Nonlinear kinetic estimate of Raman reflectivity in a hohlraum plasma with a radiation hydrodynamics code.

In this Letter, we introduce an inline model for stimulated Raman scattering (SRS), which runs on our radiation hydrodynamics code troll. This model accounts for nonlinear kinetic effects and for the SRS feedback on the plasma hydrodynamics. We dubbed it PIEM because it is a fully "PredIctivE Model," because no free parameter is to be adjusted a posteriori in order to match the experimental results. PIEM predictions are compared against experimental measurements performed at the Ligne d'Intégration Laser. From these comparisons, we discuss the PIEM ability to correctly catch the impact of nonlinear kinetic effects on SRS.

Dynamics of Nanosecond Laser Pulse Propagation and of Associated Instabilities in a Magnetized Underdense Plasma.

The propagation and energy coupling of intense laser beams in plasmas are critical issues in inertial confinement fusion. Applying magnetic fields to such a setup has been shown to enhance fuel confinement and heating. Here we report on experimental measurements demonstrating improved transmission and increased smoothing of a high-power laser beam propagating in a magnetized underdense plasma. We also measure enhanced backscattering, which our kinetic simulations show is due to magnetic confinement of hot electrons, thus leading to reduced target preheating.

Influence of a random phase plate on the growth of the backward stimulated Brillouin scatter.

We derive the analytical dispersion relation of a high-energy laser beam's backward stimulated Brillouin scattering (BSBS) in a hot plasma, that accounts both for the random phase plate (RPP) induced spatial shaping and its associated phase randomness. Indeed, phase plates are mandatory in large laser facilities where a precise control of the focal spot size is required. While the focal spot size is well controlled, such techniques produce small scale intensity variations that can trigger laser-plasma instabilities such as BSBS. Quantifying the resulting instability variability is shown to be crucial for understanding accurately the backscattering temporal and spatial growth as well as the asymptotic reflectivity. Our model, validated by means of a large number of three-dimensional paraxial simulations and experimental data, offers three quantitative predictions. The first one addresses the temporal exponential growth of the reflectivity by deriving and solving the BSBS RPP dispersion relation. A large statistical variability of the temporal growth rate is shown to be directly related to the phase plate randomness. Then, we predict the portion of the beam's section that is absolutely unstable, thus helping to precisely assess the validity of the vastly used convective analysis. Finally, a simple analytical correction to the plane wave spatial gain is extracted from our theory giving a practical and effective asymptotic reflectivity prediction that includes the impact of phase plates smoothing techniques. Hence, our study sheds light on the long-time studied BSBS, deleterious to many high-energy experimental studies related to the physics of inertial confinement fusion.

Cylindrical implosion platform for the study of highly magnetized plasmas at Laser MegaJoule.

Investigating the potential benefits of the use of magnetic fields in inertial confinement fusion experiments has given rise to experimental platforms like the Magnetized Liner Inertial Fusion approach at the Z-machine (Sandia National Laboratories) or its laser-driven equivalent at OMEGA (Laboratory for Laser Energetics). Implementing these platforms at MegaJoule-scale laser facilities, such as the Laser MegaJoule (LMJ) or the National Ignition Facility (NIF), is crucial to reaching self-sustained nuclear fusion and enlarges the level of magnetization that can be achieved through a higher compression. In this paper, we present a complete design of an experimental platform for magnetized implosions using cylindrical targets at LMJ. A seed magnetic field is generated along the axis of the cylinder using laser-driven coil targets, minimizing debris and increasing diagnostic access compared with pulsed power field generators. We present a comprehensive simulation study of the initial B field generated with these coil targets, as well as two-dimensional extended magnetohydrodynamics simulations showing that a 5 T initial B field is compressed up to 25 kT during the implosion. Under these circumstances, the electrons become magnetized, which severely modifies the plasma conditions at stagnation. In particular, in the hot spot the electron temperature is increased (from 1 keV to 5 keV) while the density is reduced (from 40g/cm^{3} to 7g/cm^{3}). We discuss how these changes can be diagnosed using x-ray imaging and spectroscopy, and particle diagnostics. We propose the simultaneous use of two dopants in the fuel (Ar and Kr) to act as spectroscopic tracers. We show that this introduces an effective spatial resolution in the plasma which permits an unambiguous observation of the B-field effects. Additionally, we present a plan for future experiments of this kind at LMJ.

[Leptospirosis: A growing health threat to fish farming and recreational activities]. / La leptospirose : une menace sanitaire croissante pour les activités piscicoles et récréatives.

Leptospirosis is a cosmopolitan infectious disease caused by the bacteria Leptospirainterrogans, which is worldwide increasing as the result of climate changes favoring the reproduction of asymptomatic reservoir rodents and also flooding that brings mammals and humans into contact with contaminated water. This disease affects many mammals among wild, domestic or farmed animals. In humans, it is manifested through frustrated to severe forms that can lead to liver and kidney failure and death in about one in ten severe cases. Diagnostic methods and treatments are satisfactory. Prophylaxis is based on individual protective measures including vaccination. The single human vaccine that is available is expensive and it protects 97% against about a third of human pathogenic serovars. Moreover, this vaccine is not covered by health insurance. Better epidemiological knowledge, particularly at European level, could stimulate research in this area in order to obtain a vaccine that would protect more comprehensively against serovars pathogenic to humans.

Recovery of central memory and naive peripheral T cells in Follicular Lymphoma patients receiving rituximab-chemotherapy based regimen.

Preclinical models and clinical studies have shown that anti-CD20-based treatment has multifaceted consequences on T-cell immunity. We have performed a prospective study of peripheral T-cell compartment in FL patients, all exhibiting high tumor burden and receiving rituximab-chemotherapy-based regimen (R-CHOP). Before treatment, FL patients harbor low amounts of peripheral naive T cells, but high levels of CD4+ TEM, CD4+ Treg and CD8+ TEMRA subsets and significant amounts of CD38+ HLA-DR+ activated T cells. A portion of these activated/differentiated T cells also expressed PD-1 and/or TIGIT immune checkpoints. Hierarchical clustering of phenotyping data revealed that 5/8 patients with only a partial response to R-CHOP induction therapy or with disease progression segregate into a group exhibiting a highly activated/differentiated T cell profile and a markedly low proportion of naive T cells before treatment. Rituximab-based therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype and of CD8+ T cells to a naive phenotype. In parallel, a decrease in the number of peripheral T cells expressing both PD-1 and TIGIT was detected. These observations suggest that the standard rituximab-based therapy partially reverts the profound alterations observed in T-cell subsets in FL patients, and that blood T-cell phenotyping could provide a better understanding of the mechanisms of rituximab-based treatment.

Synthesis and biological evaluation against Leishmania donovani of novel hybrid molecules containing indazole-based 2-pyrone scaffolds.

A series of novel indazole-pyrone hybrids were synthesized by a one pot reaction between N-alkyl-6(5)-nitroindazoles and 2-pyrone (4-hydroxy-6-methyl-2H-pyran-2-one) using indium or stannous chloride as the reducing system in the presence of acetic acid in tetrahydrofuran. The hybrid molecules were obtained in good to excellent yields (72-92%) and characterized by NMR and single crystal X-ray diffraction. Nineteen compounds were tested in vitro against both Leishmania donovani (MHOM/ET/67/HU3, also called LV9) axenic and intramacrophage amastigotes. Among all, five compounds showed anti-leishmanial activity against intracellular L. donovani with an IC50 in the range of 2.25 to 62.56 µM. 3-(1-(3-Chloro-2-ethyl-2H-indazol-6-ylamino)ethylidene)-6-methyl-3H-pyran-2,4-dione 6f was found to be the most active compound for axenic amastigotes and intramacrophage amastigotes of L. donovani with IC50 values of 2.48 ± 1.02 µM and 2.25 ± 1.89 µM, respectively. However, the cytotoxicity of the most promising compound justifies further pharmacomodulations.

Crystal growth, spectroscopy and laser performances of Pr3+:Sr0.7La0.3Mg0.3Al11.7O19 (Pr:ASL).

We report on the crystal growth, spectroscopic properties and visible laser performances of Pr3+-doped Sr0.7La0.3Mg0.3Al11.7O19 (ASL). ASL crystals doped with 2 at.% and 4 at.% Pr3+ were grown by Czochralski method. The laser experiments were carried out in a plane-concave resonator under excitation at 486 nm, provided from a 2ω-OPSL. Efficient laser emission was obtained with an 8 mm long sample of Pr(2at.%):ASL. The maximum output power amounted to 267 mW, 52 mW, and 318 mW at an absorbed power of 1.2W for red, orange, and deep red emission, respectively.

Collimated protons accelerated from an overdense gas jet irradiated by a 1 µm wavelength high-intensity short-pulse laser.

We have investigated proton acceleration in the forward direction from a near-critical density hydrogen gas jet target irradiated by a high intensity (1018 W/cm2), short-pulse (5 ps) laser with wavelength of 1.054 µm. We observed the signature of the Collisionless Shock Acceleration mechanism, namely quasi-monoenergetic proton beams with small divergence in addition to the more commonly observed electron-sheath driven proton acceleration. The proton energies we obtained were modest (~MeV), but prospects for improvement are offered through further tailoring the gas jet density profile. Also, we observed that this mechanism is very robust in producing those beams and thus can be considered as a future candidate in laser-driven ion sources driven by the upcoming next generation of multi-PW near-infrared lasers.

Experimental Investigation of the Collective Raman Scattering of Multiple Laser Beams in Inhomogeneous Plasmas.

Experiments have been performed evidencing significant stimulated Raman sidescattering (SRS) at large angles from the density gradient. This was achieved in long scale-length high-temperature plasmas in which two beams couple to the same scattered electromagnetic wave further demonstrating for the first time this multiple-beam collective SRS interaction. The collective nature of the coupling and the amplification at large angles from the density gradient increase the global SRS losses and produce light scattered in novel directions out of the planes of incidence of the beams. These findings obtained in plasmas conditions relevant of inertial confinement fusion experiments similarly apply to the more complex geometry of these experiments where anomalously large levels of SRS were measured.

Spatial and Transient Effects during the Amplification of a Picosecond Pulse Beam by a Nanosecond Pump.

Amplification of a picosecond pulse beam by a lower intensity nanosecond pulse beam was experimentally observed in a flowing plasma. Modifications of intensity distributions in beam focal spots due to nonhomogeneous energy transfer and its transient regime were investigated. The mean transferred power reached 57% of the incident power of the nanosecond pulse beam. An imaging diagnostic allowed the intensity profile of the picosecond pulse beam to be determined, bringing to evidence the spatial nonuniformity of energy transfer in the amplified beam. This diagnostic also enabled us to observe the temporal evolution of the speckle intensity distribution because of the transfer. These results are reproduced by numerical simulations of two complementary codes. The method and the observed effects are important for the understanding of experiments with multiple crossing laser beams in plasmas.

Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

New heterocyclic compounds: Synthesis and antitrypanosomal properties.

Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 µM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 µM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 µmol/kg by intraperitoneal route. Although no clear-cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series.

Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study.

We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHDIII-IV) (risk ratio (RR)=1.73, confidence interval (CI) 95% 1.09-2.73, P=0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR=1.34, CI 95% 1.00-1.80, P=0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.

Sitamaquine-resistance in Leishmania donovani affects drug accumulation and lipid metabolism.

This study focuses on the mechanism of sitamaquine-resistance in Leishmania donovani. Sitamaquine accumulated 10 and 1.4 fold more in cytosol than in membranes of wild-type (WT) and of sitamaquine-resistant (Sita-R160) L. donovani promastigotes, respectively. The sitamaquine accumulation was a concentration-dependent process in WT whereas a saturation occurred in Sita-R160 suggesting a reduced uptake or an increase of the sitamaquine efflux. Membrane negative phospholipids being the main target for sitamaquine uptake, a lipidomic analysis showed that sitamaquine-resistance did not rely on a decrease of membrane negative phospholipid rate in Sita-R160, discarding the hypothesis of reduced uptake. However, sterol and phospholipid metabolisms were strongly affected in Sita-R160 suggesting that sitamaquine-resistance could be related to an alteration of phosphatidylethanolamine-N-methyl-transferase and choline kinase activities and to a decrease in cholesterol uptake and of ergosterol biosynthesis. Preliminary data of proteomics analysis exhibited different protein profiles between WT and Sita-160R remaining to be characterized.

[Impact of anti-HLA antibodies on outcomes of allogeneic stem cell transplantation: a report by the SFGM-TC]. / Impact des anticorps anti-HLA sur le devenir de l'allogreffe de cellules souches hématopoïétiques : un rapport par la SFGM-TC.

The role of anti-HLA antibodies in allogeneic stem cell transplantation setting is still unclear. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This article offers the recommendations of the group that considered the impact that have anti-HLA antibodies on outcomes in allogeneic stem cell transplantation.

Development of antileishmanial lipid nanocomplexes.

Visceral leishmaniasis is a life-threatening disease that affects nearly a million people every year. The emergence of Leishmania strains resistant to existing drugs complicates its treatment. The purpose of this study was to develop a new lipid formulation based on nanocochleates combining two active drugs: Amphotericin B (AmB) and Miltefosine (HePC). Nanocochleates composed of dioleoylphosphatidylserine (DOPS) and Cholesterol (Cho) and Ca(2+), in which HePC and AmB were incorporated, were prepared. Properties such as particle size, zeta potential, drug payload, in-vitro drug release and storage stability were investigated. Moreover, in-vitro stability in gastrointestinal fluid was performed in view of an oral administration. AmB-HePC-loaded nanocochleates with a mean particle size of 250 ± 2 nm were obtained. The particles displayed a narrow size distribution and a drug payload of 29.9 ± 0.5 mg/g for AmB, and 14.0 ± 0.9 mg/g for HePC. Drug release occurred preferentially in intestinal medium containing bile salts. Therefore, AmB-HePC-loaded nanocochleates could be a promising oral delivery system for the treatment of visceral leishmaniasis.

Impact of HLA mismatch direction on outcomes after umbilical cord blood transplantation for hematological malignant disorders: a retrospective Eurocord-EBMT analysis.

HLA matching is a critical determinant of outcomes for patients who have undergone umbilical cord blood transplantation (UCBT). Data have been published on the importance of donor/recipient HLA mismatch direction on UCBT outcomes. HLA mismatch in the graft-versus-host (GVH) direction is defined as a donor homozygous at an HLA locus, while the recipient shares one HLA Ag with the donor. HLA mismatch in the host-versus-graft (HVG) direction is defined as a recipient homozygous with the donor sharing one HLA Ag. In our study we focused on confirming, using an independent population, whether transplantation outcomes would be different when HLA mismatch direction was considered. We analyzed 1565 patients who received a single-unit UCBT for malignant disease. Median age was 15 years and 72% of patients were transplanted for leukemia. In multivariate analysis, using the 5/6 HLA-matched population as reference, one or two HLA mismatches in the GVH or HVG direction were not associated with non-relapse related mortality and survival. On the basis of our results, there is no evidence to support a change in the current practice for cord blood unit selection.

HLA phenotypes of candidates for HSCT: comparing transplanted versus non-transplanted candidates, resulting in the predictive estimation of the probability to find a 10/10 HLA matched donor.

In order to study the impact of human leucocyte antigen (HLA) polymorphism distribution in identifying a matched haematopoietic stem cells unrelated donor (UD), we performed a multi-centric retrospective analysis with the aim of comparing the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 phenotypes of 2126 patients (772 patients for whom a donor search failed to identify a matched UD, and 1354 patients who received a 10/10 allele level matched UD). Our results showed that rare HLA-C is often responsible for difficulty in identifying a donor. This locus may add a degree of complexity to a supposed 'frequent' HLA-A HLA-B and HLA-DRB1 phenotype, turning this phenotype into a less frequent one. For example, 32.5% of the phenotypes in the non-transplanted patients could not be explained by any of the pairs of known HLA-A, HLA-B, HLA-C and HLA-DRB1 haplotypes while this percentage dropped to less than 2% if combinations of only HLA-A, HLA-B and HLA-DRB1 haplotypes were considered. Such situations can be anticipated by computing an index, based on HLA haplotype frequency, the average registry sample size (ARS). ARS is defined as the inverse of the phenotype frequency computed using all corresponding pairs of haplotype frequencies. ARS confirmed that the most significant difference between transplanted and non-transplanted patients was correlated with the introduction of the locus HLA-C in the analysis (median: 8.3e + 4 vs 3.1e + 6, P < 0.0001). The higher the ARS the lower the likelihood of finding a 10/10 match UD reflecting the rareness of the patient's HLA. The area under receiver operator characteristics (AUROC) values of the ARS computation for HLA-A, HLA-B and HLA-DRB1 was 0.82 (0.80; 0.84) at a low-resolution level (two digits). Overall, our study promotes the use of haplotype frequency-based computations to develop computer-assisted donor search.