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Abstract: This paper presents a kinematic and microphysical study of the MAP-IOP3 orographic precipitation event performed with radar observations and Meso-NH numerical simulations. Studies relying on both observations and mesoscale model simulations are of great interest for achieving a better understanding of intense precipitation events. Despite some slight discrepancies between radar observations and numerical outputs in the present work, both emphasize the same phenomena. The merging of two convective cells, which is an important mechanism to locally enhance precipitation is shown. Beyond Meso-NH outputs and radar observations similarities, the Meso-NH model completes and precises qualitative conclusions inferred from radar observations. In particular, it permits to identify and quantify the microphysical processes involved in the triggering and development of the orographic precipitation. The computation of hydrometeor mixing ratio and microphysical budgets highlights the convective nature of the IOP3 precipitation, which is characterized by efficient microphysical mechanisms such as heavy riming, warm coalescence, and melting of heavy particles (graupel and hail). More precisely, the initiation of the system is associated with warm microphysics whereas the development of the system and enhancement of rain involve graupel and hail. [Copyright &y& Elsevier]

Abstract: In this work, a capillary electrophoresis (CE) procedure was developed for the simultaneous determination of a pharmaceutical drug and its counter-ion, namely labetalol hydrochloride. For this purpose, an uncoated fused-silica capillary, a low conductivity background electrolyte (BGE) and a capacitively coupled contactless conductivity detector (C4D) were employed. This detection system is highly sensitive and enables detection of inorganic as well as organic ions unlike with direct UV detection. Moreover, to be able to simultaneously analyze the cationic drug (labetalol+) and its anionic counter-ion (Cl−) in the same electrophoretic run without the need of a coated capillary, a dual-opposite end injection was performed. In this technique, the sample is hydrodynamically injected into both ends of the capillary. This method is simple and easy to perform since the different injection steps are automated by the CE software. This novel CE-C4D procedure with dual-opposite end injection has been successfully validated and applied for the analysis of chloride content in an adrenergic antagonist (labetalol hydrochloride). Thus, the hereby developed method has been shown to enable fast (analysis time<10min), precise (repeatability of migration times<0.7% and of corrected-peak areas<3.3%; n =6) and rugged analyses for the simultaneous determination of a pharmaceutical drug and its counter-ion. [Copyright &y& Elsevier]

Abstract: Motivational interviews have been proved as efficient for treating adolescent with addictive behaviours. It improves therapists skills by giving them tools to enhance change and create therapeutic alliance, two key concepts to achieve adolescent therapeutic follow-up. Understanding adolescent psychopathology is crucial too, for it is known that adapting technique to context leads to success. [Copyright &y& Elsevier]

L’allogreffe de CSH est l’unique traitement curatif de certaines hémopathies. L’absence de donneur compatible peut empêcher sa réalisation. A contrario, chacun a un donneur intra-familial ayant un haplotype commun. Nous rapportons le 1er cas français de greffe haploidentique après une déplétion CD3/CD19. Patient: Thomas 13 ans présente un tableau d’aplasie médullaire sévère idiopathique. En l’absence de donneur intrafamilial, il reçoit 2 cures de sérum antilymphocytaire, ciclosporine et stéroïdes, sans efficacité. En l’absence de donneur volontaire ou d’unité de sang placentaire, l’indication d’une allogreffe de CSH haploidentiques 7/10e à partir de son père est posée. Méthode: La double sélection négative CD3/CD19 tend à supprimer les lymphocytes T (responsables de GvH) et les lymphocytes B (responsables de PTLD) et à conserver les CSH et l’ensemble des CD34– dont PNN, monocytes- macrophages et NK, acteurs de l’immunité innée et d’une partie de la reconstitution immunitaire ultérieure. Le patient reçoit un RIC. La prophylaxie de la GVH est réalisée par mmF. Une prophylaxie antivirale, un monitoring viral pour ADV, cmV et EBV ainsi qu’un suivi du chimérisme sanguin hebdomadaires sont réalisés. Résultats: 17.106 CD34 +/kg sont collectées chez le père. 435.106CNT/kg dont 9.106 CD34 +/kg et 85.103 CD3/kg sont réinjectées. La sortie d’aplasie survient à J12 PG après une toxicité digestive de grade IV. Il n’y a pas eu d’épisode infectieux documenté. Aucune réactivation virale n’est observée jusqu’à ce jour. Le chimérisme sanguin est constamment 100 % donneur. Discussion et Conclusion: L’absence de greffon satisfaisant ou l’urgence relative de la greffe imposent le développement de techniques alternatives dont le recours à un donneur haplo-identique. En dépit de l’amélioration de la sélection positive des CD34 +, ces greffes demeurent grevées de taux de morbidité et mortalité élevés (infections sévères, rechutes). La double sélection négative CD3/CD19 associée à un suivi rapproché du chimérisme (pour ajustement rapide de l’immunosuppression) et à un RIC pourrait permettre de limiter ces écueils, ce que semblent démontrer les premiers résultats des équipes de Tübingen et Francfort. Cette première tentative française est également encourageante. [Copyright &y& Elsevier]

The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10−8) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10−7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment. [ABSTRACT FROM AUTHOR]

Objectifs Mettre en évidence l’existence ou non d’une polyneuropathie axonale distale (PNP) chez les patients VIH présentant des paresthésies distales des membres inférieurs et déterminer les paramètres corrélés à cette polyneuropathie. Méthodes Les patients infectés par le VIH et présentant des paresthésies distales des membres inférieurs sans déficit moteur franc ont été recrutés pour cette étude. Un électroneuromyogramme standardisé (ENMG) a été pratiqué chez l’ensemble de ces patients et a permis de les classer en 3 groupes : ENMG normal, PNP à prédominance sensitive, PNP à vitesses lentes. Des études de corrélation ont été faite entre les données de l’ENMG et les paramètres suivants : âge, sexe, durée d’évolution de la maladie, existence d’une co-infection par le VHB ou le VHC, présence d’un trouble métabolico-carentiel, traitement anti-rétroviral, taux plasmatique de CD4, charge viral de VIH. Résultats Cent quatorze patients ont été retenu (42 femmes), âgés de 25 à 65 ans (46 ans en moyenne). Quarante et un pour cent avaient un ENMG normal, 38 % une PNP à prédominance sensitive et 21 % une PNP à vitesses lentes. Une association significative a été retrouvée entre les troubles métabolico-carentiels, le taux de CD4, la charge virale et la PNP à vitesses lentes. Sur le plan des traitements antirétroviraux, le test de contingence a mis en évidence une association entre le groupe d’ENMG et le type d’antiviral utilisé. Conclusions Au terme de cette étude, nous soulignons l’intérêt de pratiquer un examen ENMG chez les patients VIH ayant des paresthésies distales des membres inférieurs pour caractériser une éventuelle polyneuropathie dont certains paramètres notamment un ralentissement global et diffus des vitesses de conduction peut témoigner d’une infection virale mal contrôlée et d’une immunodépression plus sévère. [ABSTRACT FROM AUTHOR]

We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Myelodysplastic syndromes (MDS) are pre-leukaemic haematopoietic stem cell disorders. Among them, 10–20% occur after chemotherapy and/or radiotherapy, and are called ‘therapy-related MDS’ (t-MDS). The aim of this study was to identify genetic markers in t-MDS. Methods: A prospective cohort of 59 MDS patients (39 de novo MDS, 20 t-MDS) was studied. A total of 384 single nucleotide polymorphisms (SNP) selected among genes involved in DNA repair, drug metabolism and transport, signal transduction and oncogenesis, were genotyped using a custom-made SNP chip. Results: Two non-synonymous SNPs present in the methylguanine methyltransferase (MGMT) gene, in complete linkage disequilibrium, were significantly associated with t-MDS: rs2308321 and rs2308327, with a raw p value of 7.4×10–5 and a corrected p value after Benjamini–Hochberg correction of 0.014. Other associations tested between clinical and cytogenetic features and SNP chip gene variants gave corrected p values above 0.05. A validation cohort was separately constituted of 43 patients (24 de novo MDS, 19 t-MDS) and the two MGMT SNPs were genotyped; it confirmed a significant association between the variant allele of MGMT and t-MDS (p =0.038). Conclusion: We thus identified a putative marker of the risk to develop MDS after cancer treatment. [Copyright &y& Elsevier]

To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse. [Copyright &y& Elsevier]

Les vascularités cérébrales isolées touchant les vaisseaux de moyen calibre sont des pathologies rares au cours de l’infection par le VIH. Elles peuvent être secondaires à une infection opportuniste notamment par le virus VZV, une maladie lympho-proliférative ou une pathologie auto-immune. Cas cliniques: Nous rapportons 5 cas de vascularité « primitive » du système nerveux central chez des patients infectés par le VIH-1 et traités par HAART. Pour chaque patient le diagnostic a été porté sur les aspects radiologiques (IRM et ARM) associant des images d’infarctus et de sténose vasculaire. Aucune autre atteinte vasculaire clinique ou radiologique n’a été mise en évidence chez ces patients. D’autre part la recherche d’une étiologie (recherche d’infections opportunistes ou de maladies auto-immunes sur les prélèvements sanguins ou de LCR) autre celle que l’infection par le VIH s’est avérée à chaque fois négative. La mise en place d’un traitement antirétroviral n’a entraîné chez aucun patient une amélioration clinique, et ce malgré une bonne efficacité virologique prolongée. Tous les patients ont reçu un traitement par bolus de corticoïdes. Toutefois une amélioration clinique persistante n’a pu être obtenue que chez le seul patient ayant reçu également un traitement immunosuppresseur par cyclophosphamide. Discussion: Le diagnostic de vascularité isolée du système nerveux central est à évoquer devant un tableau neurologique sévère et isolé chez des patients infectés par le VIH. Le diagnostic de vascularité cérébrale du VIH devra être porté après avoir éliminé une pathologie auto-immune associée ou une infection opportuniste notamment à VZV. Un tel diagnostic impose d’associer au traitement antirétroviral un traitement par corticoïdes à forte dose et de discuter le recours à un traitement immunosuppresseur associé. [Copyright &y& Elsevier]

Background/Aims: Liver lesions associated with primary hypogammaglobulinemia have been poorly described. We aimed to assess the clinical, histological and immune features and outcome of hepatic injury in patients with primary hypogammaglobulinemia. Methods: The medical records of 51 patients (23 patients with liver biopsy) with primary hypogammaglobulinemia and liver abnormalities were retrospectively reviewed. Forty-three controls with primary hypogammaglobulinemia but with no hepatic manifestations were analyzed in parallel. Results: Cholestasis (65%), mainly anicteric, and portal hypertension (50%) were the main hepatic manifestations. Histological analysis revealed non-fibrosing architectural abnormalities consistent with nodular regenerative hyperplasia (NRH) in 84% of CVID patients and in all HIGM and XLA patients. Intrasinusoidal lymphocytic infiltration, abnormalities of portal vessels and epithelioid granulomas were observed in 90%, 43% and 44% of patients, respectively. NRH was associated with portal hypertension in 75% of the cases. These patients more often presented with autoimmune diseases and peripheral lymphocytic abnormalities than control patients (p <0.05). Conclusions: Liver involvement in primary hypogammaglobulinemia mainly consists of NRH leading to chronic cholestasis and portal hypertension. Association with intrasinusoidal T cell infiltration, portal vein endotheliitis, autoimmune diseases and peripheral lymphocytic abnormalities suggests an autoimmune mechanism. [Copyright &y& Elsevier]