There Is No Safe Dose of Prions

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay

Overweight and lifestyle behaviors of low socioeconomic elementary school children in Buenos Aires

<p>Abstract</p> <p>Background</p> <p>There is growing interest in understanding the role that lifestyle behaviors play in relation to children's weight status. The objective of the study was to determine the association between children s BMI and dietary practices and maternal BMI.</p> <p>Methods</p> <p>330 students (168M) aged 8.9 + 2 y from 4 suburban Buenos Aires elementary schools, and their mothers aged 36.2 + 7 y were examined between April and September 2007. Mothers were asked about their children s lifestyle. Data included parental education levels socioeconomic status, mothers and children s BMI, and Tanner stage.</p> <p>Results</p> <p>All families were in the low socio-economic class. 79% of parents had an elementary education or less. 61 (18.5%) of children were obese (OB) (BMI>95%ile per CDC norms), and 53 (16.1%) overweight (OW) (BMI>85<95%ile). 103 (31.2%) of mothers were OB (BMI>30 kg/m2), and102 (30.9%) OW (BMI>25<30). 63% the children were pre-pubertal. 40% had a TV set in their bedroom. 13% of the children skipped breakfast and only 38% watched TV ≤2 hours daily, as recommended. Multiple logistic regression analysis showed a positive association between children s OW/OB and drinking sweetened beverages (OR = 1.24; 95% CI, 1.02–1.52), TV viewing (OR = 1.30; 95% CI,1.05–1.62), and maternal BMI (OR: 1.07; 95% CI,1.02–1.12), and a negative association with eating breakfast (OR = 0.43; 95% CI, 0.19–0.97) adjusted for fruit and vegetables consumption, milk consumption, maternal educational level and socioeconomic class.</p> <p>Conclusion</p> <p>Our results suggest that TV viewing, drinking sweet beverages, skipping breakfast, and maternal BMI are important predictive variables for childhood OW/OB.</p

Differences in Spontaneously Avoiding or Approaching Mice Reflect Differences in CB1-Mediated Signaling of Dorsal Striatal Transmission

Approach or avoidance behaviors are accompanied by perceptual vigilance for, affective reactivity to and behavioral predisposition towards rewarding or punitive stimuli, respectively. We detected three subpopulations of C57BL/6J mice that responded with avoiding, balancing or approaching behaviors not induced by any experimental manipulation but spontaneously displayed in an approach/avoidance conflict task. Although the detailed neuronal mechanisms underlying the balancing between approach and avoidance are not fully clarified, there is growing evidence that endocannabinoid system (ECS) plays a critical role in the control of these balancing actions. The sensitivity of dorsal striatal synapses to the activation of cannabinoid CB1 receptors was investigated in the subpopulations of spontaneously avoiding, balancing or approaching mice. Avoiding animals displayed decreased control of CB1 receptors on GABAergic striatal transmission and in parallel increase of behavioral inhibition. Conversely, approaching animals exhibited increased control of CB1 receptors and in parallel increase of explorative behavior. Balancing animals reacted with balanced responses between approach and avoidance patterns. Treating avoiding animals with URB597 (fatty acid amide hydrolase inhibitor) or approaching animals with AM251 (CB1 receptor inverse agonist) reverted their respective behavioral and electrophysiological patterns. Therefore, enhanced or reduced CB1-mediated control on dorsal striatal transmission represents the synaptic hallmark of the approach or avoidance behavior, respectively. Thus, the opposite spontaneous responses to conflicting stimuli are modulated by a different involvement of endocannabinoid signaling of dorsal striatal neurons in the range of temperamental traits related to individual differences

On the fallibility of human memory for future actions

Human memory is a system that is inherently fallible and prone to distortion, and our memory for future actions is no exception. Prospective memory is defined either as remembering to carry out a task at a particular moment in the future or as the timely execution of a previously formed intention. For a variety of reasons, one may miss this prearranged moment and thus fail to fulfill an intention. This thesis focuses on the factors that may affect the fulfilment of a delayed intention and contribute to prospective memory failures. As the rather scant literature on the effect of stress on prospective memory functioning has produced contradictory findings, Part One of this Thesis investigates the role of stress in prospective memory failures in a strict sense, namely forgetting to carry out intended actions at the appointed time and place. One study involving healthy participants examines the disruptive effect of daily stress on prospective memory functioning and explores the moderating role of individual factors in modulating the harmful consequences associated with stress in everyday life. Another study carried out with healthcare workers investigates how work stress and burnout may contribute to forgetting clinical tasks, which may result in potential adverse events jeopardizing patient safety. Besides stress, misremembering future intentions may also arise from the lingering effect of misinformation on our memory, attitudes, and behaviors. Part Two of this Thesis, encompassing 6 experiments on healthy participants, shows how inaccurate and invalid information survive despite sophisticated correction attempts, influencing memory and reported future intentions. Overall, the results of the studies presented in this Thesis prove the fallibility of our memory for future actions. Various techniques to reduce the risks associated with memory failures are discussed

"Adaptive response" - some underlying mechanisms and open questions

Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A better understanding of the molecular mechanism underlying the adaptive response may lead to an improvement of cancer treatment, risk assessment and risk management strategies, radiation protection, e. g. of astronauts during long-term space flights. In this mini-review we discuss some open questions and the probable underlying mechanisms involved in adaptive response: the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses - DNA repair systems, induction of proteins synthesis, enhanced detoxification of free radicals and antioxidant production.Publisher PDFPeer reviewe