Involvement of AMPK in Alcohol Dehydrogenase Accentuated Myocardial Dysfunction Following Acute Ethanol Challenge in Mice Binge alcohol drinking often

Binge alcohol drinking often triggers myocardial contractile dysfunction although the underlying mechanism is not fully clear. This study was designed to examine the impact of cardiac-specific overexpression of alcohol dehydrogenase (ADH) on ethanol-induced change in cardiac contractile function, intracellular Ca²⁺ homeostasis, insulin and AMP-dependent kinase (AMPK) signaling.

ADH transgenic and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Oral glucose tolerance test, cardiac AMP/ATP levels, cardiac contractile function, intracellular Ca²⁺ handling and AMPK signaling (including ACC and LKB1) were examined.

Ethanol exposure led to glucose intolerance, elevated plasma insulin, compromised cardiac contractile and intracellular Ca²⁺ properties, downregulated protein phosphatase PP2A subunit and PPAR-γ, as well as phosphorylation of AMPK, ACC and LKB1, all of which except plasma insulin were overtly accentuated by ADH transgene. Interestingly, myocardium from ethanol-treated FVB mice displayed enhanced expression of PP2Cα and PGC-1α, decreased insulin receptor expression as well as unchanged expression of Glut4, the response of which was unaffected by ADH. Cardiac AMP-to-ATP ratio was significantly enhanced by ethanol exposure with a more pronounced increase in ADH mice. In addition, the AMPK inhibitor compound C (10 µM) abrogated acute ethanol exposure-elicited cardiomyocyte mechanical dysfunction.

In summary, these data suggest that the ADH transgene exacerbated acute ethanol toxicity-induced myocardial contractile dysfunction, intracellular Ca²⁺ mishandling and glucose intolerance, indicating a role of ADH in acute ethanol toxicity-induced cardiac dysfunction possibly related to altered cellular fuel AMPK signaling cascade.

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Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated.

This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo.

The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period.

Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate >In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes.

Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels.

These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

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Request Reprint E-Mail: falk.kiefer@zi-mannheim.de

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Genome-wide association study of conduct disorder symptomatology

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD.

In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence.

Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N=872 with CD and N=3091 without CD).

We find four markers that meet the criteria for genome-wide significance with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association.

These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

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Request Reprint E-Mail: ddick@vcu.edu

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Brief interventions should be integrated within diabetes care

A study has recommended that brief interventions for alcohol (or 'IBA') should be incorporated into routine diabetes care. The abstract of the report 'Alcohol use of diabetes patients: the need for assessment and intervention' identifies: > > > Read More


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Maternal alcohol consumption during pregnancy and semen quality in the male offspring: two decades of follow-up

Concurrent alcohol exposure has been associated with reduced fecundity, but no studies have estimated the effect of prenatal alcohol exposure on male fecundity.

The aim of this study was to investigate the association between maternal alcohol consumption during pregnancy, semen quality and levels of reproductive hormones in young, adult men.

From a Danish pregnancy cohort established in 1984–1987, 347 sons were selected for a follow-up study conducted in 2005–2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones, respectively, and results were related to prospectively self-reported information on maternal alcohol consumption during pregnancy.

The sperm concentration decreased with increasing prenatal alcohol exposure. The adjusted mean sperm concentration among sons of mothers drinking 4.5 drinks per week during pregnancy was 40 (95% CI: 25–60) millions/ml. This concentration was 32% lower compared with men exposed to > had a sperm concentration of 59 (95% CI: 44–77) millions/ml. The semen volume and the total sperm count were also associated with prenatal alcohol exposure; sons prenatally exposed to 1.0–1.5 drinks per week had the highest values. No associations were found for sperm motility, sperm morphology or any of the reproductive hormones, including testosterone.

These results indicate that prenatal exposure to alcohol may have a persisting adverse effect on Sertoli cells, and thereby sperm concentration. If these associations are causal they could explain some of the reported differences between populations and long-term changes in semen quality.

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Request Reprint E-Mail: ceciraml@rm.dk

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Press Release - Drinking alcohol during pregnancy may damage semen quality in sons

Mothers who drink alcohol while they are pregnant may be damaging the fertility of their future sons, according to new research to be presented at the 26th annual meeting of the European Society of Human Reproduction and Embryology in Rome today (Tuesday 29 June).

Doctors in Denmark found that if mothers had drunk 4.5 or more drinks a week while pregnant, then the sperm concentration of their sons, measured about 20 years later, was a third lower in comparison to men who were not exposed to alcohol while in the womb. A drink was measured as 12 grams of alcohol, which is the equivalent to one 330 ml beer, one small (120 ml) glass of wine or one glass of spirits (40 ml). > > > Read More

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Pregnant Teen Admissions to Substance Abuse Treatment: 1992 and 2007

A nationwide report issued by the Substance Abuse and Mental Health Services Administration (SAMHSA) reveals that from 1992 to 2007 there were significant changes in the patterns of substance abuse treatment admissions among pregnant teens both in terms of the kinds of substances involved and among different ethnic and racial groups.

According to the report, the proportion of pregnant teen admissions for marijuana abuse more than doubled from 19.3 percent in 1992 to 45.9 percent in 2007. Marijuana has surpassed alcohol as the primary substance of abuse cited in admissions for pregnant teens—alcohol represented 44.1 percent of all pregnant teen admissions in 1992 -- but dropped to 20.3 percent by 2007. In addition, the proportion of pregnant teen admissions for methamphetamine use has more than quadrupled, from 4.3 percent in 1992 to18.8 percent in 2007.

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News Release - National Study: New Data Show Teen Girls More Likely to See Benefits in Drug and Alcohol Use

Survey data released today by the Partnership for a Drug-Free America® and MetLife Foundation found that teenage girls are more likely than teenage boys to perceive potential benefits from drug use and drinking, making teen girls more vulnerable to drug and alcohol abuse.

According to a new research analysis of the 2009 Partnership Attitude Tracking Study (PATS), sponsored by MetLife Foundation, teen girls are more likely to associate "self-medicating" benefits with drinking and getting high. More than two-thirds of teen girls responded positively to the question "using drugs helps kids deal with problems at home" (an 11 percent increase, up from 61 percent in 2008 to 68 percent in 2009) and more than half reported that drugs help teens forget their troubles (a 10 percent increase, up from 48 percent in 2008 to 53 percent in 2009). Stress has been identified as a key factor leading to drinking, smoking and drug use among girls and more than three times as many young girls as boys reported having symptoms of depression in 2008 (1). > > > > Read More

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Secret of AA: After 75 Years, We Don’t Know How It Works

The church will be closed tomorrow, and the drunks are freaking out. An elderly lady in a prim white blouse has just delivered the bad news, with deep apologies: A major blizzard is scheduled to wallop Manhattan tonight, and up to a foot of snow will cover the ground by dawn. The church, located on the Upper West Side, can’t ask its staff to risk a dangerous commute. Unfortunately, that means it must cancel the Alcoholics Anonymous meeting held daily in the basement.
> > > > > Read More


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Quercetin and Ethanol Attenuate the Progression of Atherosclerotic Plaques With Concomitant Up Regulation of Paraoxonase1 (PON1) Gene Expression and P

As moderate wine drinking is atheroprotective, it is clinically relevant to elucidate its possible mechanism/s of action/s.

Our objective is to demonstrate the potential benefits of the wine components, quercetin and ethanol, on the development of aortic plaques with parallel changes in antiatherogenic factors.

The effects of quercetin and ethanol on the development of aortic atherosclerotic lesions, liver PON1 gene expression, and serum PON1 activity were measured in LDLR^−/− mice on an atherogenic diet for 4 and 8 weeks.

Depending on the duration and dosage of these modulators, 12.5 to 25 mg/dl quercetin (12.5Q to 25Q) and 18 to 25% ethanol, the magnitude of decreases in aortic lesions caused by moderate ethanol and quercetin ranged from 20 to 70% , Pearson r = 0.79 for 4-week treatment; p = 0.000004, Pearson r = 0.84 for 8-week treatment).

Concomitantly, 4-week treatments with 12.5Q and 18% ethanol up regulated liver PON1 mRNA by 41%.

Based on these findings, we conclude that quercetin and moderate ethanol significantly inhibit the progression of atherosclerosis by up regulating the hepatic expression of the antiatherogenic gene, PON1, with concomitant increased serum PON1 activity.

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Request Reprint E-Mail: raj.lakshman@va.gov

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Differential Changes in MAP Kinases, Histone Modifications, and Liver Injury in Rats Acutely Treated With Ethanol

Acute ethanol is known to affect cells and organs but the underlying molecular mechanisms are poorly explored. Recent developments highlight the potential importance of mitogen-activated protein kinases, MAPKs (i.e., ERK1/2, p38, and JNK1/2) signaling, and histone modifications (i.e., acetylation, methylation, and phosphorylation) in the actions of ethanol in hepatocytes.

We have therefore investigated significance of these molecular steps in vivo using a model in which rats were acutely administered ethanol intraperitoneally (IP).

Ethanol was administered IP (3.5 gm/kg body weight) to 12-week-old male Sprague–Dawley rats. Liver was subsequently removed at 1 and 4 hours. Serum was used for alcohol and ALT assays. At the time of the removal of liver, small portions of each liver were formalin-fixed and stained with hematoxylin and eosin (H&E) and used for light microscopy. Western blot analysis was carried out with specific primary antibodies for various parameters.

There were clear differences at 1 and 4 hours in blood ethanol, ALT, steatosis, and cleaved caspase 3. Apoptosis at 1 hour was followed by necrosis at 4 hours. Acute alcohol elicited a marked increase in the phosphorylation of ERK1/2 and moderate increases in the phosphorylation of p38 MAPK and JNK. Temporally different phosphorylation of histone H3 at ser-10 and ser-28 occurred and acetylation of histone H3 at lys 9 increased progressively.

There were distinct differences in the behavior of the activation of the 3 MAP kinases and histone modifications after acute short exposure of liver to ethanol in vivo. Although all 3 MAPKs were rapidly activated at 1 hour, the necrosis, occurring at 4 hours, correlated to sustained activation of ERK1/2. Transient activation of p38 is associated with rapid phosphorylation of histone H3, whereas prolonged activation of ERK1/2 is correlated to persistent histone H3 acetylation.

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Request Reprint E-Mail: shuklasd@missouri.edu

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Withdrawal Severity After Chronic Intermittent Ethanol in Inbred Mouse Strains

To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption.

The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling-induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens.

Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced.

Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00–2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol-exposed and air-exposed groups were tested hourly for handling-induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups.

The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high-dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.

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Request Reprint E-Mail: mettenp@ohsu.edu

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Motivation for Alcohol Becomes Resistant to Quinine Adulteration After 3 to 4 Months of Intermittent Alcohol Self-Administration

Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (>8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration.

Outbred Wistar rats underwent 3 to 4 months or approximately 1.5 months of intermittent, home-cage, two-bottle access (IAA) to 20% alcohol (v/v) or water. Then, after brief operant training, the effect of the bitter-tasting quinine (0.1 g/l) on the motivation to seek alcohol was quantified via progressive ratio (PR). Motivation for quinine-adulterated 2% sucrose under PR was assayed in a separate cohort of 3 to 4 months IAA rats. The effects of quinine on home-cage alcohol consumption in IAA rats and rats with continuous access to alcohol were also examined. Finally, a dose–response for quinine taste preference in IAA and continuous-access animals was determined.

Motivation for alcohol after 3 to 4 months IAA, measured using an operant PR procedure, was not altered by adulteration of alcohol with 0.1 g/l quinine. In contrast, after 3 to 4 months of IAA, motivation for sucrose under PR was significantly reduced by adulteration of sucrose with 0.1 g/l quinine. In addition, motivation for alcohol after only approximately 1.5 months IAA was significantly reduced by adulteration of alcohol with 0.1 g/l quinine. Furthermore, home-cage alcohol intake by IAA rats was insensitive to quinine at concentrations (0.01, 0.03 g/l) that significantly reduced alcohol drinking in animals with continuous access to alcohol. Finally, no changes in quinine taste preference after 3 to 4 months IAA or continuous access to alcohol were observed.

We have developed a novel and technically simple hybrid operant/IAA model in which quinine-resistant motivation for alcohol is evident after an experimentally tractable period of time (3 to 4 months vs. 8 months). Quinine dramatically reduced sucrose and water intake by IAA rats, indicating that continued responding for alcohol in IAA rats despite adulteration with the normally aversive quinine might reflect maladaptive or compulsive motivation for alcohol. This model could facilitate identification of novel therapeutic interventions for pathological alcohol seeking in humans.


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Request Reprint E-Mail: woody@gallo.ucsf.edu

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Effects of Alcohol Cue Exposure on Response Inhibition in Detoxified Alcohol-Dependent Patients

There is evidence that exerting self-control during alcohol craving can diminish performance on subsequent tasks that require self-control.

Based on the resource depletion model (Muraven and Baumeister, 2000), we examined the influence of alcohol cue exposure on detoxified alcohol-dependent patients' ability to inhibit ongoing responses.

Twenty alcohol-dependent patients were randomly assigned to an alcohol-cue exposure and a control-cue exposure condition and thereafter had to perform an inhibition task (i.e., stop-signal task).

Participants who sniffed alcohol before performing the inhibition task reported a stronger urge to drink alcohol than the control group that sniffed water. Participants who sniffed alcohol were also impaired in their inhibitory performance but not in their noninhibitory performance on the stop-signal task.

The urge to drink presumably reduced participants' self-control, and this interfered with their ability to inhibit responding.

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Request Reprint E-Mail: sgauggel@ukaachen.de

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Ethanol Alters Cell Fate of Fetal Human Brain-Derived Stem and Progenitor Cells

Prenatal ethanol (ETOH) exposure can lead to fetal alcohol spectrum disorder (FASD). We previously showed that ETOH alters cell adhesion molecule gene expression and increases neurosphere size in fetal brain-derived neural stem cells (NSC).

Here, our aim was to determine the effect of ETOH on the cell fate of NSC, premature glial-committed precursor cells (GCP), and premature neuron-committed progenitor cells (NCP).

NSC, GCP, and NCP were isolated from normal second-trimester fetal human brains (n = 3) by positive selection using magnetic microbeads labeled with antibodies to CD133 (NSC), A2B5 (GCP), or PSA-NCAM (NCP). As a result of the small percentage in each brain, NSC were cultured in mitogenic media for 72 hours to produce neurospheres. The neurospheres from NSC and primary isolates of GCP and NCP were used for all experiments. Equal numbers of the 3 cell types were treated either with mitogenic media or with differentiating media, each containing 0 or 100 mM ETOH, for 120 hours. Expression of Map2a, GFAP, and O4 was determined by immunoflourescence microscopy and western blot analysis. Fluorescence intensities were quantified using Metamorph software by Molecular Devices, and the bands of western blots were quantified using densitometry.

ETOH in mitogenic media promoted formation of neurospheres by NSC, GCP, and NCP. Under control conditions, GCP attached and differentiated, NSC and NCP formed neurospheres that were significantly smaller in size than those in ETOH. Under differentiating conditions, Map2a expression increased significantly in NSC and GCP and reduced significantly in NCP, and GFAP expression reduced significantly in GCP and NCP, and Gal-C expression reduced significantly in all 3 cell types in the presence of ETOH compared to controls.

This study shows that ETOH alters the cell fate of neuronal stem and progenitor cells. These alterations could contribute to the mechanism for the abnormal brain development in FASD.

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

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Delay Discounting Behavior and White Matter Microstructure Abnormalities in Youth With a Family History of Alcoholism

Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability.

The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH−).

Thirty-three healthy youth (FH+ = 15, FH− = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH− youth.

FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH− youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task.

Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD.

In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth.

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Request Reprint E-Mail: nagelb@ohsu.edu

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Interactions of Stress and CRF in Ethanol-Withdrawal Induced Anxiety in Adolescent and Adult Rats

Repeated stress or administration of corticotropin-releasing factor (CRF) prior to ethanol exposure sensitizes anxiety-like behavior in adult rats.

Current experiments determined whether adolescent rats were more sensitive to these challenges in sensitizing ethanol withdrawal-induced anxiety and altering CRF levels in brain during withdrawal.

Male adult and adolescent Sprague–Dawley rats were restraint stressed (1 hour) twice 1 week apart prior to a single 5-day cycle of ethanol diet (ED; stress/withdrawal paradigm). Other rats received control diet (CD) and three 1-hour restraint stress sessions. Rats were then tested 5, 24, or 48 hours after the final withdrawal for anxiety-like behavior in the social interaction (SI) test. In other experiments, adolescent rats were given two microinjections of CRF icv 1 week apart followed by 5 days of either CD or ED and tested in social interaction 5 hours into withdrawal. Finally, CRF immunoreactivity was measured in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) after rats experienced control diet, repeated ethanol withdrawals, or stress/withdrawal.

Rats of both ages had reduced SI following the stress/withdrawal paradigm, and this effect recovered within 24 hours. Higher CRF doses were required to reduce SI in adolescents than previously reported in adults. CRF immunohistochemical levels were higher in the PVN and CeA of CD-exposed adolescents. In adolescent rats, repeated ethanol withdrawals decreased CRF in the CeA but was not associated with decreased CRF cell number. There was no change in CRF from adult treatments.

In the production of anxiety-like behavior, adolescent rats have equal sensitivity with stress and lower sensitivity with CRF compared to adults. Further, adolescents had higher basal levels of CRF within the PVN and CeA and reduced CRF levels following repeated ethanol withdrawals. This reduced CRF within the CeA could indicate increased release of CRF, and future work will determine how this change relates to behavior

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Request Reprint E-Mail: darin_knapp@med.unc.edu

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Period 2 Gene Deletion Abolishes β-Endorphin Neuronal Response to Ethanol

Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the β-endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress- and immune-regulatory functions of β-endorphin neurons in laboratory rodents.

Our aim was to determine whether the circadian clock regulatory Per2 gene modulates the action of ethanol on β-endorphin neurons in mice.

Per2 mutant (mPer2^Brdml) and wild type (C57BL/6J) mice were used to determine the effect of Per2 mutation on ethanol-regulated β-endorphin neuronal activity during neonatal period using an in vitro mediobasal hypothalamic (MBH) cell culture model and an in vivo milk formula feeding animal model. The β-endorphin neuronal activity following acute and chronic ethanol treatments was evaluated by measuring the peptide released from cultured cells or peptide levels in the MBH tissues, using enzyme-linked immunosorbent assay (ELISA).

Per2 mutant mice showed a higher basal level of β-endorphin release from cultured MBH cells and a moderate increase in the peptide content in the MBH in comparison with control mice. However, unlike wild type mice, Per2 mutant mice showed no stimulatory or inhibitory β-endorphin-secretory responses to acute and chronic ethanol challenges in vitro. Furthermore, Per2 mutant mice, but not wild type mice, failed to show the stimulatory and inhibitory responses of MBH β-endorphin levels to acute and chronic ethanol challenges in vivo.

These results suggest for the first time that the Per2 gene may be critically involved in regulating β-endorphin neuronal function. Furthermore, the data revealed an involvement of the Per2 gene in regulating β-endorphin neuronal responses to ethanol.

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Request Reprint E-Mail: sarkar@aesop.rutgers.edu

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Milk Fat Globule EGF Factor 8 Attenuates Sepsis-Induced Apoptosis and Organ Injury in Alcohol-Intoxicated Rats

Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis.

Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 μg/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements.

Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-α and interleukin-6 and attenuates organ injury.

rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.

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Request Reprint E-Mail: pwang@nshs.edu

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Results of a Type 2 Translational Research Trial to Prevent Adolescent Drug Use and Delinquency - A Test of Communities That Care

To test whether the Communities That Care (CTC) prevention system reduces adolescent alcohol, tobacco, and other drug use and delinquent behavior communitywide.

The Community Youth Development Study is the first randomized trial of CTC.

In 2003, 24 small towns in 7 states, matched within state, were randomly assigned to control or CTC conditions.

A panel of 4407 fifth-grade students was surveyed annually through eighth grade.

A coalition of community stakeholders received training and technical assistance to install the CTC prevention system. They used epidemiological data to identify elevated risk factors and depressed protective factors in the community, and chose and implemented tested programs to address their community's specific profile from a menu of effective programs for families, schools, and youths aged 10 to 14 years.

Incidence and prevalence of alcohol, tobacco, and other drug use and delinquent behavior by spring of grade 8.

The incidences of alcohol, cigarette and smokeless tobacco initiation, and delinquent behavior were significantly lower in CTC than in control communities for students in grades 5 through 8. In grade 8, the prevalences of alcohol and smokeless tobacco use in the last 30 days, binge drinking in the last 2 weeks, and the number of different delinquent behaviors committed in the last year were significantly lower for students in CTC communities.

Using the CTC system to reduce health-risking behaviors in adolescents can significantly reduce these behaviors communitywide.

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