Effect of dietary arachidonic acid and n-3 polyunsaturated fatty acids on the production of eicosanoids

The major polyunsaturated fatty acid (PUFA) in the western diet is linoleic acid (LA), which is considered to be the major source of tissue arachidonic acid (AA), the principal precursor for the vaso-active eicosanoids via the cyclooxygenase enzymatic pathway. However, dietary AA may contribute significantly to tissue levels of AA in humans, leading to an increase in the production of eicosanoids, particularly the platelet aggregating, vasoconstricting, thromboxane (TXA2), hence increasing thrombosis risk. The aims of this study were to determine the extent to which dietary AA contributed to prostacyclin (PGI2) and TXA2 production in vivo and whether dietary long chain (LC) n-3 PUFA have a modulating influence on the metabolism of AA to these vaso-active eicosanoids. A gas chromatography -mass spectrometry (GCMS) method for urinary PGI2-M determination and a tandem GCMS/MS method for urinary TXA2-M determination were perfected for use within our laboratory (with the assistance of Dr Howard Knapp, University of Iowa and Professor Reinhard Lorenz, Ludwig Maximilian\u27s University, Munich, respectively). An initial animal study compared the in vitro production of PGI2 by aorta segments with the whole body in vivo production of PGI2 in rats fed ethyl arachidonate or the ethyl ester of eicosapentaenoic acid (EPA), at levels many times higher than encountered in human diets. During AA feeding both measures of PGI2 increased, although in vitro TXA2 production was not affected. EPA feeding lowered in vitro TXA2 and in vivo PGI2. Prior to determining the effects of AA and LC n-3 PUFA in humans, a study was carried out to determine the AA and LC n-3 PUFA content of foods and from these, an estimate of the mean daily intake of AA and other LC PUFA. Eggs, organ meats and paté were found to be the richest sources of AA. Of the meat and fish analysed, white meat was found to be relatively rich in AA but poor in LC n-3 PUFA. Lean red meat, particularly kangaroo had similar LC n-3 PUFA and AA content. Fish, although rich in AA, had extremely high levels of LC n-3 PUFA. The calculated mean daily intakes of AA in Australian adults was 130mg (males) and 96mg (females). For total LC n-3 PUFA intake, the mean daily values were 247mg (males) and 197mg (females). Two human pilot studies involving dietary intervention trials examined the effects of dietary AA and AA plus long chain n-3 PUFA on thrombosis risk, gauged by the change in the ratio of PGI2 / TXA2 as well as alterations to other recognised risk factors, such as lipoprotein lipids and platelet aggregation. The desired dietary amounts of AA and LC n-3 PUFA were achieved in the first study by combining food items with known levels of each fatty acid. In the second study, where a diet with approximately equal quantities of AA and LC n-3 PUFA was being examined, kangaroo meat was consumed, following a low-fat vegetarian diet used as a baseline. Diets rich in AA alone (~500mg/day) increased plasma phospholipid (PL) AA levels, PGIi and TXA2 production. When foods containing equal quantities of AA and EPA (∼500mg/day of each) were fed to subjects PGI2 increased, with no change in TXAs production. Low fat vegetarian diets lowered PGI2 production, the level of which was reestablished by an AA rich diet (∼300mg AA/day + ∼260mg/day LC n-3 PUFA) of kangaroo meat. However, TXA2 production was not altered. A final, larger human dietary intervention trial then examined the effects of diets relatively rich in AA alone, AA plus LC n-3 PUFA and LC n-3 PUFA, on the ratio of PGI2/TXA2- The dietary sources of these fatty acids were white meat, red meat and fish, respectively. Each contained a mean level of AA of ∼140mg/day, with varying LC n-3 PUFA levels (59, 161 and 3380mg/day, respectively). Neither meat diet altered PGI2 or TXA2 production significantly, despite increasing serum PL AA levels. The fish diet resulted in a decrease in the serum and platelet PL AA/EPA ratio and TXA2 production, thus increasing the PGI2 / TXA2 ratio. These results would indicate that stores of AA in the body are sufficiently high to have effectively saturated the cyclooxygenase pathway for production of both PGI2 and TXA2, thus making any small change in the plasma level of AA due to \u27normal\u27 dietary levels, inconsequential. However, as seen in the rat study and the two pilot studies higher dietary levels of AA can increase both PGI2 and TXA2 production. Increases in platelet levels of EPA and DHA were associated with a decrease in TXA2 production, or the maintenance of a constant TXA2 level, while AA tissue levels and PGI2 production increased. This suggests a possible inhibitory effect of LC n-3 PUFA on the metabolism of AA to TXA2, particularly in platelets. From these short term studies, conducted over 2-3 week periods, it can be concluded that diets rich in lean meats can raise plasma AA levels but do not affect TXA2 or PGI2 production, hence are not pro-thrombotic. Diets rich in long chain n-3 PUFA from fish, raise plasma EPA and DHA levels, lower TXA2 production and are anti-thrombotic. Diets which combine equal quantities of AA and LC n-3 PUFA appear to increase PGI2 production while keeping TXA2 production constant. In order for these LC PUFA to have a significant effect on eicosanoid production the dietary intake of these fatty acids through foods such as red meat or white meat would have to be higher than average current Australian consumption levels

Five Minutes with Neil Carberry,CBI: “To the extent that there is accessible academic work there, it will be used”

Part of PPG’s Impact of Social Sciences project focuses on how academic research in the social sciences influences decision-makers in business, government and civil society. Rebecca Mann talked to Neil Carberry of the CBI about the use of social science research in the business community

Singular Instantons Made Regular

The singularity present in cosmological instantons of the Hawking-Turok type is resolved by a conformal transformation, where the conformal factor has a linear zero of codimension one. We show that if the underlying regular manifold is taken to have the topology of $RP^4$, and the conformal factor is taken to be a twisted field so that the zero is enforced, then one obtains a one-parameter family of solutions of the classical field equations, where the minimal action solution has the conformal zero located on a minimal volume noncontractible $RP^3$ submanifold. For instantons with two singularities, the corresponding topology is that of a cylinder $S^3\times [0,1]$ with D=4 analogues of `cross-caps' at each of the endpoints.Comment: 23 pages, compressed and RevTex file, including nine postscript figure files. Submitted versio

A Non-singular Theory of Gravity

We present a geometrical gravitational theory which reduces to Einstein's theory for weak gravitational potentials and which has a singularity-free analog of the Schwarzschild metric.Comment: 8 pages, RevTeX, 3 figures included in compressed form, UTPT-94-0