Impact of Innovative Emotion Training in Preschool and Kindergarten Children Aged from 3 to 6 Years.

Children's emotional abilities have been shown to be related to academic performance, peer acceptance, and in-school adjustment. The main objective of this study was to evaluate the effect of innovative emotion training designed to promote the emotional abilities of 316 preschool/kindergarten children aged from 3 to 6 years old enrolled in public schools in the first three levels (L1, L2, and L3). Another objective was to examine the transfer effects on language comprehension and mathematics abilities. The emotion training (eight sessions) focused on the identification, comprehension, and expression of emotions and were co-constructed with teachers. Children were tested before and after the training on emotion, language, and mathematics skills. Results showed an improvement in emotional abilities in young children of L1 (3-4 years) and L2 (4-5 years) in the intervention group compared to those in the non-intervention group. Also, although children's emotion basic abilities were correlated with their language comprehension and mathematics abilities, the nature of this link was not demonstrated to be causal. Findings are discussed in regard to the influence of the level and in regard to links with academic variables.

Audio-Visual Perception of Gender by Infants Emerges Earlier for Adult-Directed Speech.

Early multisensory perceptual experiences shape the abilities of infants to perform socially-relevant visual categorization, such as the extraction of gender, age, and emotion from faces. Here, we investigated whether multisensory perception of gender is influenced by infant-directed (IDS) or adult-directed (ADS) speech. Six-, 9-, and 12-month-old infants saw side-by-side silent video-clips of talking faces (a male and a female) and heard either a soundtrack of a female or a male voice telling a story in IDS or ADS. Infants participated in only one condition, either IDS or ADS. Consistent with earlier work, infants displayed advantages in matching female relative to male faces and voices. Moreover, the new finding that emerged in the current study was that extraction of gender from face and voice was stronger at 6 months with ADS than with IDS, whereas at 9 and 12 months, matching did not differ for IDS versus ADS. The results indicate that the ability to perceive gender in audiovisual speech is influenced by speech manner. Our data suggest that infants may extract multisensory gender information developmentally earlier when looking at adults engaged in conversation with other adults (i.e., ADS) than when adults are directly talking to them (i.e., IDS). Overall, our findings imply that the circumstances of social interaction may shape early multisensory abilities to perceive gender.

Is the impairment in temporal allocation of visual attention in children with ADHD related to a developmental delay or a structural cognitive deficit?

We investigated the temporal allocation of visual attention in 11-year-old children with attention-deficit/hyperactivity disorder (ADHD) by comparing their attentional blink (AB) parameters (duration, amplitude and minimum performance) with those observed in three groups of healthy control participants (8-year-olds, 11-year-olds and adults). The AB is a marker of impaired ability to detect a second target following the identification of a first target when both appear randomly within a rapid sequence of distractor items. Our results showed developmental effects; with age, the AB duration decreased and the AB minimum moved to shorter lag times. Importantly, 11-year old children with ADHD presented much the same similar AB patterns (in terms of duration and minimum position) as the healthy 8-year-old controls. Our results support the hypothesis whereby impaired allocation of temporal selective attention in children with ADHD is due to a developmental delay and not a specific cognitive deficit.

Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sézary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.

Episiotomy endometrioma masquerading as peri-anal sepsis: surgeons beware!

A 34-year-old woman with peri-anal pain and swelling was operated in the emergency setting assuming a diagnosis of a perianal abscess. No pus was revealed. Later magnetic resonance imaging (MRI) suggested induration and a mass effect in the peri-anal region. Examination under anaesthesia was repeated which revealed a mobile but firm mass. Histology from trucut biopsies diagnosed it as a peri-anal endometrioma arising from an episiotomy scar. Peri-anal endometrioma can rarely developin episiotomy scars and can be easily mistaken as an abscess by junior surgeons.

Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy.

Extracorporeal photochemotherapy (ECP) is widely used to treat cutaneous T-cell lymphoma, graft-versus-host disease, and allografted organ rejection. Its clinical and experimental efficacy in cancer immunotherapy and autoreactive disorders suggests a novel mechanism. This study reveals that ECP induces a high percentage of processed monocytes to enter the antigen-presenting dendritic cell (DC) differentiation pathway, within a single day, without added cytokines, as determined by enhanced expression of relevant genes. The resulting DCs are capable of processing and presentation of exogenous and endogenous antigen and are largely maturationally synchronized, as assessed by the level of expression of costimulatory surface molecules. Principal component analysis of the ECP-induced monocyte transcriptome reveals that activation or suppression of more than 1100 genes produces a reproducible distinctive molecular signature, common to ECP-processed monocytes from normal subjects, and those from patients. Because ECP induces normal monocytes to enter the DC differentiation pathway, this phenomenon is independent of disease state. The efficiency with which ECP stimulates new functional DCs supports the possibility that these cells participate prominently in the clinical successes of the treatment. Appropriately modified by future advances, ECP may potentially offer a general source of therapeutic DCs.

Dynamic categorization and slot-filler representation in 4- and 6-year-old children.

This experiment was aimed at studying both the role of narrow/contextualized categories in the acquisition/organization of conceptual knowledge and the dynamics of categorization decisions. A forced-choice categorization task contrasting thematic and taxonomic responding was used in 4- and 6-year-old children. Before response alternatives were presented, a conceptual organization was pre-activated by means of a matching between the target stimulus and a thematically related, taxonomically related or slot-filler related object. Although taxonomic sorting was prominent overall, it varied as a function of age and of the nature of the pre-activated relation. Responses in accordance with the thematic or taxonomic activations occurred similarly in 4- and 6-year-old children. Age-related effects were however at work in the case of a slot-filler activation: 4-year-old children considered the contextual/contiguity relations between the stimuli but did not weight the equivalence relations (i.e., same occurrence of responses based on the kind of object in the slot-filler and in the thematic activation conditions). More diversified processes appeared to be at work in 6-year-old children. Slot-filler categories were this time considered throughout both their contextual/contiguity structure and their equivalence relations. Results were discussed in terms of availability of conceptual organizations, flexibility abilities, dynamic categorization and preferences. The focus was on implication of slot-filler representations in the construction of conceptual knowledge and in the development of categorization. An important point was to determine whether the age-related changes observed in the slot-filler activation condition could be consistent with Nelson's ( 1983 ) idea that slot-fillers would help passing from a schema-based to a conventional superordinate organization.

A case study of developmental phonological dyslexia: Is the attentional deficit in the perception of rapid stimuli sequences amodal?

The attentional blink (AB) refers to a decrease in accuracy that occurs when participants are required to detect the second of two rapidly sequential targets displayed randomly in a stream of distracters. Dyslexic individuals have been shown to exhibit a prolonged AB in the visual modality, interpreted as evidence of sluggish attentional shifting (SAS). However, the amodal SAS theory predicts that the disorder should further extend to the auditory modality, then resulting in a phonological disorder as typically found in developmental dyslexia. Otherwise, it has been demonstrated that a visual attention (VA) span deficit contributes to the poor reading outcome of dyslexic individuals, independently of their phonological skills. The present study assesses the amodality assumption of the SAS theory together with questioning its relation with the VA span deficit. For this purpose, visual and auditory ABs were explored in a well compensated young adult, LL, who exhibits a pure phonological dyslexia characterised by poor pseudo-word processing and poor phonological skills but preserved VA span. The investigation revealed two different kinds of deficits in LL. Her AB was prolonged and marginally deeper in the visual modality whereas a primarily deeper in amplitude and a subtle prolonged AB was found in the auditory modality. The atypical performance patterns of LL in both modalities suggest that her perceptual attention disorder is amodal as predicted by the SAS theory. This amodal disorder was here reported in a dyslexic participant with a phonological disorder, well in accordance with the hypothesis that sluggish auditory attention shifting contributes to difficulties in phoneme awareness and literacy acquisition. Furthermore, prolonged VA blink was observed in the absence of VA span disorder, thus suggesting that visual attentional shifting and VA span might be distinct mechanisms, contributing independently to reading acquisition and developmental dyslexia.

Development of immunogenic tumor-loaded dendritic cells through physical perturbation and apoptotic cell loading.

To improve understanding of the forces that drive monocytes to transition into dendritic cells (Liyanage et al., 2002), we developed an experimental system that converts monocytes to DC by passage of leukocytes through a 400 microm silica bead column. The results demonstrate that overnight culture of column-treated monocytes causes a phenotypic conversion that is characteristically displayed by immature DC. These phenotypic changes were enhanced when the DC were loaded with apoptotic cells, leading to increased expression of the DC maturation-associated markers CD83, CD80 and the chemokine receptor CCR7. The DC demonstrated potent induction of allogeneic T cell proliferation and the capacity to activate autologous CD8(+) T cells. The CD8 T cells expressed augmented levels of perforin, IFN-gamma and TNF-alpha and mediated CTCL cell apoptosis. These studies demonstrate that physical contact with silica beads combined with loading of apoptotic tumor cells induces synchronized, rapid conversion of human monocytes to DC, which can efficiently stimulate CD8(+) T cells. These results may aid in the development of more efficient DC vaccines that can be loaded with the universe of antigens available in apoptotic tumor cells in a rapid, clinically practical fashion.

Improved generation of anti-tumor immunity by antigen dose limitation.

BACKGROUND: The malignant cells of cutaneous T cell lymphoma (CTCL) display immunogenic peptides derived from the clonal T cell receptor (TCR) providing an attractive model for refinement of anti-tumor immunization methodology. To produce a clinically meaningful anti-tumor response, induction of cytotoxic anti-CTCL cells must be maximized while suppressive T regulatory cells (Treg) should be minimized. We have demonstrated that engulfment of apoptotic CTCL cells by dendritic cells (DC) can lead to either CD8 anti-CTCL responses or immunosuppressive Treg induction. Treg generation is favored when the number of apoptotic cells available for ingestion is high. METHODS: In this study, we sought to determine whether the balance between immunity and immunosuppression could be shifted towards a CD8 anti-CTCL response by lowering the ratio of apoptotic CTCL cells available for DC ingestion. CTCL cell apoptosis was produced by engagement of the TCR by anti-CD3 antibody affixed to magnetic beads. RESULTS: The physical perturbation inherent in passage through a separation column induced monocytes to differentiate into DC, demonstrated by increased expression of class II and CD86 and decreased expression of the monocyte marker CD14. The immature DC internalized and processed apoptotic CTCL cells and could potentially present the tumor-derived peptides in the context of MHC class I and II. As the number of apoptotic cells increased, there was a dose-dependent increase in the expression of Treg markers CTLA-4, CD25, and FoxP3, with a ratio of apoptotic cell/DC loading of > 10:1 corresponding to the greatest Treg induction. These inducible phenotypic Treg also functionally inhibited CD8-mediated perforin expression in vitro. At lower levels of apoptotic cell/DC loading of < 5:1, there was an expansion of the CD8 T cell compartment with increased perforin expression and increased CTCL cell death, indicating anti-tumor activity. CONCLUSION: These findings demonstrate that the ratio of apoptotic cells supplied to DC is an important determinant of whether CD8 anti-tumor immunity or immunosuppression is generated.

Transimmunization for cutaneous T cell lymphoma: a Phase I study.

Extracorporeal photochemotherapy (ECP) is a widely used immunotherapy for cutaneous T cell lymphoma (CTCL). It involves four sequential steps: conversion of blood monocytes into dendritic antigen presenting cells (DC) by repetitive adherence and disadherence to plastic surface; reinfusion of the new DC; presumed in vivo loading of the new DC with apoptotic malignant leukocytes; and expansion of the anti-tumor CD8 T cell pool. To assess the safety of a methodology designed to increase ex vivo contact between the apoptotic malignant cells and new DC prior to reinfusion, a single-center, open-label Phase I clinical study of a revised procedure--referred to as "Transimmunization"--was conducted in CTCL patients. Twenty-seven subjects were treated monthly for 3 to 5 months, alone or in combination with electron beam therapy. For those receiving Transimmunization alone, there was an overall diminution in infiltrative lesions in eleven (55%) of twenty patients. In the twelve leukemic CTCL patients, there was a significant mean reduction of 50.1% in the circulating malignant cells, as determined with family-specific anti-T cell receptor Vbeta monoclonal antibodies (P

Langerhans cells: mediators of immunity and tolerance.

Langerhans cells provide the epidermis with a surveillance network that samples the external environment influencing the decision between immunity and tolerance. Langerhans cells are immature dendritic cells acquiring antigens from foreign invaders as well as damaged native tissue for display to the immune response. The current paradigm suggests that the state of maturity of Langerhans cells, defined by the display of molecules that provoke immune responses (histocompatibility, co-stimulators, adhesion and homing receptors), determines whether emigration of the Langerhans cell to lymph nodes signals immunity or tolerance. Other factors such as type of immunogen ingested, environmental danger signals and the level of cell death may also play a role in tipping the balance towards immunity or immunosuppression. As modulators of the immune response, Langerhans cells play a role in cutaneous autoimmunity in lupus and in cancers that have an affinity for the epidermis such as cutaneous T cell lymphoma.

Quantitative PCR on 5 genes reliably identifies CTCL patients with 5% to 99% circulating tumor cells with 90% accuracy.

We previously identified a small number of genes using cDNA arrays that accurately diagnosed patients with Sézary Syndrome (SS), the erythrodermic and leukemic form of cutaneous T-cell lymphoma (CTCL). We now report the development of a quantitative real-time polymerase chain reaction (qRT-PCR) assay that uses expression values for just 5 of those genes: STAT4, GATA-3, PLS3, CD1D, and TRAIL. qRT-PCR data from peripheral blood mononuclear cells (PBMCs) accurately classified 88% of 17 patients with high blood tumor burden and 100% of 12 healthy controls in the training set using Fisher linear discriminant analysis (FLDA). The same 5 genes were then assayed on 56 new samples from 49 SS patients with blood tumor burdens of 5% to 99% and 69 samples from 65 new healthy controls. The average accuracy over 1000 resamplings was 90% using FLDA and 88% using support vector machine (SVM). We also tested the classifier on 14 samples from patients with CTCL with no detectable peripheral involvement and 3 patients with atopic dermatitis with severe erythroderma. The accuracy was 100% in identifying these samples as non-SS patients. These results are the first to demonstrate that gene expression profiling by quantitative PCR on a selected number of critical genes can be employed to molecularly diagnosis SS.

Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides -- cutaneous T cell lymphoma.

Mycosis fungoides (MF) is a low-grade lymphoma of cluster of differentiation (CD)4+, CD45RO+, cutaneous leukocyte antigen (CLA)+ T cells that homes to the skin. To understand the functional abnormalities in this disease, we study the regulation of cytotoxic T-lymphocyte antigen (CTLA)-4 in peripheral blood mononuclear cells (PBMCs) from patients with MF. CTLA-4 is a costimulatory molecule for T cells that functions in immunoregulation. Unlike the expression of CD28, which is expressed constitutively on T cells, CTLA-4 expression is highly regulated. In the analysis of PBMCs in MF, we found that CTLA-4 is stimulated by phorbol myristate acetate/A23187 to a greater level when compared to normals. This defect was seen in the dominant clones of T cells. The increased CTLA-4 expression was significant between normal and MF, with a correlation between higher expression of CTLA-4 and a higher grade of MF. In a patient whose disease progressed, the CTLA-4 level increased. The abnormal level of CTLA-4 was confirmed at both the transcription and translation levels. Although MF is associated with a Th2 bias, Th1 cytokines IL-2 and IFN-gamma enhanced CTLA-4 expression, while IL-4 did not. These findings reveal an abnormal regulation of CTLA-4 expression in MF and show that PBMCs from patients with MF have properties that are divergent from those of normal T cells.

Categorization by schema relations and perceptual similarity in 5-year-olds and adults: A study in vision and in audition.

This research explores the way in which young children (5 years of age) and adults use perceptual and conceptual cues for categorizing objects processed by vision or by audition. Three experiments were carried out using forced-choice categorization tasks that allowed responses based on taxonomic relations (e.g., vehicles) or on schema category relations (e.g., vehicles that can be seen on the road). In Experiment 1 (visual modality), prominent responses based on conceptually close objects (e.g., objects included in a schema category) were observed. These responses were also favored when within-category objects were perceptually similar. In Experiment 2 (auditory modality), schema category responses depended on age and were influenced by both within- and between-category perceptual similarity relations. Experiment 3 examined whether these results could be explained in terms of sensory modality specializations or rather in terms of information processing constraints (sequential vs. simultaneous processing).

Rapid construction of a dendritic cell vaccine through physical perturbation and apoptotic malignant T cell loading.

We have demonstrated that adherence and release of monocytes from a plastic surface drives their differentiation into immature dendritic cells (DC,) that can mature further during overnight incubation in the presence of apoptotic malignant T cells. Based on these results, we sought to develop a clinically, practical, rapid means for producing DC loaded with malignant cells. A leukapheresis harvest containing the clonal, leukemic expansion of malignant CD4+ T cells was obtained from the blood of patients with cutaneous T cell lymphoma (CTCL). CTCL cells were purified with a CD3-magnetic bead column where CD3 engagement rendered the malignant T cells apoptotic. The monocyte fraction was simultaneously activated by column passage, re-added to the apoptotic CTCL cells and co-cultured overnight. CTCL cell apoptosis, DC differentiation and apoptotic malignant T cell ingestion were measured by immunostaining. The results demonstrate that as monocytes passed through the column matrix, they became activated and differentiated into semi-mature DC expressing significantly increased levels of class II, CD83 and CD86 (markers associated with maturing DC) and reduced expression of the monocyte markers CD14 and CD36. Apoptotic malignant T cells were avidly engulfed by the phagocytic transitioning DC. The addition of supportive cytokines further enhanced the number of DC that contained apoptotic malignant T cells. Functional studies confirmed that column passaged DC increased class II expression as shown by significantly enhanced stimulation in mixed leukocyte culture compared to control monocytes. In addition, DC loaded with apoptotic CTCL cells stimulated an increase in the percentage and absolute number of CD8 T cells compared to co-cultivation with non-loaded DC. After CD8 T cells were stimulated by DC loaded with malignant cells, they mediated increased apoptosis of residual CTCL cells and TNF-alpha secretion indicating development of enhanced cytolytic function. We report a simple one-step procedure where maturing DC containing apoptotic malignant T cells can be prepared rapidly for potential use in vaccine immunotherapy. Ready access to both the DC and apoptotic cells provided by this system will allow extension to other malignancies through the addition of a variety of apoptotic tumor cells and maturation stimuli.

Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells.

Studies in an in vitro model of cutaneous T-cell lymphoma (CTCL) demonstrated that CTCL cell proliferation is stimulated by direct contact with autologous, immature dendritic cells (DCs), suggesting that CD4(+) CTCL cell division is driven by antigens presented by DC major histocompatibility complex (MHC) class 2. We now report that the T-cell receptor (TCR) of the CD4(+) CTCL cells is triggered after interaction with DCs loaded with apoptotic CTCL cells, as shown by reduced membrane expression of CD3 and the TCR, up-regulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), and calcium mobilization. CTCL cells adopt a T-regulatory (Treg) phenotype expressing CD25/CTLA-4 and FoxP3 and secreting interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-gamma (IFN-gamma). Blocking DC MHC class 2 expression or transport inhibited CTCL cell adoption of a Treg phenotype. Allogeneic CTCL cells or normal CD4 T cells served as sources of apoptotic material for CTCL cell conversion to a Treg phenotype. Conversion of CTCL cells to Treg cells may explain the anergic, immunosuppressive nature of the malignancy.

The life cycle of cutaneous T cell lymphoma reveals opportunities for targeted drug therapy.

The diverse clinical presentations of cutaneous T cell lymphoma (CTCL) have been unified by immunologic characterization of the malignant T cells as an expansion of clonal, CD4+ inducer T cells with affinity for epidermal association with Langerhans cells (LC), an immature member of the dendritic cell (DC) family. Features of the life cycle of CTCL have recently been elucidated through development of an in vitro cell culture system. In this system, the proliferation and survival of the CTCL cells is tied to an association with immature monocyte-derived DC. Growth of the CTCL cells requires direct contact with the DC and both cell types survive in the presence of supportive cytokines for 3 months. Separation of the CTCL cells and the DC, or DC maturation truncates the synergy between the two cell populations and results in rapid death of both cell types. The CTCL cells perpetuate DC immaturity and survival through secretion of interleukin 10 (IL10) and transforming growth factor-beta (TGF-beta). The immature DC are aggressively phagocytic and can engulf apoptotic CTCL cells that have exhausted their proliferative potential and present peptides derived from the apoptotic material in class II MHC molecules to the T cell receptor (TCR) of the CD4+ CTCL cell. CTCL cells are induced to become T-regulatory (Treg) cells when their TCR is triggered by DC class II presentation of peptides derived from apoptotic material. Treg CTCL cells suppress immune responses and secrete IL10 and TGF-beta, cytokines that perpetuate DC immaturity, providing continued opportunity for DC stimulation of CTCL cell growth. Understanding the CTCL cell life cycle unveils a variety of potential targets that can be exploited for therapeutic intervention.

Current concepts of the immunobiology and immunotherapy of cutaneous T cell lymphoma: insights gained through cross-talk between the clinic and the bench.

An understanding of the immunologic features of cutaneous T cell lymphoma (CTCL) has led to insights into the life cycle of the malignancy. The identification of the T cell lineage of the neoplastic CTCL cells has allowed unification of diverse clinical presentations under a single entity. The CD4 inducer T cell phenotype of the malignant cells has provided an understanding of the patient's ability to resist infection with certain bacteria. The clonality of the tumor cells, beyond its diagnostic implications, has made them a valuable resource for studying both normal and neoplastic T cell biology. The recently identified immunosuppressive features of the malignant T cells and their dependency for survival on an interaction with immature dendritic cells have explained previously cryptic clinical observations and identified new targets for immunotherapy. Future insights gained both from the bedside and the bench will provide not only an understanding of the immunobiology of the malignancy but also open new avenues for therapeutic intervention.