DOMINO-AD protocol:donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT

Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.

Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15

Several growth factors and transcription factors have been reported to play important roles in brown adipocyte differentiation and modulation of thermogenic gene expression, especially the expression of UCP1. In this study, we focused on KLF11 and KLF15, which were expressed highly in brown adipose tissue. Our data demonstrated that KLF11 and KLF15 interacted directly with the UCP1 promoter using GC-box and GT-boxes, respectively. Co-transfection of KLF11 and KLF15 in the mesenchymal stem cell line muBM3.1 during brown adipocyte differentiation enhanced the expression level of UCP1. KLF11, but not KLF15, was essential for UCP1 expression during brown adipocyte differentiation of muBM3.1.

Speciation and localization of arsenic in white and brown rice grains

Synchrotron-based X-ray fluorescence (S-XRF) was utilized to locate arsenic (As) in polished (white) and unpolished (brown) rice grains from the United States, China, and Bangladesh. In white rice As was generally dispersed throughout the grain, the bulk of which constitutes the endosperm. In brown rice As was found to be preferentially localized at the surface, in the region corresponding to the pericarp and aleurone layer. Copper, iron, manganese, and zinc localization followed that of arsenic in brown rice, while the location for cadmium and nickel was distinctly different, showing relatively even distribution throughout the endosperm. The localization of As in the outer grain of brown rice was confirmed by laser ablation ICP-MS. Arsenic speciation of all grains using spatially resolved X-ray absorption near edge structure (micro-XANES) and bulk extraction followed by anion exchange HPLC-ICP-MS revealed the presence of mainly inorganic As and dimethylarsinic acid (DMA). However, the two techniques indicated different proportions of inorganic:organic As species. A wider survey of whole grain speciation of white (n=39) and brown (n=45) rice samples from numerous sources (field collected, supermarket survey, and pot trials) showed that brown rice had a higher proportion of inorganic arsenic present than white rice. Furthermore, the percentage of DMA present in the grain increased along with total grain arsenic.

A time-resolved immunoassay to measure serum antibodies to the rotavirus VP6 capsid protein

The rotavirus (RV) inner capsid protein VP6 is widely used to evaluate immune response during natural infection and in vaccine studies. Recombinant VP6 from the most prevalent circulating rotavirus strains in each subgroup (SG) identified in a birth cohort of children in southern India [SGII (G1P[8]) and SGI (G10P[11])] were produced. The purified proteins were used to measure VP6-specific antibodies in a Dissociation-Enhanced Lanthanide Fluorometric Immunoassay (DELFIA). The ability of the assay to detect a =2 fold rise in IgG level in a panel of serum samples from a longitudinal study was compared to a gold standard virus-capture ELISA. A strong association was observed between the assays (p

Rotavirus enterotoxin NSP4 has mucosal adjuvant properties

Rotavirus nonstructural protein 4 (NSP4) is a protein with pleiotropic properties. It functions in rotavirus morphogenesis, pathogenesis, and is the first described viral enterotoxin. Since many bacterial toxins function as potent mucosal adjuvants, we evaluated whether baculovirus-expressed recombinant simian rotavirus SA11 NSP4 possesses adjuvant activity by co-administering NSP4 with keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or ovalbumin (OVA) as model antigens in mice. Following intranasal immunization, NSP4 significantly enhanced both systemic and mucosal immune responses to model immunogens, as compared to the control group, in an antigen-specific manner. Both full-length and a cleavage product of SA11 NSP4 had adjuvant activity, localizing this activity to the C-terminus of the protein. NSP4 forms from virulent and avirulent porcine rotavirus OSU strain, and SA11 NSP4 localized within a 2/6-virus-like particle (VLP) also exhibited adjuvant effects. These studies suggest that the rotavirus enterotoxin NSP4 can function as an adjuvant to enhance immune responses for a co-administered antigen.

High-contrast imaging search for planets and brown dwarfs around the most massive stars in the solar neighborhood

There has been a long-standing discussion in the literature as to whether core accretion or disk instability is the dominant mode of planet formation. Over the last decade, several lines of evidence have been presented showing that core accretion is most likely the dominant mechanism for the close-in population of planets probed by radial velocity and transits. However, this does not by itself prove that core accretion is the dominant mode for the total planet population, since disk instability might conceivably produce and retain large numbers of planets in the far-out regions of the disk. If this is a relevant scenario, then the outer massive disks of B-stars should be among the best places for massive planets and brown dwarfs to form and reside. In this study, we present high-contrast imaging of 18 nearby massive stars of which 15 are in the B2-A0 spectral-type range and provide excellent sensitivity to wide companions. By comparing our sensitivities to model predictions of disk instability based on physical criteria for fragmentation and cooling, and using Monte Carlo simulations for orbital distributions, we find that ~85% of such companions should have been detected in our images on average. Given this high degree of completeness, stringent statistical limits can be set from the null-detection result, even with the limited sample size. We find that

Ranachensinin: A Novel Aliphatic Tachykinin from the Skin Secretion of the Chinese Brown Frog, Rana chensinensis

Amphibian skin secretions contain a plethora of pharmacologically-active substances and represent established sources of bioactive peptides, including tachykinins. Tachykinins are one of the most widely-studied peptide families in animals and are found in neuroendocrine tissues from the lowest vertebrates to mammals. They are characterized by the presence of a highly-conserved C-terminal pentapeptide amide sequence motif (-FXGLM-amide) that also constitutes the bioactive core of the peptide. Amidation of the C-terminal methioninyl residue appears to be mandatory in the expression of biological activity. Here, we describe the isolation, characterization and molecular cloning of a novel tachykinin named ranachensinin, from the skin secretion of the Chinese brown frog, Rana chensinensis. This peptide, DDTSDRSN QFIGLM-amide, contains the classical C-terminal pentapeptide amide motif in its primary structure and an Ile (I) residue in the variable X position. A synthetic replicate of ranachensinin, synthesized by solid-phase Fmoc chemistry, was found to contract the smooth muscle of rat urinary bladder with an EC50 of 20.46 nM. However, in contrast, it was found to be of low potency in contraction of rat ileum smooth muscle with an EC50 of 2.98 µM. These data illustrate that amphibian skin secretions continue to provide novel bioactive peptides with selective effects on functional targets in mammalian tissues.

Beaufort trout MicroPlex:A high-throughput multiplex platform comprising 38 informative microsatellite loci for use in resident and anadromous (sea trout) brown trout Salmo trutta genetic studies

A flexible panel consisting of 38 informative microsatellite markers for Salmo trutta is described. These markers were selected from a pool of over 150 candidate loci that can be readily amplified in four multiplex PCR groups but other permutations are also possible. The basic properties of each markers were assessed in six population samples from both the Burrishoole catchment, in the west of Ireland, and Lough Neagh, in Northern Ireland. A method to assess the relative utility of individual markers for the detection of population genetic structuring is also described. Given its flexibility, technical reliability and high degree of informativeness, the use of this panel of markers is advocated as a standard for S. trutta genetic studies. © 2013 The Authors. Journal of Fish Biology © 2013 The Fisheries Society of the British Isles.