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BACKGROUND/OBJECTIVES: Isoflavones are present in soy foods and soy-based supplements. Despite low plasma isoflavone concentrations in the general Western population, concentrations in supplement users exceed those suggested to be beneficial for health in Asian populations, raising concerns for adverse effects. To aid risk assessment, quantification of the relation between isoflavone intake and plasma concentrations is essential. SUBJECTS/METHODS: Plasma samples were collected from postmenopausal women in three placebo-controlled crossover studies with 8-week periods for supplements (two studies, ~ 100 mg isoflavones/day, n = 88) or 4-week periods for soy foods (one study, ~48 mg isoflavones/day, n = 15). Plasma isoflavone concentrations (daidzein, equol, genistein and glycitein) were quantified using high-performance liquid chromatography and electrochemical detection. The association between plasma concentrations and isoflavone intake, equol producer status, intake-producer interaction and background dietary intake was assessed based on the assumption of a log-linear relation. RESULTS: Median plasma total isoflavone concentrations after the soy food and supplement interventions were respectively 2.16 and 3.47 µmol/l for equol producers and 1.30 and 2.39 µmol/l for non-producers. Regression analysis showed that doubling isoflavone intake increased plasma concentrations by 55-62% (± s.e. 1-2%, [R.sup.2] > 0.87) for daidzein, genistein, equol (only for producers) and total isoflavones; for glycitein the association was weaker (15 ± 1%, [R.sup.2] = 0.48). Adjustments for energy, carbohydrate and fat intake did not affect these estimates. Inter-individual variation, estimated based on repeated measures in one of the studies, was 30-96%. CONCLUSIONS: Although the relation between isoflavone intake and plasma concentrations was adequately quantified, the use of isoflavone intake data for risk assessment needs caution due to large inter-individual variation in plasma concentrations. European Journal of Clinical Nutrition (2014) 68, 1141-1147; doi: 10.1038/ejcn.2014.108; published online 18 June 2014, INTRODUCTION Isoflavones, present in soy products, are suggested to relieve menopausal complaints (1,2) and to have a number of other beneficial health effects, such as prevention of osteoporosis and cardiovascular [...]

Dietary proteins have an insulinotropic effect and thus promote insulin secretion, which indeed leads to enhanced glucose clearance from the blood. In the long term, however, a high dietary protein intake is associated with an increased risk of type 2 diabetes. Moreover, branched-chain amino acids (BCAA), a prominent group of amino acids, were recently identified to be associated with diabetes. Observational data and intervention studies do not point in the same direction regarding the effect of protein intake on insulin sensitivity and diabetes risk. Therefore, the first aim of this review will be to discuss human studies addressing high dietary protein intake and insulin action, with special attention for BCAA. In the second part, we will highlight the (patho) physiological consequences of high-protein diets regarding insulin action, in particular the role of the mechanistic target of the rapamycin pathway. European Journal of Clinical Nutrition (2014) 68, 973-979; doi: 10.1038/ejcn.2014.123; published online 2 July 2014, INTRODUCTION Insulin resistance is defined as tissues no longer being sensitive to the physiological actions of insulin, in particular glucose uptake. The insulin-mediated uptake of glucose can decrease when tissues [...]

Background/Objectives: The objective of this sudy was to assess the relationship between dietary intake and fatty liver as scored by the validated Fatty Liver Index (FLI) in a large cross-sectional study among a general Dutch adult population. Diet is known to affect liver fat accumulation in humans. Subjects/Methods: 1128 men and women aged 20-70 years were included. Dietary intake was assessed using a validated semiquantitative food frequency questionnaire. FLI was derived from body mass index (BMI), waist circumference, triglycerides and gamma-glutamyltransferase. Associations were adjusted for energy intake, alcohol intake, age, sex, education, smoking and prevalence of hypertension and diabetes. Results: In this population (mean age 53.0[+ or -]11.4 years; BMI 25.9[+ or -]4.0 kg/m[sup.2]; FLI 35.0[+ or -]27.7), the prevalence of fatty liver as indicated by an FLI [greater than] 60 was 21.5%. Subjects in the highest FLI category were more likely to be male, older and less physically active. Total protein intake and animal protein intake were positively associated with the highest FLI score versus the lowest (odds ratio (OR) 1.25 per 1 en%, 95% confidence interval (CI) 1.15-1.37 and OR 1.27, 95% CI 1.17-1.38, respectively); for vegetable protein, an inverse association was observed (OR 0.81, 95% CI 0.69-0.94). A similar positive association with FLI was observed when carbohydrates and fat were iso-calorically exchanged for total and animal proteins. Conclusions: Subjects in the high FLI group consumed more protein, especially from animal origin, less carbohydrates and less dietary fibre. The presence of fatty liver was associated with a higher intake of animal protein and total fat, soft drinks and snacks. European Journal of Clinical Nutrition (2018) 72, 117-123; doi: 10.1038/ejcn.2017.148; published online 13 September 2017, Author(s): A Rietman [1]; D Sluik [1]; E J M Feskens [1]; F J Kok [1]; M Mensink [1] Introduction Non-alcoholic fatty liver disease (NAFLD), the accumulation of triglycerides within [...]

Background/Objectives: To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). Subjects/Methods: In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n = 74;38 male, 36 female) and control group (CON: n = 73;37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (V[O.sub.2] max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. Results: INT decreased their saturated fat intake, increased their carbohydrate intake (P Conclusions: Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program. European journal of Clinical Nutrition (2011) 65, 1141-1147; doi:10.1038/ejcn.2011.74; published online 18 May 2011 Keywords: long-term lifestyle intervention; glucose metabolism; predictors of success, Introduction Type 2 diabetes needs effective prevention measures for curbing the growing burden worldwide. Diabetes incidence is 10-20 times greater in those with impaired glucose tolerance (IGT) or impaired fasting [...]

Background/Objectives: To assess the prevalence of vitamin D deficiency in Dutch athletes and to define the required dosage of vitamin D[sub.3] supplementation to prevent vitamin D deficiency over the course of a year. Subjects/Methods: Blood samples were collected from 128 highly trained athletes to assess total 25(OH)D concentration. Of these 128 athletes, 54 male and 48 female athletes (18-32 years) were included in a randomized, double blind, dose-response study. Athletes with either a deficient ( [less than] 50 nmol/l) or an insufficient (50-75 nmol/l) 25(OH)D concentration were randomly assigned to take 400, 1100 or 2200 IU vitamin D3 per day orally for 1 year. Athletes who had a total 25(OH)D concentration above 75 nmol/l at baseline continued with the study protocol without receiving vitamin D supplements. Serum total 25(OH)D concentration was assessed every 3 months, as well as dietary vitamin D intake and sunlight exposure. Results: Nearly 70% of all athletes showed an insufficient (50-75 nmol/l) or a deficient ( [less than] 50 nmol/l) 25(OH)D concentration at baseline. After 12 months, serum 25(OH)D concentration had increased more in the 2200 IU/day group (+50[+ or -]27 nmol/l) than the sufficient group receiving no supplements (+4[+ or -]17 nmol/l; P [less than] 0.01) and the 1100 IU/day group (+25[+ or -]23 nmol/l; P [less than] 0.05). Supplementation with 2200 IU/day vitamin D resulted in a sufficient 25(OH)D concentration in 80% of the athletes after 12 months. Conclusions: Vitamin D deficiency is highly prevalent in athletes. Athletes with a deficient or an insufficient 25(OH)D concentration can achieve a sufficient 25(OH)D concentration within 3 months by taking 2200 IU/day. European Journal of Clinical Nutrition (2016) 70, 1009-1014; doi: 10.1038/ejcn.2016.133; published online 27 July 2016, Author(s): E M P Backx [1]; M Tieland [1]; K Maase [2]; A K Kies [3]; M Mensink [1]; L J C van Loon [4]; L C P G M [...]

The CD4 + regulatory T (Treg) cell lineage, defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. As a model for Treg cells, studies employ TGF-β-induced (i)Treg cells generated from CD4 + conventional T (Tconv) cells in vitro. Here, we describe how human iTreg cells relate to human blood-derived tTreg and Tconv cells according to proteomic analysis. Each of these cell populations had a unique protein expression pattern. iTreg cells had very limited overlap in protein expression with tTreg cells, regardless of cell activation status and instead shared signaling and metabolic proteins with Tconv cells. tTreg cells had a uniquely modest response to CD3/CD28-mediated stimulation. As a benchmark, we used a previously defined proteomic signature that discerns ex vivo naïve and effector Treg cells from Tconv cells and includes conserved Treg cell properties. iTreg cells largely lacked this Treg cell core signature and highly expressed e.g. STAT4 and NFATC2, which may contribute to inflammatory responses. We also used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naïve Treg cells. iTreg cells contained part of this effector Treg cell signature, suggesting acquisition of pTreg cell features. In conclusion, iTreg cells are distinct from tTreg cells and share limited features with ex vivo Treg cells at the proteomic level., (© 2022. The Author(s).)

Tomato is an important commercial product which is perishable by nature and highly susceptible to fungal incidence once it is harvested. Not all tomatoes are equally vulnerable to pathogenic fungi, and an early detection of the vulnerable ones can help in taking timely preventive actions, ranging from isolating tomato batches to adjusting storage conditions, but also in making right business decisions like dynamic pricing based on quality or better shelf life estimate. More importantly, early detection of vulnerable produce can help in taking timely actions to minimize potential post-harvest losses. This paper investigates Near-infrared (NIR) hyperspectral imaging (1000-1700 nm) and machine learning to build models to automatically predict the susceptibility of sepals of recently harvested tomatoes to future fungal infections. Hyperspectral images of newly harvested tomatoes (cultivar Brioso) from 5 different growers were acquired before the onset of any visible fungal infection. After imaging, the tomatoes were placed under controlled conditions suited for fungal germination and growth for a 4-day period, and then imaged using normal color cameras. All sepals in the color images were ranked for fungal severity using crowdsourcing, and the final severity of each sepal was fused using principal component analysis. A novel hyperspectral data processing pipeline is presented which was used to automatically segment the tomato sepals from spectral images with multiple tomatoes connected via a truss. The key modelling question addressed in this research is whether there is a correlation between the hyperspectral data captured at harvest and the fungal infection observed 4 days later. Using 10-fold and group k-fold cross-validation, XG-Boost and Random Forest based regression models were trained on the features derived from the hyperspectral data corresponding to each sepal in the training set and tested on hold out test set. The best model found a Pearson correlation of 0.837, showing that there is strong linear correlation between the NIR spectra and the future fungal severity of the sepal. The sepal specific predictions were aggregated to predict the susceptibility of individual tomatoes, and a correlation of 0.92 was found. Besides modelling, focus is also on model interpretation, particularly to understand which spectral features are most relevant to model prediction. Two approaches to model interpretation were explored, feature importance and SHAP (SHapley Additive exPlanations), resulting in similar conclusions that the NIR range between 1390-1420 nm contributes most to the model's final decision., (© 2021. The Author(s).)

The transcription factor c-MYC regulates a multiplicity of genes involved in cellular growth, proliferation, metabolism and DNA damage response and its overexpression is a hallmark of many tumours. Since MYC promotes apoptosis under conditions of stress, such as limited availability of nutrients or cytokines, MYC-driven cells are very much dependent on signals that inhibit cell death. Stress signals trigger apoptosis via the pathway regulated by opposing fractions of the BCL-2 protein family and previous genetic studies have shown that the development of B lymphoid tumours in Eµ-Myc mice is critically dependent on expression of pro-survival BCL-2 relatives MCL-1, BCL-W and, to a lesser extent, BCL-X L , but not BCL-2 itself, and that sustained growth of these lymphomas is dependent on MCL-1. Using recently developed mice that lack expression of all three functional pro-survival A1 genes, we show here that the kinetics of lymphoma development in Eµ-Myc mice and the competitive repopulation capacity of Eµ-Myc haemopoietic stem and progenitor cells is unaffected by the absence of A1. However, conditional loss of a single remaining functional A1 gene from transplanted A1-a -/- A1-b fl/fl A1-c -/- Eµ-Myc lymphomas slowed their expansion, significantly extending the life of the transplant recipients. Thus, A1 contributes to the survival of malignant Eµ-Myc-driven B lymphoid cells. These results strengthen the case for BFL-1, the human homologue of A1, being a valid target for drug development for MYC-driven tumours.

We performed a randomised, placebo-controlled, crossover study to examine the effects of sodium and potassium supplementation on blood pressure (BP) and arterial stiffness in untreated (pre)hypertensive individuals. During the study, subjects were on a fully controlled diet that was relatively low in sodium and potassium. After a 1-week run-in period, subjects received capsules with supplemental sodium (3 g d(-1), equals 7.6 g d(-1) of salt), supplemental potassium (3 g d(-1)) or placebo, for 4 weeks each, in random order. Fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed at baseline and every 4 weeks. Of 37 randomized subjects, 36 completed the study. They had a mean pre-treatment BP of 145/81 mm Hg and 69% had systolic BP ⩾140 mm Hg. Sodium excretion was increased by 98 mmol per 24 h and potassium excretion by 63 mmol per 24 h during active interventions, compared with placebo. During sodium supplementation, office BP was significantly increased by 7.5/3.3 mm Hg, 24-h BP by 7.5/2.7 mm Hg and central BP by 8.5/3.6 mm Hg. During potassium supplementation, 24-h BP was significantly reduced by 3.9/1.6 mm Hg and central pulse pressure by 2.9 mm Hg. Pulse wave velocity and augmentation index were not significantly affected by sodium or potassium supplementation. In conclusion, increasing the intake of sodium caused a substantial increase in BP in subjects with untreated elevated BP. Increased potassium intake, on top of a relatively low-sodium diet, had a beneficial effect on BP. Arterial stiffness did not materially change during 4-week interventions with sodium or potassium.

Aims: Important risk factors for the progression from impaired glucose tolerance to type II diabetes mellitus are obesity, diet and physical inactivity. The aim of this study is to evaluate the effect of a lifestyle-intervention programme on glucose tolerance in Dutch subjects with impaired glucose tolerance (IGT)., Methods: A total of 102 subjects were studied, randomised into two groups. Subjects in the intervention group received regular dietary advice, and were stimulated to lose weight and to increase their physical activity. The control group received only brief information about the beneficial effects of a healthy diet and increased physical activity. Before and after the first year, glucose tolerance was measured and several other measurements were done., Results: Body weight loss after 1 y was higher in the intervention group. The 2-h blood glucose concentration decreased 0.8+/-0.3 mmol/l in the intervention group and increased 0.2+/-0.3 mmol/l in the control group (P<0.05). Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity., Conclusion: A lifestyle-intervention programme according to general recommendations is effective and induces beneficial changes in lifestyle, which improve glucose tolerance in subjects with IGT. Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity.