Physical Activity, Television Viewing Time, and DNA Methylation in Peripheral Blood.

INTRODUCTION: Physical activity may affect health via DNA methylation. The epigenetic influences of sedentary behaviors such as television viewing are unknown. We performed a genomewide study of DNA methylation in peripheral blood in relation to physical activity and television viewing time. METHODS: DNA methylation was measured using the Illumina Infinium HumanMethylation450K BeadChip array in blood samples collected at baseline (N = 5513) and follow-up (N = 1249) from participants in the Melbourne Collaborative Cohort Study. At baseline, times per week of leisure-time physical activity were self-reported. At follow-up, the International Physical Activity Questionnaire was used to assess MET-hours per week of total and leisure-time physical activity and hours per day of television viewing time. Linear mixed models were used to assess associations between physical activity and television viewing measures and DNA methylation at individual CpG sites, adjusted for potential confounders and batch effects. RESULTS: At follow-up, total physical activity was associated with DNA methylation at cg10266336 (P = 6.0 × 10), annotated to the SAA2 gene. Weaker evidence of associations (P < 1.0 × 10) were observed for an additional 14 CpG sites with total physical activity, for 7 CpG sites with leisure-time physical activity, and for 9 CpG sites with television viewing time. Changes in leisure-time physical activity between baseline and follow-up were associated with methylation changes (P < 0.05) at four of the seven CpG sites with weaker evidence of cross-sectional associations with leisure-time physical activity. CONCLUSION: Physical activity and television viewing may be associated with blood DNA methylation, a potential pathway to chronic disease development. Further research using accelerometer data and larger sample sizes is warranted.

Morphological predictors of BRCA1 germline mutations in young women with breast cancer.

BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90). CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.

Neurophysiology of limbic system pathways in the rat: projections from the subicular complex and hippocampus to the entorhinal cortex.

We studied the responses of rat entorhinal neurons to electrical stimulation of the dentate gyrus, hippocampus and subicular complex. Three main results were obtained. Excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation. Cell in layers II, III and V of the entorhinal cortex were responsive. Frequency potentiation of excitatory responses was observed when 10/s stimulation was used. Excitatory responses were followed by inhibitory postsynaptic potentials. The results provide evidence for an excitatory projection from the hippocampus and subiculum to the entorhinal cortex, and are consistent with the existence of feed-forward inhibition of entorhinal principal neurons.

Neurophysiology of limbic system pathways in the rat: projections from the amygdala to the entorhinal cortex.

We studied the responses of rat entorhinal neurons to electrical stimulation of the amygdala. Four main results were obtained: (1) excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation of the amygdala. Cells in layers II, III and V of the entorhinal cortex were responsive. (2) Excitatory responses were followed by inhibitory postsynaptic potentials. (3) Frequency potentiation of both excitatory and inhibitory responses was observed when 10/s stimulation was used. (4) Three amygdala neurons were antidromically activated by entorhinal stimulation; and two layer II entorhinal cells that were excited by amygdala stimulation were also antidromically activated by dentate gyrus stimulation. These results provide evidence for a monosynaptic, excitatory projection from the amygdala to the entorhinal cortex. In addition, the data indicate that amygdala neurons are only one synapse removed from the excitation of dentate gyrus granule cells.