Activity of secretory sphingomyelinase is increased in plasma of alcohol-dependent patients

Background: Acid sphingomyelinase (ASM, EC 3.1.4.12) hydrolyzes sphingomyelin to ceramide and represents a major regulator of sphingolipid metabolism. Increased activity of ASM has been observed in a variety of human diseases, and a critical contribution of ASM to medical conditions was demonstrated in several mouse models. In agreement with increased ASM activity in cell lines treated with ethanol, we have recently found higher levels of ASM activity in peripheral blood cells of active drinkers. However, the influence of ethanol on secretory ASM (S‐ASM) has not been investigated so far. Methods: ASM activity and routine blood parameters were determined in plasma samples of 27 patients with alcohol dependence during physical withdrawal and compared to a group of 36 healthy volunteers. Results: Compared to the control group, patients with alcohol dependence had S‐ASM activity increased by about 3‐fold (141 ± 69 vs. 428 ± 220 pmol/ml/h; p < 0.001) at the beginning of physical withdrawal. During withdrawal, S‐ASM activity decreased by about 50% (p < 0.001; day 0 vs. day 7 to 10) and finally approximated nearly normal values. On the day of admission, S‐ASM activity correlated positively with levels of carbohydrate‐deficient transferrin (r = 0.410, p = 0.034) and high‐density lipoprotein cholesterol (r = 0.440, p = 0.022) and inversely with body mass index (r = ?0.509; p = 0.007), glucose (r = ?0.480; p = 0.011), triglycerides (r = ?0.592; p = 0.001), and large unstained cells (r = ?0.526; p = 0.017). Conclusions: Activity of S‐ASM is increased in alcohol‐dependent patients and correlates with established biomarkers of excessive drinking. The increased S‐ASM activity is implicated in alcohol‐induced lipid alterations and might be relevant for the occurrence of alcohol‐related disorders.     

The Overlap in Predicting Alcohol Outcome for Two Measures of the Level of Response to Alcohol

Background:  Two different measures have been used to establish a person's level of response (LR) to alcohol as a risk factor for alcohol use disorders. LR values established by the alcohol challenge protocol and the Self-Report of the Effects of Ethanol (SRE) questionnaire usually correlate at 0.3 to 0.4, up to 0.6. However, it is not clear how this correlation relates to the ability of each measure to predict alcohol outcomes. This paper evaluates that overlap.
Methods:  Sixty-six Caucasian males (mean age = 22 years) from 2 protocols participated in alcohol challenges with 0.75 ml/kg of ethanol, filled out the SRE, and were followed with a structured interview ∼5 years later. The relationship between the subjective feelings of intoxication at the time of peak breath alcohol levels from the alcohol challenge and the SRE score for a time early in the drinking career were evaluated regarding predicting the drinks per occasion in the 6 months prior to follow-up.
Results:  Cross-sectional correlations between alcohol challenge and SRE LR's ranged from −0.25 ( p  < 0.05) to −0.32 ( p  = 0.02) for the full sample, and the 2 LR measures correlated with drinking at follow-up (−0.26 and 0.41, respectively). The SRE measure was more robust than the challenge in a regression analysis predicting the outcome in the context of other baseline predictors (e.g., drinking at baseline). As much as 60% of the ability of the more well established (gold standard) alcohol challenge LR to predict outcome was shared with the SRE. The alcohol challenge accounted for as much as 44% of the ability of the SRE to predict outcome.
Conclusions:  The SRE-generated LR overlapped considerably with the alcohol challenge LR in the ability to predict future heavier drinking.     

Dependence-induced alcohol drinking by alcohol-preferring (P) rats and outbred Wistar rats

Background:  Chronic intermittent alcohol vapor exposure and selective breeding procedures have been used separately for many years to model specific aspects of alcohol dependence. The purpose of the present investigation was to combine these 2 approaches by exposing alcohol-preferring (P) rats to chronic intermittent alcohol vapor for extended periods of time and then testing them for operant alcohol responding in parallel with a group of outbred Wistar rats at multiple time points following the termination of vapor exposure.
Methods:  P rats ( n  =   20) and Wistar rats ( n  =   18) were trained to respond for 10% (w/v) ethanol in an operant situation, then divided into groups matched for intake levels. Animals were then exposed to chronic intermittent alcohol vapor (14 hours ON/10 hours OFF) or air for 8 weeks. Rats were then tested for operant alcohol responding under various conditions and at multiple time points during alcohol withdrawal (6 hours) and protracted abstinence (1 to 15 days).
Results:  Chronic alcohol vapor exposure produced similar increases in operant alcohol responding in P rats and Wistar rats during acute withdrawal and protracted abstinence.
Conclusions:  These results illustrate the separate and combined effects of genetic selection for high alcohol preference and dependence on alcohol drinking behavior. Furthermore, these results confirm past findings that dependent rats consume more alcohol than nondependent controls well into abstinence following extended periods of alcohol vapor exposure.     

Effects of family history of alcohol use disorders on spatial working memory BOLD response in adolescents

Background:  A positive family history (FH) of alcohol use disorders (AUD) has been linked to increased risk for the development of AUD, and neurocognitive factors have been postulated as important underlying mechanisms of familial alcoholism transmission.
Methods:  We used functional magnetic resonance imaging (fMRI) during a spatial working memory (SWM) and vigilance paradigm to investigate potential neurodevelopmental differences linked to familial density of AUD in 72 adolescents aged 12 to 14 years.
Results:  Youth with denser family histories of AUD showed less activation during a simple vigilance condition relative to SWM in cingulate and medial frontal gyri (β = 0.28, p  = 0.03), and a trend for more relative activity during rest (β = −0.25, p  = 0.07) in this cluster.
Conclusions:  Youth with greater familial densities of AUD may be less successful at modulating activity of the default network, potentially indicating a greater propensity for task-independent thought or reduced inhibition of task-irrelevant processing. Failure to moderate activation of the default network may have implications for cognitive efficiency and goal directed behavior in youth with dense FH. Further, aberrant activation in cingulate regions may be linked to genetic variation in GABA receptor units, suggesting a useful endophenotype for risk associated with alcohol dependence.     

Trazodone for sleep disturbance after alcohol detoxification: a double-blind, placebo-controlled trial

Background:  Trazodone is a commonly prescribed off-label for sleep disturbance in alcohol-dependent patients, but its safety and efficacy for this indication is unknown.
Methods:  We conducted a randomized, double-blind, placebo-control trial of low-dose trazodone (50 to 150 mg at bedtime) for 12 weeks among 173 alcohol detoxification patients who reported current sleep disturbance on a validated measure of sleep quality or during prior periods of abstinence. Primary outcomes were the proportion of days abstinent and drinks per drinking day over 6-months; sleep quality was also assessed.
Results:  Urn randomization balanced baseline features among the 88 subjects who received trazodone and 85 who received placebo. The trazodone group experienced less improvement in the proportion of days abstinent during administration of study medication (mean change between baseline and 3 months: −0.12; 95% CI: −0.15 to −0.09), and an increase in the number of drinks per drinking day on cessation of the study medication (mean change between baseline and 6 months, 4.6; 95% CI: 2.1 to 7.1). Trazodone was associated with improved sleep quality during its administration (mean change on the Pittsburgh Sleep Quality Index between baseline and 3 months: −3.02; 95% CI: −3.38 to −2.67), but after it was stopped sleep quality equalized with placebo.
Conclusions:  Trazodone, despite a short-term benefit on sleep quality, might impede improvements in alcohol consumption in the postdetoxification period and lead to increased drinking when stopped. Until further studies have established benefits and safety, routine initiation of trazodone for sleep disturbance cannot be recommended with confidence during the period after detoxification from alcoholism.     

The -308 TNFalpha gene polymorphism in severe acute alcoholic hepatitis: identification of a new susceptibility marker

Background:  This study investigated whether genetic polymorphisms in the tumor necrosis factor alpha (TNFα) gene's promoter region play a role in severe acute alcoholic hepatitis (AAH).
Methods:  One-hundred and fifty patients (58 AAH patients, 45 cirrhosis group free-AAH, 47 healthy group) were genotyped for 3 TNFα polymorphisms (−238, −308, −863) using a polymerase chain reaction-restriction fragment length polymorphism technique. Serum TNFα levels were determined.
Results  The TNFα−308 allele A frequency was significantly lower in AAH group (0.09), than cirrhosis (0.28) ( p  < 0.001), and healthy groups ( p  < 0.001). The TNFα−308 A/G, A/A genotypes were significantly lower in AAH group, than cirrhosis ( p  = 0.005), and healthy groups ( p  < 0.001). For AAH group, there were no clinical, biological, and serum TNFα differences between the −308 G/G and A/G, A/A genotype patients, apart higher transaminase in the former group ( p  = 0.02). AAH and cirrhosis groups did not differ for the frequency of TNFα−238, −863 polymorphisms. The specific genotype did not appear to have any influence on the therapeutic response following corticotherapy or posttreatment 6-month survival. In the AAH group, nonsurvivors had higher TNFα levels than survivors (7.9 ± 8.8 vs. 3.3 ± 1.6 pg/ml, p  = 0.01).
Conclusions:  These results attest to the involvement of TNFα-related genetic factors in susceptibility to AAH.     

Results from two randomized clinical trials evaluating the impact of quarterly recovery management checkups with adult chronic substance users

Aims   Post-discharge monitoring and early reintervention have become standard practice when managing numerous chronic conditions. These two experiments tested the effectiveness of recovery management checkup (RMC) protocols for adult chronic substance users.
Intervention   RMC included quarterly monitoring; motivational interviewing to provide personalized feedback and to resolve ambivalence about substance use; treatment linkage, engagement and retention protocols to increase the amount of treatment received.
Participants and setting   Recruited from sequential addiction treatment admissions, participants in the two experiments were, on average, 36 and 38 years of age, mainly female (59% versus 46%), African American (85% versus 80%) and met past-year criteria for dependence (87% versus 76%).
Design   Participants in both experiments were assigned randomly to the RMC or control condition and interviewed quarterly for 2 years.
Measurement   The Global Appraisal of Individual Needs (GAIN) was the main assessment instrument.
Findings   RMC participant outcomes were better than control participants in both experiments. Effect sizes were larger in the second experiment in terms of reducing days to readmission (Cohen's d  = 0.41 versus d  = 0.22), successive quarters in the community using substances ( d  = −0.32 versus −0.19), past-month symptoms of abuse/dependence ( d  = −0.23 versus −0.02) and increasing the days of abstinence over 2 years ( d  = +0.29 versus 0.04).
Conclusion   RMC, which provided ongoing monitoring and linkage, is feasible to conduct and is effective for adults with chronic substance dependence.     

A double-blind, randomized, parallel group study to compare the efficacy, safety and tolerability of slow-release oral morphine versus methadone in opioid-dependent in-patients willing to undergo detoxification

Aims   Evaluation of the efficacy and safety of slow-release oral morphine (SROM) compared with methadone for detoxification from methadone and SROM maintenance treatment.
Design   Randomized, double-blind, double-dummy, comparative multi-centre study with parallel groups.
Setting   Three psychiatric hospitals in Austria specializing in in-patient detoxification.
Participants   Male and female opioid dependents (age > 18 years) willing to undergo detoxification from maintenance therapy in order to reach abstinence.
Interventions   Abstinence was reached from maintenance treatment by tapered dose reduction of either SROM or methadone over a period of 16 days.
Measurements   Efficacy analyses were based on the number of patients per treatment group completing the study, as well as on the control of signs and symptoms of withdrawal [measured using Short Opioid Withdrawal Scale (SOWS)] and suppression of opiate craving. In addition, self-reported somatic and psychic symptoms (measured using Symptom Checklist SCL-90-R) were monitored.
Findings   Of the 208 patients enrolled into the study, 202 were eligible for analysis (SROM: n  = 102, methadone: n  = 100). Completion rates were 51% in the SROM group and 49% in the methadone group [difference between groups: 2%; 95% confidence interval (CI): −12% to 16%]. The rate of discontinuation in the study was high mainly because of patients voluntarily withdrawing from treatment. No statistically significant differences between treatment groups were found in terms of signs and symptoms of opiate withdrawal, craving for opiates or self-reported symptoms. SROM and methadone were both well tolerated.
Conclusions   Detoxification from maintenance treatment with tapered dose reduction of SROM is non-inferior to methadone.     

A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia

Background:  Insomnia and other sleep disturbances are common, persistent, and associated with relapse in alcohol-dependent patients. The purpose of this pilot study was to compare gabapentin versus placebo for the treatment of insomnia and prevention of relapse in alcohol-dependent patients.
Methods:  Twenty-one subjects, including 10 women who met study criteria for alcohol dependence and insomnia and expressed a desire to abstain from alcohol, were recruited to the study. During a 1 to 2 week placebo lead-in and screening phase, a complete medical history, physical exam, blood tests, urine drug test, and structured interviews were performed to determine eligibility and patterns of alcohol use and sleep. Insomnia due to intoxication or acute withdrawal, psychiatric or medical illness, medications, and other sleep disorders were ruled out. Subjects were then randomized to either placebo ( n  = 11) or gabapentin ( n  = 10) for 6 weeks and titrated over a 10-day period to 1,500 mg or 5 pills at bedtime. After a 4-day taper, subjects were reassessed 6 weeks after ending treatment.
Results:  Gabapentin significantly delayed the onset to heavy drinking, an effect which persisted for 6 weeks after treatment ended. Insomnia improved in both treatment groups during the medication phase, but gabapentin had no differential effects on sleep as measured by either subjective report or polysomnography.
Conclusion:  Because gabapentin is a short-acting medication that was taken only at nighttime in this study, it may possibly exert a nocturnal effect that prevents relapse to heavy drinking by a physiological mechanism not measured in this pilot study.     

A haplotype of the DRD1 gene is associated with alcohol dependence

Background:  The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine-seeking behavior and the acquisition of cocaine-cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se.
Methods:  We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes.
Results:  The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence ( p  = 0.0008), with a larger excess for patients with severe dependence ( p  = 6 × 10⁻⁶), and even more for patients with severe complications such as withdrawal seizures ( p  = 7 × 10⁻⁷). A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample ( p  = 5 × 10⁻⁶).
Conclusions:  Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association.     

Elevated adiponectin serum levels in patients with chronic alcohol abuse rapidly decline during alcohol withdrawal

Background:  Adiponectin is a circulating protein with hepatoprotective effects.
Aims:  To study the relationship of excessive alcohol consumption and serum adiponectin levels (SAL).
Patients and Methods:  The SAL were determined in (i) heavy drinkers without advanced liver damage during the course of alcohol withdrawal, (ii) patients with chronic hepatitis C virus (HCV) infection, (iii) patients with alcohol-associated cirrhosis, and (iv) healthy volunteers that consumed excessive amounts of alcohol for only a short period of time. Further, primary human hepatocytes (PHH) and adipocytes were incubated in vitro with alcohol or serum of patients.
Results:  Patients with chronic alcohol consumption had significantly higher SAL than HCV-patients with comparable degrees of liver damage. In alcoholics, but not in HCV patients, SAL positively correlated with serum levels of aminotransferases. Further, SAL correlated with the amount of alcohol consumption but declined during the course of alcohol abstinence. After short-term excessive alcohol consumption SAL were not elevated in healthy individuals. Adiponectin mRNA was detectable in adipocytes but not in hepatocytes, and alcohol failed to induce adiponectin in both cell types. In contrast, serum of active drinkers induced adiponectin expression in adipocytes while serum from the same individuals collected after alcohol withdrawal had no effect.
Conclusions:  Alcohol exhibits a specific effect on SAL that is dose and time dependent, and correlates with the degree of hepatic damage. Alcohol does not seem to affect adiponectin expression directly in adipocytes but potentially via mediators systemically released as a result of the chronic alcohol intake.     

Does sports participation during adolescence prevent later alcohol,tobacco and cannabis use?

Aims   To study whether participation in organized sports during adolescence predicts increased smoking of tobacco, alcohol intoxication and cannabis use from late adolescence to adulthood when controlling for potential confounders. Moreover, to study whether such increased drug use varies according to type of sport (team versus individual), main skills needed (endurance, strength or technical) and level of competition.
Design, setting and participants   Survey of national sample of Norwegian high school students (aged 13–19 years) in 1992 (T1) followed-up in 1994 (T2), 1999 (T3) and 2006 (T4) ( n  = 3251).
Measurements   Outcome measures included smoking of tobacco and 12-month prevalences of alcohol intoxication and cannabis use, respectively. Confounders included pubertal timing, friends' drug use, perceived social acceptance, grades and parental socio-economic status.
Findings   Latent growth curve analyses showed that initial level of participation in organized sports predicted growth in alcohol intoxication. Those involved initially in team sports had greater growth in alcohol intoxication, but lower growth in tobacco use and cannabis use, during the adolescent and early adult years compared to those involved in technical or strength sports. Practising endurance sports, as opposed to technical or strength sports, predicted reduced growth in alcohol intoxication and tobacco use.
Conclusions   Sports participation in adolescence, and participation in team sports in particular, may increase the growth in alcohol intoxication during late adolescent and early adult years, whereas participation in team sports and endurance sports may reduce later increase in tobacco and cannabis use.     

The impact of depressive symptoms on alcohol and cigarette consumption following treatment for alcohol and nicotine dependence

Background:  Although depression is common among alcohol and tobacco dependent patients, its impact on treatment outcomes is not well established. The purpose of this study was to examine the impact of depressive symptoms on abstinence from tobacco and alcohol after treatment for alcohol dependence and nicotine dependence.
Methods:  The Timing of Alcohol and Smoking Cessation Study (TASC) randomized adults receiving intensive alcohol dependence treatment, who were also smokers, to concurrent or delayed smoking cessation treatment. The sample consisted of 462 adults who completed depression and substance use (alcohol and smoking) assessments at treatment entry and 6, 12, and 18 months posttreatment. Longitudinal regression models were used to examine the relationships between depression and subsequent abstinence from alcohol and tobacco after baseline characteristics, including alcohol and smoking histories, were considered.
Results:  Depressive symptoms were prospectively related to nonabstinence from alcohol. Depressive symptoms at the previous assessment increased the odds of drinking at the subsequent time point by a factor of 1.67 (95% CI 1.14, 2.43), p  < 0.01. Depressive symptoms were not significantly related to subsequent abstinence from cigarettes.
Conclusions:  Depression is an important negative predictor of the ability to maintain abstinence from alcohol within the context of intensive alcoholism and smoking treatment. It may be important to include depression-specific interventions for alcohol and tobacco dependent individuals to facilitate successful drinking treatment outcomes.     

Effect of the angiotensin II receptor blocker candesartan on fibrinolysis in patients with mild hypertension

Aim:  Impaired fibrinolysis is frequently observed in patients with the metabolic syndrome. Aim of the study was to examine the short-term effect of angiotensin II receptor blockade on the fibrinolytic system.
Methods:  Seventy-four patients with mild hypertension were randomly assigned to a 7-day treatment period with either 16 mg candesartan cilexetil or placebo. Several variables of the fibrinolytic system such as plasminogen activator inhibitor-1 (PAI-1) antigen and activity, tissue plasminogen activator (t-PA) antigen and activity as well as circulating t-PA/PAI-1 complexes were determined.
Results:  At baseline, the body mass index but not blood pressure was positively associated with PAI-1 antigen (r = 0.314, p < 0.01) and PAI-1 activity (r = 0.425, p < 0.01) but negatively with t-PA activity (r = −0.187, p < 0.05). A 7-day treatment with 16 mg candesartan cilexetil resulted in a significant greater reduction of diastolic blood pressure (−10.3 ± 10.8 mmHg vs.−5.8 ± 8.5 mmHg, p = 0.03). However, there was no significant effect of candesartan on all parameters of the fibrinolytic system under investigation, i.e. circulating PAI-1 antigen, PAI-1 activity, t-PA antigen, t-PA activity and t-PA/PAI-1 complexes. Furthermore, candesartan did not affect the characteristic circadian pattern of the variables of the fibrinolytic system.
Conclusion:  We conclude that short-term blockade of the angiotensin II receptor subtype 1 with candesartan does not have an impact on fibrinolysis in patients with mild hypertension.     

Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men

BACKGROUND: Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication. METHODS: Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program. RESULTS: Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p < 0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC >100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl). CONCLUSIONS: Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity.     

Air trapping: The major factor limiting diaphragm mobility in chronic obstructive pulmonary disease patients

Background and objective:   Patients with COPD can have impaired diaphragm mechanics. A new method of assessing the mobility of the diaphragm, using ultrasound, has recently been validated. This study evaluated the relationship between pulmonary function and diaphragm mobility, as well as that between respiratory muscle strength and diaphragm mobility, in COPD patients.
Methods:   COPD patients with pulmonary hyperinflation ( n  = 54) and healthy subjects ( n  = 20) were studied. Patients were tested for pulmonary function, maximal respiratory pressures and diaphragm mobility using ultrasound to measure the craniocaudal displacement of the left branch of the portal vein.
Results:   COPD patients had less diaphragm mobility than did healthy individuals (36.5 ± 10.9 mm vs 46.3 ± 9.5 mm, P  = 0.001). In COPD patients, diaphragm mobility correlated strongly with pulmonary function parameters that quantify air trapping (RV: r  = −0.60, P  < 0.001; RV/TLC: r  = −0.76, P  < 0.001), moderately with airway obstruction (FEV₁: r  = 0.55, P  < 0.001; airway resistance: r  = −0.32, P  = 0.02) and weakly with pulmonary hyperinflation (TLC: r  = −0.28, P  = 0.04). No relationship was observed between diaphragm mobility and respiratory muscle strength (maximal inspiratory pressure: r  = −0.11, P  = 0.43; maximal expiratory pressure: r  = 0.03, P  = 0.80).
Conclusion:   The results of this study suggest that the reduction in diaphragm mobility in COPD patients is mainly due to air trapping and is not influenced by respiratory muscle strength or pulmonary hyperinflation.     

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects

Background:  Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders.
Methods:  Participants were adolescents aged 15 to 17 who met criteria for AUD ( n  = 14), and demographically similar healthy controls ( n  = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups.
Results:  After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes ( p  = 0.09) than controls, and significant interactions between group and gender were observed ( p  < 0.001 to p  < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes.
Conclusions:  Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.     

Aldose reductase gene polymorphism is associated with progression of diabetic nephropathy in Japanese patients with type 1 diabetes mellitus

Aim: The objective of this study was to investigate cross-sectionally and longitudinally whether polymorphism of the (A-C)n dinucleotide repeat sequence of the aldose reductase ( AR ) gene may modulate risk for diabetic nephropathy or retinopathy in Japanese patients with type 1 diabetes.
Methods: We obtained DNA samples from 101 patients followed up after the onset of type 1 diabetes and analysed a (A-C)n dinucleotide repeat polymorphic marker in the AR gene by polymerase chain reaction (PCR) method.
Results: Ten alleles ranging from Z−10 (128 bp) to Z+8 (146 bp) in repeat number were identified. In cross-sectional studies, the prevalence of the Z+2 allele was higher than that of any other allele in patients with diabetic nephropathy (37.5% of patients in a microalbuminuria group, and 41.7% of those in a macroalbuminuria group including patients with chronic renal failure and maintenance haemodialysis treatment). Prevalence of the Z+2 allele was not increased in patients with diabetic retinopathy. In longitudinal Kaplan–Meier plots, the cumulative incidence of nephropathy was significantly associated with homozygosity for the Z+2 allele (log rank test, p = 0.031); respective prevalence of nephropathy after diabetes durations of 10 and 15 years was 42.9% and 100% in Z+2 homozygotes ( n  = 8), 17.6% and 27.4% in Z+2 heterozygotes ( n  = 44), and 6.1% and 17.4% in patients without the Z+2 allele ( n  = 49). However, occurrence of retinopathy was not influenced by the Z+2 allele (log rank test, p = 0.926).
Conclusions: Homozygosity for the Z+2 allele was associated with accelerated early progression of diabetic nephropathy in Japanese type 1 diabetic patients.     

The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence

Background:  Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter ( DAT1/SLC6A3 ) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence.
Methods:  To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence.
Results:  The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p  = 0.019), even when controlling for confounding factors ( p  = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs.
Conclusions:  The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.     

Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism

Background:  Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C ( ADH1C ) exists resulting in different acetaldehyde concentrations following ethanol oxidation.
Methods:  To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction.
Results:  Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110–2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p  = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors.
Conclusions:  These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis.