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This study takes us to the South Pacific and concentrates on Bislama, one of the dialects of Melanesian pidgin (Siegel 2008: 4) and one of the official languages of Vanuatu. We take a discourse analysis perspective to map out the functions of ale, a conspicuous discourse marker in conversations and narratives. Using Labov & Waletzky (1967) model, we analyze the use of ale in narratives from the book Big Wok: Storian blong Wol Wo Tu long Vanuatu (Lindstrom & Gwero 1998) and determine that ale is a discourse marker which indicates temporal sequence and consequence, frames speech reports and closes a digression. We conclude our study by considering a possible historical development of ale. We map out how French allez could have become Bislama ale using imposition and functional transfer (Siegel 2008; Winford 2013a) of vernacular discourse markers (such as go in Nguna).

Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. Determinants for CD19pos versus CD19neg relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10-2, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19neg relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19pos relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.

Many clinical studies in paediatric inflammatory bowel diseases (IBD) use infliximab trough level (IFX-TL) and detection of antibody against infliximab (ATI). Hence, comparison of commercially available assays is needed in paediatric samples to assess their reliability and their comparability. We measured IFX-TL and ATI-TL in sera samples of 53 IBD children using three ELISA kits: Lisa-Tracker® Duo Infliximab (Theradiag®), Ridascreen® IFX monitoring (R-Biopharm®) and Promonitor® IFX (Grifols®). Regarding IFX-TL, median values were comparable (p > 0.05), a good statistical correlation has been observed (0.73 ≤ R2 ≤ 0.85) between tested assays and the Bland-Altman analysis found an excellent agreement with a bias estimated between −0.56 and 0.12 and few values outside the 95% limits of agreement. However, qualitative comparison with therapeutic interval classifications showed some discrepancies (30.2%), mainly due to values near thresholds and more often than not with Theradiag® (22.6%). For ATI, because of non-standardized units, the qualitative comparison found a sensibly good agreement (98.1%). These data show a good agreement of IFX-TL and ATI measurement between three marketed ELISA assays with a small bias obtained. Variations in some results can lead to divergent therapeutic interval classifications and prompt us to be cautious in the interpretation of values near therapeutic thresholds.

International audience; Accreditation of an in vitro diagnostic assay according to the NHENI/ISO 15189 standard requires to analyze its technical performance before implementation for routine use, and annually when reviewing effectiveness of quality controls. Performance is evaluated through repeatability, intermediate fidelity, accuracy and uncertainty of measurement. The coefficients of variation (CV) of the infra-assay and inter-assay precision tests must be compared with those of ``peers'' (results from laboratories employing the same method) and also with those obtained with ``all methods'', i.e., results from all laboratories performing the same assay, irrespective of the method. To our best knowledge, there is currently no French or international recommendation on what the acceptable limits of performance for specific IgE and tryptase assays should be. Therefore, the AllergoBioNet network of hospital allergy laboratories set out to characterize the performance of their current methods as a basis for the development of recommendations. The results provided by 24 centers were analyzed and led to consensus recommendations for specific IgE, total and tryptase assays.

Introduction Thymoglobulin® and Grafalon® are 2 polyclonal rabbit anti-thymocyte globulin (ATG) used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft rejection and graft-versus-host disease (GvHD). Differences in manufacturing lead to different types and concentrations of antibodies in each product. Few studies compare their effects on post-transplant immune reconstitution: indeed, the latter is essential to prevent post-transplant infections as well as relapse (in case of hematological malignancies). Methods We conducted a retrospective study on children or adolescents who received a first unrelated allo-HSCT for an Acute Lymphoblastic Leukemia (ALL) between 2007 and 2018, in the department of pediatric hematology of the Robert Debré Hospital in Paris, France. During this time period, 2 types of ATG were used: Thymoglobulin® at 7.5mg/kg or Grafalon® at 60mg/kg. We included patients with a B or T phenotype ALL aged 2 to 18 years at the time of HSCT indication. Stem cell source could be from unrelated matched or mismatched bone marrow, peripheral blood or cord blood. All patients received a myeloablative conditioning regimen consisting of 12 grays total body irradiation and etoposide (60mg/kg). We compared patients for engraftment, counts of total lymphocytes, B and T lymphocytes, T CD4+ and CD8+ lymphocytes and their sub-types (naïve, effector memory, central memory and effector memory RA+), regulatory T cells, NK cells, and compared lymphocyte proliferation assays at 1, 3, 6 and 12 months after transplant. We used joint models of longitudinal and survival data to further analyze evolution of total lymphocytes, B and T cells, T CD4+ and T CD8+ cells, and NK cells. Finally, we compared clinical outcomes between the 2 groups. Statistical analyses were performed according to EBMT guidelines (Iacobelli, 2013). Results 76 children were included: 23 received Thymoglobulin® and 53 received Grafalon®. Stem cell source was peripheral blood or bone marrow for 61 patients and cord blood for 15 patients. Initial characteristics of patients, disease status and HSCT were similar between the two groups except for the median total nucleated cells and CD34+ progenitor cells of the graft, that were significantly higher in the Grafalon® group. We found a delayed cumulative incidence of engraftment in patients who received Grafalon® compared to those who received Thymoglobulin®: 29 days [interquartile range 22-36] versus 22 days [19.5-29.5], p=0.004. We observed significantly higher counts of total and T CD4+ lymphocytes 1 month after transplant in patients who received Thymoglobulin® as compared to those who received Grafalon®: 238/mm3 [172-466] versus 137/mm3 [51-306] respectively (p=0.005), and 40/mm3 [31.5-70.5] versus 16/mm3 [2.5-41.5], respectively (p=0.011). No differences in immune cell population counts were found 3, 6 and 12 months after transplant (figure 1). However, joint models found no difference in the evolution of lymphocyte subsets analyzed depending on the ATG used, except a non-significant difference in slopes over time for CD8+ cells (p=0.13). In patients given Thymoglobulin® compared to those given Grafalon®, we found a higher proliferation in response to stimulation by CD3 3 month after HSCT (CD3 index 20.4 [12.4;41] versus 5.9 [3.3;6.4] respectively, p=0.0039), and a higher proliferation in response to stimulation by adenovirus (ADV) antigen 1 year after HSCT (ADV index 78.6 [58.8;163.1] versus 15.7 [2.8;59.3] respectively, p=0.027). We found no effect of ATG type on overall survival (OS), disease-free survival (DFS), treatment-related mortality and chronic GvHD. In a multivariate analysis, we observed no effect of the type of ATG on OS and DFS. Conclusions We found a higher count of total and T CD4+ lymphocytes 1 month after unrelated allo-HSCT for ALL in children who received Thymoglobulin® at 7.5mg/kg compared to those who received Grafalon® at 60mg/kg. From 3 months after HSCT, we found no difference in immune reconstitution. Joint models for longitudinal data and survival found no significant difference in evolution of the lymphocyte subsets analyzed. Clinical outcomes were similar between the two groups. However, we compared an intermediate dose of Thymoglobulin® to a high dose of Grafalon® that is not still the standard in clinical practice. A prospective study comparing Thymoglobulin® to a lower dose of Grafalon® would be needed. Disclosures Baruchel: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bellicum: Consultancy. Dalle:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

This chapter concentrates on recapitulative linkage in Mavea, an Oceanic language of Vanuatu. I present the formal characteristics of recapitulative linkage and assess its discourse functions in two texts: a procedural text and a legend. Recapitulative linkage is compared to verbal repetition, another productive discourse strategy in Oceanic languages. I show that recapitulative linkage in Mavea is identified through a constellation of features. Syntactically, it is an instance of main clause coordination; prosodically it is marked with continuation intonation; semantically, it indicates temporal succession; and in discourse, it signals thematic continuity or rhetorical underlining.

The objective of this study was to evaluate whether silicon (Si) amendments, known to have a prophylactic role against biotrophic and hemibiotrophic pathogens, could protect soybean against Phytophthora sojae. To fulfill this objective, the initial challenge was to develop a method of inoculation that reproduced the natural infection process while allowing regular Si feeding to the plants. In a first set of experiments, inoculation of P. sojae zoospores directly into hydroponic solutions led to reproducible infections and expected phenotypes when using ‘Williams’ (rps), ‘L75-6141’ (Rps1a), ‘haro15’ (Rps1k), and ‘L77-1863’ (Rps1b) soybean challenged to races 3 and 7 of P. sojae. This approach offers the advantage of testing simultaneously many soybean cultivars against different races of P. sojae in a controlled environment, and the expression of partial and root resistance. In a second set of experiments aimed at testing the effect of Si, our results clearly showed that Si amendments had a significant effect on disease reduction and plant yield. The effect was particularly noticeable when combined with a cultivar displaying a certain level of resistance to the disease. These results demonstrate a useful method of direct inoculation of soybean plants with P. sojae zoospores through a hydroponic system and show that Si amendments can represent an alternative method of control of P. sojae against soybean.

Altered production of cytokines is believed to contribute to early childhood susceptibility to infection. The aim of this study was to get further insight into the developmental patterns of cytokine responses from birth to adulthood.The expression levels of 13 cytokines were compared in the supernatants of phytohemaggluttinin (PHA)-stimulated whole blood from healthy neonates (cord blood, n = 8), infants ( 1-year-old, n = 20), and school-aged children (3-15 y; n = 20). Five adults were used as reference.While Th1, Th2, and Th17 cytokine levels increased progressively from birth to childhood (Mann-Whitney, p 0.003), high IL-10 secretion at birth dropped to low adult levels in infants (p 0.004) such that a negative correlation between IL-10 and Th1, Th2, and Th17 cytokine levels at birth (Spearman's correlation, r -0.70, p 0.01) converted to a positive correlation in infants (r 0.60, p 0.001). Finally, high IL-2, IL-7, and Granulocyte-Colony Stimulating factor (G-CSF) cytokine levels at birth decreased steadily over the first year of life (Mann-Whitney, p ≤ 0.001).The most noticeable result of the study is the rapid shift from enhanced IL-10 secretion capacity at birth toward balanced IL-10/Th1/Th2/Th17 cytokine levels early in life. This change appears an essential precondition to fight pathogens and at the same time to avoid overwhelming inflammatory reactions.

We introduce the INSPIRATION bottom-up approach for the development of a strategic research agenda for spatial planning, land use and soil-sediment-water-system management in Europe. Research and innovation needs were identified by more than 500 European funders, endusers, scientists, policy makers, public administrators and consultants. We report both on the concept and on the implementation of the bottom-up approach, provide a critique of the process and draw key lessons for the development of research agendas in the future. Based on identified strengths and weaknesses we identified as key opportunities and threats 1) a high ranking and attentiveness for the research topics on the political agenda, in press and media or in public awareness, 2) availability of funding for research, 3) the resources available for creating the agenda itself, 4) the role of the sponsor of the agenda development, and 5) the continuity of stakeholder engagement as bases for identification of windows of opportunity, creating ownership for the agenda and facilitating its implementation. Our derived key recommendations are 1) a clear definition of the area for which the agenda is to be developed and for the targeted user, 2) a conceptual model to structure the agenda, 3) making clear the expected roles, tasks, input formats regarding the involvement and communication with the stakeholders and project partners, 4) a sufficient number of iterations and checks of the agenda with stakeholders to insure completeness, relevance and creation of co-ownership for the agenda, and 5) from the beginning prepare the infrastructure for the network to implement the agenda.

Summary Objectives An increased rate of indeterminate quantiferon results (low IFN-γ release in the phytohemagglutinin-stimulated tube) has been reported in children with clinical signs compatible with tuberculosis but with the final diagnosis of infectious diseases different from tuberculosis. Here, we addressed the mechanisms involved and assessed potential alternative biomarkers to overcome indeterminate quantiferon results under these conditions. Methods Cytokine concentrations were measured in residual plasma from quantiferon assays performed in immunocompetent children (cases, median age: 3 years 9 months) with indeterminate results and community acquired pneumonia (n = 7) or meningoencephalitis (n = 1). Controls were age-matched immunocompetent children with determinate quantiferon results (infected with mycobacterium tuberculosis , n = 7 or not, n = 8). Results Lower IFN-γ expression in phytohemagglutinin-stimulated cultures from cases was accompanied by lower Th1 (IL-2, TNF-α, IP-10) and Th2 (IL-5, IL-13), but similar IL-10 secretion capacities as the controls. Conclusions A state of hyporesponsiveness that resembles the concept of immunoparalysis in severe infection was observed in children with milder infections. Though IP-10, IL-2, IL-5 and IL-13 were confirmed as promising alternative biomarkers for discriminating controls with and without tuberculosis in this study, defective induction of these biomarkers by phytohemagglutinin in cases precluded their usefulness in overcoming quantiferon indeterminate results in the above-mentioned clinical conditions.

Background Data regarding the use of QuantiFERON to assist the diagnosis of active tuberculosis (TB) in HIV-infected children are limited, especially in countries with low incidence of TB/HIV coinfection. Methods QuantiFERON results were analyzed in 63 HIV-infected children who presented to our hospital in Paris, France. Seventeen HIV-uninfected children with active TB (4 culture-confirmed) were included for comparison. Results The 63 HIV-infected children (median age: 11 yr) had 113 QuantiFERON tests. Thirty-four (54%) were born in sub-Saharan Africa. Vertical HIV transmission was documented for 50 of 52 (96%) and stage III HIV-infection for 30 of 50 children (60%). Over the study period, active TB was diagnosed in 7 of 63 HIV-infected children (3 culture-confirmed). Additional ongoing or previous opportunistic infections were present in 4 of 7. QuantiFERON results were positive in 2 of 7 HIV-infected children with active TB (sensitivity: 29%) and 16 of 17 HIV-uninfected children with active TB (sensitivity: 94%). At initial QuantiFERON testing of the 63 HIV-infected children, 8 (13%) had positive results (1, active TB; 5, latent TB; 2, previous TB) and 51 (81%) had negative results. Of 33 children with repeat testing after an initially positive or negative result, the only change was one conversion from a negative to a positive result at the onset of active TB. The 4 children (6%) with indeterminate quantiFERON results had a concomitant opportunistic infection. Results of repeat testing after clinical stabilization were negative in all 4. Conclusions QuantiFERON testing performed poorly for active TB diagnosis in this series of children with advanced HIV infection.

This chapter highlights the complexity of water and chemical phenomena that control the behaviour of contaminants in the unsaturated zone (UZ). Numerous mechanisms are involved in fixing these elements in soils, and many are not fully understood. This area of study is characterised by their hierarchy, or the predominance of one mechanism over another, depending on the bio-physico-chemical conditions of the environment. Understanding this hierarchy requires site analysis and measurements which currently are not always carried out.

Objectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if > 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.

QuantiFERON value to diagnose tuberculosis (TB) in young children remains to be clarified. To this aim QF-TB-IT performance was evaluated in a large series of immunocompetent children that were stratified according to age and clinical conditions.QF-TB-IT reactivity was analyzed in 226 immunocompetent children (0-15 years old): 31 were uninfected despite TB contact; 51 presented TB disease; 39 had Latent TB (LTBI) and 105 had TB disease suspected but an alternative diagnosis (TB excluded).QF-TB-IT specificity was 100% in TB excluded. In TB disease, low sensitivity of QF-TB-IT in infants (40%) increased with aging (77% in 1-5 years and 82% in 5-15 years old subgroups). In LTBI, agreement between TST and QF-TB-IT was 0% in infants, 40% in 1-5 years and 57% in children5 years old. Finally, the incidence of indeterminate results was high (24%) in children5 years old with TB excluded, especially with non-TB pneumonitis (61%), but was low (0-6%) regardless of age group in TB disease, LTBI and uninfected contact cases.In our low burden country, i) QF-TB-IT specificity was 100%, ii) QF-TB-IT sensitivity was low in infants but commensurable to adult values in older children, and iii) indeterminate results mostly relied on ongoing infections unrelated to TB.

International audience; Le projet européen INSPIRATION « INtegrated Spatial PlannIng, land use and soil management Research ActTION » (2015-2018) qui regroupe 21 institutions de 16 pays, vise à développer un agenda stratégique de recherche européen (SRA) pour une gestion des sols et une utilisation du territoire respectueuse de l'environnement, socialement acceptable et économiquement abordable. Une approche bottom-up a été utilisée pour identifier les besoins en R&D autour de 4 thèmes intégrateurs qui sont (i) la demande en ressource naturelle, (ii) les fonctions du capital naturel, (iii) la gestion des territoires et (iv) les impacts nets à des échelles globales, européennes et locales. Le projet vise également à imaginer des modèles de mise en œuvre de m’Agenda stratégique de Recherche et à identifier et / ou construire les schémas de financement publics et / ou privés pour la mise en œuvre de cet Agenda stratégique de Recherche.

Immunity induced by influenza vaccines following hematopoietic stem-cell transplantation (HSCT) is poorly understood. Here, 14 pediatric recipients (mean age: 6 years) received H1N1 (n=9) or H1N1/H3N2 (n=5) vaccines at a median of 5.7 months post-HSCT (HLA-identical related bone-marrow graft: 10/14). Fourteen clinically-matched non-vaccinated recipients were included as controls. Cellular response to vaccination was assessed by a T-cell proliferation assay. Humoral response was assessed by H1N1-specific antibody titration. IL2 and IFNγ responses to influenza were also evaluated by an intracellular cytokine accumulation method for some of the recipients. Higher proliferative responses to H1N1 (p=0.0001) and higher H1N1-specific antibody titers (p0.02) were observed in vaccines opposed to non-vaccinated recipients. In some cases, proliferative responses to H1N1 developed while at the same time antibody titers did not reach protective (≥1:40) levels. Most recipients vaccinated with only the H1N1 strain had proliferative responses to both H1N1 and H3N2 (median stimulation index H1N1: 96, H3N2: 126 in responders). Finally, IL2 responses predominated over IFNγ responses (p0.02) to influenza viruses in responders. In conclusion, H1N1 vaccination induced substantial cell-mediated immunity, and to a lesser extent, humoral immunity at early times post-HSCT. H1N1/H3N2 T-cell cross-reactivity and protective (IL2) rather than effector (IFNγ) cytokinic profiles were elicited.

The uncommon C77G polymorphism of the Protein-Tyrosine Phosphatase (PTPRC) gene (PTPRC; previously termed CD45) could confer an increased risk of immunopathology. This study compared the outcome of children following human leucocyte antigen-matched unrelated haematopoietic-stem cell transplantations (HSCT) from donors carrying (C77G cases: n = 8) or not (controls: n = 36) the PTPRC C77G polymorphism. Transmission of the PTPRC C77G polymorphism through the graft was suggested by unusual CD45RA phenotype in the donors and/or in the recipients after, but not before HSCT. Restriction-Fragment Length Polymorphism and sequencing confirmed the polymorphism. Overall survival rates were similar in C77G cases and controls (63% vs. 61%). Acute leukaemia relapse tended to be less frequent in C77G cases (0% vs. 32%; P = 0·09). Among recipients surviving ≥ 30 d, acute GVHD (aGVHD) ≥ grade 2 tended to be more frequent (100% vs. 58%; P = 0·07) and the rate of steroid-refractory or -dependant aGVHD higher (67% vs. 28%) in C77G cases. Finally, extensive chronic GVHD tended to occur more frequently (40% vs. 9%) in C77G cases. Recovery of lymphocyte subsets and virus-specific CD4 was similar in C77G cases and controls while interleukin 2 (IL2)-responses through CD3 stimulation were higher in C77G cases (P = 0·004). In conclusion, HSCT from PTPRC C77G donors could increase GVHD risk without compromising overall survival. Altered IL2-responses could be involved in this process.

Age-related changes in memory CD4 T cells (CD4) are poorly known. To address this issue, CD4 proliferative and cytokine responses to an anti-CD3 monoclonal (CD3), to cytomegalovirus (CMV), and to adenovirus (AdV) were assessed in 57 children (age, 0.07-17.16 y) and 17 adults. Results showed i) accumulation of memory CD4 with aging, with 2-3 times more central-memory T cell (TCM; CD45RA/CD62L) than effector-memory T cell (TEM; CD45RA/62L) CD4 at any age. ii) In children older than 2 y, CMV-specific CD4-secreting IFNγ alone predominated over CD4-secreting IL2 + IFNγ and a continuous increase, with aging, in IFNγ responses to the virus was observed. In contrast, in AdV infection, CD4-secreting IL2 + IFNγ predominated and IFNγ responses to the virus reached adult levels from 3 y of age. iii) In children aged 0-2 y, lower total IFNγ responses to CMV (p < 0.02), AdV (p = 0.05), and CD3 (p < 0.01) and lower IFNγ + IL2-responses (p = 0.1, p < 0.02, p < 0.05, respectively) contrasted with no decrease in CD4-secreting IFNγ alone. Defective proliferative responses to AdV (p = 0.03) were also observed. In conclusion, the development of memory CD4 differed in acute AdV and persistent CMV infections. Young age seemed to depress mostly polyfunctional (IL2 + IFNγ secreting) CD4 in both infections.

Certains sujets sont en proie a de tels mouvements de la jouissance qu’il est parfois difficile, en tant que clinicien, de garder les pieds sur terre et toute sa raison. La course en avant pulsionnelle ne trouve alors parfois, comme butee, que le passage a l’acte, le rejet, la loi ou la protection. Les cliniciens aux prises, dans leur clinique, avec de tels affects ont l’obligation d’inventer des modalites de vidage et d’eclairage. Ici, la situation de Nathalie sera pretexte pour presenter une pratique en sessad qui propose un traitement de la jouissance prenant en compte la dimension inconsciente, tant du cote du patient que de celui du clinicien, par la modalite du travail en binome, educatrice-psychologue au quotidien.

CD4(+) T-cell functions that best correlate with CMV control were evaluated by studying the relationship between CMV infection and CMV-specific immune recovery as determined by proliferation assay and intracytoplasmic-IFNgamma assay. A total of 30 children (mean age: 8.30 years) who received an allogeneic hematopoietic SCT (HSCT) were included. In total, 13 recipients were seronegative before HSCT. None developed CMV infection or CMV-specific immunity. A total of 17 recipients were seropositive: (i) four patients spontaneously controlled CMV. The median of CMV-specific IFNgamma-secreting CD4 T cells was 9.13/microl at month 3 in these four patients and three of the four patients evidenced optimal proliferative responses since month 1; (ii) in 10 patients who received anti-CMV chemotherapy because of prolonged viremia, lower (P=0.016) IFNgamma responses (0.39/microl), together with delayed and/or depressed proliferative responses, were observed; (iii) finally, one patient with early CMV-associated disease had undetectable proliferative and IFNgamma responses until month 3. In conclusion, both intense IFNgamma responses and early proliferative responses seem to be associated with optimal CMV control.

Splicing regulates gene expression and contributes to proteomic diversity in higher eukaryotes. However, in yeast only 283 of the 6000 genes contain introns and their impact on cell function is not clear. To assess the contribution of introns to cell function, we initiated large-scale intron deletions in yeast with the ultimate goal of creating an intron-free model eukaryote. We show that about one-third of yeast introns are not essential for growth. Only three intron deletions caused severe growth defects, but normal growth was restored in all cases by expressing the intronless mRNA from a heterologous promoter. Twenty percent of the intron deletions caused minor phenotypes under different growth conditions. Strikingly, the combined deletion of all introns from the 15 cytoskeleton-related genes did not affect growth or strain fitness. Together, our results show that although the presence of introns may optimize gene expression and provide benefit under stress, a majority of introns could be removed with minor consequences on growth under laboratory conditions, supporting the view that many introns could be phased out of Saccharomyces cerevisiae without blocking cell growth.

Landfill deposits of contaminated, dredged sediments are subject to chemical alteration and especially to oxidation processes. Accordingly, sulphides are gradually oxidized leading to the formation of secondary phases and associated metals could become mobile and redistributed among the sediment components, such as carbonates, clay and freshly precipitated (hydr)oxides. Once mobilised, metals could represent a hazard for the environment and especially for drinking water supply facilities. In the present study, leaching experiments have been carried out on a dredged sediment to study metal mobilisation after 5 years of field aging. First, kinetic batch tests allowed one to evaluate the impact of solid-liquid contact time and to determine the kinetic parameters. Secondly, two types of dynamic experiments have been conducted: dynamic flush reactor and column leach test to evaluate the impact of solution renewing by excluding or not excluding the transport processes, respectively. In order to evaluate the impact of calcium on the metal mobilisation, the column leaching test is conducted with pure water and Ca(NO3)2 solution, at the beginning and at the end of the injection, respectively. Geochemical and reactive transport modelling of the experiments was performed using the geochemical code CHESS and the reactive transport model HYTEC. The studied sediment is complex with numerous reactive phases such as sulphides, (hydr)oxides, organic matter, phyllosilicates. All leaching tests highlight that zinc and cadmium are mobilised in significant concentrations and lead remains insoluble. A conceptual geochemical model of the sediment has been built to allow simulations of the whole experiments, based on a single, coherent phase description and parameter set. Simulations of the batch, flush and column experiments were performed taking into account the major reaction-controlling mechanisms including, among others, pH buffering, kinetic dissolution (carbonates, silicates) and ion exchange between calcium and exchangeable metals (Cd, Zn and Mn). The simulation results are in good agreements with the results obtained from the experiments. The experiments showed that zinc and cadmium are reversibly bound to the sediment and underline the importance of calcium concentration with respect to their mobility. Modelling confirms that ionic exchange is the main mechanism involved in metal mobilisation for this sediment. Metals can be retained as cation exchange species due to the high quantity of clays and organic matter present in dredged sediments. Cation exchange is a reversible mechanism and subsequent remobilisation of metals can be expected during oxidation and leaching phases. To quantify the mobilisation potential of polluted sediment, it is recommended to characterize the CEC properties of the sediment and calcium availability. Indeed, dissolution of minerals such as gypsum during rain events lead to metal mobilisation due to the increase of calcium concentration even for well-buffered sediments.

In this study we have identified frequent human leukocyte antigen (HLA)-A, -B, -C,-DRB1, and -DQB1 alleles, frequent HLA-B/C, HLA-DRB1/DQB1 two-allele associations, and the most common HLA-A/B/C/DRB1/DQB1 five-locus haplotypes in a population residing in the Paris, France, area. The study was carried out in 356 families of children awaiting hematopoietic stem-cell transplantation (HSCT), with the selection criterion that haplotypes could be assigned with certainty to both the patient and at least one parent. Parental haplotypes were HLA-A, -B serologically typed, and HLA-C, -DRB1, -DQB1 broadly typed by polymerase chain reaction-sequence-specific oligonucleotide probe. The alleles of the most frequent haplotypes were subsequently defined at a high-resolution level by polymerase chain reaction-sequence-specific primer. The results on the distribution of common alleles and common allele associations demonstrated similarities with the previously published data in Caucasian populations, as expected from the geographic origin of the studied population. More importantly, this study provides the largest listing of common B/C and DRB1/DQB1 associations and of common five-allele haplotypes defined with certainty in a Caucasian population to date. These results can be used to help estimate the likelihood of finding a suitable donor in unrelated HSCT and to delineate search strategies for potential donors.

International audience; Aggregate quarries play a major role in land settlement. However, like all industrial operations, they can have impacts on the environment, notably due to the use of polyacrylamide (PAM)-based flocculants, which contain residual acrylamide (AMD), a carcinogenic, mutagenic, and reprotoxicmonomer. In this study, the dissemination ofAMD throughout the environment has been investigated in a French quarry. The presence of AMD has been determined in the process water and in the sludge, as well as in the surrounding surface water and groundwater. From the results of several sampling campaigns carried out on this case study, we can (a) confirm that the AMD contained in the commercial product is found in thequarry’s water circuit (0.41 to 5.66 μg/l); (b) show that AMD is transported to the surrounding environment, as confirmed by the contamination of a pond near the installation (0.07 to 0.08 μg/l) and the presence of AMD in groundwater (0.01 to 0.02 μg/l); and (c) show that the sludge in both the current and former settling basins containsAMD (between 4 and 26 μg/kg of dry sludge). Therefore, we demonstrated in this case study that using PAM-based flocculants leads to the release of AMD to the environment beyond the treatment plant and creates a reserve of AMD in sludge basins.

QuantiFERON-TB Gold In-Tube performance was evaluated in 19 French immunocompetent children (0.29-5.36 years; median: 1.52) with active tuberculosis. The rate of indeterminates results was 0/19 and the rates of positivity were 6/10 and 9/9 in

The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naive CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR.

International audience; Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children.

Summary Objectives Detailed understanding of tuberculosis (TB) immunopathology and cytokine/chemokine responses can ultimately lead to the development of new diagnostic tools, especially useful in children where TB diagnosis remains challenging. Methods Nineteen cytokine/chemokine responses to Mycobacterium tuberculosis (M.tb) antigens were analyzed in 47 children distributed as follow: 28 with TB-disease (TD), 12 with latent TB and 7 uninfected controls. All the cytokines and chemokines were quantified in a multiplexed microsphere-based assay by using residual plasma from the quantiFERON kit (IFNγ release assay). Results IP-10, IL-2, IL-5 and IL-13 were among the best cytokines to diagnose infection as related by the area under ROC curve for IP-10 (0.96, 95%CI: 0.91–1.00), IL-2 (0.98, 95%CI: 0.93–1.02), IL-5 (0.91, 95%CI: 0.81–1.01) and IL-13 (0.97, 95%CI: 0.93–1.00). None of the 5 biomarkers, however, discriminated TB-disease from latent-TB. Finally, lower IL-5 ( p = 0.02) and IL-13 ( p = 0.02) levels were observed in severe opposed to non-severe TB. Conclusion These results suggest that IP-10, IL-2, IL-5 and IL-13 may find a diagnostic application in pediatric tuberculosis and argue against the paradigm of a negative influence of Th2 responses in severe pediatric M.tb infection.

Silicon (Si) confers several benefits to many plant species when absorbed as silicic acid through nodulin 26-like intrinsic proteins (NIPs). The NIPs belong to major intrinsic protein (MIP) family, members of which form channels with high selectivity to control transport of water and different solutes. Here, comparative genomic analysis of the MIPs was performed to investigate the presence of Si transporter MIPs in soybean. Thorough analysis of phylogeny, gene organization, transcriptome profiling and protein modeling was performed to characterize MIPs in rice, Arabidopsis and soybean. Based on several attributes, two putative Si transporter genes, GmNIP2-1 and GmNIP2-2, were identified, characterized and cloned from soybean. Expression of both genes was detected in shoot and root tissues, and decreased as Si increased. The protein encoded by GmNIP2-2 showed functionality for Si transport when expressed in Xenopus oocytes, thus confirming the genetic capability of soybean to absorb the element. Comparative analysis of MIPs in plants provides opportunities to decipher gene evolution, functionality and selectivity of nutrient uptake mechanisms. Exploitation of this strategy has helped to uncover unique features of MIPs in soybean. The identification and functional characterization of Si transporters can be exploited to optimize the benefits that plants can derive from Si absorption.

We report a 7-year-old boy with high-degree steroid-dependent idiopathic nephrotic syndrome (SDNS) who went into remission with rituximab (RTX) maintenance therapy. Four months after this patient received his first RTX infusion, there was a progressive and sustained decrease of immunoglobulin (Ig)G and IgM levels. Thirteen months after the initiation of RTX therapy he was in sustained remission without any steroid or oral immunosuppressive therapy; however, B cell depletion was still present. At this time he developed a fulminant myocarditis due to enterovirus. Despite aggressive treatment and the administration of intravenous polyvalent immunoglobulins there was no clinical improvement. He successfully underwent heart transplant surgery. We conclude that B cell depletion with RTX is efficacious in the treatment of paediatric SDNS but that it may be associated with severe infectious complications. Therefore, we recommend a close monitoring of Ig levels in children who have received RTX therapy and a supplementation with intravenous Ig as soon as the Ig levels fall below the lower limit of the normal range

Distinguishing latent tuberculosis (LTB) from tuberculosis (TB) disease may be challenging in children. Here, we analyzed cytokine profiles that can distinguish the two infection stages in a nonendemic country (France). Immunocompetent children with LTB (n = 6) or TB disease (n = 8) (median age: 6.2 and 5.7 years, respectively) were analyzed. Four young uninfected children were included as controls. A Luminex assay evaluated cytokine responses to Mycobacterium tuberculosis antigens. Poor interleukin-4 (IL-4) and IL-10 responses precluded analysis of these cytokines. Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-2, and T-helper type 1 (Th1) cytokines and IL-5, IL-13, T-helper type 2 (Th2) cytokines were simultaneously induced by antigens in 14/14 infected but 0/4 uninfected children. Th1 cytokine levels were similar in LTB and TB disease: IFN-γ: 12,254 and 10,495 pg/ml; IL-2: 2,097 and 1,869 pg/ml; and TNF-α: 1,020 and 2,875 pg/ml, respectively. Th2 cytokine levels were similar and even higher in LTB than in TB disease: IL-5: 23 and 10 pg/ml; IL-13: 284 and 109 pg/ml, respectively. Positive correlation of cytokine levels, whether Th1 or Th2, was observed. Higher (P = 0.008) TNF-α/IL-2 ratios distinguished 6/8 active TB disease cases from 6/6 LTB cases. TNF-α/IL-2 ratio may discriminate TB disease from LTB in immunocompetent children. Larger studies in TB endemic settings must verify these results.

Rituximab (RTX) is a new treatment strategy in high-degree steroid-dependent idiopathic nephrotic syndrome (SDNS) in childhood. Thirty patients (nine girls) with SDNS with steroid side effects and previously treated with immunosuppressive drugs, mostly calcineurin inhibitors, were treated with RTX and included in this non-controlled single-centre study. Patient age at first RTX infusion was 12.9 ± 0.7 years. Our aim was to evaluate disease outcome after a minimum CD19 depletion period of 15 months obtained by repeated RTX infusion. Minimum follow-up after initial CD19 depletion was 24 months. During the RTX treatment period, seven patients had nephrotic syndrome relapses, six among them at the time of an intermittent CD19 recovery and one patient relapsed under CD19 depletion. The risk for these patients to relapse after the RTX treatment period was higher than in those without intermittent relapses. After definitive CD19 recovery over a follow-up of 17.4 ± 1.9 months, 19 patients (63%) did not relapse and 11 (37%) relapsed 4.3 ± 1 months after defininitive CD19 recovery. Among these 11 patients, 6 already had intermittent relapses during the RTX treatment period. Steroid and immunosuppressive treatment could be discontinued in all patients during CD19 depletion and was re-introduced in two after CD19 recovery. Fourteen patients had mostly benign and transitory side effects, which did not require RTX discontinuation. In conclusion, RTX treatment with a 15-month CD19 depletion period induced long-term remission after definitive CD 19 recovery in almost two-thirds the of patients without oral immunosuppressive drugs.

The uncommon C77G polymorphism of the Protein-Tyrosine Phosphatase (PTPRC) gene (PTPRC; previously termed CD45) could confer an increased risk of immunopathology. This study compared the outcome of children following human leucocyte antigen-matched unrelated haematopoïetic-stem cell transplantations (HSCT) from donors carrying (C77G cases: n = 8) or not (controls: n = 36) the PTPRC C77G polymorphism. Transmission of the PTPRC C77G polymorphism through the graft was suggested by unusual CD45RA phenotype in the donors and/or in the recipients after, but not before HSCT. Restriction-Fragment Length Polymorphism and sequencing confirmed the polymorphism. Overall survival rates were similar in C77G cases and controls (63% vs. 61%). Acute leukaemia relapse tended to be less frequent in C77G cases (0% vs. 32%; P = 0·09). Among recipients surviving ≥ 30 d, acute GVHD (aGVHD) ≥ grade 2 tended to be more frequent (100% vs. 58%; P = 0·07) and the rate of steroid-refractory or -dependant aGVHD higher (67% vs. 28%) in C77G cases. Finally, extensive chronic GVHD tended to occur more frequently (40% vs. 9%) in C77G cases. Recovery of lymphocyte subsets and virus-specific CD4 was similar in C77G cases and controls while interleukin 2 (IL2)-responses through CD3 stimulation were higher in C77G cases (P = 0·004). In conclusion, HSCT from PTPRC C77G donors could increase GVHD risk without compromising overall survival. Altered IL2-responses could be involved in this process.

In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies ≥0.19% in patient families of European origin and that split into ≤2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding ≥9/10 HLA-matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 × 10−6) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into ≥3 groups of probability with ≥1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches.

International audience; Two complementary approaches were used to characterize arsenic and metal mobilizations from a dredged-sediment disposal site: a detailed field study combined with hydrogeochemical modeling. Contaminants in sediments were found to be mainly present as sulfides subject to oxidation. Secondary phases (carbonates, sulfates, (hydr)oxides) were also observed. Oxidative processes occurred at different rates depending on physicochemical conditions and contaminant contents in the sediment. Two distinct areas were identified on the site, each corresponding to a specific contaminant mobility behavior. In a reducing area, Fe and As were highly soluble and illustrated anoxic behavior. In well-oxygenated material, groundwater was highly contaminated in Zn, Cd and Pb. A third zone in which sediments and groundwater were less contaminated was also characterized. This study enabled us to prioritize remediation work, which should aim to limit infiltration and long-term environmental impact.

International audience; Although most patients with idiopathic nephrotic syndrome (NS) respond to steroid treatment, development of steroid dependency may require a long-term multidrug therapy including steroid and calcineurin inhibitor. Rituximab was shown to allow a reduction of the doses of steroid and immunosuppressive drugs in those patients. In the present series, 22 patients with steroid-sensitive, but steroid-dependent nephrotic syndrome were treated with rituximab. Rituximab reduced B cell count down to an undetectable level in all patients. A second treatment was necessary in 18 patients in order to maintain B cell depletion for up to 18 months. B cell depletion lasted 4.9 to 26 months (mean 17.2 months). At last follow-up, 9 patients were in remission without oral steroid or calcineurin inhibitor, although B cell count had recovered for 2.9 to 17 months (mean 9.5 months). A remission under ongoing B cell depletion was observed in 10 other patients in the absence of oral steroid or calcineurin inhibitor. Rituximab failed in 2 patients and 1 refused any additional treatment, despite B cell recovery and relapse. Toxicity of rituximab was limited to reversible cytokine shock in 2 patients and reversible neutropenia in 1 patient. No severe infection was observed.

The distribution of human leukocyte antigen (HLA)-DRB1-DQA1-DQB1 haplotypes was analyzed separately in two distinct French ethnic groups with type I diabetes (T1D), i.e. French North African migrants (n= 64, mean age at diagnosis = 8.25 years) and ancient French natives (n= 60, mean age at diagnosis = 7.42 years). HLA associations were determined by calculating odds ratios (ORs) between patients and two ethnic-matched control populations. Results show highly similar ORs for the conservative DRB1*0301-DQA1*0501-DQB1*0201 haplotype of susceptibility (OR: 3.22 and 3.93 in migrants and natives, respectively) and the DRB1*1501-DQA1*0102-DQB1*0602 haplotype of resistance (OR: 0.05 and 0.03, respectively). In contrast, among the more variable DRB1*04-DQB1*0302 haplotypes of susceptibility, the DRB1*0402 (OR: 3.10 and 32.84) and 0405 (OR: 5.90 and 16.25, respectively) were associated with T1D in migrants and natives, whereas an increase of DRB1*0401, a rare allele in migrants, was significant in natives only. Also, among the DRB1*11-DQA1*0505-DQB1*0301 haplotypes of resistance, the OR observed for DRB1*1104-DQA1*0505-DQB1*0301, common in migrants, was lower (OR: 0.08) than for DRB1*1101-DQA1*0505-DQB1*0301 (OR: 0.32), common in natives. How DRB1*11 subtypes might affect differently the risk conferred by DQA1*0505-DQB1*0301 will be discussed.

BACKGROUND The mechanisms responsible for the increased susceptibility of fetuses to cytomegalovirus (CMV) were studied by comparing CD8(+) T cell responses to the virus in susceptible fetuses to those in their comparatively more resistant mothers. METHODS Included in the study were 16 transmitter mothers who underwent seroconversion during the first trimester of pregnancy as well as their fetuses, who were positive for CMV in amniotic fluid by polymerase chain reaction at 17-19 weeks of gestation. Fetal and maternal blood samples were collected between the 22nd and 39th week of gestation. Cytotoxic T lymphocytes (CTLs) that had activated (HLA-DR(+)), effector/memory (CD28(-)), and memory (CD18(high)) phenotypes; that stained with the HLA-A2/pp65 or the HLA-B7/pp65 multimer; and that secreted interferon (IFN)- gamma were enumerated by flow cytometry. Viral loads were determined simultaneously. RESULTS The results showed (1) similar levels of activated, effector/memory, and memory CTLs in fetuses and mothers but a smaller pp65-specific CTL pool in fetuses (median, 0.015% vs. 0.99%; P=.003); (2) similar percentages of CTLs secreting IFN- gamma after stimulation with ionomycin/phorbol myristate acetate in fetuses and mothers but lower percentages of CTLs secreting IFN- gamma after stimulation with a CD3 monoclonal antibody in fetuses (median, 1% vs. 14%; P=.01); and (3) higher viral loads (mean, 17,290 vs.