BACKGROUND/OBJECTIVES: The aim of this study was to analyze the influence of a Mediterranean dietary pattern on plasma total antioxidant capacity (TAC) after 3 years of intervention and the associations with adiposity indexes in a randomized dietary trial (PREDIMED trial) with high cardiovascular risk patients.

SUBJECTS/METHODS: 187 subjects were randomly selected from the PREDIMED-UNAV center after they completed 3-year intervention program. Participants were following a Mediterranean-style diet with high intake of virgin olive oil or high intake of nuts, or a conventional low-fat diet. Adiposity indexes were measured at baseline and at year 3. Plasma TAC was evaluated using a commercially available colorimetric assay kit.

RESULTS: Plasma TAC in the control, olive oil and nuts groups was 2.01+/-0.15, 3.51+/-0.14 and 3.02+/-0.14 mM Trolox, respectively after adjusting for age and sex. The differences between the Mediterranean diet and control groups were statistically significant (P<0.001). Moreover higher levels of TAC were significantly associated with a reduction in body weight after 3 years of intervention among subjects allocated to the virgin olive oil group (B=-1.306; 95% CI=-2.439 to -0.173; P=0.025, after adjusting for age, sex and baseline body mass index).

CONCLUSIONS: Mediterranean diet, especially rich in virgin olive oil, is associated with higher levels of plasma antioxidant capacity. Plasma TAC is related to a reduction in body weight after 3 years of intervention in a high cardiovascular risk population with a Mediterranean-style diet rich in virgin olive oil.

BACKGROUND: A Mediterranean dietary pattern has been associated with a reduced risk of coronary heart disease, as well as a reduction of oxidative stress, but studies indicating possible interactions between food intake and inflammatory mediators production at specific sites are lacking. AIM OF THE STUDY: To assess the relationship between Mediterranean diet consumption and inflammatory related molecules production in coronary vessels.

METHODS: A previously reported Mediterranean-diet score was computed summing-up the quintiles of eight dietary components from a validated food frequency questionnaire in 24 patients with unstable angina. Tumor necrosis factor (TNF-alpha) and vascular cell adhesion molecule (VCAM-1) concentrations were measured in coronary sinus blood.

RESULTS: Both biomarkers showed an inverse association with the Mediterraneandiet score. The association between VCAM-1 and the Mediterranean-diet score had an adjusted beta coefficient of -35.1 ng/ml (95% coefficient interval, CI: -63.5 to -6.7). The adjusted beta coefficient using TNF-alpha as the dependent variable was -41.6 pg/ml (95 % CI: -76.2 to -7.1). The consumption of olive oil as a single item showed a significant inverse association, and a Mediterranean-diet score excluding olive oil was also inversely associated with TNF-alpha and VCAM-1 serum levels in coronary venous blood.

CONCLUSIONS: Adherence to a Mediterranean dietary pattern may protect against coronary artery wall production of inflammatory mediators. This finding could provide a novel mechanistic explanation for the recognized lower coronary risk associated with a Mediterranean diet.

BACKGROUND AND OBJECTIVE: Several epidemiological and experimental studies have associated the intake of antioxidants, which are abundant in the Mediterranean diet, with a low incidence of cardiovascular disease. One possible mechanism of this action is the oxidative protection in low density lipoproteins (LDL). The aim of our study was to compare the antioxidative activity of diverse phenolic compounds present in virgin olive oil on these lipoproteins.

SUBJECTS AND METHOD: LDL was isolated from blood plasma of healthy volunteers by sequential ultracentrifugation. This was followed by oxidation with CuC12 in the presence of different concentrations of phenolic compounds and virgin olive oil extract. Production of conjugated dienes was determined by the continuous monitoring of increased absorbency at 234 nm as an indicator of LDL oxidation.

RESULTS: Virgin olive oil extract prolonged the latency phase and significantly lowered the progression rate (p<0.05) at low concentrations (2 g/ml). This antioxidative effect was also observed with low concentrations (2 M) of caffeic acid and oleuropein (p<0.05). However, it was necessary to increase the concentration of flavone up to 50 times to observe a similar effect (p<0.05).

CONCLUSION: Both virgin olive oil extract enriched in phenolic compounds and phenolic compounds present in olive oil (caffeic acid and oleuropein) are potent antioxidants at very low concentrations. Thus, the beneficial effects of a Mediterranean diet may be partly due to the protective action of these compounds.

BACKGROUND: The Mediterranean diet has been shown to have beneficial effects on cardiovascular risk factors.

OBJECTIVE: To compare the short-term effects of 2 Mediterranean diets versus those of a low-fat diet on intermediate markers of cardiovascular risk.

DESIGN: Substudy of a multicenter, randomized, primary prevention trial of cardiovascular disease (Prevención con Dieta Mediterránea [PREDIMED] Study).

SETTING: Primary care centers affiliated with 10 teaching hospitals.

PARTICIPANTS: 772 asymptomatic persons 55 to 80 years of age at high cardiovascular risk who were recruited from October 2003 to March 2004. Interventions: Participants were assigned to a low-fat diet (n = 257) or to 1 of 2 Mediterranean diets. Those allocated to Mediterranean diets received nutritional education and either free virgin olive oil, 1 liter per week (n = 257), or free nuts, 30 g/d (n = 258). The authors evaluated outcome changes at 3 months.

MEASUREMENTS: Body weight, blood pressure, lipid profile, glucose levels, and inflammatory molecules.

RESULTS: The completion rate was 99.6%. Compared with the low-fat diet, the 2 Mediterranean diets produced beneficial changes in most outcomes. Compared with the low-fat diet, the mean changes in the Mediterranean diet with olive oil group and the Mediterranean diet with nuts group were -0.39 mmol/L (95% CI, -0.70 to -0.07 mmol/L) and -0.30 mmol/L (CI, -0.58 to -0.01 mmol/L), respectively, for plasma glucose levels; -5.9 mm Hg (CI, -8.7 to -3.1 mm Hg) and -7.1 mm Hg (CI, -10.0 to -4.1 mm Hg), respectively, for systolic blood pressure; and -0.38 (CI, -0.55 to -0.22) and - 0.26 (CI, -0.42 to -0.10), respectively, for the cholesterol-high-density lipoprotein cholesterol ratio. The Mediterranean diet with olive oil reduced C-reactive protein levels by 0.54 mg/L (CI, 1.04 to 0.03 mg/L) compared with the low-fat diet.

LIMITATIONS: This short-term study did not focus on clinical outcomes. Nutritional education about low-fat diet was less intense than education about Mediterranean diets.

CONCLUSION: Compared with a low-fat diet, Mediterranean diets supplemented with olive oil or nuts have beneficial effects on cardiovascular risk factors.

We are accumulating evidence to suggest that 17(th) century Renaissance foodways -largely based on the old "Mediterranean dietary traditions"- may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that "The Sacred Law of Salads" (i.e., "raw vegetables... plenty of generous (olive) oil") -originally proposed in 1614 by Giacomo Castelvetro in its book The Fruit, Herbs&Vegetables of Italy- might be considered the first (unintended) example of customised diets for breast cancer prevention based on individual genetic make-up (i.e., nutraceuticals against human breast carcinomas bearing HER2 oncogene amplification/overexpression). First, the so-called salad vegetables dietary pattern (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect mostly confined to the HER2-positive breast cancer subtype, with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid oleic acid and polyphenolic compounds such as the secoiridoid oleuropein or the lignan 1-[+]-acetoxypinoresinol) dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER2- positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats likewise decreasing HER2 expression levels. If early 1600s Castelvetro's salads can be used as dietary protocols capable to protecting women against biologically aggressive HER2-positive breast cancer subtypes is an intriguing prospect that warrants to be evaluated in human pilot studies in the future. Here, at least, we would like to recognise Giacomo Castelvetro as the father of modern nutritional genomics in oncology.

Mediterranean diet has got a favourable effect on life expectancy. One of the crucial components of the diet are onions. In an open and a randomized, placebo-controlled, double-blind, cross-over phase-I study a spontaneous pharmacological effect 5 h after administration of an onion-olive-oil maceration capsule formulation on arterial blood pressure could be demonstrated in apparently healthy subjects. In addition to a decrease in arterial blood pressure, a significant reduction in plasma viscosity and haematocrit were observed. These results are indicating a vasodilative effect of the onion-olive-oil-maceration product. The stickiness of the platelets was reduced. The effects were stronger in subjects with reduced blood fluidity compared to those subjects with normal rheological parameters.

BACKGROUND: Although an important secondary prevention trial reported an impressive protection by a Mediterranean dietary pattern on reinfarction and cardiovascular death, scarce direct epidemiologic evidence is currently available regarding the role of the Mediterranean diet in the aetiology of coronary heart disease.

AIMS: The aim of the study was to quantify the risk reduction of incident myocardial infarction provided by a Mediterranean dietary pattern.

METHODS: We included 342 subjects (171 patients who suffered their first acute myocardial infarction and 171 matched controls) in a case-control study. A validated semi-quantitative food frequency questionnaire (136 items) was used. We defined an a priori Mediterranean dietary pattern. We assessed six food items that we considered protective: 1) olive oil, 2) fiber, 3) fruits, 4)vegetables, 5) fish and 6) alcohol. For each of these six dietary factors, we calculated the distribution according to quintiles within the study and assigned each participant a score of 1 to 5 corresponding to the quintile of intake, with 1 representing the lowest and 5 representing the highest quintile. We also estimated the quintiles of two other elements assumed to be associated with a higher risk: 7) meat/meat products and 8) some items with high glycaemic load (white bread, pasta and rice). For these two elements we inversely ranked the score, with 1 representing the highest and 5 representing the lowest quintile. Finally, we summed up the eight quintile values for each participant.A second score ( post hoc pattern) was built using only a single cut-off point for these eight elements. The cut-off points for each element in this post hoc pattern were decided according to the dose-response relationships between the consumption of each food item and the risk of myocardial infarction observed in the analyses that used quintiles of each food item.

RESULTS: For both patterns, we found that the higher the score, the lower the odds ratio of myocardial infarction. A significant linear trend was apparent after adjustment for the main cardiovascular risk factors. For each additional point in the a priori Mediterranean pattern (observed range: 9-38) the odds ratio (95 % confidence intervals) was 0.92 (0.86-0.98). This estimate was 0.55 (0.42-0.73) when we used the post hoc pattern (range: 0-8).

CONCLUSIONS: Our data support the hypothesis that a Mediterranean diet (that emphasizes olive oil, fiber, fruits, vegetables, fish and alcohol and reduces meat/meat products) can be an effective measure for reducing the risk of myocardial infarction. However, our results support the exclusion of refined cereals with a high glycaemic load as healthy elements of this pattern.

The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical "Mediterranean diet", exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary fatty acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic acid (OA; 18:1n-9), the main olive oil's monounsaturated fatty acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185(Her-2/neu) protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of "cell fuel" availability capable to suppress HER2 expression via formation of inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the "Mediterranean diet" must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease.

Multiple sclerosis (MS) is an autoimmune disease triggered by a combination of genetic and environmental risk factors which are however individually insufficient to provoke the disease. Previous investigations studied the coexistence of cancer in MS patients, and only a few relations between the geographic distribution of MS and that of cancer. The aim of this research was to find an environmental link between the aetiology of MS and cancers in Croatia. Incidence and prevalence of MS in Croatia were compared with the incidence of the most frequent cancer sites: stomach cancer, cancer of the colon and the rectum, pancreatic cancer, lung cancer, cancer of the kidneys and brain cancer. Data for MS were collected from seven population-based epidemiologic studies which used Poser's diagnostic criteria and reported the number of cases and the magnitude of the studied population. Data for cancers were drawn from the Croatian National Cancer Registry. The analysis was done for single municipalities, grouped in their belonging regions or counties, and separately for the continental and the coastal area. For each rate a 95% confidence interval was calculated. The differences between rates were tested with the chi-square test as well. In addition, MS incidence or prevalence were correlated with the corresponding cancer incidence data. Pearson's correlation coefficients were used to measure the correlation between both diseases. Calculations were done with the statistical package Statistica V 7.1. and the Smith's Statistical Package freeware In the continental area of Croatia the mean annual incidence (per 100,000 inhabitants) of MS was nearly two folds higher than in the coastal area: 2.1 vs. 1.3 (p = 0.0029). The difference was lower when expressed by prevalence: 46.5 vs. 36.7 (p = 0.0601). Among the malignant neoplasms, in the continental area significantly higher incidence rates were found for stomach (32.9 vs. 20.8; p = 3.14E-14) and lung cancer (55.8 vs. 46.4; p = 1.21E-05), whilst colon cancer alone (20.4 vs. 15.7; p = 9.44E-05) or colorectal cancer (38.3 vs. 31.6; p = 8.18E-05) had a significantly higher incidence in the coastal area. The geographic distribution of MS expressed by incidence was significantly correlated with pancreatic (r = 0.62024, df=23, p = 0.00094) and lung cancer (r = 0.46380, df=23, p = 0.01953). This research adds further malignant neoplasms, possibly exposure-related, to the list of diseases with geographic distribution like MS. The similarity of MS distribution with the named malignancies is unlikely to be incidental. MS in Gorski Kotar and Slavonia seems to be associated with a diet rich in meat and fat. A diet rich in fat and meat and poor in vegetables is a risk factor for stomach, colorectum, pancreatic as well as lung cancers. Some authors have documented a possible protective role of the "Mediterranean diet" for the named cancers. Olive oil is the main source of fat in the "Mediterranean diet". Oleocanthal, aphenolic compound of the extra-virgin olive oil was found to inhibit the cyclooxigenase enzymes which are involved in demyelination and tumorigenesis. We hypothesize that the "Mediterranean diet", olive oil and particularly oleocanthal, to have a protective role in MS too.

OBJECTIVE: Epidemiology suggests that Mediterranean diets are associated with reduced risk of cardiovascular disease. Because monocyte adhesion to the endothelium is crucial in early atherogenesis, we evaluated whether typical olive oil and red wine polyphenols affect endothelial-leukocyte adhesion molecule expression and monocyte adhesion.

METHODS AND RESULTS: Phytochemicals in olive oil and red wine, including oleuropein, hydroxytyrosol, tyrosol, elenolic acid, and resveratrol, with or without antioxidant activity, were incubated with human umbilical vein endothelial cells for 30 minutes, followed by co-incubation with bacterial lipopolysaccharide or cytokines to trigger adhesion molecule expression. At nutritionally relevant concentrations, only oleuropein, hydroxytyrosol, and resveratrol, possessing a marked antioxidant activity, reduced monocytoid cell adhesion to stimulated endothelium, as well as vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein by Northern analysis and cell surface enzyme immunoassay. Reporter gene assays with deletional VCAM-1 promoter constructs indicated the relevance of nuclear factor-kappaB, activator protein-1, and possibly GATA binding sites in mediating VCAM-1 transcriptional inhibition. The involvement of nuclear factor-kappaB and activator protein-1 was finally demonstrated at electrophoretic mobility shift assays.

CONCLUSIONS: Olive oil and red wine antioxidant polyphenols at nutritionally relevant concentrations transcriptionally inhibit endothelial adhesion molecule expression, thus partially explaining atheroprotection from Mediterranean diets.

Since evidence relating diet to breast cancer risk is not sufficiently consistent to elaborate preventive proposals, the authors examined the association between dietary patterns and breast cancer risk in a large French cohort study. The analyses included 2,381 postmenopausal invasive breast cancer cases diagnosed during a median 9.7-year follow-up period (1993-2005) among 65,374 women from the E3N-EPIC cohort. Scores for dietary patterns were obtained by factor analysis, and breast cancer hazard ratios were estimated by Cox proportional hazards regression for the highest quartile of dietary pattern score versus the lowest. Two dietary patterns were identified: "alcohol/Western" (essentially meat products, French fries, appetizers, rice/pasta, potatoes, pulses, pizza/pies, canned fish, eggs, alcoholic beverages, cakes, mayonnaise, and butter/cream) and "healthy/Mediterranean" (essentially vegetables, fruits, seafood, olive oil, and sunflower oil). The first pattern was positively associated with breast cancer risk (hazard ratio = 1.20, 95% confidence interval (CI): 1.03, 1.38; P = 0.007 for linear trend), especially when tumors were estrogen receptor-positive/progesterone receptor-positive. The "healthy/Mediterranean" pattern was negatively associated with breast cancer risk (hazard ratio = 0.85, 95% CI: 0.75, 0.95; P = 0.003 for linear trend), especially when tumors were estrogen receptor-positive/progesterone receptor-negative. Adherence to a diet comprising mostly fruits, vegetables, fish, and olive/sunflower oil, along with avoidance of Western-type foods, may contribute to a substantial reduction in postmenopausal breast cancer risk.