Astrocytic modulation of cortical oscillations

Brain waves are rhythmic voltage oscillations emerging from the synchronization of individual neurons into a neuronal network. These oscillations range from slow to fast fluctuations, and are classified by power and frequency band, with different frequency bands being associated with specific behaviours. It has been postulated that at least ten distinct mechanisms are required to cover the frequency range of neural oscillations, however the mechanisms that gear the transition between distinct oscillatory frequencies are unknown. In this study, we have used electrophysiological recordings to explore the involvement of astrocytic K+ clearance processes in modulating neural oscillations at both network and cellular levels. Our results indicate that impairment of astrocytic K+ clearance capabilities, either through blockade of K+ uptake or astrocytic connectivity, enhance network excitability and form high power network oscillations over a wide range of frequencies. At the cellular level, local increases in extracellular K+ results in modulation of the oscillatory behaviour of individual neurons, which underlies the network behaviour. Since astrocytes are central for maintaining K+ homeostasis, our study suggests that modulation of their inherent capabilities to clear K+ from the extracellular milieu is a potential mechanism to optimise neural resonance behaviour and thus tune neural oscillations

Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification?

<p>Abstract</p> <p>Background</p> <p>Ireland is an example of a country that has extensive voluntary fortification with folic acid. After a public consultation process, in 2006, the Food Safety Authority in Ireland FSAI <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> recommended mandatory fortification. However due to safety considerations this decision is now on hold. Before mandatory fortification goes ahead, existing levels of unmetabolised folic acid and their anticipated increase after fortification needs investigation because of the potential of folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers. The aim of this study was to examine the levels of circulatory unmetabolised folic acid in Irish adults (both fasted and un-fasted) and new-born infants (fasted) before the proposed implementation of mandatory folic acid fortification. A secondary aim was to predict the increase in circulatory unmetabolised folic acid levels after fortification.</p> <p>Methods</p> <p><it>Study 1</it>. Setting: Irish Blood Transfusion Service (IBTS). Whole blood samples were collected from blood donors (n = 50) attending for routine blood donation sessions (representing the general population). Subjects were not fasted prior to sampling. <it>Study 2</it>. Setting: Coombe Women's and Infant's University Hospital, Dublin. Whole blood samples were collected by venipuncture from mothers (n = 20), and from their infant's umbilical-cords (n = 20) immediately after caesarean section. All women had been fasted for at least 8 hours prior to the surgery. A questionnaire on habitual and recent dietary intakes of folic acid was administered by an interviewer to all subjects. The data collection period was February to April 2006. Serum samples were analysed for plasma folate, plasma folic acid and red cell folate.</p> <p>Results</p> <p><it>Blood Donor Group</it>: Circulatory unmetabolised folic acid was present in 18 out of 20 mothers (fasted) (CI: 68.3%–99.8%) comprising 1.31% of total plasma folate, 17 out of 20 babies (fasted) (CI: 62.1%–96.8%), and 49 out of 50 blood donors (unfasted) (CI: 88.0%–99.9%), comprising 2.25% of total plasma folate,</p> <p>Conclusion</p> <p>While the levels of circulatory unmetabolised folic acid reported are low, it is persistently present in women immediately after caesarean section who were fasting indicating that there would be a constant/habitual exposure of existing tumours to folic acid, with the potential for accelerated growth. Mandatory fortification might exacerbate this. This has implications for those with responsibility for drafting legislating in this area.</p

Folate intake and bowel cancer risk

Folate is a B vitamin required for one-carbon transfer reactions including methylation of cell macromolecules including DNA and synthesis of the purines adenosine and guanosine and the pyrimidine thymidine. Epidemiological evidence suggests that diets providing higher amounts of folates lower the risk of colo-rectal cancer (CRC) and these observations are supported by plausible biological mechanisms. Inadequate folate supply results in DNA damage through (a) the incorporation of uracil (in place of thymidine) into DNA and subsequent unsuccessful attempts at DNA repair and (b) aberrant patterns of DNA methylation. However, human intervention studies using relatively large doses (500–5,000 μg/day) of folic acid (a synthetic form of folate) have provided no evidence of benefit in terms of adenoma recurrence. Indeed, there is some evidence of potential harm in increased risk of prostate cancer. Possible reasons for the apparent divergence in findings from the observational and intervention studies include the use of (unphysiologically) large doses of folic acid in the intervention studies whereas smaller intakes of food folates appeared to offer “protection” against CRC in case–control and prospective cohort studies. With intakes of folic acid greater than 400 μg/day, unmetabolised folic acid appears in peripheral blood and there are suggestions that this folic acid may have adverse effects e.g. reduced cytotoxicity of Natural Killer cells. Until the benefit-risk relationship associated with mandatory fortification with folic acid has been clarified (and, in particular, the possible risk of inducing extra cases of bowel or other cancer), it would seem wise to delay further mandatory folic acid fortification