Exposure to ethanol during the last trimester of pregnancy alters the maturation and immunity of the fetal lung

The effects of ethanol exposure on fetal lungs remain under investigation. 

Previously, we demonstrated that lambs exposed to ethanol during gestation had impaired expression of pulmonary surfactant protein A, a crucial component of lung immunity. 

In this study, we investigated the effects of in utero exposure to ethanol on maturation and immunity of the fetal lung. 

Pregnant ewes were surgically implanted with an abomasal cannula and administered 1g ethanol/kg (n=8) or water (n=8) during the last trimester of pregnancy. Lambs were delivered prematurely or naturally. Neonatal lungs were assessed for maturation markers (hypoxia-inducible factor-1α [HIF-1α], HIF-2α, HIF-3α, vascular endothelial growth factor-A [VEGF-A], VEGFR-1, VEGFR-2, glycogen, and lung protein levels) and immunity (cytokines and chemokines). 

Preterm animals exposed to ethanol had significantly reduced VEGF-A mRNA (P=.066) and protein levels, HIF-1α (P=.055), HIF-2α (P=.019), VEGFR-1 (P=.088), and VEGFR-2 (P=.067) mRNA levels but no changes in HIF-3α mRNA. 

No significant changes occurred in full-term animals exposed to ethanol. 

Glycogen levels were significantly higher in preterm animals exposed to ethanol (P=.006) but not in full-term animals. 

Ethanol exposure was associated with significantly lower lung protein levels in preterm (P=.03) but not full-term animals. 

Preterm animals exposed to ethanol had significantly reduced TNF-α (P=.05), IL-10 (P=.03), chemokine (C-C motif) ligand 5 (CCL5) (P=.017), and monocyte chemotactic protein-1 (MCP-1) (P=.0004) mRNA. 

In full-term animals exposed to ethanol, the immune alterations were either sustained (TNF-α, P=.009; IL-10, P=.03) or returned to near baseline levels (CCL5 and MCP-1). 

The ethanol-mediated alterations in fetal lung maturation and immunity may explain the increased incidence of respiratory infections in neonates exposed to ethanol in utero.

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Request Reprint E-Mail:  tlazic@iastate.edu 

Alcohol consumption, alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer in the Netherlands Cohort Study on diet and cancer

Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). 

After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. 

Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. 

In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day with the ADH1C*2/*2 genotype were associated—although not statistically significant—with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). 

The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5–<5g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). 

The interaction term however, was not statistically significant (P>.05). 

In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day were associated—although not statistically significant—with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). 

This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). 

As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. 

In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. 

Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. 

Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies.

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Request Reprint E-Mail:   Brenda.Bongaerts@epid.unimaas.nl 

Effects of ethanol on phosphorylation site mutants of recombinant N-methyl-d-aspartate receptors

N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels activated by the neurotransmitter glutamate. These channels are highly expressed by brain neurons and are critically involved in excitatory synaptic transmission. 

Results from previous studies show that both native and recombinant NMDA receptors are inhibited by ethanol at concentrations associated with signs of behavioral impairment and intoxication. 

Given the important role that NMDA receptors play in synaptic transmission and brain function, it is important to understand the factors that regulate the ethanol inhibition of these receptors. 

One dynamic mechanism for regulating ethanol action may be via phosphorylation of NMDA subunits by serine–threonine and tyrosine kinases. Both NR1 and NR2 subunits contain multiple sites of phosphorylation; and in the NR1 subunit, most of these are contained within the C1 domain, a carboxy-terminal cassette that is subject to alternative splicing. 

Although results from our previous studies suggest that single phosphorylation sites do not greatly affect ethanol sensitivity of NMDA receptors, it is likely that in vivo, these subunits are phosphorylated at multiple sites by different kinases. 

In the present study, we constructed a series of NMDA receptor mutants at serine (S) or threonine (T) residues proposed to be sites of phosphorylation by protein kinase A and various isoforms of protein kinase C. 

Ethanol (100mM) inhibited currents from wild-type NR1/2A and NR1/2B receptors expressed in human embryonic kidney 293 cells by approximately 25 and 30%, respectively. 

This inhibition was not different in single-site mutants expressing alanine (A) or aspartate/glutamate (D/E) at positions T879, S896, or T900. 

The mutant NR1(S890D) showed greater ethanol inhibition than NR1(890A) containing receptors, although this was only observed when it was combined with the NR2A subunit. 

Ethanol inhibition was not altered by aspartate substitution at four serines (positions 889, 890, 896, and 897) or when T879D was added to the four serine-substituted mutant. 

Ethanol inhibition was increased when T900E was added to the five serine-/threonine-substituted mutants, but again this was selective for NR2A containing receptors. 

Together with previously published data, these findings suggest that modification of putative phosphorylation sites could contribute to the overall acute ethanol sensitivity of recombinant NMDA receptors.

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Request Reprint E-Mail:  woodward@musc.edu 

Alcohol consumption in relation to aberrant DNA methylation in breast tumors

The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. 

We examined promoter methylation of three genes, the E-cadherin, p16, and retinoic acid-binding receptor-β2 (RAR-β2) genes in archived breast tumor tissues from participants in a population-based case–control study. 

Real time methylation-specific PCR was performed on 803 paraffin-embedded samples, and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs).  

RAR-β2 methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E-cadherin and p16 genes. 

In case–case comparisons of postmenopausal breast cancer, compared with lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E-cadherin (OR=2.39; 95% CI, 1.15–4.96), in particular for those with estrogen receptor-negative tumors (OR=4.13; 95% CI, 1.16–14.72), and decreased for p16=0.52; 95% CI, 0.29–0.92). 

There were indications that the association with p16 was stronger for drinking at younger ages. 

Methylation was also associated with drinking intensity independent of total consumption for both genes. 

We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.

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Request Reprint E-Mail:   menghua.tao@mssm.edu   

Differences in voluntary ethanol consumption in Wistar rats from five different suppliers

Understanding the mechanism of action of ethanol and the neurobiological substrates for alcohol use disorders is challenging. 

In search of this knowledge, it is imperative to use valid animal experimental models. The Wistar rat is one example of a commonly used strain that also exert foundation stock for several rat lines selectively bred for high and low voluntary ethanol intake. 

Different studies report varying ethanol intake in Wistar rats posing the question of whether this is because of the methodological differences or the rat strain. 

The purpose of this study was therefore to compare voluntary ethanol intake in Wistar rats from five different suppliers. 

Rats from B&K Universal, UK (BK); Charles River, Germany; Harlan Laboratories, IN (Hsd); Harlan Laboratories, The Netherlands (RccHan™); and Taconic, Denmark were exposed to a three-bottle free-choice paradigm with intermittent 24h access to 5 and 20% ethanol and water three times per week for 6 weeks. 

A general finding was that the RccHan™ rats differed significantly from the other groups. 

At the end of the experiment, the RccHan™ group had the highest median ethanol intake of 3.85g/kg/24h, whereas the BK rats had the lowest intake of 1.84g/kg/24h. 

The preference for ethanol was also different throughout the experiment. 

At the end of the experiment, the RccHan™ rats had the highest preference of approximately 80%, whereas the BK rats had the lowest preference around 25%. 

During the 6-week drinking period, only the Hsd rats increased their ethanol intake, as evidenced by a significant increase of 5% ethanol intake. 

Although all rats are of Wistar origin, they display profound differences in voluntary ethanol consumption depending on the supplier. 

The choice of Wistar can therefore have implications for the outcome and make comparisons between studies difficult. 

The present findings highlight the supplier as an important parameter to consider when planning and performing preclinical animal studies in the field of alcohol research.

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Request Reprint E-Mail:   Ingrid.Nylander@farmbio.uu.se

Suicide attempt, smoking, comorbid depression, and platelet serotonin in alcohol dependence

The risk of suicide in patients with alcoholism increases if alcoholism is related to comorbid depression. 

Both alcoholism and suicidal behavior are associated with reduced serotonin (5-hydroxytryptamine [5-HT]) function. 

Because suicide is enormous public health problem worldwide, to prevent suicide attempts, it is important to find peripheral marker of suicidal behavior. 

The aim of this study was to assess whether platelet 5-HT concentration is altered in alcoholic patients with or without suicide attempt. 

Platelet 5-HT concentration was evaluated in 397 male and 108 female ethnically homogenous medication-free patients with alcoholism, subdivided according to smoking status, comorbid depression, and a history of suicide attempt and in 450 male and 139 female healthy control (nonsuicidal) subjects. Suicide attempt was assessed by two measures: according to the score 4 on the item 3 from the Hamilton Rating Scale for Depression and according to the Structured Clinical Interview regarding suicidal attempt during lifetime. 

Both male and female patients with alcoholism who were nonsmokers had significantly lower platelet 5-HT concentration than the corresponding healthy subjects. 

Multifactor analyses of variance revealed the significant effects of alcoholism and smoking, but the lack of significant effects of suicide attempt, sex, or comorbid depression, and no interactions between variables, on platelet 5-HT concentration. 

Platelet 5-HT concentration did not differ significantly between suicidal patients compared with nonsuicidal patients with alcoholism. 

Because the results from the present study showed similar platelet 5-HT values between patients with or without a history of suicide attempt, our data did not support the hypothesis that platelet 5-HT concentration might be used as a peripheral marker of the pronounced suicidal behavior in alcoholism.

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Request Reprint E-Mail:  npivac@irb.hr 

Cultural and social network predictors of drinking among Korean American women

This study estimated the association of cultural and social mechanisms with Korean American women’s drinking behaviors. 

Data were drawn from telephone interviews with 591 Korean women selected from a random sample of households in California with Korean surnames during 2007. 

About 62% of eligible respondents completed the interview. 

Respondents reported any lifetime drinking (yes/no), drinking volume (typical number of drinks consumed on drinking days), level of acculturation, and described their social network by assessing who encouraged or discouraged drinking (drinking support) or drank (drinking models). Multivariable regressions were used for analyses. 

About 70% (95% confidence interval [95%CI]:, 67, 74) of Korean American women reported any lifetime drinking and current drinkers drank 1.18 (95%CI: 1.07, 1.28) drinks on drinking days. 

Acculturation was not significantly associated with any lifetime drinking or drinking volume, whereas models and support for drinking were statistically significantly associated with a higher probability of any lifetime drinking and drinking more on drinking days. 

Each additional encourager, or one or fewer discourager, for drinking in women’s social networks was associated with a 2% (95%CI: 1, 3) higher probability of any lifetime drinking and drinking 0.25 (95%CI: −0.53, 1.18) more drinks on drinking days. 

Each additional drinker in women’s networks was associated with a 4% (95%CI: 1, 8) higher probability of any lifetime drinking and drinking 0.26 (95%CI: −0.05, 0.60) more drinks on drinking days. 

Korean American women’s drinking appears to be strongly related to their social networks, although how women take on traits of their new environment was not.

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Request Reprint E-Mail: rhofstet@mail.sdsu.edu 

Alcohol News - 52/2010

Daily Mail (Finland) - The 'violent' gene: Genetic mutation found only in Finnish men that makes them fight

A genetic mutation that makes men impulsive and aggressive, especially when drunk, has been isolated in Finnish men. Research on violent criminals in Finland has uncovered a genetic variant of a brain receptor molecule that contributes that makes people more likely to be aggressive when they have been drinking.

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Bloomberg (Denmark) - Alcoholics May Stop at One Drink With Help From Lundbeck Anti-Abuse Drug

The first pill designed to curb a person’s urge to have more than a few drinks at a sitting is undergoing tests in Europe, promising doctors and public-health authorities a new approach to fighting alcoholism. The drug, nalmefene from H. Lundbeck A/S in Valby, Denmark, blocks brain signals that make activities such as sex and drinking feel good. Should trials succeed, the medicine may win clearance in Europe as early as 2012, becoming the first new alcoholism treatment approved there in more than 15 years.

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The Baltic Course (Lithuania) - Alcohol excise tax not to be cut in Lithuania

The Seimas in Lithuania has supported the presidential veto, refusing to reduce the excise duty on alcoholic beverages.

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Los Angeles Times (USA) - Infant deaths from SIDS surges on New Year's Day, new study finds

Babies who die from SIDS are 33% more likely to die on New Year's Day than any other day of the year, a new study finds. Researchers say alcohol use the night before by parents or caretakers may play a role in SIDS deaths.

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NPR - Parenting Style Plays Key Role In Teen Drinking

For teenagers, friends play a big role in the decision to take that first drink. And by the 12th grade, more than 65 percent of teens have at least experimented with alcohol. But what parents do during the high school years can also influence whether teens go on to binge drink or abuse alcohol.

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MedPage Today - Alcohol Linked to Psoriasis in Women

Women who have more than two alcoholic drinks a week -- particularly nonlight beer -- appear to be at increased risk of developing psoriasis, a large prospective study found.

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TIME - Even Small Amounts of Holiday Drinking Boost Cancer Risk

More evidence for the conventional wisdom of "everything in moderation": even a small increase in alcohol intake can up the risk of several different kinds of cancer, according to researchers at the MD Anderson Cancer Center in Texas, so revelers would be wise not to overindulge this holiday party season.

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Daily Nation (Kenya) - Festive season with a difference as new alcohol control law keeps Kenyans sober

It is Christmas once again and, for the first time in Kenya, the father of the house might just be sober, thanks to the new alcohol law. For the first time ever, bars were not allowed to open all night on Christmas Eve. They will also remain closed until 2 pm on Christmas day.

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YLE News (Finland) - Finns Willing to Pay More Tax on Alcohol and Tobacco

Finns appear willing to favour increases in taxation on alcohol, tobacco, confectionery and capital gains in order to balance public finances, a survey commissioned by YLE indicates. However, there is little enthusiasm for higher income or energy taxes, the survey carried out by pollster Taloustutkimus reveals.

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Voxy (New Zealand) - Kiwis Challenged To Give Up Alcohol In February

We're heading into the silly season, a time when Kiwis drink a lot more than usual. But a new campaign hosted by the Drug Foundation will provide New Zealanders with a much needed opportunity to give their bodies a break in February.

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UPI.com (EU) - Europe urged to address excessive drinking

Researchers in Athens for a meeting hosted by the European Association warned Europe has the highest rate of alcohol consumption in the world and 1-in-15 adults suffers serious health conditions as a result.

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Economic Times (India) - Delhi to be first city with 2D bar-coding on liquor bottles

In a move to check sale of spurious liquor and bootlegging, all alcohol bottles sold in the city will soon have two-dimensional modern bar coding with Delhi government today deciding to rope in Tata Consultancy Service for the purpose.

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AngolaPress (Angola) - Archbishop urges abstinence from exaggerated consumption of alcohol

The archbishop of Lubango, Gabriel Mbiligui, urged Tuesday in this city the population to abstain from exaggerated consumption of alcohol during Christmas and new year.

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Alcoholism booms in 'dry' Pakistan

The Pakistani banker told his story nervously, kneading his hands as he spoke. His wife had deserted him, his family was furious, and his career had stalled. "My problem is whisky," he said, shaking his head with regret.

The 32-year-old professional was sitting in an addiction clinic, hidden down a quiet street in the capital, Islamabad. He had relapsed from the expensive treatment programme twice already; now he had been dry for more than three months. "This time it's for good," he said, with just a glimmer of self-doubt.

Pakistan has been dry for much longer – since 1977 – and drinkers risk severe punishment: 80 lashes of the whip under strict Islamic laws. But the law is ignored, alcohol is widely available and, for those who go too far, addiction clinics offering help are quietly flourishing.

"There's plenty of business," said Dr Sadaqat Ali, a leading addiction counsellor whose chain of clinics treated 500 alcoholics this year. Dr Ali estimates that 10 million Pakistanis drink alcohol, 1 million of whom have a problem. "With our culture of hospitality, it's hard to say 'no'," he said.  > > > >  Read More

Severity of alcoholism in Indian males: Correlation with age of onset and family history of alcoholism

Family History of Alcoholism and earlier Age of Onset are found to predict Severity of alcoholism. Previous Indian studies in this regard have methodological issues related to the definition of alcoholism and reliability of information obtained.

To study the relationship between the Age of onset/Family History and Severity of alcoholism.  

Consecutively admitted, 20 to 50 year old men, with alcohol-related problems at an urban teaching hospital, were recruited.  

After detoxification, alcohol use detection inventory test, severity of alcohol dependence questionnaire, schedule for clinical assessment in neuropsychiatry, and family interview for genetic studies were administered. Family history density was computed.  

Pearson's correlations, linear regression, and ANOVA tests were used. 

Family history density and severity of alcoholism were positively correlated. Age of onset of initiation had a significant negative correlation with severity. The effect of family history on the rapidity of development of Problem-drinking did not reach statistical significance among those with early age of onset. The variance explained by the 'family history status' and 'age of onset' for the severity of alcoholism was similar to that reported in earlier western studies. 

This study, with enhanced methodology, using a general hospital sample of problem drinkers concludes that the age of onset of initiation is a better predictor of severity of alcoholism, than family history of alcoholism alone. Postponing the use of alcohol till the age of 25 years could be explored as a primary prevention strategy in genetically vulnerable adolescents.





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Direct assessment of multiple testing correction in case-control association studies with related individuals

Genome-wide association studies typically test large numbers of genetic variants in association with trait values. 

It is well known that linkage disequilibrium (LD) between nearby markers tends to introduce correlation among association tests. Failure to properly adjust for multiple comparisons can lead to false-positive results or missing true-positive signals. 

The Bonferroni correction is generally conservative in the presence of LD. The permutation procedure, although has been widely employed to adjust for correlated tests, is not applicable when related individuals are included in case-control samples. 

With related individuals, the dependence among relatives' genotypes can also contribute to the correlation between tests.

We present a new method P_norm to correct for multiple hypothesis testing in case-control association studies in which some individuals are related. The adjustment with P_norm simultaneously accounts for two sources of correlations of the test statistics: (1) LD among genetic markers (2) dependence among genotypes across related individuals. 

Using simulated data based on the International HapMap Project, we demonstrate that it has better control of type I error and is more powerful than some of the recently developed methods. 

We apply the method to a genome-wide association study of alcoholism in the GAW 14 COGA data set and detect genome-wide significant association. 

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Request Reprint E-Mail:  zuoheng.wang@yale.edu