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Yes / There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. Ethics and dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. Trial registration number NCT03428477. / The EMT2 trial is funded by Yorkshire Cancer Research (L387) and is sponsored by the University of Leeds. The EMT2 biospecimen collection is funded by the National Institutes of Health (1R01CA243454-01A1) and is sponsored by the University of Leeds ( governance-ethics@ leeds. ac. uk). Both studies have been adopted to the NIHR Clinical Research Network (CRN) Portfolio (CPMS ID 34700 and 47372, respectively) and have benefited from CRN research staff support.

Résumé : L’hypertension artérielle pulmonaire (HTAP) est une maladie rare dans laquelle les artères pulmonaires subissent un important remodelage et un recrutement de cellules proinflammatoires dans la paroi. Généralement les patients atteints sont diagnostiqués tardivement. Or, à son stade avancé, l’HTAP est irréversible. Aucun traitement actuel ne permet de soigner définitivement les patients. Nous émettons l’hypothèse que l’inflammation pourrait être à l’origine de plusieurs dysfonctions cellulaires et que sa résolution pourrait probablement prévenir l’HTAP. Deux modèles d’HTAP expérimentale ont été utilisés. Le premier met en jeu des artères pulmonaires humaines (APH) cultivées in vitro et rendues hyperréactives et sur lesquelles les effets des Résolvines D1 et E1 ainsi que leurs précurseurs respectifs ont été évalués. Le deuxième est un modèle in vivo bien connu de rats hypertendus à la monocrotaline (MCT) sur lesquels le rôle curatif du MAG-DHA (un monoacylglycéride de l’acide docosahexaénoïque) a été étudié quand l’HTAP est déjà installée. Les résultats démontrent que 24 h de prétraitement in vitro avec le TNFalpha, l’IL-6 ou l’ET-1 augmente la réactivité pharmaco-mécanique et la sensibilité au Ca2+ des APH stimulées avec 80 mM de KCl, 1 µM de 5-hydroxytryptamine (5-HT), 30 nM U-46619 et 1 µM de PDBu. En revanche, 300 nM de RvD1 ou de RvE1 ainsi que 1µM de MAG-DHA ou de MAG-EPA (monoacylglycéride de l’acide éicosapentaénoïque) renversent les effets induits par les traitements proinflammatoires et vasoconstricteurs. De plus, in vivo, il a été démontré que 7 jours de traitement avec le MAG-DHA peuvent permettre de résoudre le statut inflammatoire dans un modèle d’hypertension pulmonaire induite par la MCT chez le rat. Dans les deux modèles, l’expression de biomarqueurs inflammatoires (TNFalpha, COX-2, STAT3) et les niveaux de phosphorylation des activateurs nucléaires du remodelage tels que c-Fos, c-Jun, NFkB et MMP9 étaient augmentées par les traitements proinflammatoires. Cependant, les expériences d’immuno-buvardage montrent que la RvD1, la RvE1 et leurs précurseurs normalisaient les niveaux de détections de ces marqueurs de l’inflammation. En conclusion, l’ensemble des données montrent que les Résolvines D1 et E1 ainsi que leurs précurseurs sont des candidats efficaces pour résoudre l’inflammation induite pour prévenir l’hyperréactivité pharmacologique des artères pulmonaires. / Abstract : Pulmonary hypertension (PH) is rare disease characterized by an important remodelling and proinflammatory cells recruitement into the pulmonary artery wall. Because of the late diagnostic, the patient care is often performed when PH is at its irreversible and most severe stage. Unfortunatly, none of the actual treatments are able to cure the patients for the long term. We hypothesize that inflammation could be a major event at the origin of all the other cellular dysfunctions that characterise PH. Resolvins; metabolites from Oméga-3 could resolve inflammation and potentially prevent or reverse PH. In the present study, two models of PH have been used. The first one is an in vitro model involving cultured human pulmonary arteries (HPA) in which inflammatory or hyperreactive conditions have been induced to evaluate the effects of Resolvin D1 and E1 and their precursors. The second model is a well-known in vivo model of monocrotalineinduced PH in rats, treated with MAG-DHA (monoacylglyceride form of docosahexaenoic acid) to evaluate the curative ability of this compound to resolve the disease at its severe stage. Results show that 24-h pre-treatment with TNFα, IL-6 or ET-1 increased the reactivity and Ca2+ sensitivity of HPA as revealed by agonist challenges with: 80 mM KCl, 1 μM 5- hydroxytryptamine (5-HT), 30 nM U-46619 and 1 μM PDBu. However, 300 nM RvD1 or RvE1, as well as 1 μM MAG-DHA or MAG-EPA (monoacylglyceride form of eicosapentaenoic acid) strongly reversed the over responsiveness induced by proinflammatory and hyperreactive treatments.Moreover, a 7-day treatment with MAG-DHA is able to resolve the inflammatory status in a rat model of monocrotaline-induced pulmonary hypertension. In both models, the inflammatory status enhanced the expression of inflammatory biomarkers (TNF-α, COX-2, STAT-3) as well as the detection of MMP9 and phosphorylated nuclear factors such as P-c-Fos, P-c-Jun and P-NF-κB involved in the activation of wall remodeling. Hence, RvD1, RvE1 and their precursors normalized the expression of these inflammatory biomarkers. In conclusion, Resolvin D1 and E1 and their respective precursors MAG-DHA and MAGEPA could inhibit inflammation status to prevent and potentially cure pulmonary hypertension.

Thesis (MScAgric) -- University of Stellenbosch, 2000. / ENGLISH ABSTRACT: Lipids remain one of the most important nutrients required by broilers. The growing awareness that some Western societies have too high a dietary ratio of n-6/n-3 polyunsaturated fatty acids is of direct relevance to broiler nutrition and lipid metabolism. Meaningful quantities of n-3 polyunsaturates have been incorporated into major poultry tissues, so that the production of broiler meat with high n-3 polyunsaturates becomes advantageous for the broiler industry as they are perceived as having a 'healthier' lipid profile. Unfortunately, such broiler meat is rather susceptible to oxidative deterioration, and oxidation often determines shelf life of poultry meat products. The addition of a-tocopherol (vitamin E) to broiler diets is an effective means of improving the oxidative stability of broiler meat. Elevated a-tocopherol levels in broiler feeds increase tissue concentrations thereof resulting in improved stability of membranal structures which may be expected to increase the oxidative stability of broiler meat and meat products. Three investigations were done at Mariendahl Poultry Research Station in Stellenbosch. The broilers were kept in 1 x 0.4 x 0.5 m cages in a broiler rearing house. All the trials started with day-old chicks, except experiment 1 where 3-week old broilers were used. At the end of trials 2 and 3 the 6-week old broilers were slaughtered and the carcasses prepared for chemical analysis. Experiment 1: Metabolisabie energy of Canola acid oil and Famarol acid oil for broiler chickens. In trials with 21-day-old male broilers the true metabolisabie energy value, corrected for nitrogen retention (TMEn) was determined by the balance method for Canala acid oil (CAO) and Famarol acid oil (FAO). The trials were duplicated, each time using different samples of the two oils from the same source (experiment 1 and 2). Each of the two oils were blended in two ratios with a basal diet to form the test diets, viz. 100% Basal; 96% Basal: 4% Oil; 92% Basal: 8% Oil. In experiment 3, 50 % bran was added to the maize to form the basal diet. The balance trials lasted for 3 days after an adaptation period of 4 days. The TMEn values determined by regression for the broilers of CAO did not differ significantly (P>0.05) between experiments 1 and 2. However, the value for experiment 3 was significantly (P<0.05) higher than those for experiments 1 and 2. The TMEn values of FAO also did not differ significantly (P>0.05) between experiments 1 and 2, although the value for experiment 3 was significantly higher than that of experiment 1. The addition of 50 % bran to the basal diet in experiment 3 could have stimulated the digestive breakdown process and hence increase the secretion of digestive enzymes. This could lead to an increase in the utilisation of the test lipid and therefore an increase in the TMEn value. The TMEn values of CAO differed significantly (P<0.05) from those of FAO for all three the experiments (exp. 1:30.6 ± 0.399 MJ/kg for CAO vs. 25.9 ± 0.441 MJ/kg for FAO; expo 2: 31.0 ± 0.633 MJ/kg for CAO vs. 26.1 ± 0.668 MJ/kg for FAO: expo 3: 32.1 ± 0.867 MJ/kg for CAO vs. 27.1 MJ/kg for FAO).Experiment 2: of broilers. The dietary effects of various combinations of Canala acid oil (CAO, a high level of C18:3n-3 and MUFA) and Famarol Effects of various dietary n-6/n-3 fatty acid ratios on the perfonnance and body composition acid oil (FAO, a high level of 18:2n-6 and SFA) on tissue fatty acid composition were studied in broiler carcasses and abdominal fat pads. From day-old to six weeks, chicks were fed one of six diets containing 100% FAO, 80% FAO-20% CAO, 60% FAO-40% CAO, 40% FAO-60% CAO, 20% FAO-80% CAO, 100% CAO. There were no statistical differences (P>0.05) in average daily gain (1.71 ± 0.059 g) or feed conversion ratios (1.97 ± 0.051) among dietary groups. No statistical differences (P>0.05) were found in the chemical proximate composition of the carcasses for the moisture (66.20 ± 0.112 %), protein (17.63 ± 0.484 %), lipid (15.92 ± 1.507 %) and ash (0.95 ± 0.115 %) content among dietary groups. No statistical differences (P>0.05) were found in the chemical proximate composition of the abdominal fat pads for the moisture (28.77 ± 0.112 %), protein (3.03 ± 0.484 %), lipid (63.32 ± 9.789 %) and ash (0.45 ± 0.135 %) content among dietary groups. With the increase in dietary CAO levels, the percentages of C18:2n-6 and C20:4n-6 in the carcasses decreased respectively with 1.78 % from 20.88 % and 0.35 % from 1.05 %, whilst C18:3n-3 and longer chain n-3 fatty acids such as C20:5n-3 and C22:6n-3 increased respectively with 2.25 % from 1 %, 0.1 % from 0.1 % and 0.67 % from 0.2 %. The same tendency was seen in the abdominal fat pads where C18:2n-6 and C20:4n-6 decreased respectively with 1.55 % from 20.75 % and 0.98 % from 1.2 % with an increase in dietary CAO, whilst C18:3n-3, C20:5n-3 and C22:6n-3 increased respectively with 2.13 % from 1.15 %, 0.45 % from 0.03 % and 0.95 % from 0.05 %. The n-3/n-6 ratio in the carcasses and abdominal fat pads increased respectively with 0.16 % from 0.06 % and 0.19 % from 0.06 % with an increase in dietary CAO. These results clearly indicate that dietary CAO enriched with a-linolenic acid lower saturated fatty acids respectively in broiler carcasses and abdominal fat pads with 4.88 % from 31.6 % and 10.63% from 31.1 %, whilst increasing monounsaturated fatty acids with 3.87 % from 44.95 % and 7.25 % from 46.7 % respectively and polyunsaturated fatty acids with 1.02 % from 23.45 % and 2.38 % from 23.2 % respectively. Experiment 3: Effect of dietary vitamin E on the performance of broilers and oxidative stability, colour, microbiological stability, fatty acid composition and pH of broiler meat during refrigerated and frozen storage. Experiment 1 was carried out with 220 one-day-old broiler chicks to evaluate the effect of eleven concentrations of vitamin E (0, 20, 40, 60, 80, 100, 120, 140, 160, 180 and 200 mg a-tocopheryl acetate 1 kg diet) on their production performance and the oxidative stability of their frozen broiler carcasses. The diets with vitamin E levels 0 to 100 mg were fed from day-old to 42 days of age while the diets with vitamin E levels 120 to 200 mg were fed from 21 to 42 days of age. The oxidative stability, evaluated by thiobarbituric acid reactive substances (TBARS) values, was determined after 30, 90, 120 and 150 days of storage at -20°C. There were no statistical differences (P>0.05) in average daily gain (1.85 ± 0.111 g) or feed conversion ratios (2.29 ± 0.397) among dietary groups. TBARS values increased significantly (P<0.05) with increasing time of storage (basal diet: day 30 = 1.71 ± 0.51; day 150 = 4.89 ± 0.51), but decreased significantly (P<0.05) with increasing vitamin E levels (day 150: basal = 4.89 ± 0.51; 100 mg / kg = 1.09 ± 0.27). Experiment 2 was carried out with day-old broiler chicks to evaluate the effect of five concentrations of vitamin E (0, 40, 80, 120 and 160 mg atocopheryl acetate / diet) on their performance and the oxidative stability of their refrigerated carcasses. The experimental diets were fed from day-old to 42 days of age. The oxidative stability, evaluated by TBARS values, colour deterioration and microbiological stability were determined after 0, 4, 8, 10 and 12 days of storage at 4°C. Fatty acid analysis was done on the samples of days 0 and 12. There were no statistical differences (P>0.05) in average daily gain (1.88 ± 0.117 g) or feed conversion ratios (2.37 ± 0.467) among dietary groups. TBARS values increased significantly (P<0.05) with increasing time of storage, but decreased significantly (P<0.05) with increasing vitamin E levels. There were no statistical differences (P>0.05) in colour measurements for L* (44.97 ± 0.662), a* (5.23 ± 0.315) or b* (12.76 ± 0.321) values between treatments. Microbiological counts increased significantly (P<0.05) over time with vitamin E concentration showing no effect. There were no statistical differences (P>0.05) for any of the fatty acid groups measured (SFA: Day 0 = 26.1 ± 1.13%, Day 12 = 26.1 ± 1.17%; MUFA: Day 0 = 41.4 ± 1.46%, Day 12 = 40.2 ± 2.28%; PUFA: Day 0 = 32.4 ± 1.95%, Day 12 = 33.8 ± 2.52%) among dietary groups. Similarly, none of the fatty acids showed statistical significant (P>0.05) concentration changes over time. There were no statistical differences (P>0.05) in pH (6.01 ± 0.206) among dietary groups. / AFRIKAANSE OPSOMMING: Lipiede is steeds een van die mees belangrike voedingstowwe wat deur braakuikens benodig word. Die groeiende bewuswording dat sekere Westerse gemeenskappe 'n te hoë verhouding van n-6/n-3 poli-onversadigde vetsure in hul dieet het, is direk relevant vir braaikuikenvoeding en lipiedmetabolisme. Betekenisvolle hoeveelhede n-3 polionversadigde vetsure is geïnkorporeer in die belangrikste hoendersnitte, met die gevolg dat die produksie van braaikuikenvleis met hoë n-3 poli-onversadigde vetsure voordelig is vir die braaikuikenindustrie en geag word 'n meer "gesonde" beeld te hê. Ongelukkig is sodanige braaikuikenvleis redelik vatbaar vir oksidatiewe bederf, en oksidasie bepaal dikwels die rakleeftyd van hoendervleisprodukte. Die byvoeging van a-tokoferol (vitamine E) by braaikuikendiëte is 'n effektiewe manier om die oksidatiewe stabiliteit van braaikuikenvleis te verbeter. Verhoogde a-tokoferol vlakke in braakuikenvoere verhoog die weefselkonsentrasie wat verhoogde stabiliteit van die membraanstrukture en derhalwe moontlike verhoogde oksidatiewe stabiliteit van braakuikenvleis en -produkte tot gevolg het. Drie ondersoeke is onderneem by Mariendahl Pluimvee Navorsingstasie te Stellenbosch. Die braakuikens is aangehou in 1 x 0.4 x 0.5m hokke in braaikuikenhuise. In al die proewe is dagoud kuikens gebruik, behalwe eksperiment 1 waar drieweek oue kuikens gebruik is. Aan die einde van proewe 2 en 3 is die ses-week oue braaikuikens geslag en die karkasse voorberei vir analise. Eksperiment 1: braaikuikens. Die ware metaboliseerbare energie waarde van Canola voergraadolie (CAO) en Famarol voergraadolie (FAO), Metaboliseerbare energie van Canola voergraadolie en Famarol voergraadolie vir gekorregeer vir stikstof retensie (WMEn), is by wyse van proewe op 21 dae oue braaikuikenhaantjies bepaal deur van die balansrnetode gebruik te maak. Die proewe is tweemaal herhaal vir verhoogde akkuraatheid, met die gebruik van verskillende monsters van die twee olies vanaf dieselfde bron. Die olies is in twee verhoudings met 'n basale diëet gemeng om die proef dieet te vorm, nl. 100% Basaal; 96% Basaal: 4% Olie en 92% Basaal: 8% Olie. Die balans proewe het 3 dae geduur na afloop van 'n aanpassingsperiode van 4 dae. Die WMEn waardes van CAO, bepaal deur middel van regressie analise, het nie betekenisvol verskil (P>0.05) tussen eksperimente 1 en 2 nie. Die waarde van eksperiment 3 was betekenisvol hoër (P<0.05) as die van die eerste twee eksperimente. Die WMEn waardes van FAO het ook nie betekenisvol verskil (P>0.05) tussen eksperimente 1 en 2 nie, maar die waarde vir eksperiment 3 was betekenisvol hoër as dié van eksperiment 1. Die WMEn waardes van COA het betekenisvol verskil (P< 0.05) van dié van FAO vir al die eksperimente (exp. 1: 30.6 ± 0.399 MJ/kg vir CAO vs. 25.9 ± 0.441 MJ/kg vir FAO; expo 2: 31.0 ± 0.633 MJ/kg vir CAO vs. 26.1 ± 0.668 MJ/kg vir FAO: expo 3: 32.1 ± 0.867 MJ/kg vir CAO vs. 27.1 MJ/kg vir FAO). Eksperiment 2: Die invloed van verskeie rantsoen n-6/n3 vetsuurverhoudings op die produksie en liggaamsamestelling van braaikuikens. Die rantsoeneffek van verskeie kombinasies Canola voergraadolie (CAO, 'n hoë vlak van C18:3n-3 en monoonversadigde vetsure) en Famarol voergraadolie (FAO, 'n hoë vlak van 18:2n-6 en versadigde vetsure) op die weefselvetsuursamestelling is bestudeer in braaikuikenkarkasse en abdominale vetneerlegging. Die kuikens is van dagoud to op ses-weke ouderdom een van ses diëte gevoer met die volgende samestellings: 100% FAO, 80% FAO-20% CAO, 60% FAO - 40%CAO, 40% FAO - 60% CAO, 20% FAO - 80% CAO, 100% CAO. Daar was geen statistiese verskil tussen die rantsoengroepe (P>0.05) in die gemiddelde daaglikse toename (1.71 ± 0.059 g) of die voeromsetverhoudings (1.97 ± 0.051) nie. Geen statistiese verskil (P>0.05) is gevind in die chemiese samestelling van die karkasse vir vog (66.20 ± 0.112 %), proteïn (17.63 ± 0.484 %), lipied (15.92 ± 1.507 %) en as (0.95 ± 0.115 %) inhoud tussen die rantsoen groepe nie. Geen statistiese verskille (P>0.05) is gevind in die chemiese samestelling van die abdominale vetneerlegging vir vog (28.77 ± 0.112 %), proteien (3.03 ± 0.484 %), lipied (63.32 ± 9.789 %) en as (0.45 ± 0.135 %) inhoud onder die rantsoengroepe nie. Met die verhoging in die rantsoen CAO vlakke het die persentasie van C18:2n-6 en C20:4n-6 in die karkasse verminder met 1.78 % en 0.35 % respektiewelik, terwyl C18:3n-3 en langer ketting n-3 vetsure soos C20:5n-3 en C22:6n-3 respektiewelik met 2.25 %, 0.1 % en 0.67 % verhoog het. Dieselfde tendens is opgemerk in die abdominale vetneerlegging waar C18:2n-6 en C20:4n-6 afgeneem het met 1.55 % en 0.98 % respektiewelik met die verhoging van rantsoen CAO, terwyl C18:3n-3, C20:5n-3 en C22:6n-3 verhoog het met 2.13 %, 0.45 % en 0.95 % respektiewelik. Die n- 3/n-6 verhouding in die karkasse en abdominale vetneerlegging het verhoog met 0.16 % en 0.19 % respektiewelik met die verhoging van die rantsoen CAO. Die resultate toon onomwonde aan dat rantsoen CAO verryk met c-Iinoletensuur, verlaag versadigde vetsure in braaikuikenkarkasse en -adbdominale vetneerleggings met 4.88 % en 10.63% respektiewelik, terwyl die mono-onversadigde vetsure met 3.87 % en 7.25 % respektiewelik verhoog word en polionversadigde vetsure met 1.02 % en 2.38 % respektiewelik verhoog word. Eksperiment 3: Die invloed van vitamine E op die produksie van braaikuikens en die oksidatiewe stabiliteit, kleur, mikrobiologiese stabilitiet, vetsuursamestelling en pH van braaikuikenvleis gedurende verkoelde en bevrore berging. Eksperiment 1 is uitgevoer met 220 dagoud braaikuikens ten einde die effek van elf konsentrasies van vitamine E (0, 20, 40, 60, 80, 100, 120, 140, 160, 180 en 200 mg a-tokoferyl acetaat / kg voer) op hul produksieprestasie en die oksidatiewe stabiliteit van hul gevriesde braakuikenkarkasse te evalueer. Die diëte met vitamine E vlakke 0 tot 100 mg is vanaf dagoud tot 42-dae-ouderdom gevoer, terwyl die diëte met vitamine E vlakke van 120 tot 200mg gevoer is vanaf 21 tot 42- dae-ouderdom. Die oksidatiewe stabiliteit, soos geëvalueer deur tiobarbituriese suur reaktiewe stowwe (TBARS) waardes, is bepaal na 30, 90, 120 en 150 dae van berging teen -20°C. Daar was geen statistiese verskille (P>0.05) in die gemiddelde daaglikse toename (1.85 ± 0.111 g) of voeromsetverhoudings (2.29 ± 0.397) tussen die rantsoengroepe nie. TBARS waardes het betekenisvol toegeneem (P<0.05) met die verhoging in bergingsperiode, maar het betekenisvol afgeneem (P<0.05) met verhoogde vitamine E vlakke. Eksperiment 2 is uitgevoer met dagoud braaikuikens ten einde die effek van vyf konsentrasies van vitamine E (0, 40, 80, 120 and 160 mg a-tokoferyl acetaat / kg voer) op hul prestasie en die oksidatiewe stabiliteit van hul verkoelde karkasse te evalueer. Die eksperimentele diëte is gevoer vanaf dagoud tot 42- dae-ouderdom. Die oksidatiewe stabiliteit, geëvalueer deur middel van TBARS waardes, kleur afname en mikrobiologiese stabiliteit is bepaal na 0, 4, 8, 10 en 12 dae van berging teen 4°C. Vetsuuranalises is gedoen op die monsters van dae 0 en 12. Daar was geen statistiese verskille (P>0.05) in die gemiddelde daaglikse toename (1.88 ± 0.117 g) of voeromsetverhoudings (2.37 ± 0.467) tussen die rantsoengroepe nie. TBARS waardes het betekenisvol verhoog (P<0.05) met die verlengde bergingsperiode, maar het betekenisvol afgeneem (P<0.05) met verhoogde viatmine E vlakke. Daar was geen statistiese verskille (P>0.05) in kleur metings vir L* (44.97 ± 0.662), a* (5.23 ± 0.315) of b* (12.76 ± 0.321) waardes tussen behandelings nie. Mikrobiologiese tellings het betekenisvol verhoog (P<0.05) oor tyd met die vitamine E konsentrasie wat geen effek getoon het nie. Daar was geen statisties betekenisvolle verskille (P>0.05) vir enige van die vetsuurgroepe tussen die behandelings nie. Soortgelyks het geen van die vetsure statisties betekenisvolle (P>0.05) konsentrasieveranderings oor tyd aangetoon nie. Daar was geen statistiese verskil (P>0.05) in die pH (6.01 ± 0.206) tussen die rantsoengroepe nie.

Thesis (PhD (Food Science))--University of Stellenbosch, 2006. / Long-chain polyunsaturated fatty acids (LCPUFA), especially the n-3 LCPUFA metabolic products eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play an important role as regulators in many biological processes. To date hake (Merluccius capensis) heads, a rich source of EPA and DHA, have been discarded at sea. The South African Fisheries Policy Development Committee concerned with the environmental impact of this practice has rendered it undesirable. The high prevalence of under-nutrition amongst children in South Africa can be addressed by the supplementation of their diet with this unexploited fish source. The aim of the current study was to develop a microbiologically safe and sensory acceptable sandwich spread using fish flour prepared from fish heads, as a prime ingredient. The intervention trial aimed to compare the effects of an increased dietary intake of n-3 LCPUFA, specifically DHA, on the blood fatty acid levels and absenteeism (as indicator of immune function), as well as the cognitive status, of the subjects. The microbiological content of the sandwich spread was determined after storage for 20 d at 5°C and 15 d at 25°C. Sensory evaluation was performed by consumers (n = 95; M:F = 44:51; 6 – 9 yr) to determine acceptance of the five different flavours individually incorporated into the sandwich spread to mask the fishy note and to provide different flavour options. For the intervention trial subjects (n = 351) were stratified within class group (A - E) and gender and randomly assigned to two treatment categories, an experimental group (EG; n = 174) receiving 25 g sandwich spread.d-1 (191.66 mg DHA. d-1) and a control group (CG; n = 177) receiving an analogous placebo. On school days (104 d), each subject received two sandwiches consisting of two slices of bread (ca. 60 g), spread with 25 g of either the placebo or the experimental spread. Blood samples were drawn at baseline and post intervention. Plasma fatty acid and red blood cell (RBC) membrane status, C-reactive protein levels, as well as vitamin and micronutrient status, were determined. Trained test administrators conducted a battery of cognitive tests. According to South African Government health standards, the sandwich spread remained microbiologically safe after storage. Male and female consumer respondents revealed a significant difference between gender preferences of the five different spread flavours (p <0.05). Significant treatment effects (p <0.05) were observed in n-3 LCPUFA status of the EG, as well as for their absenteeism from school. The two subtests of the Hopkins Verbal Learning test, Recognition and Discrimination Index, showed significant differences between the EG and CG (p <0.05) post intervention in the Grade 2 subjects. The Spelling tests also showed a significant difference between the two groups (p <0.05). In the current study a microbiologically safe and sensory acceptable sandwich spread was developed and tested during an intervention trial, and could possibly in future, provide a healthier option in the School Nutritional Programme. This study proved that supplementation of children (6 - 9 yr) with n-3 LCPUFA, with specific reference to EPA and DHA from a marine source, could have a beneficial effect on their fatty acid status and absenteeism from school. Based on the outcomes of the Hopkins Verbal Learning test and Spelling test, the current study proved that an n-3 fatty acid-rich spread improved the learning ability and memory of children.

L'Infarctus du myocarde (IM) provoque, chez le rat, une augmentation de l'apoptose dans le système limbique en plus d'induire des symptômes qui s'apparentent à la dépression chez l'humain. Nous avons démontré qu'une diète élevée en oméga-3 ou la prise de probiotiques pouvaient être efficaces pour réduire ces effets si ces interventions débutaient avant l'induction de l'ischémie myocardique. Cette étude a pour objectif de déterminer l'efficacité de ces interventions si elles débutent après l'ischémie myocardique. L’IM a été induit chez le rat mâle Sprague-Dawley par l’occlusion de l’artère coronaire descendante antérieure gauche pendant 40 minutes. À la suite de l’ischémie, les rats ont reçu des probiotiques (1 billion de bactéries vivantes de L. helveticus R0052 et de B. longum R0175) ou un véhicule dans leur eau de boisson en présence d'une diète élevée ou faible en oméga-3. À 3 jours post-IM, l’activité enzymatique de la caspase-3 et le nombre de cellules dUTP nick-end labelling (TUNEL) positives sont diminués dans les régions CA1 et le corps godronné de l’hippocampe ainsi que dans l’amygdale en présence de la diète élevée en oméga-3. La prise de probiotiques atténue également l’activité de la caspase-3 et le nombre de cellules TUNEL positives dans le corps godronné et l’amygdale médiane. À 2 semaines post-IM, le comportement dépressif évalué par 3 tests comportementaux (test d’interaction sociale, test de nage forcée et test d’évitement passif) a été observé chez le groupe recevant la diète faible en oméga-3 sans probiotiques et le comportement dépressif a été atténué avec la diète élevée en oméga-3 et/ou la prise de probiotiques. Les probiotiques ont augmenté les niveaux plasmatiques d’interleukine-4 (IL- 4) tandis que la diète élevée en oméga-3 a montré une diminution de la protéine chimiotactique monocytaire 1 (MCP-1). Ces résultats indiquent qu’une diète élevée en oméga-3 ou la prise de probiotiques, débutant à la suite de l’IM, s’avèrent bénéfiques pour atténuer la dépression et l’apoptose dans le système limbique. / Proinflammatory cytokines play a central role in depressive-like behavior and apoptosis in the limbic system after myocardial infarction (MI). Polyunsaturated fatty acids (PUFA) omega-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before ischemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. This study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depressive-like behavior. MI was induced by the occlusion of the left anterior descending coronary artery for 40 minutes in rats. After the onset of reperfusion, animals were fed with a high or low PUFA omega-3 diet, combined or not with 1 billion live bacteria of L. helveticus R0052 and B. longum R0175. At 3 days post-MI, caspase-3 enzymatic activities and terminal dUTP nickend labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus and amygdala with the high PUFA omega-3 diet as compared to the other diet. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the dentate gyrus and the medial amygdala. At 2 weeks post-MI, depressive-like behaviour, evaluated by 3 behavioural tests (social interaction, passive avoidance and forced swim test), was observed in the low PUFA omega-3 diet without probiotics and this behavior was attenuated with the high PUFA omega-3 diet or/and probiotics. Probiotics increased interleukin-4 plasmatic concentrations while high PUFA omega-3 diet decreased monocyte chemotactic protein 1 (MCP-1). These results indicate that a high PUFA omega-3 diet or the administration of probiotics, starting iii after the onset of reperfusion, are beneficial to attenuate post-MI depression and apoptosis in the limbic system.

INTRODUÇÃO: As doenças cardiovasculares (DCV) aparecem em primeiro lugar entre as principais causas de mortalidade no mundo, representando 46,2% do total de mortes, número muito próximo aos encontrados no Brasil, impactando os gastos com saúde. A prevenção baseia-se em estilo de vida saudável, contudo, uma vez instaladas, é consenso o tratamento medicamentoso com estatinas. Alguns tratamentos alternativos vêm sendo estudados como o ômega-3 (w-3) na prevenção das DCV. Apesar das evidências clínicas favoráveis, não existem muitos estudos acerca da viabilidade econômica de tais tratamentos. OBJETIVO: Avaliar o custo-efetividade das intervenções com w-3 isolado ou associado às estatinas na redução dos fatores de risco cardiovascular sob a perspectiva do Sistema Único de Saúde (SUS). MATERIAL E MÉTODOS: Para avaliar a efetividade do w-3 isolado e combinado com estatina foram utilizados os dados secundários do ensaio clínico CARDIONUTRI no momento basal e após 8 semanas. A amostra foi composta por 186 indivíduos com idade entre 30 e 74 anos divididos entre aqueles que não tomavam medicação e os que tomavam estatinas. Aleatoriamente, uma parcela deles recebeu cápsulas de 1 g de w-3 (37% de ácido eicosapentaenoico e 23% de docosaexaenoico) ou cápsulas de placebo. A recomendação era de que todos deveriam tomar 3 cápsulas ao dia, totalizando 3g/dia (de w-3 ou placebo) durante 8 semanas. Ao final, obteve-se quatro grupos: a) w-3; b) placebo; c) w-3 + estatina; e d) estatina. Para a avaliação do impacto foi usado o método Diferenças em Diferenças com a adição de variáveis de controle: densidade calórica do consumo alimentar, Índice de Massa Corporal (IMC), prática de atividade física, idade, sexo, raça, hábito tabagista, escolaridade e grau de adesão. Os custos dos tratamentos foram estimados com base no custo médio ponderado pelas probabilidades das eventuais intercorrências relacionadas a efeitos adversos e de sucesso e fracasso por meio do método da árvore de decisão. Foi considerado para fins do cômputo dos custos o período de 2 meses de tratamento. RESULTADOS: Nos quatro grupos, a maioria eram mulheres, obesas e com escore de risco muito alto para DCV. Os grupos w-3 e placebo possuíam maior escolaridade e renda comparadas a aqueles que tomavam estatinas. Todas as variáveis de controle foram estatisticamente significantes em pelo menos um dos modelos, exceto raça. A suplementação com w-3 associada às estatinas mostrou efetividade sobre HDLPEQUENA, com diminuição de 2,211 mg/dL e custo-efetividade de R$ 109,31 por redução em mg/dl da lipoproteína em 2 meses de tratamento. CONCLUSÃO: O tratamento com 1,8g de óleo de peixe isolado ou associado às estatinas em intervenção primária não evidenciou efeitos significativos nas mudanças dos parâmetros lipídicos, exceto no caso da HDLPEQUENA com o tratamento associado, mostrando não ser custo-efetivo na redução dos fatores de risco cardiovascular em geral. Em virtude da existência de controvérsias acerca de seus potenciais efeitos, sugere-se que os ensaios clínicos utilizem métodos estatísticos mais robustos para avaliar o impacto líquido da suplementação. / INTRODUCTION: Cardiovascular diseases (CVD) are among the leading causes of death worldwide, accounting for 46.2% of all cases, very close to those found in Brazil, impacting health expenses. Current prevention is based on a healthy lifestyle, and once a CVD diagnosis is made, the current consensus is drug treatments with statins. Some alternative treatments such as omega-3 (w-3) have been studied in the prevention of these diseases. However, despite favorable clinical evidence, there are not many studies of economic viability of this treatment. OBJECTIVE: To evaluate the cost-effectiveness of interventions with w-3 alone or associated with statins in reducing cardiovascular risk factors from the perspective of the Unified Health System (SUS). METHODS: To assess the effectiveness of w-3 alone and its combination with statin, the secondary data of the classic lipid profile and lipoprotein size of the CARDIONUTRI clinical trial were used at baseline and after 8 weeks. The sample consisted of 186 subjects aged 30 to 74 years randomly received capsules containing 3g of w-3 per day (37% of eicosapentaenoic acid and 23% of docosahexaenoic acid) or 3g of mineral oil (placebo). Capsules were randomly assigned to individuals who were not taking medication or were already taking statins, separated into four groups: a) w-3; b) placebo; c) w-3 associated with statins; d) statins. Data analysis was conducted using the Difference in Differences statistical method with the addition of control variables: caloric density of food consumption, Body Mass Index (BMI), physical activity practice, age, sex, race, smoking, educational level and adherence to the treatment. The treatment costs were estimated based on the weighted average cost by the probabilities of the eventual intercurrences related to adverse effects and of success and failure by means of the decision tree method elapsed in 2 months of treatment. RESULTS: In all four groups, the majority were women, obese and with a very high-risk score for CVD. W-3 and placebo groups had higher educational level and income compared to those who were already taking statins. All control variables were statistically significant in at least one of the models except race. W-3 supplementation showed efficacy on HDLSMALL among those who consumed w-3 + statins with a reduction of 2,211 mg /dL and cost-effectiveness R$ 109.31 per mg/dL for 2 months of treatment. CONCLUSION: The treatment with 1.8g of fish oil isolated or associated with statins in primary intervention did not show significant effects on changes in lipid parameters except HDLSMALL of interventions associated with statins. Therefore it was not cost-effective in reducing cardiovascular risk factors. Due to the existence of controversies about its potential effects, it is suggested that clinical trials use more robust statistical methods to assess the net impact of supplementation.

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