Moderate doses of alcohol disrupt the functional organization of the human brain.

Acute alcohol administration decreases overall brain glucose metabolism, which serves as a marker of brain activity. The behavioral effects of alcohol, however, are likely to reflect not only changes in regional brain activity but also the patterns of brain functional organization. Here we assessed the effects of a moderate dose of alcohol on the patterns of brain activity and cerebral differentiation. We measured brain glucose metabolism in 20 healthy controls with positron emission tomography and fluorodeoxyglucose during baseline and during alcohol intoxication (0.75 g/kg). We used the coefficient of variation (CV) to assess changes in brain metabolic homogeneity, which we used as a marker for cerebral differentiation. We found that alcohol decreased the CV in the brain and this effect was independent of the decrements in overall glucose metabolism. Our study revealed marked disruption in brain activity during alcohol intoxication including decreases in global and regional brain differentiation, a loss of right versus left brain metabolic laterality and a shift in the predominance of activity from cortical to limbic brain regions. The widespread nature of the changes induced by a moderate dose of alcohol is likely to contribute to the marked disruption of alcohol on behavior, mood, cognition and motor activity.

A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users.

BACKGROUND: Dihydrofolate reductase (DHFR) converts dihydrofolate (DHF) into tetrahydrofolate (THF) and plays an essential role in cell metabolism and cellular growth. Folic acid from multivitamins needs to be reduced by DHFR before it participates in cellular reactions. OBJECTIVES: We examined the relation of a 19-base pair (bp) deletion polymorphism of the DHFR gene with the risk of breast cancer by using data from the Long Island Breast Cancer Study Project, a population-based case-control study. We also investigated the transcriptional effect of this deletion polymorphism. DESIGN: Dietary data and habitual use of multivitamins were assessed from a modified Block food-frequency questionnaire (FFQ). Genotypes of DHFR were ascertained from 1062 case subjects and 1099 control subjects by allele-specific polymerase chain reaction. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. RESULT: Although the DHFR 19-bp deletion polymorphism was not associated with overall breast cancer risk, we observed a borderline significant additive interaction (P = 0.06) between the DHFR genotype and multivitamin use. The -19-bp allele was associated with greater breast cancer risk in multivitamin users (51.2% of the study population) with an OR of 1.26 (95% CI: 0.96, 1.66) and 1.52 (95% CI: 1.08, 2.13) for the +/- and -/- genotypes, respectively (P for trend = 0.02) than in multivatimin nonusers. A dose-dependent relation (P for trend < 0.001) between DHFR expression and the deletion genotype was observed. Compared with the subjects with the 19-bp +/+ genotype, subjects with the -/- genotype had 4.8-fold DHFR mRNA levels. CONCLUSIONS: The DHFR 19-bp deletion polymorphism affects the transcription of DHFR gene in humans. Multivitamin supplements may place a subgroup of women (ie, those with the -19-bp allele) at elevated risk of developing breast cancer.

Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study.

One-carbon metabolism facilitates the crosstalk between genetic and epigenetic processes and plays critical roles in both DNA methylation and DNA synthesis, making it a good candidate for studying the risk of breast cancer. We previously reported that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) in one-carbon pathway were associated with breast cancer risk in the population-based Long Island Breast Cancer Study Project. Herein, we systematically investigated putatively functional polymorphisms of seven other one-carbon-metabolizing genes in relation to the breast cancer risk in the same population. Except for a slight indication of increased risk of breast cancer associated with the double repeat (2R) allele in the thymidylate synthase (TYMS) 5'-untranslated region (UTR) (P, trend = 0.07), polymorphisms in the other six genes did not substantially modify the risk of breast cancer, or did they modify the risk associated with dietary intakes of folate and related B vitamins. However, we observed a significant multiplicative interaction between the MTHFR 677C>T and the TYMS 5'-UTR polymorphisms (P = 0.02). We used a recursive partitioning method, RTREE, in an attempt to tease out important or rate-limiting genes encoding these intricately related enzymes. Results from RTREE analyses indicate that MTHFR and TYMS are the two leading rate-limiting enzymes in the pathway, consistent with our epidemiological findings. Our findings underscore the importance of one-carbon metabolism in breast cancer etiology. Although the pathway is a network of interrelated enzymes, redundancy exists; evaluating the rate-limiting enzyme and its interaction with environment and other genes within the same pathway is critical in assessing breast cancer risk.

Exposure to appetitive food stimuli markedly activates the human brain.

OBJECTIVE: The increased incidence of obesity most likely reflects changes in the environment that had made food more available and palatable. Here we assess the response of the human brain to the presentation of appetitive food stimuli during food presentation using PET and FDG. METHOD: Metabolic changes in response to food presentation were done in 12 healthy normal body weight subjects who were food deprived before the study. RESULTS: Food presentation significantly increased metabolism in the whole brain (24%, P < 0.01) and these changes were largest in superior temporal, anterior insula, and orbitofrontal cortices. The increases in the right orbitofrontal cortex were the ones that correlated significantly with the increases in self-reports of hunger and desire for food. DISCUSSION: The marked increase in brain metabolism by the presentation of food provides evidence of the high sensitivity of the human brain to food stimuli. This high sensitivity coupled with the ubiquitousness of food stimuli in the environment is likely to contribute to the epidemic of obesity. In particular, the activation of the right orbitofrontal cortex, a brain region involved with drive, may underlie the motivation to procure food, which may be subjectively experienced as "desire for food" and "hunger" when exposed to food stimuli.

Detection of cancer-specific markers amid massive mass spectral data.

We propose a comprehensive pattern recognition procedure that will achieve best discrimination between two or more sets of subjects with data in the same coordinate system. Applying the procedure to MS data of proteomic analysis of serum from ovarian cancer patients and serum from cancer-free individuals in the Food and Drug Administration/National Cancer Institute Clinical Proteomics Database, we have achieved perfect discrimination (100% sensitivity, 100% specificity) of patients with ovarian cancer, including early-stage disease, from normal controls for two independent sets of data. Our procedure identifies the best subset of proteomic biomarkers for optimal discrimination between the groups and appears to have higher discriminatory power than other methods reported to date. For large-scale screening for diseases of relatively low prevalence such as ovarian cancer, almost perfect specificity and sensitivity of the detection system is critical to avoid unmanageably high numbers of false-positive cases.