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's 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 'normal' 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.

Entrepreneurship education at university : the plus-zone challenge

The paper discusses the contrast between what is being done and what ought to be done about entrepreneurship education at university level. Research from the Global Entrepreneurship Monitor program demonstrates that entrepreneurship education is an issue of worldwide economic and social significance. It has major policy implications for every nation. The paper briefly discusses the network of entrepreneurship education and experiential learning of which the university is only one component – and not necessarily the most important. The strategic and organizational context of the movement towards more entrepreneurial universities is distinguished from the purely content issue of curriculum designed for aspiring entrepreneurial practitioners. An overview of actual curricula, worldwide, is contrasted with the normative entrepreneurship education framework posited by McMullan and Long (1987). Following consideration of the problems involved in measuring the success of entrepreneurship education programs, a broad, generic template for integrated program development is presented and compared with the approach usually employed in most MBA programs at university business schools. The hierarchical, functionalist approach, symbolized by a pyramid, is contrasted with a more fluid, organic and boundary-crossing approach, symbolized by a wheel. Its central hub is a ‘plus zone’ where lies the deepest challenge for development of entrepreneurship education in a university context.

Effects of long-term head-down-tilt bed rest and different training regimes on the coagulation system of healthy men

Immobility plus preexisting chronic disease or acute trauma can activate the coagulation system, thus increasing the risk for thromboembolic events. The effects of long-term bed-rest immobility and microgravity on the coagulation system of healthy persons (e.g., during crewed Mars missions) have not yet been studied. The main objective of the second Berlin BedRest Study (BBR2-2) "Coagulation Part" was to investigate adaptations of the hemostatic system during long-term bed rest (60 days) under simulated microgravity (6° head-down-tilt [6°HDT]) and after mobilization in three different volunteer groups (randomly assigned to CTR= inactive control group; RE= resistive exercise only group; and RVE= resistive exercise with whole-body vibration group). In 24 males (aged 21-45 years), before, during, and after long-term bed rest, key parameters of coagulation were measured from venous blood samples: D-dimer (DD), thrombin-antithrombin III complex (TAT), and prothrombin fragment F1 + 2 (PT-F1 + 2). Additionally, modified rotational thrombelastometry (ROTEM (®) ) analysis was performed. Times of exploratory analyses were as follows: baseline data collection 2 days before bed rest (BDC-2); eight different days of 6°HDT bed rest (HDT1-HDT60), and two different days after reambulation (R + 3 and R + 6). We found significant changes in DD, TAT, and PT-F1 + 2 over the total time course, but no consistent effect of physical interventions (RE, RVE) on these parameters. Notably, no parameter reached levels indicative of intravascular thrombin formation. All ROTEM® parameters remained within the normal range and no pathological traces were found. Sixty days of 6°HDT bed rest are not associated with pronounced activation of the coagulation system indicative of intravascular thrombus formation in healthy volunteers independent of the training type during the bed rest.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape)

AIM: To test the hypothesis that a 'basal plus' regimenadding once-daily main-meal fast-acting insulin to basal insulin once dailywould be non-inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction. METHODS: This open-label trial enrolled adults to an 8- or 12-week run-in period, during which oral therapies except metformin were stopped and insulin glargine dose was titrated. Those with fasting glucose <7 mmol/l but HbA1c >7% (53 mmol/mol) were randomized to insulin glargine/glulisine once daily (n = 170) or insulin aspart/aspart protamine 30/70 twice daily (n = 165) for 24 weeks, with dose titration to glucose targets using standardized algorithms. RESULTS: For HbA1c, the basal plus regimen was non-inferior to biphasic insulin (least squares mean difference, 0.21%, upper 97.5% confidence limit 0.38%) meeting the predefined non-inferiority margin of 0.4%. Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version and Insulin Treatment Satisfaction Questionnaire total scores) significantly favoured basal plus. No difference was observed between the basal plus and the biphasic insulin groups in responders (HbA1c <7%, 20.6 vs 27.9%; p = 0.12), weight gain (2.06 vs 2.50 kg; p = 0.2), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life average weighted impact (AWI) score) and generic health status (five-dimension European Quality of Life questionnaire). Overall hypoglycaemia rates were similar between groups (15.3 vs 18.2 events/patient-year; p = 0.22); nocturnal hypoglycaemia was higher with the basal plus regimen (5.7 vs 3.6 events/patient-year; p = 0.02). CONCLUSION: In long-standing type 2 diabetes with suboptimal glycaemia despite oral therapies and basal insulin, the basal plus regimen was non-inferior to biphasic insulin for biomedical outcomes, with a similar overall hypoglycaemia rate but more nocturnal events.