgavage, liver triglyceride increased in EtOH-treated mice as did lipid peroxidation. Acute EtOH treatment of Egr-1-null mice showed no Egr-1 expression, but these animals still developed elevated triglycerides, although significantly lower than EtOH-fed wild-type littermates. Despite showing decreased fatty liver, EtOH-treated Egr-1 null mice exhibited greater liver injury. After chronic EtOH feeding, steatosis and liver enlargement were clearly evident, but there was no indication of elevated endotoxin. Egr-1 levels in EtOH-fed mice were equal to those of pair-fed controls.

Acute EtOH administration induced the synthesis of Egr-1 in mouse liver. However, despite its robust increase, the transcription factor had a smaller, albeit significant, function in steatosis development after acute EtOH treatment. We propose that the rise in Egr-1 after acute EtOH is an hepatoprotective adaptation to acute liver injury from binge drinking that is triggered by EtOH metabolism and elevated levels of endotoxin.

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Request Reprint E-Mail: tdonohue@unmc.edu

Nociceptin/Orphanin FQ Blockade of Corticotropin-Releasing Factor-Induced Gamma-Aminobutyric Acid Release in Central Amygdala Is Enhanced After Chroni

The central nucleus of the amygdala (CeA) mediates stress- and addiction-related processes. Corticotropin-releasing factor (CRF) and nociceptin/orphanin FQ (nociceptin) regulate ethanol intake and anxiety-like behavior. In the rat, CRF and ethanol significantly augment CeA gamma-aminobutyric acid (GABA) release, whereas nociceptin diminishes it.

Using electrophysiologic techniques in an in vitro slice preparation, we investigated the interaction of nociceptin and CRF on evoked and spontaneous GABAergic transmission in CeA slices of naive and ethanol-dependent rats and the mechanistic role of protein kinase A.

In neurons from naive animals, nociceptin dose-dependently diminished basal-evoked GABA_A receptor-mediated inhibitory postsynaptic potentials (IPSPs) by decreasing GABA release and prevented, as well as reversed, CRF-induced augmentation of IPSPs, actions that required PKA signaling. In neurons from ethanol-dependent animals, nociceptin decreased basal GABAergic transmission and blocked the CRF-induced increase in GABA release to a greater extent than in naive controls.

These data provide new evidence for an interaction between the nociceptin and CRF systems in the CeA. Nociceptin opposes CRF effects on CeA GABAergic transmission with sensitization of this effect in dependent animals. These properties of nociceptin may underlie its anti-alcohol and anxiolytic properties and identify the nociceptin receptor as a useful therapeutic target for alcoholism.

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Request Reprint E-Mail: mroberto@scripps.edu

Synchrony of Corticostriatal-Midbrain Activation Enables Normal Inhibitory Control and Conflict Processing in Recovering Alcoholic Men

Alcohol dependence is associated with inhibitory control deficits, possibly related to abnormalities in frontoparietal cortical and midbrain function and connectivity.

We examined functional connectivity and microstructural fiber integrity between frontoparietal and midbrain structures using a Stroop Match-to-Sample task with functional magnetic resonance imaging and diffusion tensor imaging in 18 alcoholic and 17 control subjects. Manipulation of color cues and response repetition sequences modulated cognitive demands during Stroop conflict.

Despite similar lateral frontoparietal activity and functional connectivity in alcoholic and control subjects when processing conflict, control subjects deactivated the posterior cingulate cortex (PCC), whereas alcoholic subjects did not. Posterior cingulum fiber integrity predicted the degree of PCC deactivation in control but not alcoholic subjects. Also, PCC activity was modulated by executive control demands: activated during response switching and deactivated during response repetition. Alcoholics showed the opposite pattern: activation during repetition and deactivation during switching. Here, in alcoholic subjects, greater deviations from the normal PCC activity correlated with higher amounts of lifetime alcohol consumption. A functional dissociation of brain network connectivity between the groups further showed that control subjects exhibited greater corticocortical connectivity among middle cingulate, posterior cingulate, and medial prefrontal cortices than alcoholic subjects. In contrast, alcoholic subjects exhibited greater midbrain-orbitofrontal cortical network connectivity than control subjects. Degree of microstructural fiber integrity predicted robustness of functional connectivity.

Thus, even subtle compromise of microstructural connectivity in alcoholism can influence modulation of functional connectivity and underlie alcohol-related cognitive impairment.

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Request Reprint E-Mail: tilman.schulte@sri.com

Early age alcohol use and later alcohol problems in adolescents: Individual and peer mediators in a bi-national study.

This paper examines whether there is cross-national similarity in the longitudinal relationship between early age alcohol use and adolescent alcohol problems. Potential mechanisms underlying this relationship also are examined, testing adolescent alcohol use, low self-regulation, and peer deviance as possible mediators.

Students (N = 1,945) participating in the International Youth Development Study, a longitudinal panel survey study, responded to questions on alcohol use and influencing factors, and were followed annually over a 3-year period from 2002 to 2004 (98% retention rate). State-representative, community student samples were recruited in grade 7 in Washington State, United States (US, n = 961, 78% of those eligible; Mage = 13.09, SD = .44) and Victoria, Australia (n = 984, 76% of those eligible; Mage = 12.93, SD = .41). Analyses were conducted using multiple-group structural equation modeling.

In both states, early age alcohol use (age 13) had a small but statistically significant association with subsequent alcohol problems (age 15).

Overall, there was little evidence for mediation of early alcohol effects. Low self-regulation prospectively predicted peer deviance, alcohol use, and alcohol problems in both states.

Peer deviance was more positively related to alcohol use and low self-regulation among students in Victoria compared to students in Washington State.

The small but persistent association of early age alcohol use with alcohol problems across both samples is consistent with efforts to delay alcohol initiation to help prevent problematic alcohol use.

Self-regulation was an important influence, supporting the need to further investigate the developmental contribution of neurobehavioral disinhibition.



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Request Reprint E-Mail: wamason@u.washington.edu

Preventing Alcohol Abuse and Alcoholism—An Update

133 In This Issue

135 The Risks Associated With Alcohol Use and Alcoholism
Jürgen Rehm, Ph.D.

144 Defining Risk Drinking
Deborah A. Dawson, Ph.D.

157 School-Based Programs to Prevent and Reduce Alcohol Use Among Youth
Melissa H. Stigler, Ph.D., M.P.H.; Emily Neusel, M.P.H.; and Cheryl L. Perry, Ph.D.

163 A Review of Environmental-Based Community Interventions
Traci L. Toomey, Ph.D., and Kathleen M. Lenk, M.P.H.

167 Engaging Communities to Prevent Underage Drinking
Abigail A. Fagan, Ph.D.; J. David Hawkins, Ph.D.; and Richard F. Catalano, Ph.D.

175 Prevention Interventions of Alcohol Problems in the Workplace: A Review and Guiding Framework
Genevieve M. Ames, Ph.D., and Joel B. Bennett, Ph.D.

180 Prevention in the Military: Early Results of an Environmental Strategy
Genevieve M. Ames, Ph.D., and Christopher Spera, Ph.D.

188 Translating Family-Focused Prevention Science Into Public Health Impact: Illustrations From Partnership-Based Research
Richard L. Spoth, Ph.D.; Lisa M. Schainker, Ph.D., M.P.H.; and Susanne Hiller-Sturmhöefel, Ph.D.

204 Environmental Approaches to Prevention in College Settings
Robert F. Saltz, Ph.D.

210 Individual-Focused Approaches to the Prevention of College Student Drinkin]
Jessica M. Cronce, Ph.D., and Mary E. Larimer, Ph.D.

222 College Prevention: A View of Present (and Future) Web-Based Approaches
Scott T. Walters, Ph.D., and Clayton Neighbors, Ph.D.

225 Preventing Impaired Driving: Opportunities and Problems
Robert B. Voas, Ph.D., and James C. Fell, M.S.

236 The Effects of Prices on Alcohol Use and Its Consequences
Xin Xu, Ph.D., and Frank J. Chaloupka, Ph.D.

246 The Alcohol Policy Information System (APIS) and Policy Research At NIAAA
Gregory Bloss, M.A.

248 Regulating Availability: How Access to Alcohol Affects Drinking and Problems in Youth and Adults
Paul J. Gruenewald, Ph.D.

257 The Road to a World Health Organization Global Strategy for Reducing the Harmful Use of Alcohol
Maristela G. Monteiro, M.D., Ph.D.

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The Fraction of Cancer Attributable to Lifestyle and Environmental Factors in the UK in 2010

This supplement provides up-to-date estimates of the numbers (and percentages) of new cancer cases in the UK that are attributable to factors that have been established by international consensus as potentially avoidable causes of the disease. It therefore offers a useful guide to the relative importance of different preventive interventions.

Excluded from consideration are factors that, although known to be effective in reducing the risk of numerically important cancers, do not offer acceptable or practical preventive strategies at present. Early and multiple childbearing (to prevent breast cancer) and the widespread use of anti-androgen drugs (to prevent prostate cancer) come under this category. What remains is a limited number of important factors that can, at least to some extent, be affected by personal or political choices. The most important among these is continuation of the significant reduction in tobacco exposure. Next in importance are reductions in obesity and in heavy alcohol consumption, and certain other dietary changes. Each of these four main strategies for cancer control would also substantially reduce the burden of other non-communicable diseases, particularly cardiovascular, diabetic, renal and hepatic disease.

Whether, and to what extent, changes in these major causes of cancer can be achieved is another consideration. Thus, for example, although substantial progress has been made in reducing the number of young people who start smoking, and in helping those who smoke to escape their addiction in time to avoid most of the risk of premature death, tobacco still remains the most important avoidable cause of cancer, responsible for almost 20% of all cases of cancer (and, although this supplement does not quantify cancer mortality, for about 25% of all deaths from cancer, plus similar numbers of deaths from other diseases).

Taken together, the causative factors reviewed in this supplement account for an estimated 43% of all new cases of cancer in the UK (approximately 134 000 new cases in 2010), and about 50% of all cancer deaths. Most of these cases of cancer (excluding a few thousand due to the natural background of ionising radiation, or due to certain infections that are currently neither preventable nor treatable) could have been prevented by methods that would also prevent many premature deaths from other non-communicable disease. Over the past 40 years in the UK, the probability of death before the age of 70 years has been halved, and over the next few decades it could be halved again by continued improvements in the treatment of disease and by paying appropriate attention to the few major avoidable causes of disease. This supplement will help focus the attention of researchers, individuals and policy makers on the relative importance of the currently known causes of cancer.


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Adolescents Living with a Parent Who Drives Under the Influence Are at Increased Risk for Driving Under the Influence Themselves

According to the National Survey on Drug Use and Health, an annual average1 of 932,000 16 to 17 year olds (11.5 percent) drove under the influence of alcohol or illicit drugs in the 12 months prior to the interview. Youths in this age group were more likely to drive under the influence if they lived with a mother or father who also had driven under the influence in the past year. These data suggest the importance of parents as role models in promoting children’s healthy behavior.


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'Alcohol pricing and taxation policies': IFS still favours taxation over minimum pricing

The economics think-tank the Institute for Fiscal Studies (IFS) have published a new report on Alcohol pricing and taxation policies. It echoes many of the findings from a report last year in which it suggested minimum pricing would transfer further profits to industry and retailers, therefore favouring increased taxation.

The new report however suggests the current alcohol taxation system is not optimal and a "sensible starting point would be to tax all alcohols at an equivalent rate per unit. Such a change would require policy action at the EU level which the Government should pursue." > > > > Read More

African women are non-drinkers

In the latest round of the WHO World Health Surveys 40.739 women from 20 African countries were interviewed also about their alcohol drinking habits. Close to 34.000 reported lifetime abstinence from alcohol. This is 81 % of the respondents in the survey. The proportion of current alcohol drinkers ranged from 1% in Malawi to 20% in Burkina Faso. > > > > Read More

A Sobering Look at Alcohol: 10-Year Study Finds High Death Rate

A number of studies in the past few years have suggested health benefits from drinking small or moderate amounts of alcohol. This can encourage people to look at alcohol almost as if it's medicine. A recent study of alcohol use in Italy paints a much more sobering picture. > > > > Read More

Alcoholism expert Dora Goldstein dies at 89

Pharmacologist Dora B. “Dody” Goldstein, MD, one of the world’s leading experts on alcoholism and a pioneer of women in medicine, died Oct. 2 at Stanford Hospital after suffering a fall in her Palo Alto home. She was 89.

A professor emerita of molecular pharmacology at the Stanford University School of Medicine, Goldstein was widely recognized for her research on the effects of alcohol on the body. Her work established some of the basic biological principles underlying alcoholism, including the mechanisms of alcohol dependence and tolerance. One of the first women to graduate from Harvard Medical School, she also became a champion for women in medicine and served in leadership positions in the civil rights and gay rights movements. > > > > Read More

Ethanol Exposure During Pregnancy Persistently Attenuates Cranially Directed Blood Flow in the Developing Fetus: Evidence from Ultrasound Imaging in a

Ethanol (EtOH) consumption during pregnancy can lead to fetal growth retardation, mental retardation, and neurodevelopmental delay. The fetal brain initiates neurogenesis and vasculogenesis during the second trimester, and depends on maternal-fetal circulation for nutrition and growth signals. We used high-resolution in vivo ultrasound imaging to test the hypothesis that EtOH interferes with fetal brain-directed blood flow during this critical developmental period.

Pregnant mice were lightly anesthetized on gestational day 12 with an isoflurane/oxygen mixture. We assessed the effect of single and repeated binge-like maternal EtOH exposures at 3 g/kg, administered by intragastric gavage or intraperitoneal injection, on maternal circulation and fetal umbilical, aortic, internal carotid, and middle cerebral arterial circulation.

Binge maternal EtOH exposure, regardless of exposure route, significantly reduced fetal arterial blood acceleration and velocity time integral (VTI), from umbilical to cerebral arteries, without a change in fetal heart rate and resistivity indices. Importantly a single maternal binge EtOH exposure induced persistent suppression of fetal arterial VTI for at least 24 hours. Repeated binge episodes resulted in a continuing and persistent suppression of fetal VTI. Qualitative assessments showed that maternal EtOH exposure induced oscillatory, nondirectional blood flow in fetal cerebral arteries. Maternal cardiac and other physiological parameters remained unaltered.

These data show that binge-type maternal EtOH exposure results in rapid and persistent loss of blood flow from the umbilical artery to the fetal brain, potentially compromising nutrition and the maternal/fetal endocrine environment during a critical period for neuron formation and angiogenesis in the maturing brain.

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Request Reprint E-Mail: miranda@medicine.tamhsc.edu

Early Growth Response-1 Contributes to Steatosis Development After Acute Ethanol Administration

Previous work demonstrated that the transcription factor, early growth response-1 (Egr-1), participates in the development of steatosis (fatty liver) after chronic ethanol (EtOH) administration. Here, we determined the extent to which Egr-1 is involved in fatty liver development in mice subjected to acute EtOH administration.

In acute studies, we treated both wild-type and Egr-1 null mice with either EtOH or phosphate-buffered saline (PBS) by gastric intubation. At various times after treatment, we harvested sera and livers and quantified endotoxin, indices of liver injury, steatosis, and hepatic Egr-1 content. In chronic studies, groups of mice were fed liquid diets containing either EtOH or isocaloric maltose-dextrin for 7 to 8 weeks.

Compared with controls, acute EtOH-treated mice showed a rapid, transient elevation in serum endotoxin beginning 30 minutes after treatment. One hour postgavage, livers from EtOH-treated mice exhibited a robust elevation of both Egr-1 mRNA and protein. By 3 hours postgavage, liver triglyceride increased in EtOH-treated mice as did lipid peroxidation. Acute EtOH treatment of Egr-1-null mice showed no Egr-1 expression, but these animals still developed elevated triglycerides, although significantly lower than EtOH-fed wild-type littermates. Despite showing decreased fatty liver, EtOH-treated Egr-1 null mice exhibited greater liver injury. After chronic EtOH feeding, steatosis and liver enlargement were clearly evident, but there was no indication of elevated endotoxin. Egr-1 levels in EtOH-fed mice were equal to those of pair-fed controls.

Acute EtOH administration induced the synthesis of Egr-1 in mouse liver. However, despite its robust increase, the transcription factor had a smaller, albeit significant, function in steatosis development after acute EtOH treatment. We propose that the rise in Egr-1 after acute EtOH is an hepatoprotective adaptation to acute liver injury from binge drinking that is triggered by EtOH metabolism and elevated levels of endotoxin.

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Request Reprint E-Mail: tdonohue@unmc.edu

A Longitudinal Analysis of Circulating Stress-Related Proteins and Chronic Ethanol Self-Administration in Cynomolgus Macaques

Alcoholics have alterations in endocrine and immune functions and increased susceptibility to stress-related disorders. A longitudinal analysis of chronic ethanol intake on homeostatic mechanisms is, however, incompletely characterized in primates.

Plasma proteins (n = 60; Luminex) and hormones (adrenocorticotropic hormone [ACTH]; cortisol) were repeatedly measured in adult male cynomolgus monkeys (Macaca fascicularis, n = 10) during a 32-month experimental protocol at baseline, during induction of water and ethanol (4% w/v in water) self-administration, after 4 months, and after 12 months of 22-hour daily concurrent access to ethanol and water.

Significant changes were observed in ACTH, cortisol, and 45/60 plasma proteins: a majority (28/45) were suppressed as a function of ethanol self-administration, 8 proteins were elevated, and 9 showed biphasic changes. Cortisol and ACTH were greatest during induction, and correlations between these hormones and plasma proteins varied across the experiment. Pathway analyses implicated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) as possible mediators of ethanol-induced effects on immune-related proteins in primates.

Chronic ethanol consumption in primates leads to an allostatic state of physiological compromise with respect to circulating immune- and stress-related proteins in NF-κB- and STAT/JAK-related pathways in correlation with altered endocrine activity.

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Request Reprint E-Mail: helmsc@ohsu.edu

Chronic Intermittent Ethanol Exposure and Its Removal Induce a Different miRNA Expression Pattern in Primary Cortical Neuronal Cultures

Increasing evidence indicates that repeated exposure to and withdrawal from alcohol can result in persistent molecular and cellular adaptations. One molecular adaptation that occurs is the regulation of gene expression, which is thought to lead to the functional alterations that characterize addiction: tolerance, dependence, withdrawal, craving, and relapse. MicroRNAs (miRNAs) have been recently identified as master regulators of gene expression through post-transcriptional regulation. However, the role of miRNAs in the neuroadaptations after alcohol removal has not yet been directly addressed.

We employed a chronic intermittent ethanol (CIE) model in primary cortical neuronal cultures to examine the global extent of differential miRNA expression using a TaqMan real-time PCR miRNA array.

Sixty-two miRNAs were differentially expressed after 10 days of CIE (CIE10) treatment (n = 42 with false discovery rate [FDR] < 0.05 and fold change > 2) and 5 days post-CIE (P5) treatment (n = 26) compared with untreated control values. Compared to CIE10, ethanol (EtOH) removal experience in P5 induced a distinct expression pattern, including 20 differentially expressed miRNAs, which did not exhibit a significant change at CIE10. The predicted target molecules of EtOH removal-induced miRNAs function mainly in the regulation of gene transcription, but also function in neuron differentiation, embryonic development, protein phosphorylation, and synaptic plasticity. Interestingly, some of the miRNAs differentially expressed 5 days after CIE treatment were found to cluster on chromosomes near CpG islands, suggesting that they share functional similarity by targeting alcohol-related genes.

Taken together, these results suggest a potential role of differentially expressed miRNAs in mediating EtOH removal-related phenotypes.

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qiang@uthscsa.edu