TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.

A dose-response investigation of the attentional blink during sleep restriction /

Recent dose-response sleep restriction studies, in which nightly sleep is curtailed to varying degrees (e.g., 3-, 5-, 7-hours), have found cumulative, dose-dependent changes in sleepiness, mood, and reaction time. However, brain activity has typically not been measured, and attentionbased tests employed tend to be simple (e.g., reaction time). One task addressing the behavioural and electrophysiological aspects of a specific attention mechanism is the Attentional Blink (AB), which shows that the report accuracy of a second target (T2) is impaired when it is presented soon after a first target (Tl). The aim of the present study was to examine behavioural and electrophysioiogical responses to the AB task to elucidate how sleep restriction impacts attentional capacity. Thirty-six young-adults spent four consecutive days and nights in a sleep laboratory where sleep, food, and activity were controlled. Nightly sleep began with a baseline sleep (8 hours), followed by two nights of sleep restriction (3,5 or 8 hours of sleep), and a recovery sleep (8 hours). An AB task was administered each day at 11 am. Results from a basic battery oftests (e.g., sleepiness, mood, reaction time) confirmed the effectiveness of the sleep restriction manipulation. In terms of the AB, baseline performance was typical (Le., T2 accuracy impaired when presented soon after Tl); however, no changes in any AB behavioural measures were observed following sleep restriction for the 3- or 5-hour groups. The only statistically significant electrophysiological result was a decrease in P300 amplitude (for Tl) from baseline to the second sleep restriction night for the 3-hour group. Therefore, following a brief, two night sleep restriction paradigm, brain functioning was impaired for the TI of the AB in the absence of behavioural deficit. Study limitations and future directions are discussed.

A Bayesian approach for dose-escalation in a phase I clinical trial incorporating pharmacodynamic endpoints

Bayesian decision procedures have already been proposed for and implemented in Phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations. However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modeling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations. Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

Measles vaccination and antibody response in autism spectrum disorders

Objective: To test the hypothesis that measles vaccination was involved in the pathogenesis of autism spectrum disorders (ASD) as evidenced by signs of a persistent measles infection or abnormally persistent immune response shown by circulating measles virus or raised antibody titres in children with ASD who had been vaccinated against measles, mumps and rubella (MMR) compared with controls. Design: Case-control study, community based. Methods: A community sample of vaccinated children aged 10-12 years in the UK with ASD (n = 98) and two control groups of similar age, one with special educational needs but no ASD (n = 52) and one typically developing group (n = 90), were tested for measles virus and antibody response to measles in the serum. Results: No difference was found between cases and controls for measles antibody response. There was no dose-response relationship between autism symptoms and antibody concentrations. Measles virus nucleic acid was amplified by reverse transcriptase-PCR in peripheral blood mononuclear cells from one patient with autism and two typically developing children. There was no evidence of a differential response to measles virus or the measles component of the MMR in children with ASD, with or without regression, and controls who had either one or two doses of MMR. Only one child from the control group had clinical symptoms of possible enterocolitis. Conclusion: No association between measles vaccination and ASD was shown.

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.

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.

Physiological dose response of coffee (Coffea arabica L.) plants to glyphosate depends on growth stage

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)