Mapping the platelet profile for functional genomic studies and demonstration of the effect size of the GP6 locus

BACKGROUND: Evidence suggests the wide variation in platelet response within the population is genetically controlled. Unraveling the complex relationship between sequence variation and platelet phenotype requires accurate and reproducible measurement of platelet response. OBJECTIVE: To develop a methodology suitable for measuring signaling pathway-specific platelet phenotype, to use this to measure platelet response in a large cohort, and to demonstrate the effect size of sequence variation in a relevant model gene. METHODS: Three established platelet assays were evaluated: mobilization of [Ca(2+)](i), aggregometry and flow cytometry, each in response to adenosine 5'-diphosphate (ADP) or the glycoprotein (GP) VI-specific crosslinked collagen-related peptide (CRP). Flow cytometric measurement of fibrinogen binding and P-selectin expression in response to a single, intermediate dose of each agonist gave the best combination of reproducibility and inter-individual variability and was used to measure the platelet response in 506 healthy volunteers. Pathway specificity was ensured by blocking the main subsidiary signaling pathways. RESULTS: Individuals were identified who were hypo- or hyper-responders for both pathways, or who had differential responses to the two agonists, or between outcomes. 89 individuals, retested three months later using the same methodology, showed high concordance between the two visits in all four assays (r(2) = 0.872, 0.868, 0.766 and 0.549); all subjects retaining their phenotype at recall. The effect of sequence variation at the GP6 locus accounted for approximately 35% of the variation in the CRP-XL response. CONCLUSION: Genotyping-phenotype association studies in a well-characterized, large cohort provides a powerful strategy to measure the effect of sequence variation in genes regulating the platelet response.

Age and flexible thinking: an experimental demonstration of the beneficial effects of increased cognitively stimulating activity on fluid intelligence in healthy older adults

The disuse hypothesis of cognitive aging attributes decrements in fluid intelligence in older adults to reduced cognitively stimulating activity. This study experimentally tested the hypothesis that a period of increased mentally stimulating activities thus would enhance older adults' fluid intelligence performance. Participants (N = 44, mean age 67.82) were administered pre- and post-test measures, including the fluid intelligence measure, Cattell's Culture Fair (CCF) test. Experimental participants engaged in diverse, novel, mentally stimulating activities for 10-12 weeks and were compared to a control condition. Results supported the hypothesis; the experimental group showed greater pre- to post-CCF gain than did controls (effect size d = 0.56), with a similar gain on a spatial-perceptual task (WAIS-R Blocks). Even brief periods of increased cognitive stimulation can improve older adults' problem solving and flexible thinking.

Reversing the emotional Stroop effect reveals that it is not what it seems: the role of fast and slow components

The relative contributions of slow and fast (online) components in a modified emotional Stroop task were evaluated. The slow component, neglected in previous research, was shown to lead to the prediction of a reversed emotional intrusion effect using pseudorandomly mixed negative and neutral stimuli. This prediction was supported in Experiments 1 and 2. In Experiments 3 and 4, a new paradigm was developed that allowed a more direct observation of the nature of disruptive effects from negative stimuli. The results provided a clear demonstration of the presence of the slow component. The fast component, which has generally been assumed to be the source of the interference, was shown, in fact, to have little or no role in the disruption.

A little learning is a dangerous thing: an experimental demonstration of ignorance-driven inference

Studies of ignorance-driven decision making have been employed to analyse when ignorance should prove advantageous on theoretical grounds or else they have been employed to examine whether human behaviour is consistent with an ignorance-driven inference strategy (e. g., the recognition heuristic). In the current study we examine whether-under conditions where such inferences might be expected-the advantages that theoretical analyses predict are evident in human performance data. A single experiment shows that, when asked to make relative wealth judgements, participants reliably use recognition as a basis for their judgements. Their wealth judgements under these conditions are reliably more accurate when some of the target names are unknown than when participants recognize all of the names (a "less-is-more effect"). These results are consistent across a number of variations: the number of options given to participants and the nature of the wealth judgement. A basic model of recognition-based inference predicts these effects.

In vitro examination of the effect of Orlistat on the ability of the faecal microbiota to utilize dietary lipids

Orlistat is an anti-obesity treatment with which several gastrointestinal (GI) side-effects are commonly associated in the initial stages of therapy. There is no physiological explanation as to why two-thirds of those who take the drug experience one or more side-effects. It has been hypothesized that the GI microbiota may protect from or contribute to these GI disturbances. Using in vitro batch culture and human gut model systems, studies were conducted to determine whether increased availability of dietary lipids and/or orlistat affect the composition and/or activity of the faecal microbiota. Results from 24-h batch culture fermentation experiments demonstrated no effect of orlistat in the presence or absence of a dietary lipid (olive oil) on the composition of bacterial communities [as determined by fluorescence in situ hybridization (FISH) and denaturing gradient gel electrophoresis (DGGE) analyses], but did show there was great variability in the lipolytic activities of the microbiotas of individuals, as determined by gas chromatography analysis of long-chain fatty acids in samples. Subsequent studies focused on the effect of orlistat in the presence and absence of lipid in in vitro human gut model systems. Systems were run for 14 days with gut model medium (GMM) only (to steady state, SS), then fed at 12-h intervals with 50 mg orlistat, 2 g olive oil or a mixture of both for 14 days. FISH and DGGE were used to monitor changes in bacterial populations. Bacteria were cultivated from the GMM only (control) systems at SS. All strains isolated were screened for lipolytic activity using tributyrin agar. FISH and DGGE demonstrated that none of the compounds (singly or in combination) added to the systems had any notable effect on microbial population dynamics for any of the donors, although Subdoligranulum populations appeared to be inhibited by orlistat in the presence or absence of lipid. Orlistat had little or no effect on the metabolism of indigenous and added lipids in the fermentation systems, but there was great variability in the way the faecal microbiotas of the donors were able to degrade added lipids. Variability in lipid degradation could be correlated with the number and activity of isolated lipolytic bacteria. The mechanism by which orlistat and the GI microbiota cause side-effects in individuals is unknown, but several hypotheses have been proposed to account for their manifestation. The demonstration of great variability in the lipolytic activity of microbiotas to degrade lipids led to a large-scale cultivation-based study of lipolytic/lipase-positive bacteria present in the human faecal microbiota. Of 4,000 colonies isolated from 15 donors using five different agars, 378 strains were identified that had lipase activity. Molecular identification of strains isolated from five donors demonstrated that lipase activity is more prevalent in the human GI microbiota than previously thought, with members of the phyla Firmicutes, Bacteroidetes and Actinobacteria identified. Molecular identification and characterization of the substrate specificities of the strains will be carried out as part of ongoing work.

When's your birthday? The self-reference effect in retrieval of dates

Material encoded with reference to the self is better remembered. One interpretation of this effect is that the self operates to organise retrieval of memories. We were motivated to find out whether this organisational principle extended to everyday information and for material not explicitly related to the self. Participants generated friends' birthdays from memory and then gave their own birthday. We found that participants were particularly likely to recall birthdays from on or around the date of their own birthday. Thus, memory for birthdays clusters around self-relevant information, even when there is no specific attempt to recall self-related material. Birthdays clustered somewhat around the time of testing, important dates in the calendar, and for a close other, but not to the extent of the participants' birthdays. We suggest this is a demonstration of the organisational structure of the self in memory. Copyright (C) 2010 John Wiley & Sons, Ltd.