In humans, ethanol exposure during pregnancy causes a spectrum of developmental defects (fetal alcohol syndrome or FAS). Individuals vary in phenotypic expression. Zebrafish embryos develop FAS-like features after ethanol exposure. In this study, we ask whether stage-specific effects of ethanol can be identified in the zebrafish, and if so, whether they allow the pinpointing of sensitive developmental mechanisms. We have therefore conducted the first large-scale (>1500 embryos) analysis of acute, stage-specific drug effects on zebrafish development, with a large panel of readouts.
Zebrafish embryos were raised in 96-well plates. Range-finding indicated that 10% ethanol for 1 h was suitable for an acute exposure regime. High-resolution magic-angle spinning proton magnetic resonance spectroscopy showed that this produced a transient pulse of 0.86% concentration of ethanol in the embryo within the chorion. Survivors at 5 days postfertilisation were analysed. Phenotypes ranged from normal (resilient) to severely malformed. Ethanol exposure at early stages caused high mortality (≥88%). At later stages of exposure, mortality declined and malformations developed. Pharyngeal arch hypoplasia and behavioral impairment were most common after prim-6 and prim-16 exposure. By contrast, microphthalmia and growth retardation were stage-independent.
Our findings show that some ethanol effects are strongly stage-dependent. The phenotypes mimic key aspects of FAS including craniofacial abnormality, microphthalmia, growth retardation and behavioral impairment. We also identify a critical time window (prim-6 and prim-16) for ethanol sensitivity. Finally, our identification of a wide phenotypic spectrum is reminiscent of human FAS, and may provide a useful model for studying disease resilience.
Few clinical studies have focused on the alcohol-independent cardiovascular effects of the phenolic compounds of red wine (RW).
We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease.
Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated.
Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule-1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1.
The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients.
Request Reprint E-Mail: restruch@clinic.ub.es
To conduct a cost–benefit analysis of Early Start, an integrated prenatal intervention program for stopping substance use in pregnancy.
A retrospective cohort study was conducted of 49,261 women who had completed prenatal substance abuse screening questionnaires at obstetric clinics and who had undergone urine toxicology screening tests. Four study groups were compared: women screened and assessed positive and followed by Early Start (screened-assessed-followed, n=2,032), women screened and assessed positive without follow-up (screened-assessed, n=1,181), women screened positive only (screened-positive-only, n=149), women in the control group who screened negative (control, n=45,899). Costs associated with maternal health care (prenatal through 1 year postpartum), neonatal birth hospitalization care, and pediatric health care (through 1 year) were adjusted to 2009 dollars. Mean costs were calculated and adjusted for age, race, education, income, marital status, and amount of prenatal care.
Screened-positive-only group adjusted mean maternal total costs ($10,869) were significantly higher than screened-assessed-followed, screened-assessed, and control groups ($9,430; $9,230; $8,282; all P<.001). Screened-positive-only group adjusted mean infant total costs ($16,943) were significantly higher than screened-assessed-followed, screened-assessed, and control groups ($11,214; $11,304; $10,416; all P<.001). Screened-positive-only group adjusted mean overall total costs ($27,812) were significantly higher than screened-assessed-followed, screened-assessed, and control groups ($20,644; $20,534; $18,698; all P<.001). Early Start implementation costs were $670,600 annually. Cost–benefit analysis showed that the net cost benefit averaged $5,946,741 per year.
Early Start is a cost-beneficial intervention for substance use in pregnancy that improves maternal–infant outcomes and leads to lower overall costs by an amount significantly greater than the costs of the program.
It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated.
To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence.
The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases.
Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
The aim of this study was to investigate the potential capability of an alcalase-hydrolyzed corn protein and fractions with different molecular mass (Mm) to facilitate alcohol metabolism by activating hepatic alcohol dehydrogenase (ADH).
Results showed that corn peptide (CP) fraction with Mm fewer than 1,000 Da (CP < 1,000) exhibited the highest activity to activate ADH in vitro.
The fraction administration (200 mg/kg body weight) with Mm fewer than 5,000 Da (CP < 5,000) demonstrated maximum ability to decrease blood alcohol concentration (BAC) in mice. There was a 45.1% reduction in BAC compared with that of the control group.
Moreover, there was a strong linear relationship between BAC elimination rate and hepatic ADH activation rate (r = 0.9961).
CP's potent capability to facilitate alcohol metabolism could be mainly correlated with the activation of hepatic ADH by hydrophobic CP with low Mm. CP's ·OH scavenging activity may also have synergistic contribution to the oxidative stress release.
Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.
In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.
Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10−8). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10−8) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10−8) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.
Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.
Difficulties regulating emotions have implications for the development, maintenance, and recovery from alcohol problems.
One construct thought to impede the regulation of emotion is alexithymia. Alexithymia is characterized by difficulties identifying, differentiating and expressing feelings, a limited imagination and fantasy life, and an externally-oriented thinking style (e.g., prefer talking about daily activities rather than feelings).
Given that poor emotion regulation skills have been found to predict posttreatment levels of alcohol use, and that several defining characteristics of alexithymia bear similarity to deficits in emotion regulation skills, it is possible that alexithymia may predict poorer alcohol treatment outcomes.
Thus, the present study first examined the relationship of alexithymia to several other emotion regulation measures and then investigated the impact of alexithymia on attrition and alcohol treatment outcomes in men and women (N = 77) enrolled in a 12-week cognitive-behavioral intervention for alcohol dependence.
At baseline, higher scores on alexithymia were associated poorer emotion regulation skills, fewer percent days abstinent, greater alcohol dependence severity, and several high-risk drinking situations. Alexithymia was unrelated to attrition and to level of alcohol consumption at posttreatment
Overall, the construct of alexithymia is shown to be related to several theoretically-related constructs (e.g., emotion regulation, mindfulness) but demonstrated a limited relationship to drinking outcomes in those seeking treatment for alcohol dependence.
Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence.
Baclofen, a GABAB receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis.
The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients.
Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10 mg t.i.d. and 12 received placebo for 12-weeks.
With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p = 0.0123).
Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p = 0.0132) and a trend toward a significant reduction in INR levels from baseline (p = 0.0716).
In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some LFTs (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients.
Request Reprint E-Mail: Lorenzo_Leggio@brown.edu
To measure alcohol-related harms to the health of young people presenting to emergency departments (EDs) of Gold Coast public hospitals before and after the increase in the federal government “alcopops” tax in 2008.
Interrupted time series analysis over 5 years (28 April 2005 to 27 April 2010) of 15–29-year-olds presenting to EDs with alcohol-related harms compared with presentations of selected control groups.
Proportion of 15–29-year-olds presenting to EDs with alcohol-related harms compared with (i) 30–49-year-olds with alcohol-related harms, (ii)15–29-year-olds with asthma or appendicitis, and (iii) 15–29-year-olds with any non-alcohol and non-injury related ED presentation.
Over a third of 15–29-year-olds presented to ED with alcohol-related conditions, as opposed to around a quarter for all other age groups. There was no significant decrease in alcohol-related ED presentations of 15–29-year-olds compared with any of the control groups after the increase in the tax. We found similar results for males and females, narrow and broad definitions of alcohol-related harms, under-19s, and visitors to and residents of the Gold Coast.
The increase in the tax on alcopops was not associated with any reduction in alcohol-related harms in this population in a unique tourist and holiday region. A more comprehensive approach to reducing alcohol harms in young people is needed.
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This year’s Christmas in Papua New Guinea (PNG) has been labelled ‘the bloodiest’ Christmas ever in Port Moresby with two deaths, four life threatening cases and several injuries from alcohol related cases.
This remark was made by chief of emergency medicine and director of emergency at the Port Moresby General Hospital Dr Sam Yockopua.
He said that they were expecting even the worst in the New Year celebrations citing that if worse come to worse, they were prepared to shut down and walk out.
And he has called for a total ban on alcohol during the week leading to the New Year celebrations. > > > > Read More
Beliefs, attitudes, and preferences about the risk and benefits of genetic testing are important determinants of willingness to undergo testing.
The purpose of this study was to evaluate the perceived importance of genetic testing for alcohol dependence compared with other multifactorial diseases among African Americans.
Surveys were conducted with 258 participants using the Genetic Psycho-Social Implications (GPSI) questionnaire to evaluate several areas of hypothetical genetic testing for alcohol dependence. Respondents were divided into two groups: those who perceived testing for alcohol dependence to be equally important as testing for cancer and those who did not. Using chi-square, the groups' responses were compared for nine GPSI items measuring beliefs about the severity of alcohol dependence, general benefits of genetic testing, and specific benefits of genetic testing for diabetes, hypertension, or a disease affecting a family member.
Nearly 86% of respondents believed that genetic testing for alcoholism was equally as important as testing for cancer. Those who reported parity of importance of alcohol dependence and cancer screening were more likely to believe that alcoholism is a deadly disease (p<0.001) and genetic testing influences health (p<0.001). Conclusion: African Americans reported favorable attitudes and beliefs in possible availability of susceptibility genetic testing for alcohol dependence. The perceived importance of testing for alcohol dependence was associated with beliefs about the severity of alcoholism and certain benefits of genetic testing in general.
Request Reprint E-Mail: vjmarshall@howard.edu
The Prime Minister David Cameron is reportedly instructing officials to look at minimum pricing options, the much debated population level policy approach to reducing alcohol-related harm. Although Whitehall officials say no decision has yet been made, a Daily Telegraph report suggests measures could be outlined in the forthcoming national alcohol strategy expected in February 2012.
Cameron is reported to have instructed Whitehall officials to look at options to achieve a minimum price by either tax restructuring or, as currently being sought in Scotland, a standard minimum price per unit. Both could face difficulties under EU law as minimum pricing opponents state it breaches competition law, whilst the IFS recently advised lobbying for EU law changes to achieve tax restructuring for this purpose. > > > > Read More
Despite the predictive value of combined healthy lifestyles in maintaining physical and cognitive functioning in late life, little is known about the clustering patterns of healthy lifestyle behaviors in older people. The aim of the present study was to examine the prevalence, clustering and population characteristics of adherence to multiple health behaviors in community-dwelling older Korean adults.
The study population consisted of a nationally representative sample of 4165 Korean adults aged 65 years and older in 2006. Healthy lifestyles, defined as adherence to recommended guidelines, included non-smoking, no heavy drinking, physical activity and healthy weight. Combinations of behavioral patterns and prevalence odds ratios for pairwise clusters were analyzed. Multinomial logistic regression was used to identify demographic and health-related characteristics associated with the number of adherence to guideline recommendations.
Those who adhered to all four guideline recommendations constituted the minority (11.7%). More women than men engaged in a higher number of healthy lifestyles. Clustering was more pronounced in men for whom no heavy alcohol drinking and physical activity centered around non-smoking. In women, clustering patterns were less obvious. Men, those with low levels of education, income and wealth, and the functionally impaired were less likely to adhere to multiple healthy lifestyles.
Clustering of healthy lifestyles, especially among older men, supports the potential benefit of a multiple behavior change approach. Health promotion efforts should target the socially disadvantaged and functionally compromised segment of the older population presenting low adherence to recommended behaviors.
At this event, we were joined by Dr Bruce Ritson who responded to our presentation, in which we:
his in the wider context, highlighting areas in which we can further influence a change in behaviour.