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Gonadotropin response to insulin and lipid infusion reproduces the reprometabolic syndrome of obesity in eumenorrheic lean women: a randomized crossover trial.
Santoro, N, Schauer, IE, Kuhn, K, Fought, AJ, Babcock-Gilbert, S, Bradford, AP
Fertility and sterility. 2021;(2):566-574
Abstract
OBJECTIVE To study the reprometabolic syndrome in normal-weight, eumenorrheic women by infusing a combination of insulin and lipid. Women with obesity have been shown to have reduced gonadotropins and impaired luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to gonadotropin-releasing hormone (GnRH). DESIGN Randomized crossover. SETTING Academic medical center. PARTICIPANT(S): Fifteen women, median age 32 (interquartile ranged [IQR] 26, 36) years and body mass index 21.9 (IQR 20.2, 22.9) kg/m2 were recruited. INTERVENTION(S): Early follicular phase, 6-hour infusions of insulin (20-40 mU/m2 per minute) and lipid (Intralipid)-insulin/lipid infusion; or saline infusion (controls). The first 4 hours of each study assessed endogenous gonadotropins; at 4 hours, GnRH (75 ng/kg) bolus was administered and sampling continued until 6 hours. MAIN OUTCOME MEASURE(S): Linear mixed model analysis was used to determine differences between insulin/lipid and saline influence on endogenous LH pulse amplitude (primary outcome), mean FSH, and area under the curve (AUC) response to GnRH (secondary outcomes). RESULT(S): Twelve women completed both intended studies and an additional 3 women completed only 1 of the 2 studies. LH pulse amplitude, mean FSH, and both AUC responses to GnRH were reduced by insulin/lipid, mean FSH and AUC for LH were at or near statistical significance. LH response to GnRH was significantly reduced when 1 participant with very high LH and antimullerian hormone levels was excluded. CONCLUSION(S): Acute infusion of insulin/lipid to eumenorrheic, normal-weight women recapitulated the reprometabolic syndrome of obesity. These findings imply that specific circulating factors in obese women contribute to their subfertility and thus may be amenable to discovery and treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT02653092.
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Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy.
Hilvo, M, Wallentin, L, Ghukasyan Lakic, T, Held, C, Kauhanen, D, Jylhä, A, Lindbäck, J, Siegbahn, A, Granger, CB, Koenig, W, et al
Journal of the American Heart Association. 2020;(10):e015258
Abstract
Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
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Using joint models to disentangle intervention effect types and baseline confounding: an application within an intervention study in prodromal Alzheimer's disease with Fortasyn Connect.
van Oudenhoven, FM, Swinkels, SHN, Hartmann, T, Soininen, H, van Hees, AMJ, Rizopoulos, D
BMC medical research methodology. 2019;(1):163
Abstract
BACKGROUND Many prodromal Alzheimer's disease trials collect two types of data: the time until clinical diagnosis of dementia and longitudinal patient information. These data are often analysed separately, although they are strongly associated. By combining the longitudinal and survival data into a single statistical model, joint models can account for the dependencies between the two types of data. METHODS We illustrate the major steps in a joint modelling approach, motivated by data from a prodromal Alzheimer's disease study: the LipiDiDiet trial. RESULTS By using joint models we are able to disentangle baseline confounding from the intervention effect and moreover, to investigate the association between longitudinal patient information and the time until clinical dementia diagnosis. CONCLUSIONS Joint models provide a valuable tool in the statistical analysis of clinical studies with longitudinal and survival data, such as in prodromal Alzheimer's disease trials, and have several added values compared to separate analyses.
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The LipiDiDiet trial: what does it add to the current evidence for Fortasyn Connect in early Alzheimer's disease?
Rasmussen, J
Clinical interventions in aging. 2019;:1481-1492
Abstract
Nutritional factors can influence the risk of developing Alzheimer's disease (AD) and its rate of progression, and there is, therefore, increasing interest in nutrition as a modifiable risk factor for the disease. Synaptic loss is an important feature of early AD, and the formation of new synapses is dependent on key nutritional elements that are known to be deficient in patients with AD. The daily medical food, Souvenaid, contains Fortasyn Connect, a multinutrient combination developed to specifically address these deficiencies, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, phospholipids, selenium, folic acid, and vitamins B12, B6, C, and E. Although yielding heterogeneous findings, clinical studies of Fortasyn Connect provide preliminary evidence of clinically relevant benefits on cognitive outcomes in prodromal and early AD. The LipiDiDiet trial investigated the effects of Fortasyn Connect on cognition and related measures in prodromal AD, and is the first randomized, controlled, double-blind, multicenter trial study of a non-pharmacological intervention in this setting. The primary efficacy endpoint was change over 24 months in a composite score of cognitive performance using a neuropsychological test battery. Fortasyn Connect had no significant effect on this endpoint, but demonstrated a significant benefit on secondary endpoints, including domains of cognition affected by AD (attention, memory, executive function) and hippocampal atrophy, suggesting a potential benefit on disease progression. Other studies have demonstrated benefits for Fortasyn Connect on nutritional markers and levels of plasma homocysteine. Taken together, current evidence indicates that Fortasyn Connect may show benefit on domains of cognition affected by AD and nutritional measures that influence risk factors for its progression; that it has greater potential for benefit earlier rather than later in the disease; and that it is safe and well tolerated, alone or in combination with AD medications. Further research into its potential role in AD management is therefore warranted.
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Comparing patterns of volatile organic compounds exhaled in breath after consumption of two infant formulae with a different lipid structure: a randomized trial.
Smolinska, A, Baranska, A, Dallinga, JW, Mensink, RP, Baumgartner, S, van de Heijning, BJM, van Schooten, FJ
Scientific reports. 2019;(1):554
Abstract
Infant formulae have been used since decades as an alternative to or a complement to human milk. Human milk, the "gold standard" of infant nutrition, has been studied for its properties in order to create infant formulae that bring similar benefits to the infant. One of the characteristics of milk is the size of the lipid droplets which is known to affect the digestion, gastric emptying and triglyceride metabolism. In the current study a concept infant milk formula with large, phospholipid coating of lipid droplets (mode diameter 3-5 μm; NUTURIS, further described as "active"), was compared to a commercially available formula milk characterised by smaller lipid droplets, further described as "control" (both products derived from Nutricia). We investigated whether we could find an effect of lipid droplet size on volatile compounds in exhaled air upon ingestion of either product. For that purpose, exhaled breath was collected from a group of 29 healthy, non-smoking adult males before ingestion of a study product (baseline measurements, T0) and at the following time points after the test meal: 30, 60, 120, 180 and 240 min. Volatile organic compounds (VOCs) in breath were detected by gas chromatography-time-of-flight-mass spectrometry. Any differences in the time course of VOCs patterns upon intake of active and control products were investigated by regularised multivariate analysis of variance (rMANOVA). The rMANOVA analysis revealed statistically significant differences in the exhaled breath composition 240 min after ingestion of the active formula compared to control product (p-value < 0.0001), but did not show significant changes between active and control product at any earlier time points. A set of eight VOCs in exhaled breath had the highest contribution to the difference found at 240 minutes between the two formulas. A set of ten VOCs was different between baseline and the two formulae at T240 with p-value < 0.0001. To our knowledge this is the first study that shows the ability of VOCs in exhaled breath to monitor metabolic effects after ingestion of infant formulae with different lipid structure. The statistically significant differences in compound abundance found between active and control formula milk may be related to: (i) specific differences in the digestion, (ii) absorption of lipids and proteins and (iii) assimilation of the products in the gut.
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Eight-week hempseed oil intervention improves the fatty acid composition of erythrocyte phospholipids and the omega-3 index, but does not affect the lipid profile in children and adolescents with primary hyperlipidemia.
Del Bo', C, Deon, V, Abello, F, Massini, G, Porrini, M, Riso, P, Guardamagna, O
Food research international (Ottawa, Ont.). 2019;:469-476
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Abstract
Children affected by primary hyperlipidemia have a high risk of developing cardiovascular diseases (CVDs) during adulthood. Several studies have reported a positive association between the intake of polyunsaturated fatty acids (PUFAs) and improvements in lipid markers and CVD risk. Dietary supplements may represent a potential strategy in the management of hyperlipidemia. In this context, the effectiveness of hempseed oil (HSO) rich in PUFAs (particularly linoleic acid (LA) and α-linolenic acid (ALA)) in the modulation of hyperlipidemia has been poorly investigated. The present pilot study aimed to explore the impact of HSO supplementation on the serum lipid profile and fatty acid (FA) composition of red blood cells (RBCs) in children and adolescents with primary hyperlipidemia. A randomized, 8 week long, parallel dietary intervention study was performed. Thirty-six hyperlipidemic probands (6-16 years) on diet therapy were randomized into two groups: the HSO group, receiving 3 g of HSO providing 1.4 g of LA and 0.7 g/day of ALA, and the control group. Both groups received specific dietary guidelines. Before and after the intervention, blood samples were collected and the serum lipid profile, FA composition of RBCs and omega-3-index were analyzed. Eight weeks of supplementation with HSO significantly (p < .01) reduced the RBC content of total saturated and monounsaturated FAs (-5.02 ± 7.94% and - 2.12 ± 2.23%, respectively), increased the levels of total n-3 and n-6 PUFAs (+1.57 ± 1.96% and + 5.39 ± 7.18%, respectively) and the omega-3 index (+1.18 ± 1.42%), but failed to affect the serum lipid profile compared to the control group. In conclusion, our findings seem to support the contribution of HSO supplementation in improving the RBC phospholipid composition and omega-3 index, while no effect was observed regarding modulation of the lipid profile. Further controlled studies are necessary to achieve a complete understanding of the effects of HSO in the modulation of hyperlipidemia and CVD risk in this and other target groups.
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Chokeberry Juice Containing Polyphenols Does Not Affect Cholesterol or Blood Pressure but Modifies the Composition of Plasma Phospholipids Fatty Acids in Individuals at Cardiovascular Risk.
Pokimica, B, García-Conesa, MT, Zec, M, Debeljak-Martačić, J, Ranković, S, Vidović, N, Petrović-Oggiano, G, Konić-Ristić, A, Glibetić, M
Nutrients. 2019;(4)
Abstract
Chokeberry polyphenols have been suggested to reduce cholesterol and blood pressure and thus protect against cardiovascular diseases (CVD), but the evidence in humans is limited and inconsistent. This randomized double-blinded three-parallel groups trial investigated the changes in various anthropometric and clinical biomarkers, and in plasma phospholipids fatty acids (PPFA) in volunteers at cardiovascular risk after a four-week intervention with 100 mL/day of (1) chokeberry juice with a high-dose of polyphenols (1177.11 mg gallic acid equivalents, GAE); (2) chokeberry juice with a low-dose of polyphenols (294.28 mg GAE) and; (3) a nutritionally matched polyphenol-free placebo drink. Our results indicate that the intake of chokeberry juice containing either the low or the high dose of polyphenols cannot be linked with a reduction in total- and low-density lipoprotein (LDL)cholesterol or in systolic (SBP) and diastolic (DBP) blood pressure in comparison with the consumption of the placebo drink. However, we found evidence of moderate changes in the PPFA, i.e., increased saturated fatty acids (SFA), mostly palmitic acid, and reduced n-6 polyunsaturated fatty acids (PUFA), principally linoleic acid (LA) with the intake of chokeberry against the placebo. These effects may be associated with the polyphenols but we could not differentiate a clear dose-response effect. Further research is still needed to elucidate the contribution of the polyphenolic fraction to the potential cardiovascular effects of the chokeberry and to build up the evidence of its potential benefit via the modulation of PPFA composition.
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Effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound for uterine fibroids: a randomised controlled trial.
Chen, Y, Jiang, J, Zeng, Y, Tian, X, Zhang, M, Wu, H, Zhou, H
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2018;(8):1311-1315
Abstract
OBJECTIVE To investigate the effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound (HIFU) treatment of uterine fibroids. METHODS A total of 120 patients with solitary uterine fibroid were randomly assigned into Groups A, B, C and D. Patients in Groups A and B received 1.5 ml of SonoVue, Groups C and D received 1.5 ml of saline before HIFU ablation. HIFU sonication started at 6 min after administration of SonoVue or saline in Groups A and C, whereas it started at 10 min in Groups B and D. On day 1 after HIFU, magnetic resonance imaging was performed. Patients were followed up via phone or clinic visit during the first week after HIFU. RESULTS No significant difference was observed in terms of age, fibroid location, diameter of fibroids, signal intensity on T2-weighted imaging, or tumour volume among the four groups (p > 0.05). The use of SonoVue significantly shortened the treatment time and sonication time. The sonication start time of 6 min, relative to 10 min, had significant effects on the treatment time and sonication time. The use of intravenous SonoVue followed by HIFU ablation 6 min later significantly increased the rate of significant grey-scale changes (55.9%) and the non-perfused volume ratio (94.2% ± 10.6%). No significant differences were observed in the incidence of intra-procedure and post-HIFU adverse effects among the four groups (p > 0.05). CONCLUSIONS SonoVue could be safely used to enhance the ablation effects of HIFU treatment of uterine fibroids.
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Effects of a hypoenergetic diet rich in α-linolenic acid on fatty acid composition of serum phospholipids in overweight and obese patients with metabolic syndrome.
Egert, S, Baxheinrich, A, Lee-Barkey, YH, Tschoepe, D, Stehle, P, Stratmann, B, Wahrburg, U
Nutrition (Burbank, Los Angeles County, Calif.). 2018;:74-80
Abstract
OBJECTIVES Plant-derived α-linolenic acid (ALA) may exert cardioprotective effects. Dietary ALA can undergo desaturation and elongation to form long-chain ω-3 polyunsaturated fatty acids, but the extent to which this occurs in humans is unclear. The aim of the study was to examine the effects of an energy-restricted diet enriched with ALA on fatty acid composition of serum phospholipids in patients with metabolic syndrome. METHODS The present analysis compared the effects of a hypoenergetic diet high in ALA (3.4 g/d) with a control diet low in ALA (0.9 g/d) on fatty acid composition of serum phospholipids in 81 overweight or obese patients with features of metabolic syndrome. RESULTS After a 26-wk intervention, concentration of ALA in serum phospholipids remained constant in both diet groups. The control group had a significant decrease in serum phospholipid eicosapentaenoic acid concentration, although no significant intergroup difference was observed. Serum phospholipid docosahexaenoic acid concentration significantly decreased to a similar extent with both interventions. Additionally, both interventions significantly decreased serum phospholipid concentrations of palmitic acid, stearic acid, total saturated fatty acids, linoleic acid, total ω-6 and ω-3 polyunsaturated fatty acids, with no effect of diet group on these changes. Compared with the ALA diet, the control diet led to a significant increase in serum phospholipid oleic acid concentration. CONCLUSION Daily intake of 3.4 g of ALA during a 26-wk energy-restricted diet did not lead to an enrichment of serum phospholipids with ALA and did not increase eicosapentaenoic acid due to conversion. Additionally, dietary ALA was unable to compensate for a decrease in serum phospholipid docosahexaenoic acid.
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Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial.
Capoulade, R, Yeang, C, Chan, KL, Pibarot, P, Tsimikas, S
JAMA cardiology. 2018;(12):1212-1217
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Abstract
IMPORTANCE Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear. OBJECTIVE To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018. INTERVENTIONS After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years. MAIN OUTCOMES AND MEASURES Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity. RESULTS In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (β coefficient, ≥ 0.25; SE, ≤ 0.004 [P ≤ .005]; OR, ≥1.10 [P ≤ .007]). CONCLUSIONS AND RELEVANCE This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00800800.