Tissue distribution of lignans in rats in response to diet, dose−response, and competition with isoflavones

This paper investigates the occurrence and distribution of the lignan metabolites enterodiol (END) and enterolactone (ENL) and the isoflavone daidzein (DAID) in rat tissues by use of liquid chromatography−electrospray ionization mass spectrometry (LC−ESI/MSn) following a variety of dietary regimes. Furthermore, we examined the dose−response and distribution of END and ENL in liver, testes, prostate, and lung, and we investigated the effects of competition between lignans and isoflavones on metabolite distribution. In liver, testes, prostate, and lung tissue, dose-related increases in END concentration were observed. In the testes, coadministration of 60 mg/kg secoisolariciresinol diglycoside (SDG) with 60 mg/kg isoflavones produced alterations in the resulting metabolite profile, causing increased END concentration and decreased DAID concentration. Results indicate lignan accumulation in tissues occurs, and coadministration of lignans with isoflavones affects the metabolite profile, with effects dependent on tissue type.

Dose-response associations between screen time and overweight among youth

Objective. To examine dose-response associations between screen time and overweight, independent of physical activity and dietary intake.

Methods. Participants were 580 Dutch youth (13 years; 48% boys). Body mass index, waist circumference and skinfold thickness at four sites determined weight status. Questionnaires examined television viewing and computer use, participation in organized sport and high caloric snack and sugar-containing beverage consumption.

Results. There were no significant associations among boys. Compared with girls spending less than two hours/day in screen time, those who spent three to four hours/day were more likely to be classified as overweight by waist circumference (odds ratio [OR]=3.4; 95% confidence intervals [CI]=1.1-10.7; p=0.03), and this likelihood increased substantially among those spending more than four hours/day (OR=5.5; 95% CI=2.1-14.1; p≤0.0001).

Conclusions. Girls who spend three or more hours/day in screen time are at increased risk of being classified as overweight by waist circumference.

Reconstruction of in vivo time-evolving neuroendocrine dose - response properties unveils admixed deterministic and stochastic elements

Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cells via quantifiable effector-response functions. On the other hand, in vivo interglandular signaling dynamics have not been estimable to date. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effector-response properties via a composite model comprising (i) a deterministic basic feedback and feedforward ensemble structure; (ii) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose–response properties; and (iii) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human (i) illustrates probabilistic estimation of endogenous effector dose–response properties; and (ii) unmasks statistically vivid (2- to 5-fold) random fluctuations in inferred target-gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to (i) reconstruct deterministic properties of interglandular signaling in the intact mammal and (ii) quantify apparent signal-response variability over short time scales in vivo. The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal-response relationships without isotope infusion or pathway disruption.

Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT)

OBJECTIVE:
Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke.

METHODS:
Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group.

RESULTS:
A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization amount constant. Increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI 0.91 to 0.97, p < 0.001). Session frequency was the most important variable in the CART analysis, after prognostic variables age and baseline stroke severity.

CONCLUSION:
These data suggest that shorter, more frequent mobilization early after acute stroke is associated with greater odds of favorable outcome at 3 months when controlling for age and stroke severity.

CLASSIFICATION OF EVIDENCE:
This study provides Class III evidence that shorter, more frequent early mobilization improves the chance of regaining independence after stroke.

Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?

Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the  mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (As^III) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.

Low dose supplementation with two different marine oils does not reduce pro-inflammatory eicosanoids and cytokines in vivo

In view of the reported potential anti-inflammatory activity of the New Zealand green lipped mussel (NZGLM), we aimed to compare the effect of low dose marine oil supplementation, from mussels and fish, in reducing blood markers of inflammation. Thirty apparently healthy males and females were recruited from the general public in Melbourne, Australia to participate in a double blind, randomised, parallel intervention study. Subjects were consuming approximately 73 mg of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) daily in their background diet prior to the commencement of the intervention. Subjects were randomly assigned to consume either 2 mL/day of the NZGLM oil preparation (mixed with olive oil and dl-alpha-tocopherol) or fish oil preparation (also mixed with olive oil and dl-alpha-tocopherol) for six weeks. Two mL of the oils contained 241 mg and 181 mg of n-3 LCPUFA, respectively. Neutrophil phospholipid fatty acids, serum thromboxane B2 (TXB2), stimulated monocyte production of prostaglandin E2 (PGE2), interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNFalpha) were measured. During the intervention, the total intakes of n-3 LCPUFA from the background diet and the supplements were 199 mg/d and 173 mg/day for the NZGLM and FO groups, respectively. Following six weeks of supplementation, both groups showed a small, but significant increase in neutrophil phospholipid proportion of eicosapentaenoic acid. The NZGLM group also showed a significant increase in docosahexaenoic acid levels. There were no significant changes with time or treatment for TXB2, PGE2, IL-1 beta or TNFalpha. This study showed that low dose supplementation with n-3 LCPUFA from two different marine oil preparations showed no difference in inflammatory markers in this group of healthy individuals. Further studies are warranted including dose response trials and studies in populations with inflammatory conditions.

Characterization of the MEK5-ERK5 module in human neutrophils and its relationship to ERK1/ERK2 in the chemotactic response

The role of the extracellular signal-regulated kinase (ERK) 1 and ERK2 in the neutrophil chemotactic response remains to be identified since a previously used specific inhibitor of MEK1 and MEK2, PD98059, that was used to provide evidence for a role of ERK1 and ERK2 in regulating chemotaxis, has recently been reported to also inhibit MEK5. This issue is made more critical by our present finding that human neutrophils express mitogen-activated protein (MAP) kinase/ERK kinase (MEK)5 and ERK5 (Big MAP kinase), and that their activities were stimulated by the bacterial tripeptide, formyl methionyl-leucyl-phenylalanine (fMLP). Dose response studies demonstrated a bell-shaped profile of fMLP-stimulated MEK5 and ERK5 activation, but this was left-shifted when compared with the profile of fMLP-stimulated chemotaxis. Kinetics studies demonstrated increases in kinase activity within 2 min, peaking at 3–5 min, and MEK5 activation was more persistent than that of ERK5. There were some similarities as well as differences in the pattern of activation between fMLP-stimulated ERK1 and ERK2, and MEK5-ERK5 activation. The up-regulation of MEK5-ERK5 activities was dependent on phosphatidylinositol 3-kinase. Studies with the recently described specific MEK inhibitor, PD184352, at concentrations that inhibited ERK1 and ERK2 but not ERK5 activity demonstrate that the ERK1 and ERK2 modules were involved in regulating fMLP-stimulated chemotaxis and chemokinesis. Our data suggest that the MEK5-ERK5 module is likely to regulate neutrophil responses at very low chemoattractant concentrations whereas at higher concentrations, a shift to the ERK1/ERK2 and p38 modules is apparent.

Evaluating irradiation dose for sterility induction and quality control of mass-produced fruit fly Bactrocera tryoni (Diptera : Tephritidae)

The sterile insect technique has been routinely used to eradicate fruit fly Bactrocera tryoni (Froggatt) incursions. This study considers whether fly quality in a mass-rearing facility can be improved by reducing irradiation doses, without sacrificing reproductive sterility. Pupae were exposed to one of five target irradiation dose ranges: 0, 40-45, 50-55, 60-65, and 70-75 Gy. Pupae were then assessed using routine quality control measures: flight ability, sex ratio, longevity under nutritional stress, emergence, and reproductive sterility. Irradiation did not have a significant effect on flight ability or sex ratio tests. Longevity under nutritional stress was significantly increased at 70-75 Gy, but no other doses differed from 0 Gy. Emergence was slightly reduced in the 50-55, 60-65, and 70-75 Gy treatments, but 40-45 Gy treatments did not differ from 0 Gy, though confounding temporal factors complicate interpretation. Reproductive sterility remained acceptable (> 99.5%) for all doses--40-45 Gy (99.78%), 50-55 Gy (100%), 60-65 Gy (100%), and 70-75 Gy (99.99%). We recommend that B. tryoni used in sterile insect technique releases be irradiated at a target dose of 50-55 Gy, providing improved quality and undiminished sterility in comparison with the current 70-75 Gy standard while also providing a substantial buffer against risk of under dosing.

The maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial

OBJECTIVE: To determine how much physical activity, in the form of walking, can be safely and feasibly tolerated for people with severe knee osteoarthritis (OA). DESIGN: Phase I dose response trial with escalating walking doses of 10, 20, 35, 50, 70, and 95 min over 1 week, were prescribed non-randomly to people with severe knee OA. The primary stopping rule was a substantial increase in knee pain. The primary outcomes were an estimation of the maximum tolerated dose of walking; and the proportion of people who did not complete the dose for feasibility reasons. The secondary outcomes were pain, stiffness and activity limitation Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Twenty-four participants (13 women) aged 53-83 years, and average body mass index (BMI) of 34 kg/m(2) (SD 9) were recruited. Three participants were assigned to each dose between 10 and 70 min, and nine participants assigned to the 95-min dose. The trial was stopped at 95 min due to the maximum number of adverse events occurring at this dose. Therefore, the maximum tolerated dose was 70 min. No participant stopped due to reasons related to feasibility. There was a moderate association between dose and increased activity (linear R(2) = 0.31, cubic R(2) = 0.69) and reduced stiffness (linear R(2) = 0.20, cubic R(2) = 0.52), with increased benefits at moderate to higher doses. CONCLUSIONS: There is preliminary evidence that 70 min per week of moderate intensity supervised walking was safe and feasible for people with severe OA of the knee; for higher doses there was a risk of exacerbating knee pain levels.

An ecological study of the relationship between social and environmental determinants of obesity

There is growing concern with the increasing prevalence of obesity in industrialised countries, a trend that is more apparent in the poor than in the rich. In an ecological study, the relationship between an area measure of socioeconomic status (SES) and the density of fast-food outlets was examined as one possible explanation for the phenomenon. It was found that there was a dose-response between SES and the density of fast-food outlets, with people living in areas from the poorest SES category having 2.5 times the exposure to outlets than people in the wealthiest category. The findings are discussed.