Assessing Theory of Mind in Children: A Tablet-Based Adaptation of a Classic Picture Sequencing Task.

Correctly assessing children's theory of mind (TOM) is essential to clinical practice. Yet, most tasks heavily rely on language, which is an obstacle for several populations. Langdon and Coltheart's (Cognition 71(1):43-71, 1999) Picture Sequencing Task (PST), developed for research purposes, avoids this limitation through a minimally-verbal procedure. We thus developed a tablet adaptation of this task for individual application, engaging children's motivation and allowing response times collection. To assess this tablet-PST, we first tested a large sample of neurotypical children (6-11 years-old, N = 248), whose results confirmed the task's structural and content validity, and permitted the construction of three standardized clinical indices. In a second experiment, we applied those to previously diagnosed autistic children (N = 23), who were expected to show atypical TOM performance. Children's outcomes were consistent with what was hypothesized and confirmed the task's external validity and moderate clinical sensitivity. The tablet-PST thus appears as a suitable tool, providing detailed profiles to inform clinical decisions.

Food anaphylaxis in the elderly: Analysis of allergy vigilance network data from 2002 to 2021.

BACKGROUND: Few studies have focused on food allergies in the elderly, even though it may persist or appear de novo. METHODS: We reviewed data for all cases of food-induced anaphylaxis in people age ≥ 60 reported to the French "Allergy Vigilance Network" (RAV) between 2002 and 2021. RAV collates data reported by French-speaking allergists regarding cases of anaphylaxis graded II to IV according to the Ring and Messmer classification. RESULTS: In total, 191 cases were reported, with an even sex distribution and mean age was 67.4 years (range 60 to 93). The most frequent allergens were mammalian meat and offal (31 cases, 16.2%), often associated with IgE to α-Gal. Legumes were reported in 26 cases (13.6%), fruits and vegetables in 25 cases (13.1%), shellfish 25 cases (13.1%), nuts 20 cases (10.5%), cereals 18 cases (9.4%), seeds 10 cases (5.2%), fish 8 cases (4.2%) and anisakis 8 cases (4.2%). Severity was grade II in 86 cases (45%), grade III in 98 cases (52%) and grade IV in 6 cases (3%) with one death. Most episodes occurred at home or in a restaurant and in most cases adrenaline was not used to treat the acute episode. Potentially relevant cofactors such as beta-blocker, alcohol or non-steroidal anti-inflammatory drug intake were present in 61% of cases. Chronic cardiomyopathy, present in 11.5% of the population, was associated with greater, grade III or IV reaction severity (OR 3.4; 1.24-10.95). CONCLUSION: Anaphylaxis in the elderly has different causes to younger people and requires detailed diagnostic testing and individualized care plans.

Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model.

BACKGROUND: Graft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells. METHODS: Here, we assessed whether a monoclonal antibody (mAb) to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG). RESULTS: In this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans. CONCLUSION: A mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL.

Lessons From HIV-1 Gene Therapy in Humanized Mice: Is Targeting Viral Entry the Road to Success?

Immunodeficient mice reconstituted with human CD4(+) T cells, which can be achieved either by transfer of mature cells or immature progenitors, represent the only animal model to study HIV-1 infection of human lymphocytes in vivo. However, the immunocompromised status of most of these models currently rule out their use for vaccine studies. Nevertheless, the model might be ideally suited for HIV-1 gene therapy studies since eliciting an efficient anti-viral immune response is not the primary end-point. Rather, HIV-1 gene therapy should protect CD4(+) T cells from HIV-1- induced deletion and/or reduced viral replication. Here, we describe recent advancements in the field of HIV-1 gene therapy, focusing on tools and targets validated in various models of humanized mice. From the analysis of this literature, it appears that strategies targeting viral entry, by means of neutralizing antibodies or fusion inhibitors, are the most promising so far. Indeed, strategies targeting viral entry have moved to the clinic with encouraging results. Thus, humanized mice should be considered as the prime model to devise the safer and most effective HIV-1 gene therapy strategy.

HIV Replication Is Not Controlled by CD8+ T Cells during the Acute Phase of the Infection in Humanized Mice.

HIV replication follows a well-defined pattern during the acute phase of the infection in humans. After reaching a peak during the first few weeks after infection, viral replication resolves to a set-point thereafter. There are still uncertainties regarding the contribution of CD8(+) T cells in establishing this set-point. An alternative explanation, supported by in silico modeling, would imply that viral replication is limited by the number of available targets for infection, i.e. CD4(+)CCR5(+) T cells. Here, we used NOD.SCID.gc(-/-) mice bearing human CD4(+)CCR5(+) and CD8(+) T cells derived from CD34(+) progenitors to investigate the relative contribution of both in viral control after the peak. Using low dose of a CCR5-tropic HIV virus, we observed an increase in viral replication followed by "spontaneous" resolution of the peak, similar to humans. To rule out any possible role for CD8(+) T cells in viral control, we infected mice in which CD8(+) T cells had been removed by a depleting antibody. Globally, viral replication was not affected by the absence of CD8(+) T cells. Strikingly, resolution of the viral peak was equally observed in mice with or without CD8(+) T cells, showing that CD8(+) T cells were not involved in viral control in the early phase of the infection. In contrast, a marked and specific loss of CCR5-expressing CD4(+) T cells was observed in the spleen and in the bone marrow, but not in the blood, of infected animals. Our results strongly suggest that viral replication during the acute phase of the infection in humanized mice is mainly constrained by the number of available targets in lymphoid tissues rather than by CD8(+) T cells.

High genetic diversity and absence of founder effects in a worldwide aquatic invader.

The introduced oriental shrimp Palaemon macrodactylus has recently become widespread in temperate estuaries worldwide. However, this recent worldwide spread outside of its native range arises after a previous introduction to the US Pacific coast, where it was restricted for more than 30 years. Using a phylogeographic approach, the present work investigates the genetic history of the invasion of this decapod worldwide. Japan acted as the main native source area for worldwide introduced populations, but other native areas (likely South Korea and China) may act as source populations as well. The recently introduced European and NW Atlantic populations result from colonization from both Japan and an unknown area of the native range, although colonization from the NE Pacific could not be ruled out. Most introduced populations had higher haplotypic diversity than most native populations. P. macrodactylus has a strong potential to become one of the most widespread introduced species and may become the dominant estuarine shrimp in Europe. The ecological and economic consequences of this invasion remain to be thoroughly evaluated.

Targeting both viral and host determinants of human immunodeficiency virus entry, using a new lentiviral vector coexpressing the T20 fusion inhibitor and a selective CCL5 intrakine.

Numerous strategies targeting early and late steps of the HIV life cycle have been proposed for gene therapy. However, targeting viral and host determinants of HIV entry is the only strategy that would prevent viral DNA-mediated CD4(+) cell death while diminishing the possibility for the virus to escape. To this end, we devised a bicistronic lentiviral vector expressing the membrane-bound form of the T20 fusion inhibitor, referred to as the C46 peptide, and a CCR5 superagonist, modified to sequester CCR5 away from the cell surface, referred to as the P2-CCL5 intrakine. We tested the effects of the vector on HIV infection and replication, using the human CEMR5 cell line expressing CD4 and CCR5, and primary human T cells. Transduced cells expressed the C46 peptide, detected with the 2F5 monoclonal antibody by flow cytometry. Expression of the P2-CCL5 intrakine correlates with lower levels of cell surface CCR5. Complete protection against HIV infection could be observed in cells expressing the protective transgenes. Importantly, we show that the combination of the transgenes was more potent than either transgene alone, showing the interest of expressing two entry inhibitors to inhibit HIV infection. Last, genetically modified cells possessed a selective advantage over nonmodified cells on HIV challenge in vitro, showing that modified cells were protected from HIV-induced cell death. Our results demonstrate that lentiviral vectors coexpressing the T20 fusion inhibitor and the P2-CCL5 intrakine represent promising tools for HIV gene therapy.

Half of the T-cell repertoire combinatorial diversity is genetically determined in humans and humanized mice.

In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human ß chain of the T-cell receptor (hTRBV) in NOD.SCID.γc(-/-) (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.1+1.2 and BV6-J1.1+1.2 rearrangements. Finally, comparison of CD3(-) and CD3(+) thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.

Neonatal bone marrow transplantation prevents liver disease in a murine model of erythropoietic protoporphyria.

BACKGROUND & AIMS: Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin IX (PPIX) accumulation in erythrocytes, responsible for skin photosensitivity. In some EPP patients, the development of cholestatic liver injury due to PPIX accumulation can lead to hepatic failure. In adult EPP mice, bone marrow transplantation (BMT) leads to skin photosensitivity correction but fails to reverse liver damages, probably because of the irreversible nature of liver fibrosis. Our aim was to determine the time course of liver disease progression in EPP mice and to evaluate the protective effect of BMT into neonates. METHODS: We studied the development of liver disease from birth in EPP mice, in relation with erythroid and hepatic PPIX accumulation. To prevent the development of liver disease, BMT was performed into newborn mice using a novel busulfan-mediated preconditioning assay. RESULTS: We showed that hepatic PPIX accumulates during the first 2 weeks and correlates with the onset of a progressive liver fibrosis in 12-day-old EPP mice. Transplantation of normal congenic hematopoietic stem cells into EPP neonates led to long-term donor hematopoiesis recovery. A full correction of erythroid PPIX accumulation and skin photosensitivity was obtained. Furthermore, five months after neonatal BMT, liver damage was almost completely prevented. CONCLUSIONS: We demonstrated for the first time that BMT could be successfully used to prevent liver disease in EPP mice and suggested that BMT would be an attractive therapeutic option to prevent severe liver dysfunction in EPP patients.

Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy.

BACKGROUND: Current diagnosis of peanut allergy relies on natural extracts that lack standardization. Recombinant DNA technology allows production of pure biochemically characterized proteins. Their usefulness for peanut allergy diagnosis is not established. OBJECTIVE: This study aimed to evaluate the diagnostic value of the 3 major recombinant peanut allergens. METHODS: Recombinant (r) Ara h 1, rAra h 2, and rAra h 3 were produced according to the recommendations of good manufacturing practice for recombinant allergens. Skin prick tests (SPTs) and IgE ELISA assays were performed in 30 patients with peanut allergy and 30 control subjects without food allergy: 15 nonatopic and 15 sensitized to birch pollen. Disease severity was graded by clinical scoring. RESULTS: All patients with peanut allergy showed positive SPT results to rAra h 2; 40% reacted with rAra h 1 and 27% with rAra h 3. No control subjects reacted with any of the recombinant allergens. Monosensitization to rAra h 2 was observed in 53% of patients. Neither SPT size nor levels of specific IgE were correlated with the disease severity. However, patients with monosensitization to rAra h 2 had a significantly lower severity score than polysensitized subjects and a lower level of specific IgE against peanut extract and rAra h 2. CONCLUSION: Skin prick tests to individual recombinant peanut allergens appear to be a safe and effective diagnostic tool. Cosensitization to rAra h 2 and rArah 1 and/or rAra h 3 is predictive of more severe reactions. CLINICAL IMPLICATIONS: Recombinant peanut allergens can be used by SPTs for diagnosis and evaluation of allergy severity.