Moderate exercise increases affinity of large very low density lipoproteins for hydrolysis by lipoprotein lipase

Context: Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations but the mechanisms responsible are unclear. Objective: To determine the effects of exercise on affinity of chylomicrons, large very low density lipoproteins (VLDL1) and smaller VLDL (VLDL2) for lipoprotein lipase (LPL) mediated TG hydrolysis. Design: Within-participant cross-over study. Setting: A University metabolic investigation unit. Participants: Ten overweight/obese men. Interventions: Participants undertook two oral fat tolerance tests, separated by 7–14 days, in which they had blood taken fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (EX); no exercise was performed before the control test (CON). Main outcome measures: Circulating TG-rich lipoprotein concentrations; affinity of chylomicrons, VLDL1, VLDL2 for LPL-mediated TG hydrolysis. Results: Exercise significantly reduced fasting VLDL1-TG concentration (CON: 0.49(0.33–0.72) mmol.l−1, EX: 0.36(0.22–0.59) mmol.l−1, [geometric means (95% confidence interval)]; p=0.04). Time-averaged postprandial chylomicron-TG (CON: 0.55±0.10 mmol.l−1, EX: 0.39±0.08 mmol.l−1, [mean±SEM], p=0.03) and VLDL1-TG (CON: 0.85±0.13 mmol.l−1, EX: 0.66±0.10 mmol.l−1, p=0.01) concentrations were both lower in EX than CON. Affinity of VLDL1 for LPL-mediated TG hydrolysis increased by 2.2(1.3–3.7) fold (geometric mean (95% confidence interval)) (p=0.02) in the fasted state and 2.6(1.8–2.6) fold (p=0.001) postprandially. Affinity of chylomicrons and VLDL2 was not significantly different between trials. Conclusions: Exercise increases affinity of VLDL1 for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to exercise's TG-lowering effect

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study) : study protocol for a randomized controlled trial

This study is funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate.BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).Publisher PDFPeer reviewe

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial.

BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).This study is funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate.This is the final published version. It first appeared at http://www.trialsjournal.com/content/15/1/202

Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial.

BACKGROUND: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid β (Aβ, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. METHODS: TOP-COG was a feasibility/pilot, double-blind RCT of 12 months simvastatin 40 mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E (APOE) ε4 allele status, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre randomisation and at 12 months post randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework Approach to determine recruitment motivators/barriers, and participation experience. RESULTS: We identified 181 (78 %) of the likely eligible Down syndrome population, and recruited 21 (11.6 %), from an area with a general population size of 3,135,974. Recruitment was highly labour-intensive. Thirteen (62 %) participants completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 levels changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. CONCLUSION: A full-scale RCT is feasible. It will need 37 % UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population. TRIAL REGISTRATION: ISRCTN67338640 .This study was funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate. The study was supported by Down Syndrome Scotland, and we thank them, and all members of the Trial Steering Committee and Data Management and Ethics Committee.This is the final version of the article. It first appeared from BioMed Central via https://doi.org/10.1186/s13063-016-1370-

Consumption of fish oil providing amounts of eicosapentaenoic acid and docosahexaenoic acid that can be obtained from the diet reduces blood pressure in adults with systolic hypertension: a retrospective analysis

Background: Although a large number of randomized controlled trials (RCTs) have examined the impact of the n-3 (ω-3) fatty acids EPA (20:5n-3) and DHA (22:6n-3) on blood pressure and vascular function, the majority have used doses of EPA+DHA of > 3 g per d,which are unlikely to be achieved by diet manipulation. Objective: The objective was to examine, using a retrospective analysis from a multi-center RCT, the impact of recommended, dietary achievable EPA+DHA intakes on systolic and diastolic blood pressure and microvascular function in UK adults. Design: Healthy men and women (n = 312) completed a double-blind, placebo-controlled RCT consuming control oil, or fish oil providing 0.7 g or 1.8 g EPA+DHA per d in random order each for 8 wk. Fasting blood pressure and microvascular function (using Laser Doppler Iontophoresis) were assessed and plasma collected for the quantification of markers of vascular function. Participants were retrospectively genotyped for the eNOS rs1799983 variant. Results: No impact of n-3 fatty acid treatment or any treatment * eNOS genotype interactions were evident in the group as a whole for any of the clinical or biochemical outcomes. Assessment of response according to hypertension status at baseline indicated a significant (P=0.046) fish oil-induced reduction (mean 5 mmHg) in systolic blood pressure specifically in those with isolated systolic hypertension (n=31). No dose response was observed. Conclusions: These findings indicate that, in those with isolated systolic hypertension, daily doses of EPA+DHA as low as 0.7 g bring about clinically meaningful blood pressure reductions which, at a population level, would be associated with lower cardiovascular disease risk. Confirmation of findings in an RCT where participants are prospectively recruited on the basis of blood pressure status is required to draw definite conclusions

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study). Pilot randomised controlled trial.

Background Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid ß (Aß, coded on chromosome 21) deposition and therefore delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs). Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. Methods TOP-Cog was a feasibility/pilot double-blind RCT of 12 months simvastatin 40mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E ε4, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre-randomisation and 12 months post-randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework approach to determine recruitment motivators/barriers, and participation experience. Results We identified 181 (78%) of the likely eligible Down syndrome population, and recruited 21 (11.6%), from an area with a general population size of 3,135,974. Recruitment was highly labour intensive. Thirteen (62%) completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. Conclusion A full-scale RCT is feasible. It will need 37% UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population.This study was funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate. The study was supported by Down Syndrome Scotland, and we thank them, and all members of the Trial Steering Committee and Data Management and Ethics Committee.This is the final version of the article. It first appeared from BioMed Central via https://doi.org/10.1186/s13063-016-1370-

Intravascular transfer contributes to postprandial increase in numbers of very-low-density hepatitis C virus particles

BACKGROUND & AIMS: The physical association of hepatitis C virus (HCV) particles with lipoproteins in plasma results in distribution of HCV in a broad range of buoyant densities. This association is thought to increase virion infectivity by mediating cell entry via lipoprotein receptors. We sought to determine if factors that affect triglyceride-rich lipoprotein (TRL) metabolism alter the density and dynamics of HCV particles in the plasma of patients with chronic HCV infection. METHODS: Fasting patients (n = 10) consumed a high-fat milkshake; plasma was collected and fractionated by density gradients. HCV-RNA was measured in the very-low-density fraction (VLDF, d < 1.025 g/mL) before and at 7 serial time points postprandially. RESULTS: The amount of HCV RNA in the VLDF (HCV(VLDF)) increased a mean of 26-fold, peaking 180 minutes after the meal (P < .01). Quantification of HCV RNA throughout the density gradient fractions revealed that HCV(VLDF) rapidly disappeared, rather than migrating into the adjacent density fraction. Immuno-affinity separation of the VLDF, using antibodies that recognize apolipoprotein B-100 and not apolipoprotein B-48, showed that HCV(VLDF) is composed of chylomicron-and VLDL-associated HCV particles; peaking 120 and 180 minutes after the meal, respectively. Plasma from fasting HCV-infected patients mixed with uninfected plasma increased the quantity of HCV(VLDF), compared with that mixed with phosphate-buffered saline, showing extracellular assembly of HCV(VLDF). CONCLUSIONS: Dietary triglyceride alters the density and dynamics of HCV in plasma. The rapid clearance rate of HCV(VLDF) indicates that association with TRL is important for HCV infectivity. HCV particles, such as exchangeable apolipoproteins, appear to reassociate with TRLs in the vascular compartment