153 research outputs found

    Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

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    The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4–6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking “drive”

    Development of a novel protocol based on blood clot to improve the sensitivity of qPCR detection of toxoplasma gondii in peripheral blood specimens

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    Quantitative polymerase chain reaction (qPCR) for Toxoplasma gondii multicopy genes has emerged as a promising strategy for sensitive detection of parasite DNA. qPCR can be performed from blood samples, which are minimally invasive to collect. However, there is no consensus about what type of blood specimen yields the best sensitivity. The development of a novel protocol for qPCR detection of T. gondii using blood clot, involving an appropriate DNA extraction method and the use of an internal amplification control to monitor the reaction is presented in the current study. Assays directed to the B1 and REP529 genes were performed in spiked specimens of whole blood, guanidine–ethylenediaminetetraacetic acid blood, and clot. The clot-based qPCR was shown to be more sensitive when compared with other types of specimens, detecting five and 0.05 T. gondii genomes, using B1 and REP529 targets, respectively. Finally, a comparative analysis with samples from HIV patients with clinical suspicion of toxoplasmosis was performed, demonstrating the detection of four positive suspected cases with clots compared with only one using guanidine–ethylenediaminetetraacetic acid blood. The high analytical sensitivity and the cost-effective advantages offered by clot supports this methodology as a good laboratory tool to monitor parasite burden

    A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

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    Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies

    Are identities oral? Understanding ethnobotanical knowledge after Irish independence (1937-1939)

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    BACKGROUND: The Schools' Folklore Scheme (1937-1939) was implemented at a pivotal time in Irelands' political history. It resulted in a body of ethnological information that is unique in terms of when, why and how it was collected. This material consists of over 700,000 pages of information, including ethnomedicinal and ethnobotanical traditions, reflecting an oral identity that spans generations and that in many cases was not documented in writing until the 1930s. The intention of this study is to highlight the importance of the Schools' Folklore Scheme and to demonstrate an ethnographic approach based on recollections of original participants of the scheme, to further understand the material in the collection and the impact it had on the participants. METHODS: This study involves an analysis of both oral and archival data. Eleven semi-structured interviews with original participants of the scheme were carried out between April and September 2016. Their corresponding schools' archival contributions to the scheme were located, and ethnomedicinal information was analysed and compared with the participants' recollections. RESULTS: The majority of participants' stated the scheme had a positive impact on them. Five participants' recalled collecting ethnomedicinal information, and there was a direct correlation between three of the participants' ethnomedicinal recollections and their entries in the archives. One third of all the ethnomedicinal entries analysed included the use of a plant. There were 191 plant mentions and 64 plant species named. CONCLUSIONS: Contacting the original participants offers a novel approach of analysing this archival material. It provides a unique first-hand account of this historical initiative, an insight into how the scheme was implemented and how it impacted upon the children. The ethnomedicinal and ethnobotanical information provides an understanding of the medicinal practices in Ireland during the 1930s. The plant species that were both orally recalled by participants and documented in the archives are in keeping with key ethnomedicinal systems throughout the world

    HOMES FOR BIRDS

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    Birds appeal strongly to the interest and affection of mankind. Not only do they charm by their graceful forms, harmonious colors, sprightly actions, and usually pleasing notes, but they have an even more important claim upon our esteem because of their great economic value. Birds feed upon practically all insect pests. They are voracious, able to move freely from place to place, and exert a steady influence in keeping down the swelling tide of insect life. For economic as well as for esthetic reasons, therefore, an effort should be made to attract and protect birds and to increase their numbers. Where proper measures of this kind have been taken an increase of several fold in the bird population has resulted, with decreased losses from depredations of injurious insects. This bulletin, one of a series (see footnote, page 2) describing the best methods of attracting birds, deals with nest boxes and other homes for birds, and is adapted for use throughout the United States. It supersedes Farmers\u27 Bulletin No. 609, Bird Houses and How to Build Them

    Common birds of Southeastern United States in Relation to Agriculture

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    From a purely practical point of view the most important of the relations of native birds to man are the economic. The esthetic value of birds is great, greater indeed than that of any other group of animals; and that this is a real and especially a treasured value is not to be denied. But it is in their relation to insect and other enemies of crops that birds are most directly associated with the welfare of mankind, and their value in this particular should be made as widely known as possible. This bulletin is one of a series designed to assist in doing this. Not all birds are beneficial, and all facts tending to show in which class each species belongs will be set forth. The useful kinds far outnumber the injurious, however, and so great is their value as insect destroyers in the United States that to them may be given the credit of being one of the greatest controlling factors in limiting the development of insect pests and in preventing many disastrous outbreaks. In the following pages are discussed the food habits and relation to agriculture of 23 species of birds common in the Southeastern States. The bulletin will be of general interest, but is especially applicable to the section shown by the shaded portion of the map on page 1
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