Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele.

Various types of alcoholics have been described and heredity has been shown to be involved in some of these types. An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism. In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene. The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics. The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested.

Assimilation of Both Column- and Layer-Integrated Dust Opacity Observations in the Martian Atmosphere.

A new dust data assimilation scheme has been developed for the UK version of the Laboratoire de Météorologie Dynamique Martian General Circulation Model. The Analysis Correction scheme (adapted from the UK Met Office) is applied with active dust lifting and transport to analyze measurements of temperature, and both column-integrated dust optical depth (CIDO), τ ref (rescaled to a reference level), and layer-integrated dust opacity (LIDO). The results are shown to converge to the assimilated observations, but assimilating either of the dust observation types separately does not produce the best analysis. The most effective dust assimilation is found to require both CIDO (from Mars Odyssey/THEMIS) and LIDO observations, especially for Mars Climate Sounder data that does not access levels close to the surface. The resulting full reanalysis improves the agreement with both in-sample assimilated CIDO and LIDO data and independent observations from outside the assimilated data set. It is thus able to capture previously elusive details of the dust vertical distribution, including elevated detached dust layers that have not been captured in previous reanalyzes. Verification of this reanalysis has been carried out under both clear and dusty atmospheric conditions during Mars Years 28 and 29, using both in-sample and out of sample observations from orbital remote sensing and contemporaneous surface measurements of dust opacity from the Spirit and Opportunity landers. The reanalysis was also compared with a recent version of the Mars Climate Database (MCD v5), demonstrating generally good agreement though with some systematic differences in both time mean fields and day-to-day variability.

Alternatively spliced platelet-derived growth factor A-chain transcripts are not tumor specific but encode normal cellular proteins.

Two platelet-derived growth factor A-chain proteins, termed short and long A chains, are generated as a result of alternative mRNA splicing of exon 6 of the A-chain gene. S1 nuclease mapping and polymerase chain reaction analyses demonstrate that both short and long A-chain transcripts are expressed in a variety of normal tissues. In addition, immunohistochemical localization of long A-chain protein reveals a cellular distribution identical to that observed with platelet-derived growth factor heteroserum.

Chronotherapy of ovarian cancer: effect on blood variables and serum cytokines. A case report.

A 7-year-old patient with Stage III-c ovarian cancer was subjected to 8 cycles, approximately four weeks apart, of chronobiologically-optimized treatments with combination of three anti-cancer agents: Four cycles at AM, Cytoxan and PM, cis-Platinum; four cycles at AM, Adriamycin and PM, cis-Platinum. A second look laporoscopy revealed clean intestines, no definite masses in the pelvis area although there was an apparent mass in the right upper pelvis and several slightly enlarged lymph nodes in the base of mesentery. Six cycles of Taxol were administered at about Noon. Seven months remission appeared evident as judged by no changes in monthly examinations, in blood work or in CA-125 marker levels which remained below 12 U/ml. During the eight month the CA-125 marker began to rise, 36 then to 52 U/ml. A second 6 cycle series of Taxol was initiated but the CA-125 marker continued to rise, 57, 65, 72, 86, and 87 U/ml level. The patient declined in spirit, in well-being and expired 2 weeks later, 31 months after the initial diagnosis of cancer. Blood hematology, chemistry, and cytokines variables were analyzed at about weekly intervals. Significant reductions in total WBC, neutrophiles and platelet levels were evident during the second week of all cycle treatments, while increases were noted in serum levels of IL-2, IL-6 and IL-10 following Cytoxan-cis-Platinum-Adriamycin, but not Taxol. After each infusion moderate and temporary increases in RBC levels were noted. The treatments impact on hematology, chemistry, cytokine variables and on the integrity of the patient, are presented and briefly discussed.

Rotational dynamics of luteinizing hormone receptors and MHC class I antigens on murine Leydig cells.

We have examined the molecular motions of luteinizing hormone (LH) receptor and the Major Histocompatibility Complex Class I antigen on murine Leydig cells. Using time-resolved phosphorescence anisotropy methods, erythrosin (ErITC)-derivatized ovine luteinizing hormone (oLH) bound to the LH receptor appears rotationally mobile with rotational correlation times of 19.6 +/- 1.3 microseconds, 13.3 +/- 2.4 microseconds, 9.5 +/- 0.7 microseconds and 4.7 +/- 0.5 microseconds at 4 degrees C, 15 degrees C, 25 degrees C and 37 degrees C, respectively. Rotational correlation times for human chorionic gonadotropin (hCG)-occupied LH receptors were similar to those of the ErITC-oLH occupied receptor at each temperature. In addition, both oLH- and hCG-occupied LH receptors were laterally mobile in fluorescence photobleaching recovery experiments with diffusion coefficients at 29 degrees C of (5.8 +/- 0.9) x 10(-10) cm2 s-1 and (2.9 +/- 0.4) x 10(-10) cm2 s-1, respectively. We also measured the rotational correlation time of Class I antigen on murine Leydig cells using ErITC-derivatized 34-12-2S, an anti-Class I monoclonal antibody. Because there was no decay of the anisotropy function at 4 degrees C, 15 degrees C, 25 degrees C or 37 degrees C in the absence of oLH or following preincubation of Leydig cells with 1 nM oLH, it appears that Class I is rotationally immobile on the 1 ms timescale of our experiments. This result is consistent with the presence of Class I antigen in large molecular weight structures and may be the result of Class I self-aggregation. Further, treatment of cells with anti-Class I antibody had no effect on either basal or oLH-stimulated testosterone secretion. Thus, it appears that this anti-Class I antibody is not LH-mimetic on murine Leydig cells.

A novel function for the Xslug gene: control of dorsal mesendoderm development by repressing BMP-4.

The Snail family of genes comprise a group of transcription factors with characteristic zinc finger motifs. One of the members of this family is the Slug gene. Slug has been implicated in the development of neural crest in chick and Xenopus by antisense loss of function experiments. Here, we have generated functional derivatives of Xslug by constructing cDNAs that encode the Xslug protein fused with the transactivation domain of the virus-derived VP16 activator or with the repressor domain of the Drosophila Engrailed protein. Our results suggest that Xslug normally functions as a transcriptional repressor and that Xslug-VP16 behaves as a dominant negative of Xslug. In the present work, we confirm and extend previous results that suggest that Xslug has an important function in neural crest development, by controlling its own transcription. In addition we have uncovered a new function for Xslug. We show that Xslug is expressed in the dorsal mesendoderm at the beginning of gastrulation, where is it able to upregulate the expression of dorsal genes. On the other hand when Xslug is expressed outside of the organizer it represses the expression of ventral genes. Our results indicate that this effect on mesodermal patterning depends on BMP activity, showing that Xslug can directly control the transcription of BMP-4.

Dysbindin (DTNBP1) variants are associated with hallucinations in schizophrenia.

BACKGROUND: Dystrobrevin binding protein 1 (DTNBP1) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP). METHODS: Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models. RESULTS: Post hoc tests determined that SNP rs1997679 was associated with visual hallucination; SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations; and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations; and rs9370822 for olfactory hallucinations. CONCLUSION: These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity.

Brain-specific epigenetic markers of schizophrenia.

Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) samples from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with individual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post-mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment.

Association of the D2 dopamine receptor A1 allele with alcoholism: medical severity of alcoholism and type of controls.

D2 dopamine receptor (DRD2) A1 allele frequency was determined in alcoholics of varying medical severity from three different inpatient settings and in various controls. A1 frequency was .15 in 68 alcoholics in a detoxification unit (group A), .19 in 90 alcoholics in a rehabilitation unit (group B), and .31 in 43 alcoholics in a gastroenterology unit (group C). Group C had a higher A1 frequency than group B (p = .045) or group A (p = .005) alcoholics. In 46 controls (group D), A1 frequency was .18. In subsets of these controls, A1 frequency was .14 in 39 subjects with a negative family history (FH-) of alcoholism (group E), .06 in 34 subjects without previous hazardous alcohol consumption (group F), and .05 in 30 subjects with FH- and without previous hazardous alcohol consumption (group G). A1 frequency was significantly higher in group C alcoholics than group F (p = .0002) or group G (p = .0002) controls; however, no A1 frequency difference was found among group A alcoholics and any of the control groups. The severity of alcoholism and the type of controls used are important determinants of DRD2 A1 allele association with alcoholism.

Elevated plasma aluminum levels in normal infants receiving antacids containing aluminum.

Aluminum toxicity is a documented cause of encephalopathy, anemia, and osteomalacia. Excretion is primarily renal; therefore, patients with renal insufficiency are at risk for aluminum accumulation and toxicity. This has been demonstrated in uremic children treated with aluminum-containing antacids. The purpose of this study was to determine whether plasma aluminum levels were elevated in infants with normal renal function during prolonged aluminum-containing antacid use. Ten study infants (mean age = 5.8 months), who had been receiving antacids for at least 1 week, were compared with 16 control infants (mean age = 9.8 months) not receiving antacids. The study patients consumed 123 +/- 16 mg/kg per day (mean +/- SEM) of elemental aluminum for an average of 4.7 weeks. Their plasma aluminum level (37.2 +/- 7.13 micrograms/L) was significantly greater than that of the control group (4.13 +/- 0.66 micrograms/L) (P less than .005). It is concluded that plasma aluminum levels may become elevated in infants with normal renal function who are consuming high doses of aluminum-containing antacids. The safety of antacids containing aluminum should not be assumed and they should be used judiciously in infants, with careful monitoring of the aluminum dose and plasma level.

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment.

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Xanthoderma: an unusual presentation of hypothyroidism.

A young woman presented with progressive yellowing of her skin over a period of six months. Liver function tests were requested by her general practitioner and the results prompted the Chemical Pathology Department to instigate further tests to reach the final diagnosis. Hypercarotenaemia had caused her yellow skin, and various other biochemical abnormalities pointed towards primary hypothyroidism as an underlying cause. Thyroxine replacement treatment successfully corrected all the biochemical abnormalities including hypercarotenaemia. As far as is known, yellow skin as a sole presenting feature of hypothyroidism is extremely rare.

Pharmacokinetics of oral pramiracetam in normal volunteers.

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (+/- SD) peak plasma concentrations of the four dose groups (2.71 +/- 0.54, 5.40 +/- 1.34, 6.13 +/- 0.71, 8.98 +/- 0.71 micrograms/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5 hours), the mean total body clearance (4.45-4.85 mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.

Maritally distressed women with alcohol problems: the impact of a short-term alcohol-focused intervention on drinking behaviour and marital satisfaction.

AIM: To evaluate the efficacy of a short-term alcohol-focused intervention for maritally distressed women, and to explore changes in relationship functioning. DESIGN: Participants were assigned randomly to an alcohol-focused treatment or to a waiting-list control group. The waiting-list control group began the intervention at 1-month follow-up. SETTING: The intervention took place at a research and training centre offering outpatient psychology services to the community. PARTICIPANTS: A sample of 32 women with alcohol and marital problems were recruited through the media. Participants reported protracted alcohol problems, moderate to severe impact of alcohol on social and occupational functioning, and moderate to severe marital distress. MEASUREMENTS: Measures of average alcohol consumption, marital distress, relational efficacy and depression were administered at pre- and post-therapy, and at 1, 6 and 12-month follow-up. INTERVENTION: The intervention involved six 1-hour sessions, consisting of clinical assessment, motivational interviewing, cognitive-behavioural strategies and relapse prevention. RESULTS: At 1-month follow-up, the intervention was associated with statistically significant improvements in alcohol consumption, marital satisfaction, relational efficacy and depression, and these effects were sustained at 12-month follow-up. CONCLUSIONS: At 1-month follow-up the intervention was associated with decreased alcohol consumption and depression, and increased marital satisfaction and relational efficacy, with evidence of maintained effects at 12-month follow-up. However, it is unlikely that reduced problem drinking and improved confidence in resolving problems were the only factors producing low marital quality in these couples. Further research is needed to identify those individuals who might benefit from marital interventions.

Helping the female partners of men abusing alcohol: a comparison of three treatments.

AIM: To evaluate the effectiveness of three approaches to assisting the female partners of male problem drinkers with the stress imposed by the male's drinking. DESIGN: Participants were assigned randomly via random number tables to one of three treatment conditions: supportive counselling, stress management or alcohol-focused couples therapy. SETTING: The intervention took place at the Behaviour Research and Therapy Centre (BRTC), The University of Queensland. This research and training centre offers outpatient psychology services to the community. PARTICIPANTS: Sixty-one married women whose husbands drank heavily. Participants reported protracted alcohol problems, severe impact of alcohol on social functioning and severe marital distress. MEASUREMENT: The women's stress, alcohol consumption by the male, and relationship functioning were assessed at pre- and post-treatment and at 6-month follow-up. INTERVENTIONS: All three treatments involved 15 1-hour sessions with the woman. In the alcohol-focused couple therapy, attempts were made to engage the man in these sessions. RESULTS: Contrary to our predictions, there were few differences between the treatments. All three treatments were associated with reductions in the women's reported stress, with trends for somewhat greater reduction in the women's stress in the stress management and alcohol-focused couples therapy conditions than for supportive counselling. None of the treatments produced clinically significant reductions in men's drinking or relationship distress. CONCLUSION: The treatments ease stresses and burden but do not improve drinking or relationships. Limited power in the design restricted the capacity to detect differential treatment effects.

Gender stereotypes and drinking cognitions as indicators of moderate and high risk drinking among young women and men.

The study examined differences in gender stereotypes, restrained drinking and self-efficacy for alcohol refusal between moderate and high risk drinkers among a university sample of 301 women and 118 men. Both female and male high risk drinkers displayed a response conflict, typified by high scores on restrained drinking but low scores on self-efficacy. This pattern of response conflict was more pronounced for high risk drinking women, who also identified poorly with feminine traits (e.g. 'nurturing', 'love children', 'appreciative'). The findings are discussed in relation to society's double standard that accepts intoxication in men but condemns it in women.

Tubular damage in patients with hypokalaemia.

Severe hypokalaemia is occasionally associated with gross changes in renal tubular function. We have looked for lesser degrees of renal tubular damage in unselected patients with hypokalemia by measuring the urine excretion of total protein, albumin, the low molecular mass protein beta 2-microglobulin (B2M) and two enzymes, N-acetyl-glucosaminidase (NAG) and alanine aminopeptidase (AAP). The frequency of abnormal values for these tests separately (compared with matched patients without hypokalaemia) was 39-56%. Many patients had an abnormal value for more than one of the tests, but this was at least partly due to chance association rather than to an underlying common mechanism for the several abnormalities. The frequency of abnormal values was greatest in the patients with the lowest plasma potassium concentrations, but not all of these patients had abnormal values for even one of the tests. Repeated measurements during treatment with potassium supplements showed that the tubular damage resolved in some patients but more slowly than the hypokalemia. These results demonstrate that renal tubular damage is common amongst patients with hypokalaemia and is probably a consequence of the hypokalaemia in most of them. The measurements allow detection of patients whose tissues (at least the kidney) are adversely affected by the hypokalaemia, but the clinical usefulness of this information is yet to be established.

The results of in situ prosthetic replacement for infected aortic grafts.

BACKGROUND: Treatment of aortic graft infection with graft excision and axillofemoral bypass may carry an increased risk of limb loss, aortic stump blowout, and pelvic ischemia. A review of patients with aortic graft infection treated with in situ prosthetic graft replacement was undertaken to determine if mortality, limb loss, and reinfection rates were improved with this technique. METHODS: The clinical data of 25 patients, 19 males and 6 females, with a mean age of 68 years (range 35 to 83), with aortic graft infection, treated between January 1, 1989, and December 31, 1998, by in situ prosthetic graft replacement were reviewed. Follow-up was complete in the 23 surviving patients and averaged 36 months (range 4 to 103). RESULTS: Twenty aortofemoral, 3 aortoiliac, and 2 straight aortic graft infections were treated with excision and in situ replacement with standard polyester grafts in 16 patients (64%), or with rifampin-soaked collagen or gelatin-impregnated polyester grafts in 9 patients (36%). Fifteen patients (60%) had aortic graft enteric fistulas, 8 patients (32%) had abscesses or draining sinuses, and 2 patients (8%) had bacterial biofilm infections. Thirty-day mortality was 8% (2 of 25). There were no early graft occlusions or amputations. There was one late graft occlusion. There were no late amputations. The reinfection rate was 22% (5 grafts). All reinfections occurred in patients operated upon for occlusive disease. Only one reinfection occurred in the rifampin-soaked graft group (11% versus 29%, P = NS). Reinfection tended to be lower in patients with aortoenteric fistulas and without abscess. Autogenous tissue coverage provided statistically significant protection against reinfection. There were no late deaths related to in situ graft infection. CONCLUSIONS: Patients treated with in situ graft replacement had an 8% mortality and 100% limb salvage rate. Reinfection rates were similar to those of extra-anatomic bypass, but a trend of lower reinfection rates with rifampin-impregnated grafts was apparent. Patients with aortoenteric fistula and without abscess appear to be well treated by the technique of in situ prosthetic grafting and autogenous tissue coverage.

GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

D2 dopamine receptor and GABA(A) receptor beta3 subunit genes and alcoholism.

As the dopaminergic and GABAergic systems have been implicated in alcohol-related behaviors, variants of the D2 dopamine receptor (DRD2) and GABA(A) receptor beta3 subunit (GABRB3) genes were determined in a population-based association study of Caucasian non-alcoholic and alcoholic subjects. In severe alcoholics, compared to non-alcoholics, a significant increase was found in the prevalence (P = 1.7 x 10(-5)) and frequency (P = 1.6 x 10(-5)) of the DRD2 minor (A1) allele. Moreover, a significant progressive increase was observed in A1 allelic prevalence (P = 3.1 x 10(-6)) and frequency (P = 2.7 x 10(-6)) in the order of non-alcoholics, less severe and severe alcoholics. In severe alcoholics, compared to non-alcoholics, a significant decrease was found in the prevalence (P = 4.5 x 10(-3)) and frequency (P = 2.7 x 10(-2)) of the GABRB3 major (G1) allele. Furthermore, a significant progressive decrease was noted in G1 allelic prevalence (P = 2.4 x 10(-3)) and frequency (P = 1.9 x 10(-2)) in non-alcoholics, less severe and severe alcoholics, respectively. In sum, in the same population of non-alcoholics and alcoholics studied, variants of both the DRD2 and GABRB3 genes independently contribute to the risk for alcoholism, with the DRD2 variants revealing a stronger effect than the GABRB3 variants. However, when the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately.