Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men.

BACKGROUND & AIMS: Serum lipids and lipoproteins are established biomarkers of cardiovascular disease risk that could be influenced by impaired gut barrier function via effects on the absorption of dietary and biliary cholesterol. The aim of this study was to examine the potential relationship between gut barrier function (gut permeability) and concentration of serum lipids and lipoproteins, in an ancillary analysis of serum samples taken from a previous study. METHODS AND RESULTS: Serum lipids, lipoproteins and functional gut permeability, as assessed by the percentage of the urinary recovery of 51Cr-labelled EDTA absorbed within 24 h, were measured in a group of 30 healthy men. Serum lipopolysaccharide, high sensitivity C-reactive protein and interleukin-6 were also measured as markers of low-grade inflammation. The group expressed a 5-fold variation in total gut permeability (1.11-5.03%). Gut permeability was unrelated to the concentration of both serum total and low density lipoprotein (LDL)-cholesterol, but was positively associated with serum high density lipoprotein (HDL)-cholesterol (r = 0.434, P = 0.015). Serum HDL-cholesterol was also positively associated with serum endotoxaemia (r = 0.415, P = 0.023). CONCLUSION: The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or ß-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study.

AIMS: To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and ß-cell function. METHODS: An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. RESULTS: After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: ß = -0.357; waist circumference: ß = -0.380; body fat mass: ß = -0.375) and disposition index (BMI: ß = -0.215; waist circumference: ß = -0.248; body fat mass: ß = -0.221) and positively associated with acute insulin response to glucose [BMI: ß = 0.200; waist circumference: ß = 0.195; body fat mass ß = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (ß = -0.133), acute insulin response to glucose (ß = -0.148) and disposition index [ß = -0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. CONCLUSIONS: Plasma free fatty acid levels have a modest negative association with insulin sensitivity, ß-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or ß-cell dysfunction.

The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome 'at-risk' population.

INTRODUCTION AND OBJECTIVES: An obese-type human microbiota with an increased Firmicutes:Bacteroidetes ratio has been described that may link the gut microbiome with obesity and metabolic syndrome (MetS) development. Dietary fat and carbohydrate are modifiable risk factors that may impact on MetS by altering the human microbiome composition. We determined the effect of the amount and type of dietary fat and carbohydrate on faecal bacteria and short chain fatty acid (SCFA) concentrations in people 'at risk' of MetS. DESIGN: A total of 88 subjects at increased MetS risk were fed a high saturated fat diet (HS) for 4 weeks (baseline), then randomised onto one of the five experimental diets for 24 weeks: HS; high monounsaturated fat (MUFA)/high glycemic index (GI) (HM/HGI); high MUFA/low GI (HM/LGI); high carbohydrate (CHO)/high GI (HC/HGI); and high CHO/low GI (HC/LGI). Dietary intakes, MetS biomarkers, faecal bacteriology and SCFA concentrations were monitored. RESULTS: High MUFA diets did not affect individual bacterial population numbers but reduced total bacteria and plasma total and LDL-cholesterol. The low fat, HC diets increased faecal Bifidobacterium (P=0.005, for HC/HGI; P=0.052, for HC/LGI) and reduced fasting glucose and cholesterol compared to baseline. HC/HGI also increased faecal Bacteroides (P=0.038), whereas HC/LGI and HS increased Faecalibacterium prausnitzii (P=0.022 for HC/HGI and P=0.018, for HS). Importantly, changes in faecal Bacteroides numbers correlated inversely with body weight (r=-0.64). A total bacteria reduction was observed for high fat diets HM/HGI and HM/LGI (P=0.023 and P=0.005, respectively) and HS increased faecal SCFA concentrations (P<0.01). CONCLUSION: This study provides new evidence from a large-scale dietary intervention study that HC diets, irrespective of GI, can modulate human faecal saccharolytic bacteria, including bacteroides and bifidobacteria. Conversely, high fat diets reduced bacterial numbers, and in the HS diet, increased excretion of SCFA, which may suggest a compensatory mechanism to eliminate excess dietary energy.

Neighborhood socioeconomic status and coronary heart disease risk prediction in a nationally representative sample.

OBJECTIVES: Test the association between coronary heart disease (CHD) risk scores and neighborhood socioeconomic status (NSES) in a US nationally-representative sample and describe whether the association varies by gender and race/ethnicity. STUDY DESIGN: Cross-sectional study. METHODS: We use Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 linked with Census tract data. Multivariable regression models and propensity score adjusted models are employed to test the association between NSES and 10-year risk of CHD based on the Framingham Risk Score (FRS), adjusting for individual-level characteristics. RESULTS: An individual living in a neighborhood at the 75th percentile of NSES (high NSES) has, on average, a 10-year CHD risk that is 0.16 percentage points lower (95% Confidence Interval 0.16, 0.17) than a similar person residing in a neighborhood at the 25th percentile of NSES (low NSES). Race/ethnicity and gender were found to significantly modify the association between NSES and CHD risk: the association is larger in men than women and in whites than minorities. Propensity score models showed that findings on the main effects of NSES were robust to self-selection into neighborhoods. Similar results were observed between NSES and risk of cardiovascular disease events. CONCLUSIONS: NSES is significantly associated with CHD risk, and the relationship varies by gender and race/ethnicity.

Lack of effect of cold water prawns on plasma cholesterol and lipoproteins in normo-lipidaemic men.

OBJECTIVE: Dietary guidelines for the prevention of coronary heart disease (CHD) have restricted the intake of foods rich in dietary cholesterol, on the grounds that the dietary cholesterol will increase blood cholesterol. In the case of shellfish, this recommendation may limit the intake of a valuable dietary source of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA). The objective of this study was to undertake a dietary intervention to determine the effects of cold water prawns on plasma lipids and lipoproteins. METHODS: 23 healthy male subjects were randomised to receive either 225 g of cold water prawns or an equivalent weight of fish ('crab') sticks as a control for 12 weeks in a cross-over design. Blood samples were taken at the beginning and end of each intervention for the determination of plasma lipids and lipoproteins by routine enzymatic assays and iodixanol density gradient centrifugation respectively. RESULTS: The diets were well matched for the intake of total energy and macronutrients, and body weight remained stable throughout the study. The prawn intervention increased the intake of dietary cholesterol to 750 mg/d against 200 mg/d on the control. The intake of LC n-3 PUFA from prawns was estimated to be between 0.5-0.7 g/d. The consumption of prawns produced no significant effects on the concentration of plasma total or LDL cholesterol, triacylglycerol, HDL cholesterol or apolipoproteins A-I and B relative to the control, or within each intervention group over time. There was also no significant effect on LDL density (particle size) relative to the control, or any difference between and within treatments in total plasma lipoprotein profiles by density gradient centrifugation. CONCLUSION: These findings provide evidence to suggest that the consumption of cold water prawns, at least in healthy, male subjects, should not be restricted on the grounds of this seafood producing an adverse effect on plasma LDL cholesterol.

The influence of alcohol consumed with a meal on endothelial function in healthy individuals.

BACKGROUND: Alcohol and polyphenols in wine and fruit juices have been strongly implicated in the favourable effects on of these beverages on vascular function. Despite a wealth of information on the metabolic and vascular effects of alcohol and polyphenols, the combined influences of these substances on vascular function, especially when consumed with food, is poorly understood. A study was designed to determine the effects of a phenolic-rich grape juice, with or without alcohol, on vascular endothelial function in the postprandial state. METHODS: Ten subjects consumed a standard meal with a test drink on three separate occasions. On each occasion, the test drink accompanying the meal was either red grape juice, red grape juice plus alcohol (12% v/v), or water. Endothelial function was measured by flow mediated dilatation (FMD) prior to then 30 and 60 minutes after consuming the meal. Blood samples were taken for the determination of plasma glucose, triacylglycerol (TAG) and non esterified fatty acids (NEFA) at regular intervals. RESULTS: There was a significant effect of the three treatments (P = 0.0026) and time (P = 0.021) on percentage FMD. The meals with the grape juice and grape juice plus alcohol produced similar FMD responses but were both significantly greater than the meal with water. The concentration of plasma glucose, TAG and NEFA were similar after each treatment. CONCLUSION: Alcohol had no effect on vascular function in the early postprandial phase. These findings provide new evidence to support the potential benefit of non-alcoholic components within alcoholic beverages on vascular function in the fed state.

Specific covalent labeling of recombinant protein molecules inside live cells.

Recombinant proteins containing four cysteines at the i, i + 1, i + 4, and i + 5 positions of an alpha helix were fluorescently labeled in living cells by extracellular administration of 4',5'-bis(1,3, 2-dithioarsolan-2-yl)fluorescein. This designed small ligand is membrane-permeant and nonfluorescent until it binds with high affinity and specificity to the tetracysteine domain. Such in situ labeling adds much less mass than does green fluorescent protein and offers greater versatility in attachment sites as well as potential spectroscopic and chemical properties. This system provides a recipe for slightly modifying a target protein so that it can be singled out from the many other proteins inside live cells and fluorescently stained by small nonfluorescent dye molecules added from outside the cells.

Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors.

OBJECTIVE: To investigate the relative efficacy of four popular weight-loss programmes on plasma lipids and lipoproteins as measures of CVD risk. DESIGN: A multi-centred, randomised, controlled trial of four diets - Dr Atkins' New Diet Revolution, The Slim-Fast Plan, Weight Watchers Pure Points programme and Rosemary Conley's 'Eat yourself Slim' Diet and Fitness Plan - against a control diet, in parallel for 6 months. SETTING AND SUBJECTS: The trial was conducted at five universities across the UK (Surrey, Nottingham, Ulster (Coleraine), Bristol and Edinburgh (Queen Margaret University College)) and involved the participation of 300 overweight and obese males and females aged 21-60 years in a community setting. RESULTS: Significant weight loss was achieved by all dieting groups (5-9 kg at 6 months) but no significant difference was observed between diets at 6 months. The Weight Watchers and Rosemary Conley (low-fat) diets were followed by significant reductions in plasma LDL cholesterol (both -12.2 % after 6 months, P < 0.01), whereas the Atkins (low-carbohydrate) and Weight Watchers diets were followed by marked reductions in plasma TAG (-38.2 % and -22.6 % at 6 months respectively, P < 0.01). These latter two diets were associated with an increase in LDL particle size, a change that has been linked to reduced CVD risk. CONCLUSIONS: Overall, these results demonstrate the favourable effects of weight loss on lipid-mediated CVD risk factors that can be achieved through commercially available weight-loss programmes. No detrimental effects on lipid-based CVD risk factors were observed in participants consuming a low-carbohydrate diet.

Design and analysis of arm-in-cage experiments: inference for three-state progressive disease models with common periodic observation times.

We develop statistical methods for designing and analyzing arm-in-cage experiments used to test the efficacy of insect repellents and other topical treatments. In these experiments, a controlled amount of the treatment is applied to a volunteer's forearm, which then is exposed to the insects by being placed into a special cage. Arms are not kept in the cages continuously, but rather placed there periodically for a brief period of time, during which it is noted whether an insect lands (but does not bite) or (lands and) bites. Efficacy of a repellent can be described using a progressive three-state model in which the first two states represent varying degrees of protection (no landing and landing without biting) and the third state occurs once protection is completely lost (biting). Because subjects within a treatment group follow the same cage visit schedule, transition times between states are interval censored into one of several fixed intervals. We develop an approach that uses a mixture of nonparametric and parametric techniques for estimating the parameters of interest when sojourn times are dependent. Design considerations for arm-in-cage experiments are addressed and the proposed methods are illustrated on data from a recent arm-in-cage experiment as well as simulated data.

Relevance of liver fat to the impact of dietary extrinsic sugars on lipid metabolism.

In contrast to the decline in mortality from many non-infectious, chronic diseases in the UK, death from liver disease has increased exponentially in men and women over the past 40 years. This is primarily because of the over consumption of alcohol, but also the increased prevalence of obesity, which is linked to early pathology through the accumulation of liver fat. Supra-physiological intakes of fructose-containing sugar can produce acute, adverse effects on lipid metabolism, and deliver excess energy that increases bodyweight and the deposition of fat in sites other than adipose tissue, including the liver. This review addresses the variable metabolic origins of liver fat, and the key importance of postprandial lipid metabolism in this respect. The effects of supra-physiological intakes of sugar are also considered in context of the real world and established threshold for the adverse effects of sugar on cardio-metabolic risk factors. The review concludes that while the average intake of sugar in the UK falls well below this critical threshold, intakes in subgroups of adults, and especially adolescents, may be cause for concern. There is also evidence to suggest that raised liver fat, acquired, in part, through an impaired removal of postprandial lipaemia, can increase sensitivity to the adverse effects of sugar at all ages.