640 research outputs found
The importance of endpoint selection: how effective does a drug need to be for success in a clinical trial of a possible Alzheimer's disease treatment?
To date, Alzheimer's disease (AD) clinical trials have been largely unsuccessful. Failures have been attributed to a number of factors including ineffective drugs, inadequate targets, and poor trial design, of which the choice of endpoint is crucial. Using data from the Alzheimer's Disease Neuroimaging Initiative, we have calculated the minimum detectable effect size (MDES) in change from baseline of a range of measures over time, and in different diagnostic groups along the AD development trajectory. The Functional Activities Questionnaire score had the smallest MDES for a single endpoint where an effect of 27% could be detected within 3Â years in participants with Late Mild Cognitive Impairment (LMCI) at baseline, closely followed by the Clinical Dementia Rating Sum of Boxes (CDRSB) score at 28% after 2Â years in the same group. Composite measures were even more successful than single endpoints with an MDES of 21% in 3Â years. Using alternative cognitive, imaging, functional, or composite endpoints, and recruiting patients that have LMCI could improve the success rate of AD clinical trials
Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals
To date nearly all clinical trials of Alzheimer’s disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volume (HV) and assess the added benefit of combining HV and rate of hippocampal atrophy over time in relation to disease progression. Following the cross-validation of previously published estimates of the predictive value of HV, we consider a series of combinations of HV metrics and show that a combination of HV and rate of hippocampal atrophy characterises disease progression better than either measure individually. Furthermore, we demonstrate that the risk of disease progression associated with HV metrics does not differ significantly between clinical states. HV and rate of hippocampal atrophy should therefore be used in tandem when describing AD progression in at-risk individuals. Analyses also suggest that the effects of HV metrics are constant across the continuum of the early stages of the disease
Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence
Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes
Theory of Star Formation
We review current understanding of star formation, outlining an overall
theoretical framework and the observations that motivate it. A conception of
star formation has emerged in which turbulence plays a dual role, both creating
overdensities to initiate gravitational contraction or collapse, and countering
the effects of gravity in these overdense regions. The key dynamical processes
involved in star formation -- turbulence, magnetic fields, and self-gravity --
are highly nonlinear and multidimensional. Physical arguments are used to
identify and explain the features and scalings involved in star formation, and
results from numerical simulations are used to quantify these effects. We
divide star formation into large-scale and small-scale regimes and review each
in turn. Large scales range from galaxies to giant molecular clouds (GMCs) and
their substructures. Important problems include how GMCs form and evolve, what
determines the star formation rate (SFR), and what determines the initial mass
function (IMF). Small scales range from dense cores to the protostellar systems
they beget. We discuss formation of both low- and high-mass stars, including
ongoing accretion. The development of winds and outflows is increasingly well
understood, as are the mechanisms governing angular momentum transport in
disks. Although outstanding questions remain, the framework is now in place to
build a comprehensive theory of star formation that will be tested by the next
generation of telescopes.Comment: 120 pages, to appear in ARAA. No changes from v1 text; permission
statement adde
In vitro analysis of the effects on wound healing of high- and low-molecular weight chains of hyaluronan and their hybrid H-HA/L-HA complexes
Abstract
Background: Recent studies have reported the roles of Hyaluronic acid (HA) chains of diverse length in wound
repair, especially considering the simultaneous occurrence in vivo of both high- (H-HA) and low-molecular weight
(L-HA) hyaluronan at an injury site. It has been shown that HA fragments (5 ≤ MW ≤ 20 kDa) usually trigger an
inflammatory response that, on one hand, is the first signal in the activation of a repair mechanism but on the
other, when it’s overexpressed, it may promote unwanted side effects. The present experimental research has
aimed to investigate H-HA, L-HA and of a newly developed complex of the two (H-HA/L-HA) for stability (e.g.
hyaluronidases digestion), for their ability to promote wound healing of human keratinocytes in vitro and for their
effect on cellular biomarker expression trends.
Results: Time-lapse video microscopy studies proved that the diverse HA was capable of restoring the monolayer
integrity of HaCat. The H-HA/L-HA complex (0.1 and 1%w/v) proved faster in regeneration also in co-culture
scratch test where wound closure was achieved in half the time of H-HA stimulated cells and 2.5-fold faster than
the control. Gene expression was evaluated for transformation growth factor beta 1 (TGF-β1) proving that L-HA
alone increased its expression at 4 h followed by restoration of similar trends for all the stimuli. Depending on
the diverse stimulation (H-HA, L-HA or the complex), metalloproteinases (MMP-2, -9, -13) were also modulated differently.
Furthermore, type I collagen expression and production were evaluated. Compared to the others, persistence of a
significant higher expression level at 24 h for the H-HA/L-HA complex was found.
Conclusions: The outcomes of this research showed that, both at high and low concentrations, hybrid complexes
proved to perform better than HA alone thus suggesting their potential as medical devices in aesthetic and
regenerative medicine.
Keywords: Wound healing, Hyaluronan, MMPs, Hybrid complexe
Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease
DNA methylation [1], [2] is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimer's disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities
Lentiviral-Mediated Transgene Expression Can Potentiate Intestinal Mesenchymal-Epithelial Signaling
Mesenchymal-epithelial signaling is essential for the development of many organs and is often disrupted in disease. In this study, we demonstrate the use of lentiviral-mediated transgene delivery as an effective approach for ectopic transgene expression and an alternative to generation of transgenic animals. One benefit to this approach is that it can be used independently or in conjunction with established transgenic or knockout animals for studying modulation of mesenchymal-epithelial interactions. To display the power of this approach, we explored ectopic expression of a Wnt ligand in the mouse intestinal mesenchyme and demonstrate its functional influence on the adjacent epithelium. Our findings highlight the efficient use of lentiviral-mediated transgene expression for modulating mesenchymal-epithelial interactions in vivo
Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters
Recent progress in studies of globular clusters has shown that they are not
simple stellar populations, being rather made of multiple generations. Evidence
stems both from photometry and spectroscopy. A new paradigm is then arising for
the formation of massive star clusters, which includes several episodes of star
formation. While this provides an explanation for several features of globular
clusters, including the second parameter problem, it also opens new
perspectives about the relation between globular clusters and the halo of our
Galaxy, and by extension of all populations with a high specific frequency of
globular clusters, such as, e.g., giant elliptical galaxies. We review progress
in this area, focusing on the most recent studies. Several points remain to be
properly understood, in particular those concerning the nature of the polluters
producing the abundance pattern in the clusters and the typical timescale, the
range of cluster masses where this phenomenon is active, and the relation
between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review
An 84 microGauss Magnetic Field in a Galaxy at Redshift z=0.692
The magnetic field pervading our Galaxy is a crucial constituent of the
interstellar medium: it mediates the dynamics of interstellar clouds, the
energy density of cosmic rays, and the formation of stars. The field associated
with ionized interstellar gas has been determined through observations of
pulsars in our Galaxy. Radio-frequency measurements of pulse dispersion and the
rotation of the plane of linear polarization, i.e., Faraday rotation, yield an
average value B ~ 3 microGauss. The possible detection of Faraday rotation of
linearly polarized photons emitted by high-redshift quasars suggests similar
magnetic fields are present in foreground galaxies with redshifts z > 1. As
Faraday rotation alone, however, determines neither the magnitude nor the
redshift of the magnetic field, the strength of galactic magnetic fields at
redshifts z > 0 remains uncertain. Here we report a measurement of a magnetic
field of B ~ 84 microGauss in a galaxy at z =0.692, using the same
Zeeman-splitting technique that revealed an average value of B = 6 microGauss
in the neutral interstellar gas of our Galaxy. This is unexpected, as the
leading theory of magnetic field generation, the mean-field dynamo model,
predicts large-scale magnetic fields to be weaker in the past rather than
stronger
Is income or employment a stronger predictor of smoking than education in economically less developed countries? A cross-sectional study in Hungary
Background: In developed European countries in the last phase of the smoking epidemic, education is a stronger predictor of smoking than income or employment. We examine whether this also applies in economically less developed countries. Methods. Data from 7218 respondents in the 25-64 age group came from two National Health Interview Surveys conducted in 2000 and 2003 in Hungary. Independent effects of educational level, income and employment status were studied in relation to smoking prevalence, initiation and continuation for all age groups combined and separately for 25-34, 35-49 and 50-64 years old. Absolute levels were evaluated by using age-standardized prevalence rates. Relative differences were assessed by means of logistic regression. Results: Education and income, but not employment, were associated with equally large differences in smoking prevalence in Hungary in the 25-64 age group. Among men, smoking initiation was related to low educational level, whereas smoking continuation was related to low income. Among women, low education and low income were associated with both high initiation and high continuation rates. Considerable differences were found between the age groups. Inverse social gradients were generally strongest in the youngest age groups. However, smoking continuation among men had the strongest association with low income for the middle-aged group. Conclusions: Patterns of inequalities in smoking in Hungary can be best understood in relation to two processes: the smoking epidemic, and the additional effects of poverty. Equity orientated tobacco control measures should target the low educated to prevent their smoking initiation, and the poor to improve their cessation rates
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