Safety Study of Single-Dose Intravenously Administered DOTA-Siglec-9 Peptide in Sprague Dawley Rats

The peptide-based radioactive compound [Ga-68]Ga-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of [Ga-68]Ga-DOTA-Siglec-9 is vascular adhesion protein 1. Previous studies have obtained promising results with [Ga-68]Ga-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats. The study was performed using 60 adult Hsd: Sprague Dawley rats and included a control group and a treatment group to investigate the toxicity of DOTA-Siglec-9 solution at a final concentration of 0.2 mg/mL after a single iv injection of 582 mu g/kg. The maximum dose tested was 1,000-fold the clinical dose on a mg/kg basis as indicated in European Medicines Agency International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline M3(R2). The planned human clinical dose is approximately 0.582 mu g of DOTA-Siglec-9 per kg of body mass. This study demonstrates that iv administration of DOTA-Siglec-9 at a dose of 582 mu g/kg was well tolerated in rats and did not produce toxicologically significant adverse effects

Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model

The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.</p

Magnetic field protects plants against high light by slowing down production of singlet oxygen

Recombination of the primary radical pair of photosystem II (PSII) of photosynthesis may produce the triplet state of the primary donor of PSII. Triplet formation is potentially harmful because chlorophyll triplets can react with molecular oxygen to produce the reactive singlet oxygen (1O(2)). The yield of 1O(2) is expected to be directly proportional to the triplet yield and the triplet yield of charge recombination can be lowered with a magnetic field of 100-300 mT. In this study, we illuminated intact pumpkin leaves with strong light in the presence and absence of a magnetic field and found that the magnetic field protects against photoinhibition of PSII. The result suggests that radical pair recombination is responsible for significant part of 1O(2) production in the chloroplast. The magnetic field effect vanished if leaves were illuminated in the presence of lincomycin, an inhibitor of chloroplast protein synthesis, or if isolated thylakoid membranes were exposed to light. These data, in turn, indicate that 1O(2) produced by the recombination of the primary charge pair is not directly involved in photoinactivation of PSII but instead damages PSII by inhibiting the repair of photoinhibited PSII. We also found that an Arabidopsis thaliana mutant lacking alpha-tocopherol, a scavenger of 1O(2), is more sensitive to photoinhibition than the wild-type in the absence but not in the presence of lincomycin, confirming that the target of 1O(2) is the repair mechanism

Searches for Point-like and extended neutrino sources close to the Galactic Centre using the ANTARES neutrino Telescope

A search for cosmic neutrino sources using six years of data collected by the ANTARES neutrino telescope has been performed. Clusters of muon neutrinos over the expected atmospheric background have been looked for. No clear signal has been found. The most signal-like accumulation of events is located at equatorial coordinates R.A. = -46 degrees.8 and decl. = -64 degrees.9 and corresponds to a 2.2 sigma background fluctuation. In addition, upper limits on the flux normalization of an E-2 muon neutrino energy spectrum have been set for 50 pre-selected astrophysical objects. Finally, motivated by an accumulation of seven events relatively close to the Galactic Center in the recently reported neutrino sample of the IceCube telescope, a search for point sources in a broad region around this accumulation has been carried out. No indication of a neutrino signal has been found in the ANTARES data and upper limits on the flux normalization of an E-2 energy spectrum of neutrinos from point sources in that region have been set. The 90% confidence level upper limits on the muon neutrino flux normalization vary between 3.5 and 5.1 x 10(-8) GeV cm(-2) s(-1), depending on the exact location of the source

A search for time dependent neutrino emission from microquasars with the ANTARES telescope

Results are presented on a search for neutrino emission from a sample of six microquasars, based on the data collected by the ANTARES neutrino telescope between 2007 and 2010. By means of appropriate time cuts, the neutrino search has been restricted to the periods when the acceleration of relativistic jets was taking place at the microquasars under study. The time cuts have been chosen using the information from the X-ray telescopes RXTE/ASM and Swift/BAT, and, in one case, the gamma-ray telescope Fermi/LAT. No statistically significant excess has been observed, thus upper limits on the neutrino fluences have been derived and compared to the predictions by models. Constraints have been put on the ratio of proton to electron luminosity in the jets

Searches for clustering in the time integrated skymap of the ANTARES neutrino telescope

This paper reports a search for spatial clustering of the arrival directions of high energy muon neutrinos detected by the ANTARES neutrino telescope. An improved two-point correlation method is used to study the autocorrelation of 3058 neutrino candidate events as well as cross-correlations with other classes of astrophysical objects: sources of high energy gamma rays, massive black holes and nearby galaxies. No significant deviations from the isotropic distribution of arrival directions expected from atmospheric backgrounds are observed

A search for neutrino emission from the Fermi bubbles with the ANTARES telescope

Analysis of the Fermi-LAT data has revealed two extended structures above and below the Galactic Centre emitting gamma rays with a hard spectrum, the so-called Fermi bubbles. Hadronic models attempting to explain the origin of the Fermi bubbles predict the emission of high-energy neutrinos and gamma rays with similar fluxes. The ANTARES detector, a neutrino telescope located in the Mediterranean Sea, has a good visibility to the Fermi bubble regions. Using data collected from 2008 to 2011 no statistically significant excess of events is observed and therefore upper limits on the neutrino flux in TeV range from the Fermi bubbles are derived for various assumed energy cutoffs of the source

Search for muon neutrinos from gamma-ray bursts with the ANTARES neutrino telescope using 2008 to 2011 data

9 pages, 8 figures; added Fig. 1 with effective area, updated Fig. 8 (b) according to arXiv:1204.4219 ; Références publication Astron Astrophys 559 (2013) A9International audienceAims. We search for muon neutrinos in coincidence with GRBs with the ANTARES neutrino detector using data from the end of 2007 to 2011. Methods. Expected neutrino fluxes were calculated for each burst individually. The most recent numerical calculations of the spectra using the NeuCosmA code were employed, which include Monte Carlo simulations of the full underlying photohadronic interaction processes. The discovery probability for a selection of 296 GRBs in the given period was optimised using an extended maximum-likelihood strategy. Results. No significant excess over background is found in the data, and 90% confidence level upper limits are placed on the total expected flux according to the model

Deep sea tests of a prototype of the KM3NeT digital optical module

The first prototype of a photo-detection unit of the future KM3NeT neutrino telescope has been deployed in the deepwaters of the Mediterranean Sea. This digital optical module has a novel design with a very large photocathode area segmented by the use of 31 three inch photomultiplier tubes. It has been integrated in the ANTARES detector for in-situ testing and validation. This paper reports on the first months of data taking and rate measurements. The analysis results highlight the capabilities of the new module design in terms of background suppression and signal recognition. The directionality of the optical module enables the recognition of multiple Cherenkov photons from the same (40)Kdecay and the localisation of bioluminescent activity in the neighbourhood. The single unit can cleanly identify atmospheric muons and provide sensitivity to the muon arrival directions

Constraining the neutrino emission of gravitationally lensed Flat-Spectrum Radio Quasars with ANTARES data

This paper proposes to exploit gravitational lensing effects to improve the sensitivity of neutrino telescopes to the intrinsic neutrino emission of distant blazar populations. This strategy is illustrated with a search for cosmic neutrinos in the direction of four distant and gravitationally lensed Flat-Spectrum Radio Quasars. The magnification factor is estimated for each system assuming a singular isothermal profile for the lens. Based on data collected from 2007 to 2012 by the ANTARES neutrino telescope, the strongest constraint is obtained from the lensed quasar B0218+357, providing a limit on the total neutrino luminosity of this source of 1.08 x 10(46) erg s(-1) This limit is about one order of magnitude lower than those previously obtained in the ANTARES standard point source searches with non-lensed Flat-Spectrum Radio Quasars