The feasibility of a multidimensional intervention in lymphoma survivors with chronic fatigue.

PURPOSE: Chronic fatigue (CF) affects 25-30% of lymphoma survivors, but interventions designed to reduce fatigue are lacking. The main aim of this study was to test the feasibility of a multidimensional intervention study in lymphoma survivors with CF. Secondary aims were to describe individual changes in fatigue, quality of life (QoL) and physical performance from pre (T0) to post (T1) intervention. METHODS: This feasibility study was as a one-armed intervention study performed in 2021. Hodgkin or aggressive non-Hodgkin lymphoma survivors received mailed study information and Chalder Fatigue Questionnaire and were asked to respond if they suffered from fatigue. The 12-week intervention included patient education, physical exercise, a cognitive behavioural therapy (CBT)-based group program and nutritional counselling. Feasibility data included patient recruitment, completion of assessments, adherence to the intervention and patient-reported experience measures. Participants responded to questionnaires and underwent physical tests at T0 and T1. RESULTS: Seven lymphoma survivors with CF were included. Of all assessments, 91% and 83% were completed at T0 and T1, respectively. Adherence to the interventional components varied from 69% to 91%. At T1, all participants rated exercise as useful, of whom five rated the CBT-based program and five rated individual nutritional counselling as useful. Five participants reported improved fatigue, QoL and physical performance. CONCLUSION: Lymphoma survivors with CF participating in a multidimensional intervention designed to reduce the level of fatigue showed high assessment completion rate and intervention adherence rate. Most of the participants evaluated the program as useful and improved their level of fatigue, QoL and physical performance after the intervention. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT04931407. Registered 16. April 2021-Retrospectively registered. https://www. CLINICALTRIALS: gov/ct2/show/NCT04931407.

Antioxidant-rich foods and response to altitude training: A randomized controlled trial in elite endurance athletes.

High doses of isolated antioxidant supplements such as vitamin C and E have demonstrated the potential to blunt cellular adaptations to training. It is, however, unknown whether intake of high doses of antioxidants from foods has similar effects. Hence, the aim of the study was to investigate whether intake of antioxidant-rich foods affects adaptations to altitude training in elite athletes. In a randomized controlled trial, 31 national team endurance athletes (23 ± 5 years) ingested antioxidant-rich foods (n = 16) or eucaloric control foods (n = 15) daily during a 3-week altitude training camp (2320 m). Changes from baseline to post-altitude in hemoglobin mass (Hbmass ; optimized CO rebreathing), maximal oxygen uptake (VO2max ; n = 16) or 100 m swimming performance (n = 10), and blood parameters were compared between the groups. The antioxidant group significantly increased total intake of antioxidant-rich foods (~118%) compared to the control group during the intervention. The total study population improved VO2max by 2.5% (1.7 mL/kg/min, P = .006) and Hbmass by 4.7% (48 g, P < .001), but not 100 m swimming performance. No difference was found between the groups regarding changes in Hbmass , VO2max or swimming performance. However, hemoglobin concentration increased more in the antioxidant group (effect size = 0.7; P = .045) with a concomitantly larger decrease in plasma and blood volumes compared to control group. Changes in ferritin and erythropoietin from pre- to post-altitude did not differ between the groups. Doubling the intake of antioxidant-rich foods was well tolerated and did not negatively influence the adaptive response to altitude training in elite endurance athletes.

A low proportion of malnourished patients receive nutrition treatment - results from nutritionDay.

NutritionDay is a yearly point-prevalence study of malnutrition in hospitals from more than 50 countries. The aim of the present study was to quantify the frequency of malnutrition and the proportion of malnourished patients receiving nutritional treatment in two university hospitals in Norway using data from nutritionDay. All units at Oslo University Hospital (OUH) and University Hospital of Northern Norway (UNN) were invited to participate in nutritionDay 2014, and 28 out of 85 eligible units agreed to take part. Malnutrition was diagnosed based on body mass index (BMI), weight reduction and food intake in the previous week, according to national guidelines and ESPEN criteria. Data from 488 patients were available, representing 90.1% of occupied beds in participating units. Thirty percent of the patients were diagnosed malnourished when national criteria were used, and only 41% of these patients received nutritional treatment. The estimated malnutrition rate was 11% when the ESPEN consensus criteria were used. Data on weight or height were frequently missing in the patient records, and BMI could only be calculated in two-thirds of the patients. The frequency of low BMI (<18.5 kg/m2) was only 5%. Involuntary weight loss was present in 37% of the patients, and 60% had eaten less than normal in the previous week. Oncology units had the highest frequency of patients with low BMI, and the highest weight loss and overall malnutrition rate. Surgery and geriatric units had the highest rate of patients with low food intake. In this study, nearly 60% of the malnourished patients did not receive any nutritional treatment, and this indicates a potential for improved nutritional care and cost savings. Low food intake and weight loss were frequent at these two Norwegian hospitals, and in line with previous reports from nutritionDay in other countries.

A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hip fractures in elderly Norwegians: a NOREPOS study.

UNLABELLED: The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures. INTRODUCTION: This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. METHODS: The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994-2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K1 ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l. RESULTS: Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18-1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only. CONCLUSION: Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures.

Vitamin C and E supplementation blunts increases in total lean body mass in elderly men after strength training.

The aim of this study was to investigate the effects of vitamin C and E supplementation on changes in muscle mass (lean mass and muscle thickness) and strength during 12 weeks of strength training in elderly men. Thirty-four elderly males (60-81 years) were randomized to either an antioxidant group (500 mg of vitamin C and 117.5 mg vitamin E before and after training) or a placebo group following the same strength training program (three sessions per week). Body composition was assessed with dual-energy X-ray absorptiometry and muscle thickness by ultrasound imaging. Muscle strength was measured as one-repetition maximum (1RM). Total lean mass increased by 3.9% (95% confidence intervals: 3.0, 5.2) and 1.4% (0, 5.4) in the placebo and antioxidant groups, respectively, revealing larger gains in the placebo group (P = 0.04). Similarly, the thickness of m. rectus femoris increased more in the placebo group [16.2% (12.8, 24.1)] than in the antioxidant group [10.9% (9.8, 13.5); P = 0.01]. Increases of lean mass in trunk and arms, and muscle thickness of elbow flexors, did not differ significantly between groups. With no group differences, 1RM improved in the range of 15-21% (P < 0.001). In conclusion, high-dosage vitamin C and E supplementation blunted certain muscular adaptations to strength training in elderly men.

Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study.

UNLABELLED: We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51% higher risk in the lowest compared to the highest quartile. INTRODUCTION: Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up. METHODS: We performed a case-cohort analysis among 21,774 men and women aged 65-79 years who participated in four community-based health studies in Norway 1994-2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed. RESULTS: Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) µmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95% confidence interval (CI) 1.04-1.20) per 10-µmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95% CI 1.17-1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95% CI 1.05-1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio. CONCLUSIONS: Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.

Kiwifruit decreases blood pressure and whole-blood platelet aggregation in male smokers.

Lifestyle modifications to reduce risk factors for cardiovascular diseases such as blood pressure (BP) and smoking have been emphasized. Fruits and vegetables may modify such risk factors. The major aim of this randomized, controlled trial was to investigate the effects of (1) kiwifruits and (2) an antioxidant-rich diet compared with (3) a control group on BP and platelet aggregation (that is, whole-blood platelet aggregation) after 8 weeks in male smokers (age 44-74 years, n=102). The kiwifruit group received 3 kiwifruits per day, whereas the antioxidant-rich diet group received a comprehensive combination of antioxidant-rich foods. In the kiwifruit group, reductions of 10 mm Hg in systolic BP and 9 mm Hg in diastolic BP were observed (P=0.019 and P=0.016 (change from baseline in the kiwifruit group compared with change from baseline in the control group)). In the antioxidant-rich diet group, a reduction of 10 mm Hg in systolic BP was observed among hypertensives (P=0.045). Additionally, a 15% reduction in platelet aggregation and an 11% reduction in angiotensin-converting enzyme activity was observed in the kiwifruit group (P=0.009 and P=0.034). No effects on these parameters were observed in the antioxidant-rich diet group. This study suggest that intake of kiwifruit may have beneficial effects on BP and platelet aggregation in male smokers.

Apo-10'-lycopenoic acid impacts adipose tissue biology via the retinoic acid receptors.

Apo-10'-lycopenoic acid (apo-10-lycac), a metabolite of lycopene, has been shown to possess potent biological activities, notably via the retinoic acid receptors (RAR). In the current study, its impact on adipose tissue and adipocytes was studied. In microarray experiments, the set of genes regulated by apo-10-lycac treatments was compared to the set of genes regulated by all-trans retinoic acid (ATRA), the natural ligand of RAR, in adipocytes. Approximately 27.5% of the genes regulated by apo-10-lycac treatments were also regulated by ATRA, suggesting a common ability in terms of gene expression modulation, possibly via RAR transactivation. The physiological impact of apo-10-lycac on adipose tissue biology was evaluated. If it had no effect on adipogenesis in the 3T3-L1 cell model, this metabolite may have a preventative effect against inflammation, by preventing the increase in the inflammatory markers, interleukin 6 and interleukin 1ß in various dedicated models. The ability of apo-10-lycac to transactivate the RAR and to modulate the transcription of RAR target gene was brought in vivo in adipose tissue. While apo-10-lycac was not detected in adipose tissue, a metabolite with a molecular weight with 2Da larger mass was detected, suggesting that a dihydro-apo-10'-lycopenoic acid, may be present in adipose tissue and that this compound could active or may lead to further active RAR-activating apo-10-lycac metabolites. Since apo-10-lycac treatments induce anti-inflammatory effects in adipose tissue but do not inhibit adipogenesis, we propose that apo-10-lycac treatments and its potential active metabolites in WAT may be considered for prevention strategies relevant for obesity-associated pathologies.

Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells.

Small intestinal lamina propria (SI-LP) CD103(+) dendritic cells (DCs) are imprinted with an ability to metabolize vitamin A (retinol), a property underlying their enhanced capacity to induce the gut-homing receptors CC chemokine receptor-9 and α4ß7 on responding T cells. In this study, we demonstrate that imprinting of CD103(+) DCs is itself critically dependent on vitamin A and occurs locally within the small intestine (SI). The major vitamin A metabolite retinoic acid (RA) induced retinol-metabolizing activity in DCs both in vitro and in vivo, suggesting a direct role for RA in this process. Consistent with this, SI-LP CD103(+) DCs constitutively received RA signals in vivo at significantly higher levels than did colonic CD103(+) DCs. Remarkably, SI CD103(+) DCs remained imprinted in mice depleted of dietary but not of systemic retinol. We found that bile contained high levels of retinol, induced RA receptor-dependent retinol-metabolizing activity in bone marrow-derived DCs, and imprinted these cells with the ability to generate gut-tropic T cells. Taken together, these results suggest a novel and unexpected role for bile in SI-LP CD103(+) DC imprinting.

Plasma antioxidant responses and oxidative stress following a soccer game in elite female players.

We aimed to investigate markers of oxidative stress and levels of endogenous and dietary antioxidants in 16 elite female soccer players in response to a 90-min game (average intensity 82+/-3% HRpeak). Blood samples were taken before, immediately and 21 h after the game. Plasma-oxidized glutathione, the ratio of reduced to oxidized glutathione (GSH:GSSG) and lipid peroxidation measured by d-ROMs were used as markers of oxidative stress. Plasma endogenous [uric acid, total glutathione (TGSH)] and dietary antioxidants (alpha-tocopherol, ascorbic acid, total carotenoids and polyphenols) were analyzed using liquid chromatography and the Folin-Ciocalteu method. Exercise induced an acute increase (P<0.05) in GSSG, uric acid, TGSH, alpha-tocopherol, and ascorbic acid. In parallel, the GSH:GSSG ratio and polyphenols decreased (P<0.05). GSSG, GSH:GSSG ratio, uric acid, TGSH, and ascorbic acid returned to baseline at 21 h, while polyphenols and alpha-tocopherol remained altered. Total carotenoids increased above baseline only at 21 h (P<0.05). Lipid peroxidation, measured by d-ROMs, remained unchanged throughout the study. Thus, intermittent exercise in well-trained female athletes induces a transient increase in GSSG and a decrease in the GSH:GSSG ratio, which is effectively balanced by the recruitment of both endogenous and dietary antioxidants, resulting in the absence of lipid peroxidation measured by d-ROMs.

Differences in the inflammatory plasma cytokine response following two elite female soccer games separated by a 72-h recovery.

We investigated changes in a large battery of pro- and anti-inflammatory cytokines in elite female soccer players following two 90-min games separated by a 72-h active or passive recovery. Blood samples were taken from 10 players before, within 15-20 min, 21, 45 and 69 h after the first game and within 15-20 min after the second game. The leukocyte count was analyzed, together with several plasma pro- and anti-inflammatory cytokines, using a multiplex bead array system. After the first and second game, the total leukocytes and neutrophils increased significantly. Likewise, increases (P<0.05) in pro-inflammatory cytokines [interleukin (IL)-12, tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), IL-17], chemokines [monocyte chemotactic protein-1 (MCP-1), IL-8 and monokine induced by gamma interferon (MIG)], anti-inflammatory cytokines (IL-2R, IL-4, IL-5, IL-7, IL-10, IL-13, INF-α) and the mixed cytokine IL-6 were observed. Leukocyte and cytokine levels were normalized within 21 h. Active recovery (low-intensity exercises) did not affect the cytokine responses. A dampened cytokine response was observed after the second game as only IL-12, IL-6, MCP-1, IL-8 and MIG increased (P<0.05). In conclusion, a robust pro- and anti-inflammatory cytokine response occurs after the first but not the second soccer game. The implications of the dampened cytokine response in female players after the second game are unknown.

Lutein prevents the effect of high glucose levels on immune system cells in vivo and in vitro.

Diabetic patients present an increased susceptibility to frequent and protracted infections. The recognition of an impaired immune system has implications for the diagnosis, treatment and outcome of infections. Nuclear Factor kappa B (NF-kappaB) is a redox sensitive transcription factor involved in immune response, cell proliferation and apoptosis that has been associated to the development of diabetic complications. Herein we study the effects of high glucose on oxidative stress markers (malondialdeyde and glutathione contents) and NF-kappaB activity in U937 cells (a human promonocytic cell line). Furtheremore effects of lutein treatment in lymphocytes from diabetic rats was studied. The results show that high glucose induces oxidative stress in immune system cells, both in vitro and in vivo, as well as an increase in their NF-kappaB activity. It is also showed that lutein, a natural antioxidant without hypoglycemiant properties, is able to prevent all the alterations observed. Thus, this study confirms the role of oxidative stress in the immune system impairment described in diabetes, and allows the proposal of antioxidants for the clinical management of the diabetes-associated susceptibility to infections.

Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells.

Recent studies have highlighted a central role for intestinal dendritic cells (DCs) and vitamin A metabolite retinoic acid (RA) in the generation of alpha4beta7(+) CCR9(+)"gut tropic" effector T cells. Here, using RA-responsive element reporter mice, we demonstrate that both splenic and mesenteric lymph node (MLN) DCs enhanced retinoic acid receptor (RAR) signaling in CD8(+) T cells; however, only a subset of MLN DCs, expressing the integrin alpha-chain CD103, induced an early RAR signal that is required for efficient CCR9 induction. MLN-primed CD8(+) T cells also received enhanced RAR-dependent signals compared with splenic-primed CD8(+) T cells in vivo. Further DC-mediated induction of gut homing receptors was inhibited at a high antigen dose without influencing RAR signaling events, and resulted in less efficient CD8(+) T-cell entry into the small intestinal mucosa. These results highlight a complex interplay between antigen dose and DC subset-induced RAR signaling events in the generation of tissue tropic effector T-cell subsets.

Lutein prevents the effect of high glucose levels on immune system cells in vivo and in vitro

Diabetic patients present an increased susceptibility to frequent and protractedinfections. The recognition of an impaired immune system has implications for thediagnosis, treatment and outcome of infections. Nuclear Factor kappa B (NF-êB) isa redox sensitive transcription factor involved in immune response, cell proliferationand apoptosis that has been associated to the development of diabetic complications.Herein we study the effects of high glucose on oxidative stress markers (malondialdeydeand glutathione contents) and NF-êB activity in U937 cells (a humanpromonocytic cell line). Furtheremore effects of lutein treatment in lymphocytesfrom diabetic rats was studied. The results show that high glucose induces oxidativestress in immune system cells, both in vitro and in vivo, as well as an increase in theirNF-êB activity. It is also showed that lutein, a natural antioxidant without hypoglycemiantproperties, is able to prevent all the alterations observed. Thus, this studyconfirms the role of oxidative stress in the immune system impairment described indiabetes, and allows the proposal of antioxidants for the clinical management of thediabetes-associated susceptibility to infections (AU)

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Extracts of dietary plants are efficient modulators of nuclear factor kappa B.

Convincing evidence suggest that a plant-based diet is associated with a reduced risk of several chronic diseases, but the mechanisms for this association is not fully elucidated. The transcription factor nuclear factor kappa B (NF-kappa B) plays a critical role in cellular stress-, immune- and inflammatory responses. Also, NF-kappa B is identified as a promising therapeutic target both in cancer and chronic inflammation. We used monocytes stably transfected with a NF-kappa B-luciferase reporter construct in a screening of plant extracts for NF-kappa B modulators. Our aim was to identify dietary components which could induce basal NF-kappa B activity to produce a preconditioning effect, or inhibit induction of disease related NF-kappa B activity. When screening 34 dietary plants for their ability to induce basal NF-kappa B activity or inhibit lipopolysaccharide induced NF-kappa B activity we observed that 23 dietary plant extracts induced basal NF-kappa B activity, while 15 extracts attenuate induced NF-kappa B activation. These results indicate that dietary plants contain compounds that efficiently modulate NF-kappa B activity. We suggest dietary modulation of NF-kappa B may contribute to the observed beneficial effects of dietary plants on the risk of chronic diseases.

Stability of whole blood and plasma ascorbic acid.

The objective of this study was to evaluate the impact of pre-analytical factors on the short and long term stability of ascorbic acid (AA), the main form of vitamin C in whole blood and plasma. The effects of various anticoagulants, acidification, storage temperature and time were tested. A recently developed fast and sensitive HPLC method was used to measure AA levels. AA baseline values observed in heparin plasma were significantly higher than values observed in EDTA, citrate and Stabilyte plasma, as well as in serum. pH and temperature were identified as additional critical pre-analytical factors during the short, medium and long term handling and storage. Thus, assessment of reliable and accurate AA status in biological samples demonstrates to be highly dependent on whether the initial conditions during sample handling are controlled. In conclusion, heparin tubes should be used for blood sample collection. As AA is rapidly degraded, sample collection should be followed by immediate centrifugation and plasma acidification. To avoid further degradation during sample handling, samples should be stored at -70 degrees C without delay and analyzed within 80 days.

The effect of an increased intake of vegetables and fruit on weight loss, blood pressure and antioxidant defense in subjects with sleep related breathing disorders.

OBJECTIVE: To assess the effect of an increased consumption of vegetables and fruit on body weight, risk factors for cardiovascular disease (CVD) and antioxidant defense in obese patients with sleep-related breathing disorders (SRBD). DESIGN: Randomized, controlled trial of an intervention to increase the intake of vegetables to 400 g/day and fruit to 300 g/day. Dietary intake was calculated from a food frequency questionnaire. Antioxidant status was assessed with the ferric-reducing/antioxidant power (FRAP) assay. Plasma carotenoids were biomarkers for the intake of vegetables and fruit. SETTING: A hospital clinic preventing risk factors for CVD. SUBJECTS: Subjects were 103 men and 35 women with a body mass index of 36.7+/-5.8 kg/m(2) of which 57 (86%) in the control and 68 (94%) in the intervention group completed the study. INTERVENTION: Group-based behavioral program during 3 months. RESULTS: The mean between group differences in body weight was -2.0% (95% CI -3.6, -0.5), P<0.0001. The mean between group difference in systolic and diastolic blood pressure (BP) was -7.1 mm Hg (95% CI: -11.6, -2.6), P=0.0022 and -3.9 mm Hg (95% CI: -7.0, -0.9), P=0.0120, respectively. The mean change in daily intake of vegetables and fruit was 12 g (95% CI: -33, 57) and -4 g (95% CI: -79, 71) versus 245 g (95% CI: 194, 296) and 248 g (95% CI: 176, 320) in the control and intervention groups, respectively. This was reflected in higher concentrations of alpha-carotene and beta-carotene. No change in FRAP was seen. In a multiple regression analysis the change in intake of vegetables was a significant contributor (R(adj)(2)=0.073 (95% CI: 0.019, 0.214)) to the change in weight. CONCLUSION: Targeted dietary advice to increase the intake of vegetables and fruit among subjects with SRBD contributed to weight reduction and reduced systolic and diastolic BP, but had no effect on antioxidant defense measured with FRAP.

A robust characterization of retinoic acid response elements based on a comparison of sites in three species.

The availability of high-throughput genomic sequencing has allowed us to construct a more robust characterization of retinoic acid response elements than was possible in the past. We located human, mouse, and rat homologs for each of 51 well-documented, conserved retinoic acid response elements. Mathematical and statistical analyses of these 153 sites, 78 of which are new, shows that 92% of response elements have direct-repeat symmetry, but that only 76% exhibit canonical spacing attributes. While the familiar '(a/g)g(g/t)tca' hexamer motif is upheld, the more relaxed sequence, '(a/g)g(g/t)(g/t)(g/c)a', represents a 10% consensus. Sites are as likely to be on the coding strand as on the non-coding strand, and 86% of them are in upstream locations. From a statistical point of view, DR1 elements are fundamentally different from DR2 and DR5 elements, but this is only evident in the 5' hexamer. While there is considerable variation in core positions, and while no nucleotide can be considered forbidden at any position, variation among species at a fixed locus appears surprisingly constrained once a functional site has been attained.

Six carotenoids in plasma used to assess recommended intake of fruits and vegetables in a controlled feeding study.

BACKGROUND: There is a need for objective and universally applicable biomarkers for the intake of foods believed to affect human health. OBJECTIVE: The purpose of this feeding study was to test whether plasma concentrations of carotenoids could be used to distinguish recommended consumption of mixed fruits and vegetables (five a day) from the current national intake of fruits and vegetables (two a day). DESIGN: A strict crossover design was chosen to correct for observed interindividual variations in carotenoid response. A total of 40 healthy subjects were included in the study. After 1 week run-in period with no fruits and vegetables in the diet, one group was given two portions (300 g) of fruits and vegetables daily, while another group was given five portions (750 g) for 14 days. Following a 2 week wash-out period and 1 week run-in, the regimens were switched between the groups. Fruits and vegetables were combined to match a typical Norwegian diet. RESULTS: Enhanced intake from two to five portions of mixed fruits and vegetables increased plasma concentrations of alpha-carotene (P=0.033) and lutein (P=0.051) in a crossover analysis. Analysis of data in the parallel part of the study revealed differences between the high and low intake for plasma concentrations of alpha-carotene (P=0.013) and beta-carotene (P=0.016). A trend was also evident for plasma concentrations of lycopene (P=0.057) and lutein (P=0.076) in the parallel analysis. No effect of high vs low intake of fruits and vegetables was observed for plasma concentrations of beta-cryptoxanthin, zeaxanthin, cholesterol and triacylglycerols. CONCLUSION: The study indicates that plasma concentration of alpha-carotene, beta-carotene and lutein may be used to assess changes of fruit and vegetable intake corresponding to an increase from the present national intake in Norway to the recommended amount of five portions of fruits and vegetables daily. SPONSORSHIP: Norwegian Research Council, National Nutrition Council, Throne Holst Foundation for Nutrition Research and Freia Chokoladefabriks Medisinske Fond.

Gamma-glutamyltransferase and diabetes--a 4 year follow-up study.

AIMS/HYPOTHESIS: Gamma-glutamyltransferase (GGT) is located on the external surface of most cells and mediates the uptake of gluthathione, an important component of intracellular antioxidant defenses. An increase in GGT concentration has been regarded as a marker of alcohol consumption or liver disease. However, more subtle gradations in GGT could be informative because its expression is enhanced by oxidative stress and it could be released by several conditions inducing cellular stress. Recently, serum GGT concentrations have been associated with many cardiovascular disease risk factors or components of the insulin resistance syndrome. We did a prospective study with the hypothesis that serum GGT is a predictor of incident diabetes. METHODS: A total of 4,088 healthy men working in a steel manufacturing company were examined in 1994 and 1998. Diabetes was defined as a serum fasting glucose concentration of more than 126 mg/dl or the use of diabetes medication. RESULTS: There was a strong dose-response relation between serum GGT concentrations at baseline and the incidence of diabetes. In contrast to the 31% of men with GGT concentrations under 9 U/l, adjusted relative risks for incidence of diabetes for GGT concentrations 10-19, 20-29, 30-39, 40-49, and over 50 U/l were 8.0, 13.3, 12.6, 19.6 and 25.8, respectively. The associations of age and BMI with incident diabetes became stronger the higher the value of baseline serum GGT concentration. CONCLUSION/INTERPRETATION: This study suggests that an increase in GGT concentration within its physiological range is a sensitive and early biomarker for the development of diabetes.