269 research outputs found

    Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

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    Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

    Addressing the welfare needs of farmed lumpfish: knowledge gaps, challenges and solutions

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    Lumpfish (Cyclopterus lumpus L.) are increasingly being used as cleaner fish to control parasitic sea lice, one of the most important threats to salmon farming. However, lumpfish cannot survive feeding solely on sea lice, and their mortality in salmon net pens can be high, which has welfare, ethical and economic implications. The industry is under increasing pressure to improve the welfare of lumpfish, but little guidance exists on how this can be achieved. We undertook a knowledge gap and prioritisa tion exercise using a Delphi approach with participants from the fish farming sector, animal welfare, academia and regulators to assess consensus on the main challenges and potential solutions for improving lumpfish welfare. Consensus among participants on the utility of 5 behavioural and 12 physical welfare indicators was high (87–89%), reliable (Cronbach's alpha = 0.79, 95CI = 0.69–0.92) and independent of participant background. Participants highlighted fin erosion and body damage as the most use ful and practical operational welfare indicators, and blood parameters and behav ioural indicators as the least practical. Species profiling revealed profound differences between Atlantic salmon and lumpfish in relation to behaviour, habitat preferences, nutritional needs and response to stress, suggesting that applying a common set of welfare standards to both species cohabiting in salmon net-pens may not work well for lumpfish. Our study offers 16 practical solutions for improving the welfare of lumpfish and illustrates the merits of the Delphi approach for achieving consensus among stakeholders on welfare needs, targeting research where is most needed and generating workable solutions.info:eu-repo/semantics/publishedVersio

    Search for Light Gluinos via the Spontaneous Appearance of pi+pi- Pairs with an 800 GeV/c Proton Beam at Fermilab

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    We searched for the appearance of pi+pi- pairs with invariant mass greater than 648 MeV in a neutral beam. Such an observation could signify the decay of a long-lived light neutral particle. We find no evidence for this decay. Our null result severely constrains the existence of an R0 hadron, which is the lightest bound state of a gluon and a light gluino, and thereby also the possibility of a light gluino. Depending on the photino mass, we exclude the R0 in the mass and lifetime ranges of 1.2 -- 4.6 GeV and 2E-10 -- 7E-4 seconds, respectively. (To Appear in Phys. Rev. Lett.)Comment: Documentstyle aps,epsfig,prl (revtex), 6 pages, 7 figure

    Search for the Decay K_L -> pi^0 nu nubar using pi^0 -> e^+ e^- gamma

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    We report on a search for the decay K_L -> pi^0 nu nubar, carried out as a part of E799-II, a rare K_L decay experiment at Fermilab. Within the Standard Model, the K_L -> pi^0 nu nubar decay is dominated by direct CP violating processes, and thus an observation of the decay implies confirmation of direct CP violation. Due to theoretically clean calculations, a measurement of B(K_L -> pi^0 nu nubar) is one of the best ways to determine the CKM parameter eta. No events were observed, and we set an upper limit B(K_L -> pi^0 nu nubar) < 5.9 times 10^-7 at the 90% confidence level.Comment: 5 pages, 4 figure

    Observation of the Decay KLμ+μγγK_L\to \mu^+\mu^- \gamma \gamma

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    We have observed the decay KLμ+μγγK_L\to \mu^+\mu^- \gamma \gamma at the KTeV experiment at Fermilab. This decay presents a formidable background to the search for new physics in KLπ0μ+μK_L\to\pi^0\mu^+\mu^-. The 1997 data yielded a sample of 4 signal events, with an expected background of 0.155 ±\pm 0.081 events. The branching ratio is B(KLμ+μγγ{\mathcal B}(K_L\to \mu^+\mu^- \gamma \gamma) =(10.45.9+7.5(stat)±0.7(sys))×109 = (10.4^{+7.5}_{-5.9} {\rm (stat)} \pm 0.7 {\rm (sys)})\times 10^{-9} with mγγ1MeV/c2m_{\gamma\gamma} \geq 1 {\rm MeV/c}^2, consistent with a QED calculation which predicts (9.1±0.8)×109(9.1\pm 0.8)\times 10^{-9}.Comment: See also the paper "Search for the Decay KLπ0μ+μK_L \to \pi^0 \mu^+ \mu^-", also by the KTeV collaboratio

    Search for the Decay Kl -> pi0 e+ e-

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    We report on a search for the decay Kl -> pi0 e+ e- carried out by the KTeV/E799 experiment at Fermilab. This decay is expected to have a significant CP violating contribution and the measurement of its branching ratio could support the CKM mechanism for CP violation or could point to new physics. Two events were observed in the 1997 data with an expected background of 1.06 +-0.41 events, and we set an upper limit Br(Kl -> pi0 e+ e-) < 5.1 x 10^-10 at the 90% confidence level.Comment: 13 pages, 2 figure

    Search for the Decay KLπ0μ+μK_L \to \pi^0 \mu^+ \mu^-

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    We report on a search for the decay \klpimumu carried out as a part of the KTeV experiment at Fermilab. This decay is expected to have a significant CPCP violating contribution and a direct measurement will either support the CKM mechanism for CP violation or point to new physics. Two events were observed in the 1997 data with an expected background of 0.87±0.150.87 \pm 0.15 events, and we set an upper limit \BR{\klpimumu} <3.8×1010 <3.8 \times 10^{-10} at the 90% confidence level.Comment: See also "Observation of the Decay KLμ+μγγK_L\to \mu^+\mu^- \gamma \gamma", also by the KTeV collaboratio

    Measurement of the Decay KL -> Pi0 Gamma Gamma

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    We report on a new measurement of the decay KL -> pi0 gamma gamma by the KTeV experiment at Fermilab. We determine the KL -> pi0 gamma gamma branching ratio to be (1.68 +/- 0.07 +/- 0.08)x10**-6. Our data shows the first evidence for a low-mass gamma gamma signal as predicted by recent O(p**6) chiral perturbation calculations that include vector meson exchange contributions. From our data, we extract a value for the effective vector coupling aV = -0.72 +/- 0.05 +/- 0.06.Comment: 5 pages, 4 figure

    Opposite temperature effect on transport activity of KCC2/KCC4 and N(K)CCs in HEK-293 cells

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    <p>Abstract</p> <p>Background</p> <p>Cation chloride cotransporters play essential roles in many physiological processes such as volume regulation, transepithelial salt transport and setting the intracellular chloride concentration in neurons. They consist mainly of the inward transporters NCC, NKCC1, and NKCC2, and the outward transporters KCC1 to KCC4. To gain insight into regulatory and structure-function relationships, precise determination of their activity is required. Frequently, these analyses are performed in HEK-293 cells. Recently the activity of the inward transporters NKCC1 and NCC was shown to increase with temperature in these cells. However, the temperature effect on KCCs remains largely unknown.</p> <p>Findings</p> <p>Here, we determined the temperature effect on KCC2 and KCC4 transport activity in HEK-293 cells. Both transporters demonstrated significantly higher transport activity (2.5 fold for KCC2 and 3.3 fold for KCC4) after pre-incubation at room temperature compared to 37°C.</p> <p>Conclusions</p> <p>These data identify a reciprocal temperature dependence of cation chloride inward and outward cotransporters in HEK-293 cells. Thus, lower temperature should be used for functional characterization of KCC2 and KCC4 and higher temperatures for N(K)CCs in heterologous mammalian expression systems. Furthermore, if this reciprocal effect also applies to neurons, the action of inhibitory neurotransmitters might be more affected by changes in temperature than previously thought.</p
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