PET imaging using (18)Ffluorodeoxyglucose (FDG) and (11)CPittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid ...protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.
Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts.
Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42).
PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. (18)Ffluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. ...The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants.
APOE epsilon4 allele frequency, CSF proteins (Abeta(1-42), total tau, hyperphosphorylated tau p-tau(181p)), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer's Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subscale) during a variable follow-up period (1.9 +/- 0.4 years).
Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures (p <or= 0.02). In addition, the CSF ratio p-tau(181p)/Abeta(1-42) (beta = 1.10 +/- 0.53; p = 0.04) and, marginally, FDG-PET predicted cognitive decline.
Baseline FDG-PET and episodic memory predict conversion to AD, whereas p-tau(181p)/Abeta(1-42) and, marginally, FDG-PET predict longitudinal cognitive decline. Complementary information provided by these biomarkers may aid in future selection of patients for clinical trials or identification of patients likely to benefit from a therapeutic intervention.
Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the ...airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2
neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.
The properties of supersonic, compressible plasma turbulence determine the behavior of many terrestrial and astrophysical systems. In the interstellar medium and molecular clouds, compressible ...turbulence plays a vital role in star formation and the evolution of our galaxy. Observations of the density and velocity power spectra in the Orion B and Perseus molecular clouds show large deviations from those predicted for incompressible turbulence. Hydrodynamic simulations attribute this to the high Mach number in the interstellar medium (ISM), although the exact details of this dependence are not well understood. Here we investigate experimentally the statistical behavior of boundary-free supersonic turbulence created by the collision of two laser-driven high-velocity turbulent plasma jets. The Mach number dependence of the slopes of the density and velocity power spectra agree with astrophysical observations, and supports the notion that the turbulence transitions from being Kolmogorov-like at low Mach number to being more Burgers-like at higher Mach numbers.
We examine the relationship of convection electric fields to the formation of a polar cap tongue of ionization (TOI) from midlatitude plumes of storm enhanced density (SED). Observations from the ...geomagnetic storm on 26–27 September 2011 are presented for two distinct SED events. During an hour‐long period of geomagnetic activity driven by a coronal mass ejection, a channel of high‐density F region plasma was transported from the dayside subauroral ionosphere and into the polar cap by enhanced convection electric fields extending to middle latitudes. This TOI feature was associated with enhanced HF backscatter, indicating that it was the seat of active formation of small‐scale irregularities. After the solar wind interplanetary magnetic field conditions quieted and the dayside convection electric fields retreated to higher latitudes, an SED plume was observed extending to, but not entering, the dayside cusp region. This prominent feature in the distribution of total electron content (TEC) persisted for several hours and elongated in magnetic local time with the rotation of the Earth. No ionospheric scatter from SuperDARN radars was observed within this SED region. The source mechanism (enhanced electric fields) previously drawing the plasma from midlatitudes and into the polar cap as a TOI was no longer active, resulting in a fossil feature. We thus demonstrate the controlling role exercised by the convection electric field in generating a TOI from midlatitude SED.
Key Points
Present observations of ionospheric electric field controlling SED/TOI formationAnalyze extent of small‐scale irregularity backscatter within high‐TEC featuresDiscuss characteristics of fossil SED feature which persists for several hours
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In many forested ecosystems, the architecture and functional ecology of certain tree species define forest structure and their species-specific traits control ecosystem dynamics. Such foundation tree ...species are declining throughout the world due to introductions and outbreaks of pests and pathogens, selective removal of individual taxa, and over-harvesting. Through a series of case studies, we show that the loss of foundation tree species changes the local environment on which a variety of other species depend; how this disrupts fundamental ecosystem processes, including rates of decomposition, nutrient fluxes, carbon sequestration, and energy flow; and dramatically alters the dynamics of associated aquatic ecosystems. Forests in which dynamics are controlled by one or a few foundation species appear to be dominated by a small number of strong interactions and may be highly susceptible to alternating between stable states following even small perturbations. The ongoing decline of many foundation species provides a set of important, albeit unfortunate, opportunities to develop the research tools, models, and metrics needed to identify foundation species, anticipate the cascade of immediate, short- and long-term changes in ecosystem structure and function that will follow from their loss, and provide options for remedial conservation and management.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Current theories assume a functional role for covert attention in the maintenance of spatial information in working memory. Consistent with this view, both the locus of attention and positions stored ...in working memory can be decoded based on the topography of oscillatory alpha-band (8–12 Hz) activity on the scalp. Thus far, however, alpha modulation has been studied in isolation for covert attention and working memory tasks. Here, we applied an inverted spatial encoding model in combination with EEG to study the temporal dynamics of spatially specific alpha activity during a task that required observers to visually select a target location while maintaining another independently varying location in working memory. During the memory delay period, alpha-based spatial tuning functions shifted from the position stored in working memory to the covertly attended position and back again after the attention task was completed. The findings provide further evidence for a common oscillatory mechanism in both the selection and the maintenance of relevant spatial visual information and demonstrate the dynamic trade-off in prioritization between two spatial tasks.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With declining sea ice conditions in Arctic regions owing to changing climate, the large prospective reservoirs of oil and gas in Baffin Bay and Davis Strait are increasingly accessible, and the ...interest in offshore exploration and shipping through these regions has increased. Both of these activities are associated with the risk of hydrocarbon releases into the marine ecosystem. However, hydrocarbons are also present naturally in marine environments, in some cases deriving from oil seeps. We have analyzed hydrocarbon concentrations in eleven sediment cores collected from northern Baffin Bay during 2008 and 2009 Amundsen expeditions and have examined the hydrocarbon compositions in both pre- and post-industrial periods (i.e., before and after 1900) to assess the sources of hydrocarbons, and their temporal and spatial variabilities. Concentrations of ΣPAHs ranged from 341 to 2693 ng g(-1) dw, with concentrations in cores from sites within the North Water (NOW) Polynya generally higher. Individual PAH concentrations did not exceed concentrations of concern for marine aquatic life, with one exception found in a core collected within the NOW (one of the seven sediment core samples). Hydrocarbon biomarkers, including alkane profiles, OEP (odd-to-even preference), and TAR (terrigenous/aquatic ratios) values indicated that organic carbon at all sites is derived from both terrigenous higher plants and marine algae, the former being of greater significance at coastal sites, and the latter at the deepest sites at the southern boundary of the NOW. Biomarker ratios and chemical profiles indicate that petrogenic sources dominate over combustion sources, and thus long-range atmospheric transport is less significant than inputs from weathering. Present-day and historic pre-1900 hydrocarbon concentrations exhibited less than an order of magnitude difference for most compounds at all sites. The dataset presented here provides a baseline record of hydrocarbon concentrations in Baffin Bay sediments in advance of offshore exploration and increased shipping activities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ObjectivesDesigning studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or ...‘progression’ criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase.DesignA structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders.ResultsThere is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decision-making process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented.ConclusionsSystematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials.
Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to ...treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs.
To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients.
A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden.
Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments.
Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.
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