Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA’s original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning–60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth–weaning period per dose ÷ (body weight(0.75)-day) for mutagenic carcinogens and a somewhat smaller increase—centered about 5-fold—for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth–weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the “adult” period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90–105 days of age)

Sit still and pay attention: Using the Wii Balance-Board to detect lapses in concentration in children during psychophysical testing.

During psychophysical testing, a loss of concentration can cause observers to answer incorrectly, even when the stimulus is clearly perceptible. Such lapses limit the accuracy and speed of many psychophysical measurements. This study evaluates an automated technique for detecting lapses based on body movement (postural instability). Thirty-five children (8-11 years of age) and 34 adults performed a typical psychophysical task (orientation discrimination) while seated on a Wii Fit Balance Board: a gaming device that measures center of pressure (CoP). Incorrect responses on suprathreshold catch trials provided the "reference standard" measure of when lapses in concentration occurred. Children exhibited significantly greater variability in CoP on lapse trials, indicating that postural instability provides a feasible, real-time index of concentration. Limitations and potential applications of this method are discussed

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

A Framework for Modelling the Electronic Medical Record

This paper presents a model for an electronic medical record which satisfies the requirements for a faithful and structured record of patient care set out in the previous paper in this series. The model is underlies the PEN&PAD clinical workstation, and it provides for a permanent, completely attributable record of patient care and the process of medical decision making. The model separates the record into two levels: direct observations of the patient and meta statements about the use of observations in decision making and the clinical dialogue. The model is presented in terms of `descriptions' formulated in the Structured Meta Knowledge (SMK) formalism, but many of its features are more general than the specific implementation. The use of electronic medical records based on the model for decision support and the analysis of aggregated data are discussed along with potential use of the model in distributed information systems

Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers.

Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease. OBJECTIVE: This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response. METHODS: This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days). RESULTS: Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment. CONCLUSIONS: Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD)

Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers

Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease.ObjectiveThis study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response.MethodsThis was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days).ResultsForty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment.ConclusionsOur results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD)

Biomolecular annotation integration and querying to help unveiling new biomedical knowledge

Targeting biological questions requires comprehensive evaluation of multiple types of annotations describing current biological knowledge; they are increasingly available, but their fast evolution, heterogeneity and dispersion in many different sources hamper their effective use. Leveraging on innovative flexible data schema and automatic software procedures that support the integration of data sources evolving in number, data content and structure, while assuring quality and provenance tracking of the integrated data, we created a multi-organism Genomic and Proteomic Knowledge Base (GPKB) and easily maintained it updated. From several well-known databases it imports and integrates very numerous gene and protein data, external references and annotations, expressed through multiple biomedical terminologies. To easily query such integrated data, we developed intuitive web interfaces and services for programmatic access to the GPKB; they are publicly available respectively at http://www.bioinformatics. deib.polimi.it/GPKB/ and http://www.bioinformatics.deib.polimi.it/ GPKB-REST/. The created GPKB is a very valuable resource used in several projects by many users; the developed interfaces enhance its relevance to the community by allowing the seamlessly composition of queries, although complex, on all data integrated in the GPKB, which can help unveiling new biomedical knowledge