Event categories in the EDELWEISS WIMP search experiment

Four categories of events have been identified in the EDELWEISS-I dark matter experiment using germanium cryogenic detectors measuring simultaneously charge and heat signals. These categories of events are interpreted as electron and nuclear interactions occurring in the volume of the detector, and electron and nuclear interactions occurring close to the surface of the detectors(10-20 mu-m of the surface). We discuss the hypothesis that low energy surface nuclear recoils,which seem to have been unnoticed by previous WIMP searches, may provide an interpretation of the anomalous events recorded by the UKDMC and Saclay NaI experiments. The present analysis points to the necessity of taking into account surface nuclear and electron recoil interactions for a reliable estimate of background rejection factors.Comment: 11 pages, submitted to Phys. Lett.

Background discrimination capabilities of a heat and ionization germanium cryogenic detector

The discrimination capabilities of a 70 g heat and ionization Ge bolometer are studied. This first prototype has been used by the EDELWEISS Dark Matter experiment, installed in the Laboratoire Souterrain de Modane, for direct detection of WIMPs. Gamma and neutron calibrations demonstrate that this type of detector is able to reject more than 99.6% of the background while retaining 95% of the signal, provided that the background events distribution is not biased towards the surface of the Ge crystal. However, the 1.17 kg.day of data taken in a relatively important radioactive environment show an extra population slightly overlapping the signal. This background is likely due to interactions of low energy photons or electrons near the surface of the crystal, and is somewhat reduced by applying a higher charge-collecting inverse bias voltage (-6 V instead of -2 V) to the Ge diode. Despite this contamination, more than 98% of the background can be rejected while retaining 50% of the signal. This yields a conservative upper limit of 0.7 event.day^{-1}.kg^{-1}.keV^{-1}_{recoil} at 90% confidence level in the 15-45 keV recoil energy interval; the present sensitivity appears to be limited by the fast ambient neutrons. Upgrades in progress on the installation are summarized.Comment: Submitted to Astroparticle Physics, 14 page

First Results of the EDELWEISS WIMP Search using a 320 g Heat-and-Ionization Ge Detector

The EDELWEISS collaboration has performed a direct search for WIMP dark matter using a 320 g heat-and-ionization cryogenic Ge detector operated in a low-background environment in the Laboratoire Souterrain de Modane. No nuclear recoils are observed in the fiducial volume in the 30-200 keV energy range during an effective exposure of 4.53 kg.days. Limits for the cross-section for the spin-independent interaction of WIMPs and nucleons are set in the framework of the Minimal Supersymmetric Standard Model (MSSM). The central value of the signal reported by the experiment DAMA is excluded at 90% CL.Comment: 14 pages, Latex, 4 figures. Submitted to Phys. Lett.

Identification of backgrounds in the EDELWEISS-I dark matter search experiment

This paper presents our interpretation and understanding of the different backgrounds in the EDELWEISS-I data sets. We analyze in detail the several populations observed, which include gammas, alphas, neutrons, thermal sensor events and surface events, and try to combine all data sets to provide a coherent picture of the nature and localisation of the background sources. In light of this interpretation, we draw conclusions regarding the background suppression scheme for the EDELWEISS-II phase

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Comparison of F(ab') versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

BACKGROUND: Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. METHODS: We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm(3), fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. RESULTS: 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. CONCLUSIONS: In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation

Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m−2 plus 5-fluorouracil 425 mg m−2. Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve0→3h in the index patient was 24.1 mg h l−1 compared to 9.8±3.6 (range 5.4–15.3) mg h l−1 in control patients. The 5-fluorouracil clearance was 520 ml min−1 vs 1293±302 (range 980–1780) ml min−1 in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h−1) compared to the six controls (10.3±1.6, range 8.0–11.7 nmol mg h−1). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (5-FU). In this study, we tried to reverse 5-FU resistance by using a double-punch strategy: combining 5-FU with a biochemical modulator to improve its tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation