Dose-dependent dissociation of pro-cognitive effects of donepezil on attention and cognitive flexibility in rhesus monkeys

BACKGROUND Donepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. Two brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning. METHODS To test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry. RESULTS The highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. CONCLUSIONS The donepezil dose for maximally improving attention differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in two major brain systems supporting these functions. These results suggest that in our small cohort of adult monkeys donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.National Institute of Mental Healt

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Team leadership in the intensive care unit: the perspective of specialists

Objectives: To identify the behaviors senior physicians (e.g., specialists, staff attendings) report using to lead multidisciplinary teams in the intensive care unit. Design: Semistructured interviews focusing on team leadership, crisis management, and development of an environment that enable effective team performance in the intensive care unit. Setting: Seven general intensive care units based in National Health Service hospitals in the United Kingdom. Participants: Twenty-five senior intensive care medicine physicians. Measurements and Main Results: Responses to a semistructured interview were transcribed and subjected to “content” analysis. The interview analysis focused on references to the “functional” behaviors used by leaders to manage team performance and the “team development behaviors” used to build the conditions that enable effective team performance. Seven of the interviews were coded by a second psychologist to measure inter-rater reliability. Inter-rater reliability (Cohen's κ) was acceptable for both scales (κ = 0.72 and κ = 0.75). In total, 702 functional leadership behaviors (behaviors for information gathering, planning and decision-making, managing team members) were coded as being used to manage the intensive care unit, along with 216 team development behaviors (for providing team direction and establishing team norms). These behaviors were grouped together in a theoretically driven framework of intensive care unit team leadership. Conclusions: Intensive care unit senior physicians report using a variety of leadership behaviors to ensure high levels of team performance. The data described in this study provide insight into the team leadership behaviors used by intensive care unit team leaders and have implications for the development of team leadership training and assessment tools

The Cryogenian Ghaub Formation of Namibia – New insights into Neoproterozoic glaciations

The Neoproterozoic Cryogenian (‘Marinoan’) Ghaub Formation of northwestern Namibia represents an important founding pillar of the Snowball Earth hypothesis and its derivative, the Panglacial Earth hypothesis. These hypotheses assume oceans and continents covered by thick ice, even in the tropics, which caused a very distinct drop in eustatic sea-level. Over time, strongly increased CO2 contents of the atmosphere led to sudden ice melting, very substantial sea-level rise, and strong weathering on the continents associated with the deposition of cap carbonates in the newly ice-free oceans. The ongoing controversy about Snowball-type glaciations in Namibia and elsewhere is reviewed, and other hypotheses (Slushball Earth, Waterbelt Earth, Jormungand state of the Earth, Thin Ice state of the Earth, Zipper-Rift Earth, High-Obliquity Earth) are discussed. We prefer the term ‘Waterbelt Earth’ instead of the originally proposed ‘Waterbelt state’ because of the clearer contrast with ‘Snowball Earth’. Because a great deal of information related to Cryogenian glaciations comes from the Ghaub Formation of northwestern Namibia, these hypotheses should be tested independently based on a time-equivalent depositional system. This analogue was found in the carbonate-dominated successions of the Otavi Mountainland (OML), northeastern Namibia, and is highly comparable with the successions in the well-investigated northwest of the country. An extreme eustatic sea-level drop caused by a global glaciation of oceans and continents and imposed on a carbonate platform or ramp such as the one in the OML would have led either to glacial cover or widespread subaerial exposure and extensive erosion, including deeply incised valleys. The presence of such features would strongly support the Snowball Earth hypotheses if tectonic effects did not play a major role. During the post- glacial transgression, distinct reworking of the carbonate platform/ramp surface would have occurred, leaving behind lag deposits, as well as infills of incised valleys with fluvial, reworked glacial, and marine deposits. The main objective of our research was to weigh and investigate the strengths and weaknesses of the proposed Snowball Earth model of glacially induced large-amplitude sea-level changes during Ghaub time, and to compare different models to obtain a rough estimate of the amount of glaciation. The study area in the OML includes two different, age-equivalent facies realms: platform sedimentation in the Southern area without diamictites, and slope deposits, including Ghaub diamictites, in the Northern area. The southern, continuously shallow-marine area shows a shallowing-upward succession from the pre-glacial lower Auros Formation, often varve-like laminated shales formed below wave base, to metre-high columnar stromatolites and microbial mat-related carbonates with intervals of vertical tubes (degassing features) of the upper Auros Formation, overlain by cap carbonates of the Maieberg Formation. The columnar stromatolites and the microbial tubestone lithotypes were clearly deposited in the euphotic zone. Indications for tidal conditions or subaerial exposure were not recorded in this platform succession without unconformities. Neither dropstones, nor incised channels, nor transgressive lag deposits were observed. The facies changes from below storm wave base to the photic zone and finally a shallow subtidal zone is explained by a prolonged, modest sea-level fall, partly counterbalanced by subsidence, followed by a slow transgression