Ensemble forecasts of a flood-producing storm: comparison of the influence of model-state perturbations and parameter modifications

High-resolution ensemble simulations (Δx = 1 km) are performed with the Met Office Unified Model for the Boscastle (Cornwall, UK) flash-flooding event of 16 August 2004. Forecast uncertainties arising from imperfections in the forecast model are analysed by comparing the simulation results produced by two types of perturbation strategy. Motivated by the meteorology of the event, one type of perturbation alters relevant physics choices or parameter settings in the model's parametrization schemes. The other type of perturbation is designed to account for representativity error in the boundary-layer parametrization. It makes direct changes to the model state and provides a lower bound against which to judge the spread produced by other uncertainties. The Boscastle has genuine skill at scales of approximately 60 km and an ensemble spread which can be estimated to within ∼ 10% with only eight members. Differences between the model-state perturbation and physics modification strategies are discussed, the former being more important for triggering and the latter for subsequent cell development, including the average internal structure of convective cells. Despite such differences, the spread in rainfall evaluated at skilful scales is shown to be only weakly sensitive to the perturbation strategy. This suggests that relatively simple strategies for treating model uncertainty may be sufficient for practical, convective-scale ensemble forecasting.

Plant- and marine-derived n-3 polyunsaturated fatty acids have differential effects on fasting and postprandial blood lipid concentrations and on the susceptibility of LDL to oxidative modification in moderately hyperlipidemic subjects

Background: Dietary a-linolenic acid (ALA) can be converted to long-chain n-3 polyunsaturated fatty acids (PUFAs) in humans and may reproduce some of the beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular disease risk factors. Objective: This study aimed to compare the effects of increased dietary intakes of ALA and EPA+DHA on a range of atherogenic risk factors. Design: This was a placebo-controlled, parallel study involving 150 moderately hyperlipidemic subjects randomly assigned to 1 of 5 interventions: 0.8 or 1.7 g EPA+DHA/d, 4.5 or 9.5 g ALA/d, or an n-6 PUFA control for 6 mo. Fatty acids were incorporated into 25 g of fat spread and 3 capsules to be consumed daily. Results: The change in fasting or postprandial lipid, glucose, or insulin concentrations or in blood pressure was not significantly different after any of the n-3 PUFA interventions compared with the n-6 PUFA control. The mean (+/-SEM) change in fasting triacylglycerols after the 1.7-g/d EPA+DHA intervention (-7.7 +/- 4.99%) was significantly (P < 0.05) different from the change after the 9.5-g/d ALA intervention (10.9 +/- 4.5%). The ex vivo susceptibility of LDL to oxidation was higher after the 1.7-g/d EPA+DHA intervention than after the control and ALA interventions (P < 0.05). There was no significant change in plasma a-tocopherol concentrations or in whole plasma antioxidant status in any of the groups. Conclusion: At estimated biologically equivalent intakes, dietary ALA and EPA+DHA have different physiologic effects.

The nutritional and clinical significance of lipid rafts

Purpose of review Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Recent findings In-vitro and ex-vivo studies suggest that dietary n-3 polyunsaturated fatty acids (PUFAs) may exert immunosuppressive and anticancer effects through changes in lipid raft organization. In addition, gangliosides and cholesterol may modulate lipid raft organization in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth. The roles of fatty acids and gangliosides, especially in relation to lipid rafts, in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer’s disease are poorly understood and require further investigation. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are starting to emerge, and indicate compelling evidence for the growing importance of membrane microdomains in health and disease. Summary In-vitro and animal studies show that n-3 PUFAs, cholesterol, and gangliosides modulate the structure and composition of lipid rafts, potentially influencing a wide range of biological processes, including immune function, neuronal signaling, cancer cell growth, entry of pathogens through the gut barrier, and insulin resistance in metabolic disorders. The physiological, clinical, and nutritional relevance of these observations remains to be determined.

A novel method for production of lipid hydroperoxide- or oxysterol-rich low-density lipoprotein

LDL oxidation may be important in atherosclerosis. Extensive oxidation of LDL by copper induces increased uptake by macrophages, but results in decomposition of hydroperoxides, making it more difficult to investigate the effects of hydroperoxides in oxidised LDL on cell function. We describe here a simple method of oxidising LDL by dialysis against copper ions at 4 degrees C, which inhibits the decomposition of hydroperoxides, and allows the production of LDL rich in hydroperoxides (626 +/- 98 nmol/mg LDL protein) but low in oxysterols (3 +/- 1 nmol 7-ketocholesterol/mg LDL protein), whilst allowing sufficient modification (2.6 +/- 0.5 relative electrophoretic mobility) for rapid uptake by macrophages (5.49 +/- 0.75 mu g I-125-labelled hydroperoxide-rich LDL vs. 0.46 +/- 0.04 mu g protein/mg cell protein in 18 h for native LDL). By dialysing under the same conditions, but at 37 degrees C, the hydroperoxides are decomposed extensively and the LDL becomes rich in oxysterols. This novel method of oxidising LDL with high yield to either a hydroperoxide- or oxysterol-rich form by simply altering the temperature of dialysis may provide a useful tool for determining the effects of these different oxidation products on cell function. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

The Nutritional Significance of Lipid Rafts

The structure, size, stability, and functionality of lipid rafts are still in debate, but recent techniques allowing direct visualization have characterized them in a wide range of cell types. Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. However, it is not clear whether dietary polyunsaturated fatty acids (PUFAs) are incorporated into raft lipids or whether their low affinity to cholesterol disallows this and causes phase separation from rafts and displacement of raft proteins. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Although there is increasing evidence to suggest that membrane microdomains, and their modulation, have an impact in health and disease, it is too early to judge whether modulation of lipid rafts is responsible for the immunomodulatory effects of n-3 PUFA. In addition to dietary fatty acids, gangliosides and cholesterol may also modulate microdomains in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth by n-3 PUFA. The roles of fatty acids and gangliosides in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require clarification, particularly with respect to the contribution of lipid rafts. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are only just emerging, but compelling evidence indicates the growing importance of membrane microdomains in health and disease.

Effects of dietary fat modification on skeletal muscle fatty acid handling in the metabolic syndrome

Objective: In the metabolic syndrome (MetS), increased fat storage in ‘nonadipose’ tissues such as skeletal muscle may be related to insulin resistance (‘lipid overflow’ hypothesis). The objective of this study was to examine the effects of dietary fat modification on the capacity of skeletal muscle to handle dietary and endogenous fatty acids (FAs). Subjects and Methods: In total, 29 men with the MetS were randomly assigned to one of four diets for 12 weeks: a high-fat saturated fat diet (HSFA, n=6), a high-fat monounsaturated fat diet (HMUFA, n=7) and two low-fat high-complex carbohydrate diets supplemented with (LFHCCn−3, n=8) or without (LFHCC, n=8) 1.24 g per day docosahexaenoic and eicosapentaenoic acid. Fasting and postprandial skeletal muscle FA handling was examined by measuring arteriovenous concentration differences across the forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and free fatty acids in the circulation and subjects received a high-fat mixed meal (2.6 MJ, 61 energy% fat) containing [U-13C]-palmitate to label chylomicron-TAG. Results: Postprandial circulating TAG concentrations were significantly lower after dietary intervention in the LFHCCn−3 group compared to the HSFA group (ΔiAUC −139±67 vs 167±70 μmol l−1 min−1, P=0.009), together with decreased concentrations of [U-13C]-labeled TAG, representing dietary FA. Fasting TAG clearance across forearm muscle was decreased on the HSFA diet, whereas no differences were observed in postprandial forearm muscle FA handling between diets. Conclusion: Chronic manipulation of dietary fat quantity and quality did not affect forearm muscle FA handling in men with the MetS. Postprandial TAG concentrations decreased on the LFHCCn−3 diet, which could be (partly) explained by lower concentration of dietary FA in the circulation.

Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome—LIPGENE: a European randomized dietary intervention study

Background:Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other components of the MetS. Objective:This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS. Design:A free-living, single-blinded dietary intervention study. Subjects and Methods:MetS subjects (n=417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined. Results:In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P<0.01), particularly in men. Conclusion:There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.

Effect of incremental levels of fish oil in the diet on ruminal lipid metabolism in growing steers

Based on the potential benefits to human health, there is interest in developing sustainable nutritional strategies to enhance the concentration of long-chain n-3 fatty acids in ruminant-derived foods. Four Aberdeen Angus steers fitted with rumen and duodenal cannulae were used in a 4 × 4 Latin square experiment with 21 d experimental periods to examine the potential of fish oil (FO) in the diet to enhance the supply of 20 : 5n-3 and 22 : 6n-3 available for absorption in growing cattle. Treatments consisted of total mixed rations based on maize silage fed at a rate of 85 g DM/kg live weight0·75/d containing 0, 8, 16 and 24 g FO/kg diet DM. Supplements of FO reduced linearly (P < 0·01) DM intake and shifted (P < 0·01) rumen fermentation towards propionate at the expense of acetate and butyrate. FO in the diet enhanced linearly (P < 0·05) the flow of trans-16 : 1, trans-18 : 1, trans-18 : 2, 20 : 5n-3 and 22 : 6n-3, and decreased linearly (P < 0·05) 18 : 0 and 18 : 3n-3 at the duodenum. Increases in the flow of trans-18 : 1 were isomer dependent and were determined primarily by higher amounts of trans-11 reaching the duodenum. In conclusion, FO alters ruminal lipid metabolism of growing cattle in a dose-dependent manner consistent with an inhibition of ruminal biohydrogenation, and enhances the amount of long-chain n-3 fatty acids at the duodenum, but the increases are marginal due to extensive biohydrogenation in the rumen.

Strategies for optimizing nitrogen use by ruminants

The efficiency of N utilization in ruminants is typically low (around 25%) and highly variable (10% to 40%) compared with the higher efficiency of other production animals. The low efficiency has implications for the production performance and environment. Many efforts have been devoted to improving the efficiency of N utilization in ruminants, and while major improvements in our understanding of N requirements and metabolism have been achieved, the overall efficiency remains low. In general, maximal efficiency of N utilization will only occur at the expense of some losses in production performance. However, optimal production and N utilization may be achieved through the understanding of the key mechanisms involved in the control of N metabolism. Key factors in the rumen include the efficiency of N capture in the rumen (grams of bacterial N per grams of rumen available N) and the modification of protein degradation. Traditionally, protein degradation has been modulated by modifying the feed (physical and chemical treatments). Modifying the rumen microflora involved in peptide degradation and amino acid deamination offers an alternative approach that needs to be addressed. Current evidence indicates that in typical feeding conditions there is limited net recycling of N into the rumen (blood urea-N uptake minus ammonia-N absorption), but understanding the factors controlling urea transport across the rumen wall may reverse the balance to take advantage of the recycling capabilities of ruminants. Finally, there is considerable metabolism of amino acids (AA) in the portal-drained viscera (PDV) and liver. However, most of this process occurs through the uptake of AA from the arterial blood and not during the ‘absorptive’ process. Therefore, AA are available to the peripheral circulation and to the mammary gland before being used by PDV and the liver. In these conditions, the mammary gland plays a key role in determining the efficiency of N utilization because the PDV and liver will use AA in excess of those required by the mammary gland. Protein synthesis in the mammary gland appears to be tightly regulated by local and systemic signals. The understanding of factors regulating AA supply and absorption in the mammary gland, and the synthesis of milk protein should allow the formulation of diets that increase total AA uptake by the mammary gland and thus reduce AA utilization by PDV and the liver. A better understanding of these key processes should allow the development of strategies to improve the efficiency of N utilization in ruminants.

Impact of probiotics, prebiotics and synbiotics on lipid metabolism in humans

Public health strategies for reducing the risk of coronary heart disease have focused on lowering plasma lipids, particularly cholesterol levels, with recent studies also highlighting triacylglycerol (TAG) as an important modifiable risk factor. One approach is to supplement the diet with probiotics, prebiotics or synbiotics. Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Putative health benefits include improved resistance to gastrointestinal infections, reduction in lipid levels and stimulation of the immune system. Prebiotics are selectively fermented dietary components that are aimed at improving host health through selective fermentation by the gut microbiota, such as bifidobacteria and lactobacilli. Animal studies have shown prebiotics to markedly reduce circulating TAG and to a lesser extent cholesterol concentrations, with favourable but inconsistent findings with respect to changes in lipid levels in human studies. Here we provide an overview of the effects, and possible mechanisms, of probiotics, prebiotics and synbiotics (combination of a probiotic and prebiotic) on circulating lipeamia in humans.

Variation in genes related to hepatic lipid metabolism and changes in waist circumference and body weight.

We analysed single nucleotide polymorphisms (SNPs) tagging the genetic variability of six candidate genes (ATF6, FABP1, LPIN2, LPIN3, MLXIPL and MTTP) involved in the regulation of hepatic lipid metabolism, an important regulatory site of energy balance for associations with body mass index (BMI) and changes in weight and waist circumference. We also investigated effect modification by sex and dietary intake. Data of 6,287 individuals participating in the European prospective investigation into cancer and nutrition were included in the analyses. Data on weight and waist circumference were followed up for 6.9 ± 2.5 years. Association of 69 tagSNPs with baseline BMI and annual changes in weight as well as waist circumference were investigated using linear regression analysis. Interactions with sex, GI and intake of carbohydrates, fat as well as saturated, monounsaturated and polyunsaturated fatty acids were examined by including multiplicative SNP-covariate terms into the regression model. Neither baseline BMI nor annual weight or waist circumference changes were significantly associated with variation in the selected genes in the entire study population after correction for multiple testing. One SNP (rs1164) in LPIN2 appeared to be significantly interacting with sex (p = 0.0003) and was associated with greater annual weight gain in men (56.8 ± 23.7 g/year per allele, p = 0.02) than in women (-25.5 ± 19.8 g/year per allele, p = 0.2). With respect to gene-nutrient interaction, we could not detect any significant interactions when accounting for multiple testing. Therefore, out of our six candidate genes, LPIN2 may be considered as a candidate for further studies.

Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study

Background: Public health strategies to lower cardiovascular disease (CVD) risk involve reducing dietary saturated fatty acid (SFA) intake to ≤10% of total energy (%TE). However, the optimal type of replacement fat is unclear. Objective: We investigated the substitution of 9.5-9.6%TE dietary SFA with either monounsaturated (MUFA) or n-6 polyunsaturated fatty acids (PUFA) on vascular function and other CVD risk factors. Design: Using a randomized, controlled, single-blind, parallel group dietary intervention, 195 men and women aged 21-60 y with moderate CVD risk (≥50% above the population mean) from the United Kingdom followed one of three 16-wk isoenergetic diets (%TE target compositions, total fat:SFA:MUFA:n-6 PUFA): SFA-rich (36:17:11:4, n = 65), MUFA-rich (36:9:19:4, n = 64) or n-6 PUFA-rich (36:9:13:10, n = 66). The primary outcome measure was flow-mediated dilatation (%FMD); secondary outcome measures included fasting serum lipids, microvascular reactivity, arterial stiffness, ambulatory blood pressure, and markers of insulin resistance, inflammation and endothelial activation. Results: Replacing SFA with MUFA or n-6 PUFA did not significantly impact on %FMD (primary endpoint) or other measures of vascular reactivity. Of the secondary outcome measures, substitution of SFA with MUFA attenuated the increase in night systolic blood pressure (-4.9 mm Hg, P = 0.019) and reduced E-selectin (-7.8%, P = 0.012). Replacement with MUFA or n-6 PUFA lowered fasting serum total cholesterol (TC; -8.4% and -9.2%, respectively), low-density lipoprotein cholesterol (-11.3% and -13.6%) and TC to high-density lipoprotein cholesterol ratio (-5.6% and -8.5%) (P ≤ 0.001). These changes in low-density lipoprotein cholesterol equate to an estimated 17-20% reduction in CVD mortality. Conclusions: Substitution of 9.5-9.6%TE dietary SFA with either MUFA or n-6 PUFA did not impact significantly on %FMD or other measures of vascular function. However, the beneficial effects on serum lipid biomarkers, blood pressure and E-selectin offer a potential public health strategy for CVD risk reduction.

Insulin resistance determines a differential response to changes in dietary fat modification on metabolic syndrome risk factors: the LIPGENE study

Background: Previous data support the benefits of reducing dietary saturated fatty acids (SFAs) on insulin resistance (IR) and other metabolic risk factors. However, whether the IR status of those suffering from metabolic syndrome (MetS) affects this response is not established. OBJECTIVE: Our objective was to determine whether the degree of IR influences the effect of substituting high-saturated fatty acid (HSFA) diets by isoenergetic alterations in the quality and quantity of dietary fat on MetS risk factors. DESIGN: In this single-blind, parallel, controlled, dietary intervention study, MetS subjects (n = 472) from 8 European countries classified by different IR levels according to homeostasis model assessment of insulin resistance (HOMA-IR) were randomly assigned to 4 diets: an HSFA diet; a high-monounsaturated fatty acid (HMUFA) diet; a low-fat, high-complex carbohydrate (LFHCC) diet supplemented with long-chain n-3 polyunsaturated fatty acids (1.2 g/d); or an LFHCC diet supplemented with placebo for 12 wk (control). Anthropometric, lipid, inflammatory, and IR markers were determined. RESULTS: Insulin-resistant MetS subjects with the highest HOMA-IR improved IR, with reduced insulin and HOMA-IR concentrations after consumption of the HMUFA and LFHCC n-3 diets (P < 0.05). In contrast, subjects with lower HOMA-IR showed reduced body mass index and waist circumference after consumption of the LFHCC control and LFHCC n-3 diets and increased HDL cholesterol concentrations after consumption of the HMUFA and HSFA diets (P < 0.05). MetS subjects with a low to medium HOMA-IR exhibited reduced blood pressure, triglyceride, and LDL cholesterol levels after the LFHCC n-3 diet and increased apolipoprotein A-I concentrations after consumption of the HMUFA and HSFA diets (all P < 0.05). CONCLUSIONS: Insulin-resistant MetS subjects with more metabolic complications responded differently to dietary fat modification, being more susceptible to a health effect from the substitution of SFAs in the HMUFA and LFHCC n-3 diets. Conversely, MetS subjects without IR may be more sensitive to the detrimental effects of HSFA intake. The metabolic phenotype of subjects clearly determines response to the quantity and quality of dietary fat on MetS risk factors, which suggests that targeted and personalized dietary therapies may be of value for its different metabolic features.