María Luisa Miranda

Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension.

BACKGROUND Olive oil polyphenols have been associated with several cardiovascular health benefits. This study aims to examine the influence of a polyphenol-rich olive oil on blood pressure (BP) and endothelial function in 24 young women with high-normal BP or stage 1 essential hypertension. METHODS We conducted a double-blind, randomized, crossover dietary-intervention study. After a run-in period of 4 months (baseline values), two diets were used, one with polyphenol-rich olive oil (∼30 mg/day), the other with polyphenol-free olive oil. Each dietary period lasted 2 months with a 4-week washout between diets. Systolic and diastolic BP, serum or plasma biomarkers of endothelial function, oxidative stress, and inflammation, and ischemia-induced hyperemia in the forearm were measured. RESULTS When compared to baseline values, only the polyphenol-rich olive oil diet led to a significant (P < 0.01) decrease of 7.91 mm Hg in systolic and 6.65 mm Hg of diastolic BP. A similar finding was found for serum asymmetric dimethylarginine (ADMA) (-0.09 ± 0.01 µmol/l, P < 0.01), oxidized low-density lipoprotein (ox-LDL) (-28.2 ± 28.5 µg/l, P < 0.01), and plasma C-reactive protein (CRP) (-1.9 ± 1.3 mg/l, P < 0.001). The polyphenol-rich olive oil diet also elicited an increase in plasma nitrites/nitrates (+4.7 ± 6.6 µmol/l, P < 0.001) and hyperemic area after ischemia (+345 ± 386 perfusion units (PU)/sec, P < 0.001). CONCLUSIONS We concluded that the consumption of a diet containing polyphenol-rich olive oil can decrease BP and improve endothelial function in young women with high-normal BP or stage 1 essential hypertension.

Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect.

Background Hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors have beneficial effects beyond their cholesterol-lowering properties. The antioxidant mechanism of HMGCoA reductase inhibitors is not completely understood. Objectives To elucidate the antioxidant effect of simvastatin. Methods We studied the influence of simvastatin treatment on the development of hypertension, modification of antioxidant systems, and reactivity of aortic rings in Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Results Simvastatin had no effect on blood pressure (BP). Simvastatin treatment (either 1 or 2 mg/kg body weight for 12 or 20 weeks) increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in SHR rats compared with untreated control SHR rats. Carbachol-induced relaxation of aortic rings was impaired in control SHR rats and was restored by simvastatin treatment. Addition of SOD improved the response in control SHR rats and did not have any effect in treated SHR rats. Addition of diethyldithiocarbamic acid, a selective inhibitor of SOD, produced a mild non-significant impairment in carbachol-induced relaxation in control SHR rats, suggesting a deficient antioxidant system in these animals. However, in treated SHR and in WKY rats, impairment of the relaxation was marked, implying that SOD activity in these animals was important to maintain endothelial function. In aortic rings without endothelium from SHR rats, contraction induced by free radicals was substantially higher than in WKY rats. This effect was attenuated in 1-mg-treated rats and abolished in 2-mg-treated rats. Conclusions Simvastatin promotes intracellular antioxidant systems, fundamentally SOD, restoring endothelial function but not having any effect on blood pressure.

Decreased Level of Cord Blood Circulating Endothelial Colony–Forming Cells in Preeclampsia

Preeclampsia is a pregnancy-related disorder associated with increased cardiovascular risk for the offspring. Endothelial colony–forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that participate in the formation of vasculature during development. However, the effect of preeclampsia on fetal levels of ECFCs is largely unknown. In this study, we sought to determine whether cord blood ECFC abundance and function are altered in preeclampsia. We conducted a prospective cohort study that included women with normal (n=35) and preeclamptic (n=15) pregnancies. We measured ECFC levels in the umbilical cord blood of neonates and characterized ECFC phenotype, cloning-forming ability, proliferation, and migration toward vascular endothelial growth factor-A and fibroblast growth factor-2, in vitro formation of capillary-like structures, and in vivo vasculogenic ability in immunodeficient mice. We found that the level of cord blood ECFCs was statistically lower in preeclampsia than in control pregnancies (P=0.04), a reduction that was independent of other obstetric factors. In addition, cord blood ECFCs from preeclamptic pregnancies required more time to emerge in culture than control ECFCs. However, once derived in culture, ECFC function was deemed normal and highly similar between preeclampsia and control, including the ability to form vascular networks in vivo. This study demonstrates that preeclampsia affects ECFC abundance in neonates. A reduced level of ECFCs during preeclamptic pregnancies may contribute to an increased risk of developing future cardiovascular events.

Role of Circulating Cell-free DNA Levels in Patients With Severe Preeclampsia and HELLP Syndrome

BACKGROUND Increased plasma levels of circulating cell-free DNA (c-f DNA) have been recently described in diseases related to ischemia and/or hypoxia. Preeclampsia (PCL) is a hypertensive disorder of pregnancy, of unknown origin, where a defective placentation resulting in placental ischemia plays an important role. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is the most serious form of PCL. The origin of the disease is unknown, and there are no markers to help us to make an early diagnosis of disease or to predict patients who are at risk of suffering serious complications. METHODS We measured circulating c-f DNA levels in a group of control pregnant women (n = 20), patients with mild PCL (n = 9), patients with severe PCL (n = 24), and patients with HELLP syndrome (n = 8). RESULTS Values of circulating c-f DNA were 333.59 ± 64.3 ng/ml in control subjects; 635.11 ± 111.7 ng/ml in patients with mild PCL; 1,264.63 ± 127.1 ng/ml in patients with severe PCL, and 1,595.95 ± 269.8 ng/ml in patients with HELPP syndrome. (P < 0.0001). Values of c-f DNA >950 ng/ml had a sensitivity and specificity for detecting severe PCL and/or HELLLP syndrome of 0.71 and 0.93, respectively. CONCLUSIONS As far as we know, this is the first report of increased c-f DNA levels in HELLP syndrome. In this preliminary report, we have observed a gradual and strong relation between c-f DNA levels and range of severity of PCL, with it the highest in patients with HELLP syndrome. Further studies are needed for evaluating the utility of this technique in hypertensive disorders of pregnancy and, particularly, in HELLP syndrome.

Genotype of the CYBA promoter -930A/G, polymorphism C677T of the MTHFR and APOE genotype in patients with hypertensive disorders of pregnancy: an observational study.

BACKGROUND AND OBJECTIVE Hypertensive disorders of pregnancy could be favoured by polymorphisms in genes affecting vascular physiology. The aim of our work was to study several variants in the genes regulating oxidative stress, plasma lipids metabolism and endothelial function (observational study). MATERIAL AND METHODS We studied the -930A/G polymorphism of the CYBA gene promoter, the apolipoprotein E (APOE) genotype and the methylene-tetrahydrofolate reductase (MTHFR) gene C677T polymorphism in 134 healthy pregnant women, 266 pregnant with non-proteinuric hypertension (NPH) and 184 patients with preeclampsia (PE). RESULTS The GG genotype of the CYBA gene promoter was present in 32.1% of the control population, 38.7% of patients with NPH (P=0.19) and 21.2% of the women with PE (P=0.03). A higher frequency of epsilon 3/epsilon 4 and epsilon 4/epsilon 4 genotypes of APOE was observed in patients with PE or NPH compared with controls (P<0.01). There were no significant differences detected in genotype or allele distribution of the MTHFR, C677T polymorphism. APOE epsilon 3/epsilon 4 and epsilon 4/epsilon 4 genotypes had a worse lipoprotein profile characterized by higher plasma values of total cholesterol (P<0.05) and triglycerides (P<0.005). Despite no differences in MTHFR C677T polymorphism distribution, higher levels of plasma homocysteine were observed in patients with PE than in patients with NPH or controls. CONCLUSIONS CYBA and APOE polymorphism showed a different distribution in the groups studied, while no differences were observed in MTHFR C677T polymorphism. APOE genotype was associated with changes in lipid and lipoprotein profiles in pregnant women.

Maternal Body-Mass Index and Cord Blood Circulating Endothelial Colony-Forming Cells

OBJECTIVE Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that are particularly abundant in umbilical cord blood. We sought to determine whether ECFC abundance in cord blood is associated with maternal body-mass index (BMI) in nonpathologic pregnancies. STUDY DESIGN We measured the level of ECFCs in the cord blood of neonates (n = 27) born from non-obese healthy mothers with nonpathologic pregnancies and examined whether ECFC abundance correlated with maternal BMI. We also examined the effect of maternal BMI on ECFC phenotype and function using angiogenic and vasculogenic assays. RESULTS We observed variation in ECFC abundance among subjects and found a positive correlation between prepregnancy maternal BMI and ECFC content (r = 0.51, P = .007), which was independent of other obstetric factors. Despite this variation, ECFC phenotype and functionality were deemed normal and highly similar between subjects with maternal BMI <25 kg/m(2) and BMI between 25-30 kg/m(2), including the ability to form vascular networks in vivo. CONCLUSIONS This study underlines the need to consider maternal BMI as a potential confounding factor for cord blood levels of ECFCs in future comparative studies between healthy and pathologic pregnancies.

Seasonality and edge effect determine herbivory risk according to different plant association models.

We report evidence of hierarchical resource selection by large herbivores and plant neighbouring effects in a Mediterranean ecosystem. Plant palatability was assessed according to herbivore foraging decisions. We hypothesize that under natural conditions large herbivores follow a hierarchical foraging pattern, starting at the landscape scale, and then selecting patches and individual plants. A between- and within-patch selection study was carried out in an area formed by scrubland and pasture patches, connected by habitat edges. With regard to between-patch selection, quality-dependent resource selection is reported: herbivores mainly consume pasture in spring and woody plants in winter. Within-patch selection was also observed in scrub habitats, influenced by season, relative patch palatability and edge effect. We defined a Proximity Index (PI) between palatable and unpalatable plants, which allowed verification of neighbouring effects. In spring, when the preferred food resource (i.e. herbs) is abundant, we observed that in habitat edges large herbivores basically select the relatively scarce palatable shrubs, whereas inside scrubland, unpalatable shrub consumption was related to increasing PI. In winter, a very different picture was observed; there was low consumption of palatable species surrounded by unpalatable species in habitat edges, where the latter were more abundant. These outcomes could be explained though different plant associations described in the literature. We conclude that optimal foraging theory provides a conceptual framework behind the observed interactions between plants and large herbivores in Mediterranean ecosystems.

Role of ketoconazole treatment in urinary-free cortisol-to-cortisone and tetrahydrocortisol-to-tetrahydrocortisone ratios in nonectopic Cushing's syndrome.

We hypothesized that in nonectopic Cushing syndrome there is an insufficient activity of type II (renal) 11β-hydroxysteroid dehydrogenase (11β-HSD2) that is related to cortisol excess, rather than to corticotropin (adrenocorticotropic hormone [ACTH]) levels. We measured plasma ACTH and urinary-free cortisol (UFF), urinary-free cortisone (UFE), tetrahydrocortisol (UTHF), and tetrahydrocortisone (UTHE) in 24-h urine samples of 24 healthy subjects and 15 patients diagnosed with nonectopic Cushing syndrome. Then, in the group of patients, a new 24-h urine sample was collected after treatment with 800 mg daily of ketoconazole. The UFF/UFE and UTHF/UTHE ratios were calculated as an estimation of 11β-HSD2 activity. The patients had an increase in both the UFF/UFE (19.95±10.3 vs 5.78±4.72 nmol/24 h; p<0.0001) and UTHF/UTHE ratios (5.36±5.23 vs 1.39±0.95 nmol/24 h; p<0.001). Both UFF/UFE and UTHF/UTHE ratios decreased after ketoconazole treatment (19.95±10.3 vs 12.2±6.9 nmol/24 h; p<0.005; and 5.36±5.23 vs 1.62 vs 1.21 nmol/24 h; p<0.001, respectively). The control subjects had a significant relationship between UFF and UFE (r=0.70, p<0.0001), and between UTHF and UTHE (r=0.75, p<0.0001) that did not exist in the patient group. After ketoconazole treatment, the decrease in cortisol excretion in the patient group allowed a positive and significant relation between UFF and UFE (r=0.64, p<0.01) and between UTHF and UTHE (r=0.56, p<0.05) to appear. There was not any significant relationship between either UFF/UFE or UTHF/UTHE ratios and plasma levels of ACTH.

The importance of individual variation in the dynamics of animal collective movements

Animal collective movements are a key example of a system that links two clearly defined levels of organization: the individual and the group. Most models investigating collective movements have generated coherent collective behaviours without the inclusion of individual variability. However, new individual-based models, together with emerging empirical information, emphasize that within-group heterogeneity may strongly influence collective movement behaviour. Here we (i) review the empirical evidence for individual variation in animal collective movements, (ii) explore how theoretical investigations have represented individual heterogeneity when modelling collective movements and (iii) present a model to show how within-group heterogeneity influences the collective properties of a group. Our review underscores the need to consider variability at the level of the individual to improve our understanding of how individual decision rules lead to emergent movement patterns, and also to yield better quantitative predictions of collective behaviour. This article is part of the theme issue ‘Collective movement ecology’.

Arterial hypertension as a complication of prolonged ketoconazole treatment.

Two of 14 patients with Cushings syndrome treated on a long-term basis with ketoconazole developed sustained hypertension. In both cases normal plasma and urinary free cortisol levels had been achieved following ketoconazole therapy, yet continuous blood pressure monitoring demonstrated hypertension 31 (patient 1) and 52 weeks (patient 2) after treatment. In patient 1, plasma levels of deoxycorticosterone and 11-deoxycortisol were elevated. In patient 2, in addition to an increase in both deoxycorticosterone and 11-deoxycortisol levels, plasma aldosterone values were raised, with a concomitant suppression of renin levels. Our findings show that long-term treatment with high doses of ketoconazole may induce enzyme blockade leading to mineralocorticoid-related hypertension.