Hyperlipidemia is associated with endothelial dysfunction, an early event in atherosclerosis and predictor of risk for future coronary artery disease. Epidemiological studies suggest that increased ...dietary intake of antioxidants reduces the risk of coronary artery disease. The purpose of this study was to determine whether antioxidant vitamin therapy improves endothelial function and affects surrogate biomarkers for oxidative stress and inflammation in hyperlipidemic children.
In a randomized, double-blind, placebo-controlled trial, the effects of antioxidant vitamins C (500 mg/d) and E (400 IU/d) for 6 weeks and the National Cholesterol Education Program Step II (NCEP-II) diet for 6 months on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery were examined in 15 children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). Antioxidant vitamin therapy improved FMD of the brachial artery compared with baseline (P<0.001) without an effect on biomarkers for oxidative stress (autoantibodies to epitopes of oxidized LDL, F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine), inflammation (C-reactive protein), or levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide.
Antioxidant therapy with vitamins C and E restores endothelial function in hyperlipidemic children. Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis.
Background: The contemporary American diet figures centrally in the pathogenesis of numerous chronic diseases--'diseases of civilization'. We investigated in humans whether a diet similar to that ...consumed by our preagricultural hunter-gatherer ancestors (that is, a paleolithic type diet) confers health benefits. Methods: We performed an outpatient, metabolically controlled study, in nine nonobese sedentary healthy volunteers, ensuring no weight loss by daily weight. We compared the findings when the participants consumed their usual diet with those when they consumed a paleolithic type diet. The participants consumed their usual diet for 3 days, three ramp-up diets of increasing potassium and fiber for 7 days, then a paleolithic type diet comprising lean meat, fruits, vegetables and nuts, and excluding nonpaleolithic type foods, such as cereal grains, dairy or legumes, for 10 days. Outcomes included arterial blood pressure (BP); 24-h urine sodium and potassium excretion; plasma glucose and insulin areas under the curve (AUC) during a 2 h oral glucose tolerance test (OGTT); insulin sensitivity; plasma lipid concentrations; and brachial artery reactivity in response to ischemia. Results: Compared with the baseline (usual) diet, we observed (a) significant reductions in BP associated with improved arterial distensibility (-3.12.9, P=0.01 and +0.190.23, P=0.05);(b) significant reduction in plasma insulin vs time AUC, during the OGTT (P=0.006); and (c) large significant reductions in total cholesterol, low-density lipoproteins (LDL) and triglycerides (-0.80.6 (P=0.007), -0.70.5 (P=0.003) and -0.30.3 (P=0.01) mmol/l respectively). In all these measured variables, either eight or all nine participants had identical directional responses when switched to paleolithic type diet, that is, near consistently improved status of circulatory, carbohydrate and lipid metabolism/physiology. Conclusions: Even short-term consumption of a paleolithic type diet improves BP and glucose tolerance, decreases insulin secretion, increases insulin sensitivity and improves lipid profiles without weight loss in healthy sedentary humans.
The European drought of 1921 is assessed in terms of its impacts on society and in terms of its physical characteristics. The development of impacts of the drought are categorized by a systematic ...survey of newspaper reports from five European newspapers covering the area from England to the Czech Republic and other parts of Europe. This is coupled to a reconstruction of daily temperature and precipitation based on meteorological measurements to quantify the drought severity and extent, and reanalysis data are used to identify its drivers. This analysis shows that the first impacts of the drought started to appear in early spring and lingered on until well into autumn and winter, affecting water supply and agriculture and livestock farming. The dominant impact in western Europe is on agriculture and livestock farming while in central Europe the effects of wildfires were reported on most often. The peak in the number of reports is in late summer. Preceding the first impacts was the dry autumn of 1920 and winter 1920-1921. The area hardest hit by the drought in the following spring and summer was the triangle between Brussels, Paris and Lyon, but a vast stretch of the continent, from Ireland to the Ukraine, was affected. The reported impacts on water supply and water-borne transport in that region were matched by an analysis of the hydrological situation over the Seine catchment. On average, the 1921 summer was not particularly hot, but the heatwave which was observed at the end of July saw temperatures matching those of the heatwaves in modern summers. Similar to modern droughts, an anticyclone was present roughly over the British Isles, maintaining sunny and dry weather in Europe and steering away cyclones to the north. Its persistence makes it exceptional in comparison to modern droughts.
The European project WASA (Waves and Storms in the North Atlantic) has been set up to verify or disprove hypotheses of a worsening storm and wave climate in the northeast Atlantic and its adjacent ...seas in the present century. Its main conclusion is that the storm and wave climate in most of the northeast Atlantic and in the North Sea has undergone significant variations on timescales of decades; it has indeed roughened in recent decades, but the present intensity of the storm and wave climate seems to be comparable with that at the beginning of this century. Part of this variability is found to be related to the North Atlantic oscillation.
An analysis of a high-resolution climate change experiment, mimicking global warming due to increased greenhouse gas concentrations, results in a weak increase of storm activity and (extreme) wave heights in the Bay of Biscay and in the North Sea, while storm action and waves slightly decrease along the Norwegian coast and in most of the remaining North Atlantic area. A weak increase in storm surges in the southern and eastern part of the North Sea is expected. These projected anthropogenic changes at the time of CO₂ doubling fall well within the limits of variability observed in the past.
A major methodical obstacle for the assessment of changes in the intensity of storm and wave events are inhomogeneities in the observational record, both in terms of local observations and of analyzed products (such as weather maps), which usually produce an artificial increase of extreme winds. This occurs because older analyses were based on fewer observations and with more limited conceptual and numerical models of the dynamical processes than more recent analyses. Therefore the assessment of changes in storminess is based on local observations of air pressure and high-frequency variance at tide gauges. Data of this sort is available for 100 yr and sometimes more. The assessment of changes in the wave climate is achieved using a two-step procedure; first a state-of-the-art wave model is integrated with 40 yr of wind analysis; the results are assumed to be reasonably homogeneous in the area south of 70°N and east of 20°W; then a regression is built that relates monthly mean air pressure distributions to intramonthly percentiles of wave heights at selected locations with the help of the 40-yr simulated data; finally, observed monthly mean air pressure fields from the beginning of this century are fed into the regression model to derive best guesses of wave statistics throughout the century.
The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, ...affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated.
In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography.
FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet.
This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.
Objective: To measure endothelium-dependent vascular relaxation in children with two genetic hyperlipidemias and to assess the effect of antioxidant vitamins on endothelial dysfunction.
Study design: ...Vascular reactivity in the brachial artery was measured in 45 individuals between 6 and 21 years of age (18 with familial hypercholesterolemia FH, 15 with familial combined hyperlipoproteinemia FCH, 12 control subjects) with the use of high-resolution two-dimensional ultrasonography. Follow-up studies were done for 11 children after 6 weeks of treatment with tocopherol (400 IU twice a day) and ascorbic acid (500 mg twice a day).
Results: The mean percent change in diameter during reactive hyperemia was 2.1 ± 2.2 (SD) and 2.7 ± 4.4, in FH and FCH, respectively, compared with 12.4 ± 4.9 among control subjects (
p < 0.001 in each case). The mean percent dilation was significantly increased (2.8 ± 1.6 to 9.1 ± 2.3) (
p < 0.001) after antioxidant therapy.
Conclusions: Impaired endothelium-dependent vasoregulation occurs in children with FCH as well as in those with FH. The improvement in vascular reactivity observed during supplementation with antioxidant vitamins suggests that reactive oxygen species derived from oxidized lipoproteins may be responsible for the impairment of vasoregulation in subjects with hyperlipidemia. (J Pediatr 1998;133:35-40)
We have previously demonstrated that the acetylated low density lipoprotein (LDL), or scavenger, receptor expressed by rabbit smooth muscle cells (SMCs) is regulated. Phorbol ester treatment of the ...cells increased the number of scavenger receptors expressed and the metabolism of acetoacetylated (AcAc) LDL. The current studies examined the interaction of oxidized (Ox) LDL with the rabbit scavenger receptor. The internalization and degradation of both Ox-LDL and AcAc-LDL were increased to a similar extent by phorbol ester treatment of the SMCs. In cross-competition experiments, both Ox-LDL and AcAc-LDL competed equally for the degradation of 125I-Ox-LDL, suggesting that there is no independent receptor for Ox-LDL on these cells. In contrast, only AcAc-LDL competed totally for the degradation of 125I-AcAc-LDL. Similar results were obtained in cross-competition experiments with rabbit macrophages. To determine whether these data were consistent with the binding of both ligands to a single receptor, competition studies were conducted in Chinese hamster ovary fibroblasts transfected with the bovine scavenger receptor. After transfection, the metabolism of both AcAc-LDL and Ox-LDL was increased, in agreement with the previous data from other investigators, and cross-competition studies yielded essentially identical results to those obtained in the SMCs and macrophages. Northern blot analysis with an antisense rabbit scavenger receptor probe detected the same mRNA species in total RNA from rabbit macrophages and SMCs and showed that scavenger receptor mRNA increased dramatically after phorbol ester treatment of SMCs. The probe also detected bovine scavenger receptor mRNA.
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