History of offending behavior in first episode psychosis patients: A marker of specific clinical needs and a call for early detection strategies among young offenders.

OBJECTIVES: Previous literature suggests that early psychosis (EP) patients with a history of offending behavior (HOB) have specific clinical needs. The aims of this study were to assess: (1) the prevalence of HOB in a representative sample of EP; (2) the premorbid and baseline characteristics of patients with HOB, and (3) the potential differences in short-term outcome of such patients when compared to patients without HOB. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) admitted 786 EP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. Data of 647 patients could be analyzed. RESULTS: HOB patients (29% of the sample) were more likely to be male with lower level of premorbid functioning and education, have used illicit substances and have attempted suicide. They presented with a more complex clinical picture and had poorer 18-month outcome. Most importantly, they had a significantly longer duration of untreated psychosis. CONCLUSIONS: On the basis of the high prevalence and specific features of EP patients with HOB, our study confirms a need for additional research in this domain and for the development of specific treatment strategies. Most importantly, it suggests a need for the promotion of early detection strategies among the populations of young offenders, considering that some of them may be going through the early phases of a psychotic disorder and that reduction of treatment delay and provision of well adapted interventions may have a significant impact at numerous levels in such patients.

A Study of Sexual Health Issues, Attitudes and Behaviours: The Views of Early School Leavers

This research aimed to explore the sexual attitudes, beliefs and behaviours of early school leavers and how a group of young people, without the advantage of completing post-primary education, deal with the complicated issues of constructing, defining and experiencing sexual practice.This resource was contributed by The National Documentation Centre on Drug Use.

Epidemiological pattern and mortality rates for hepatitis A in Brazil, 1980-2002: a review

The prevalence of hepatitis A virus (HAV) infection is high in developing countries, in which low standards of sanitation promote the transmission of the virus. In Latin America, which is considered an area of high HAV endemicity, most HAV-positive individuals are infected in early childhood. However, recent studies have shown that prevalence rates are decreasing. Herein, we review the data on HAV prevalence and outbreaks available in scientific databases. We also use official government data in order to evaluate mortality rates in Brazil over the last two decades. Studies conducted in the northernmost regions of Brazil have indicated that, although improved hygiene has led to a reduction in childhood exposure to HAV, the greatest exposure still occurs early in life. In the Southeastern region, the persistence of circulating HAV has generated outbreaks among individuals of low socioeconomic status, despite adequate sanitation. Nationwide, hepatitis A mortality rates declined progressively from 1980 to 2002. During that period, mortality rates in the Northern region consistently exceeded the mean national rate and those for other regions. Excluding the North, the rates in all regions were comparable. Nevertheless, the trend toward decline observed in the South was paralleled by a similar trend in the North.

Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma.

Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare tumors mainly occurring in early childhood. Our recent results showed that ectopic overexpression of human Prox1 gene, a lymphatic endothelial nuclear transcription factor, promoted an aggressive behavior in 2 murine models of KHE. This dramatic Prox1-induced phenotype prompted us to investigate immunohistochemical staining pattern of Prox1, podoplanin (D2-40), LYVE-1, and Prox1/CD34 as well as double immunofluorescent staining pattern of LYVE-1/CD31 in KHE and TA, compared with other pediatric vascular tumors. For this purpose, we examined 75 vascular lesions: KHE (n=18), TA (n=13), infantile hemangioma (n=13), pyogenic granuloma (n=18), and granulation tissue (n=13). Overall, KHE and TA shared an identical endothelial immunophenotype: the neoplastic spindle cells were Prox1, podoplanin, LYVE-1, CD31, and CD34, whereas endothelial cells within glomeruloid foci were Prox1, podoplanin, LYVE-1, CD31, and CD34. The lesional cells of all infantile hemangiomas and pyogenic granulomas were negative for Prox1 in the presence of positive internal control. These findings provide immunophenotypic evidence to support a preexisting notion that KHE and TA are closely related, if not identical. Overall, our results show, for the first time, that Prox1 is an immunohistochemical biomarker helpful in confirming the diagnosis of KHE/TA and in distinguishing it from infantile hemangioma and pyogenic granuloma.

Phenotype of two Consanguineous Autosomic Recessive Retinitis Pigmentosa Families Caused by PDE6A and PDE6B Mutations

Purpose: To assess the clinical phenotype in two consanguineous Tunisian families with non syndromic autosomic recessive retinitis Pigmentosa (RP) caused by a PDE6A and PDE6B mutations.Methods: All accessible familiy members were included. Affected members from each family underwent full ophthalmic examination with best corrected Snellen visual acuity, fundus photography, optical coherence tomography and full field electroretinography. Haplotype analyses were used to test linkage in the family to 20 arRP loci, including ABCA4, LRAT, USH2A, RP29, CERKL, CNGA1, CNGB1, CRB1, EYS, RP28, MERTK, NR2E3, PDE6A, PDE6B, RGR, RHO, RLBP1, TULP1. All exons and intron-exon junctions of candidate genes not excluded by haplotype analysis were PCR amplified and directly sequenced.Results: Two family members were clinically affected with arRP in each pedigree. Age range at baseline was 43 to 54 years (mean age at baseline was 48 years). For all affected members, night blindness appeared since early childhood (at 4-5 years old) without nystagmus but with a severe progression and mild to severe loss of central vision at the second decade. Visual acuity at baseline ranged from 20/500 to 20/63. Kinetic visual field was severely constricted for one patient and unrealizable for the others. Funduscopic examination revealed bone spicule-shaped pigment deposits in the mid periphery along with atrophy of the retina, narrowing of the vessels and waxy optic discs. Tomograms showed macular atrophy in both cases of family A, and macular edema in the patients of family B. ERG showed a loss of both rod and cone responses. Haplotype analysis revealed homozygosity for microsatellites markers flanking PDE6A and PDE6B in family A and B, respectively. Sequencing of PDE6A in family A showed a homozygous R102S mutation. In family B, sequencing identified a D600N homozygous mutation. Both mutations cosegregated within each respective pedigree.Conclusions: For these families, affected members developed a severe form of non syndromic arRP. The two reported mutations have already been described. Our data further contribute to our understanding of genotype-phenotype correlations.

The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis

BACKGROUND The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors.

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption.

Early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up : 2nd ESMO Consensus Conference on Lung Cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.

Early Cretaceous life, climate and anoxia

Early Cretaceous life and the environment were strongly influenced by the accelerated break up of Pangaea, which was associated with the formation of a multitude of rift basins, intensified spreading, and important volcanic activity on land and in the sea. These processes likely interacted with greenhouse conditions, and Early Cretaceous climate oscillated between "normal" greenhouse, predominantly arid conditions, and intensified greenhouse, predominantly humid conditions. Arid conditions were important during the latest Jurassic and early Berriasian, the late Barremian, and partly also during the late Aptian. Humid conditions were particularly intense and widespread during shorter episodes of environmental change (EECs): the Valanginian Weissert, the latest Hauterivian Faraoni, the latest Barremian earliest Aptian Taxy, the early Aptian Selli, the early late Aptian Fallot and the late Aptian-early Albian Paquier episodes. Arid conditions were associated with evaporation, low biogeochemical weathering rates, low nutrient fluxes, and partly stratified oceans, leading to oxygen depletion and enhanced preservation of laminated, organic-rich mud (LOM). Humid conditions enabled elevated biogeochemical weathering rates and nutrient fluxes, important runoff and the buildup of freshwater lids in proximal basins, intensified oceanic and atmospheric circulation, widespread upwelling and phosphogenesis, important primary productivity and enhanced preservation of LOM in expanded oxygen-minimum zones. The transition of arid to humid climates may have been associated with the net transfer of water to the continent owing to the infill of dried-out groundwater reservoirs in internally drained inland basins. This resulted in shorter-term sea-level fall, which was followed by sea-level rise. These sea-level changes and the influx of freshwater into the ocean may have influenced oxygen-isotope signatures. Climate change preceding and during the Early Cretaceous EECs may have been rapid, but in general, the EECs had a "pre"-history, during which the stage was set for environmental change. Negative feedback on the climate through increased marine LOM preservation was unlikely, because of the low overall organic-carbon accumulation rates during these episodes. Life and climate co-evolved during the Early Cretaceous. Arid conditions may have affected continental life, such as across the Tithonian/Berriasian boundary. Humid conditions and the corresponding tendency to develop dys- to anaerobic conditions in deeper ocean waters led to phases of accelerated extinction in oceans, but may have led to more luxuriant vegetation cover on continents, such as during the Valanginian, to the benefit of herbivores. During Early Cretaceous EECs, reef systems and carbonate platforms in general were particularly vulnerable. They were the first to disappear and the last to recover, often only after several million years. (C) 2011 Elsevier Ltd. All rights reserved.

Frequency and characteristics of familial melanoma in Spain: the FAM-GEM-1 Study.

INTRODUCTION Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. PATIENTS AND METHODS An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. RESULTS In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. CONCLUSIONS Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior.

Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10(-9)-1.01×10(-12)). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10(-3)). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10(-88)]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

SOURCE, FATE AND FUNCTION OF EARLY GLIAL CELLS EXPRESSING NKX2.1 IN MOUSE EMBRYONIC BRAINS

The brain tissue is made of neuronal and glial cells generated in the germinal layer bordering the ventricles. These cells divide, differentiate and migrate following specific pathways. The specification of GABAergic interneurons and glutamatergic neurons has been broadly studied but little is known about the origin, the fate and the function of early glial cells in the embryonic telencephalon. It has been commonly accepted since long that the glial cells and more particularly the astrocytes were generated after neurogenesis from the dorsal telencephalon. However, our work shows that, unlike what was previously thought, numerous glial cells (astroglia and polydendrocytes) are generated during neurogenesis in the early embryonic stages from E14.5 to E16.5, and originate from the ventral Nkx2.1-expressing precursors instead. NK2 homeobox 1 (Nkx2.1) is a member of the NK2 family of homeodomaincontaining transcription factors. The specification of the MGE precursors requires the expression of the Nkx2.1 homeobox gene. Moreover, Nkx2.1 is previously known to regulate the specification of GABAergic interneurons and early oligodendrocytes in the ventral telencephalon. Here, in my thesis work, I have discovered that, in addition, Nkx2.1 also regulates astroglia and polydendrocytes differentiation. The use of Nkx2.1 antibody and Nkx2.1 riboprobe have revealed the presence of numerous Nkx2.1-positive cells that express astroglial markers (like GLAST and GFAP) in the entire embryonic brain. Thus, to selectively fate map MGE-derived GABAergic interneurons and glia, we crossed Nkx2.1-Cre mice, Glast-Cre ERT+/- inducible mice and NG2-Cre mice with the Cre reporter Rosa26-lox-STOP-lox-YFP (Rosa26-YFP) mice. The precise origin of Nkx2.1-positive astroglia has been directly ascertained by combining glial immunostaining and focal electroporation of the pCAG-GS-EGFP plasmids into the subpallial domains of organotypic slices, as well as, by using in vitro neurosphere experiments and in utero electroporation of the pCAG-GS-tomato plasmid into the ventral pallium of E14.5 Nkx2.1-Cre+/Rosa-YFP+/- embryos. We have, thus, confirmed that the three germinal regions of the ventral telencephalon i.e. the MGE, the AEP/POA and the triangular septal nucleus are able to generate early astroglial cells. Moreover, immunohistochemistry for several astroglial cells and polydendrocyte markers, both in the Nkx2.1-/- and control embryos and in the neurospheres, has revealed a severe loss of both glial cell types in the Nkx2.1 mutants. We found that the loss of glia corresponded to a decrease of Nkx2.1-derived precursor division capacity and glial differentiation. There was a drastic decrease of BrdU+ dividing cells labeled for Nkx2.1 in the MGE*, the POA* and the septal nucleus* of Nkx2.1 mutants. In addition, we noticed that while some remaining Nkx2.1+ precursors still succeeded to give rise to post-mitotic neurons in vitro and in vivo in the Nkx2.1-/-, they completely lost the capacity to differentiate in astrocytes. Altogether, these observations indicate for the first time that the transcription factor Nkx2.1 regulates the proliferation and differentiation of precursors in three subpallial domains that generate early embryonic astroglia and polydendrocytes. Furthermore, in order to investigate the potential function of these early Nkx2.1- derived glia, we have performed multiple immunohistochemical stainings on Nkx2.1-/- and wild-type animals, and Nkx2.1-Cre mice that were crossed to Rosa-DTA+/- mice in which the highly toxic diphtheria toxin aided to selectively deplete a majority of the Nkx2.1-derived cells. Interestingly, in these two mutants, we observed a drastic and significant loss of GFAP+, GLAST+, NG2+ and S100ß+ astroglial cells at the telencephalic midline and in the medial cortical areas. This cells loss could be directly correlated with severe axonal guidance defects observed in the corpus callosum (CC), the hippocampal commissure (HIC), the fornix (F) and the anterior commissure (AC). Axonal guidance is a key step allowing neurons to form specific connections and to become organized in a functional network. The contribution of guidepost cells inside the CC and the AC in mediating the growth of commissural axons have until now been attributed to specialized midline guidepost astroglia. Previous published results in our group have unravelled that, during embryonic development, the CC is populated in addition to astroglia by numerous glutamatergic and GABAergic guidepost neurons that are essential for the correct midline crossing of callosal axons. Therefore, the relative contribution of individual neuronal or glial populations towards the guidance of commissural axons remains largely to be investigated to understand guidance mechanisms further. Thus, we crossed Nkx2.1-Cre mice with NSE-DTA+/- mice that express the diphtheria toxin only in neurons and allowed us to selectively deplete Nkx2.1-derived GABAergic neurons. Interestingly, in the Nkx2.1-/- mice, the CC midline was totally disorganized and the callosal axons partly lost their orientation, whereas in the Nkx2.1Cre+/Rosa-DTA+/- and the Nkx2.1Cre+/NSE-DTA+/- mice, the axonal organization of the CC was not affected. In the three types of mice, hippocampal axons of the fornix were not properly fasciculated and formed disoriented bundles through the septum. Additionally, the AC formation was completely absent in Nkx2.1-/- mice and the AC was divided into two/three separate paths in the Nkx2.1Cre+/Rosa-DTA+/- mice that project in wrong territories. On the other hand, the AC didn't form or was reduced to a relatively narrower tract in the Nkx2.1Cre+/NSE-DTA+/- mice as compared to wild-type AC. These results clearly indicate that midline Nkx2.1-derived cells play a major role in commissural axons pathfinding and that both Nkx2.1-derived guidepost neurons and glia are necessary elements for the correct development of these commissures. Furthermore, during our investigations on Nkx2.1-/- and Nkx2.1Cre+/Rosa-DTA+/- mice, we noticed similar and severe defects in the erythrocytes distribution and the blood vessels network morphology in the embryonic brain of both mutants. As the Cre-mediated recombination was never observed to occur in the blood vessels of Nkx2.1-Cre mice, we inferred that the vessels defects observed were due to the loss of Nkx2.1-derived cells and not to the cells autonomous effects of Nkx2.1 in regulating endothelial cell precursors. Thereafter, the respective contribution of individual Nkx2.1-regulated neuronal or glial populations in the blood vessels network building were studied with the use of transgenic mice strains. Indeed, the use of Nkx2.1Cre+/NSE-DTA+/- mice indicated that the Nkx2.1-derived neurons were not implicated in this process. Finally, to discriminate between the two Nkx2.1-derived glial cell populations, the GLAST+ astroglia and the NG2+ polydendrocytes, an NG2-Cre mouse strain crossed to the Rosa-DTA+/- mice was used. In that mutant, the blood vessel network and the erythrocytes distribution were similarly affected as observed in Nkx2.1Cre+/Rosa-DTA+/- animals. Therefore, this result indicates that most probably, the NG2+ polydendrocytes are involved in helping to build the vessels network in the brain. Taken altogether, these observations show that during brain development, Nkx2.1- derived embryonic glial cells act as guidepost cells on the guidance of axons as well as forming vessels. Both Nkx2.1-regulated guidepost GABAergic neurons and glia collaborate to guide growing commissural axons, while polydendrocytes are implicated in regulating brain angiogenesis. - Le tissu cérébral est composé de cellules neuronales et gliales générées dans les couches germinales qui bordent les ventricules. Ces cellules se divisent, se différencient et migrent selon des voies particulières. La spécification des interneurones GABAergiques et des neurones glutamatergiques a été largement étudiée, par contre, l'origine, le destin et la fonction des cellules gliales précoces du télencéphale embryonnaire restent peu élucidées. Depuis longtemps, il était communément accepté que les cellules gliales, et plus particulièrement les astrocytes, sont générés après la neurogénèse à partir du télencéphale dorsal. Toutefois, notre travail montre que de nombreuses cellules gliales sont générées à partir de précurseurs ventraux qui expriment le gène Nkx2.1, entre E14.5 et E16.5, c'est-à dire,à des stades embryonnaires très précoces. Le gène NK2 homéobox 1 (Nkx2.1) appartient à une famille de facteurs de transcription appelée NK2. Il s'agit de protéines qui contiennent un homéo-domaine. La spécification des précurseurs de la MGE requiert l'expression du gène homéobox Nkx2.1. De plus, la fonction du gène Nkx2.1 dans la régulation de la spécification des interneurones GABAergiques et des oligodendrocytes dans le télencéphale ventral était déjà connue. Au cours de mon travail de thèse, j'ai également mis en évidence que, Nkx2.1 régule aussi les étapes de prolifération et de différenciation de divers sous-types de cellules gliales soit de type astrocytes ou bien polydendrocytes. L'utilisation d'un anticorps contre la protéine Nkx2.1 ainsi qu'une sonde à ribonucléotides contre l'ARN messager du gène Nkx2.1 ont révélé la présence de nombreuses cellules positives pour Nkx2.1 qui exprimaient des marqueurs astrocytaires (comme GLAST et GFAP) dans le télencéphale embryonnaire. Afin de déterminer de manière sélective le sort des interneurones GABAergiques, des polydendrocytes et des astrocytes dérivés de la MGE, nous avons croisé soit des souris Nkx2.1-Cre, des souris Glast-Cre ERT+/- inductibles ou bien des souris NG2-Cre avec des souris Rosa26-lox-STOP-lox-YFP (Rosa26-YFP) Cre rapportrices. L'origine précise des astroglies positives pour Nkx2.1 a été directement établie en combinant une coloration immunologique pour les glies et une électroporation focale d'un plasmide pCAG-GS-EGFP dans les domaines subpalliaux de tranches organotypiques, puis également, par des cultures de neurosphères in vitro et des expériences d'électroporation in utero d'un plasmide pCAG-GS-tomato dans le pallium ventral d'embryons Nkx2.1-Cre+/Rosa- YFP+/- au stade E14.5. Nous avons donc confirmé que les trois régions germinales du télencéphale ventral, c'est-à-dire, la MGE, l'AEP/POA et le noyau triangulaire septal sont capables de générer des cellules astrogliales. D'autre part, l'immunohistochimie pour plusieurs marqueurs d'astrocytes ou de polydendrocytes, dans les embryons Nkx2.1-/- et contrôles ainsi que dans les neurosphères, a révélé une sévère perte de ces deux types gliaux chez les mutants. Nous avons trouvé que la perte de glies correspondait à une diminution de la capacité de division des précurseurs dérivés de Nkx2.1, ainsi que l'incapacité de ces précurseurs de se différencier en cellules gliales. Nous avons en effet observé une diminution importante des cellules BrdU+ en division exprimant Nkx2.1dans la MGE*, la POA* et le noyau septal* des mutants pour Nkx2.1. D'autre part, nous avons pu mettre en évidence aussi bien in vitro, qu'in vivo, que certains précurseurs Nkx2.1+ chez le mutant gardent la capacité à se différencier en neurones tandis qu'ils perdent celle de se différencier en cellules gliales. Prises dans leur ensemble, ces observations indiquent pour la première fois que le facteur de transcription Nkx2.1 régule les étapes de prolifération et de différentiation des précurseurs des trois domaines subpalliaux qui génèrent les astroglies et polydendrocytes embryonnaires précoces. Par la suite, dans le but de comprendre la fonction potentielle de ces glies précoces, nous avons procédé à de multiples colorations immunohistochimiques sur des animaux Nkx2.1-/- et sauvages, ainsi que sur des souris Nkx2.1-Cre croisées à des souris Rosa-DTA+/- dans lesquelles la toxine diphthérique hautement toxique a permis de supprimer sélectivement la majorité des cellules dérivées de Nkx2.1. De manière intéressante, nous avons observé dans ces deux mutants, une perte drastique et significative de cellules astrogliales GFAP+, GLAST+ et polydendrocytaires NG2+ et S100ß+ dans le télencéphale, à la midline et dans les aires corticales médianes. Ces pertes ont pu être directement corrélées avec des défauts de guidage axonal observés dans le corps calleux (CC), la commissure hippocampique (HIC), le fornix (F) et la commissure antérieure (AC). Le guidage axonal est une étape clé permettant aux neurones de former des connections spécifiques et de s'organiser dans un réseau fonctionnel. La contribution des cellules « guidepost » dans le CC et dans la AC comme médiateurs de la croissance des axones commissuraux à jusqu'à aujourd'hui été attribuée spécifiquement à des astroglies « guidepost » de la midline. Des résultats publiés précédemment dans notre groupe, ont permis de montrer que, pendant le développement embryonnaire, le CC est peuplé en plus de la glie par de nombreux neurones « guidepost » glutamatergiques et GABAergiques qui sont essentiels pour le croisement correct des axones callosaux à la midline. Ainsi, la contribution relative des populations individuelles neuronales ou gliales pour le guidage des axones commissuraux demande à être approfondie afin de mieux comprendre les mécanismes de guidage. A ces fins, nous avons croisé des souris Nkx2.1-Cre avec des souris NSE-DTA+/- qui expriment la toxine diphthérique uniquement dans les neurones et ainsi, nous avons pu sélectivement supprimer les neurones dérivés de domaines Nkx2.1+. Dans les souris Nkx2.1-/-,nous avons découvert que le CC était désorganisé avec des axones callosaux perdant partiellement leur orientation, alors que dans les souris Nkx2.1Cre+/Rosa-DTA+/- et Nkx2.1Cre+/NSE-DTA+/-, l'organisation axonale n'était pas affectée. De plus, les faisceaux hippocampiques du fornix étaient défasciculés dans les trois types de mutants. Par ailleurs, la formation de la commissure antérieure (AC) était complètement absente dans les souris Nkx2.1-/- d'une part, et d'autre part, celle-ci était divisée en deux à trois voies séparées dans les souris Nkx2.1Cre+/Rosa-DTA+/-. Finalement, la AC était soit absente, soit réduite de manière ne former plus qu'un faisceau relativement plus étroit dans les souris Nkx2.1Cre+/NSE-DTA+/- en comparaison avec la AC sauvage. Ces derniers résultats indiquent clairement que les cellules dérivées de Nkx2.1 à la midline, jouent un rôle majeur dans le guidage des axones commissuraux et que, autant les neurones, que les astrocytes « guidepost » dérivés de Nkx2.1, sont des éléments nécessaires au développement correct de ces commissures. En outre, lors de nos investigations sur les souris Nkx2.1-/- et Nkx2.1Cre+/Rosa-DTA+/-, nous avons remarqués des défauts sévères et similaires dans la distribution des erythrocytes et dans la morphologie du réseau de vaisseaux sanguins dans le cerveau embryonnaire des deux mutants précités. Puisque nous n'avons jamais observé de recombinaison de la Cre recombinase dans les vaisseaux sanguins des souris Nkx2.1Cre, nous en avons déduit que les défauts de vaisseaux observés étaient dus à la perte de cellules dérivées de Nkx2.1. Il existerait donc en plus de la fonction cellulaire autonome de Nkx2.1 reconnue pour régulée directement la spécification des cellules endothéliales, une fonction indirecte de Nkx2.1. Afin de déterminer la contribution respective des populations individuelles neuronales ou gliales régulées par Nkx2.1 dans la construction du réseau de vaisseaux sanguins, nous avons utilisé diverses lignées de souris transgéniques. L'utilisation de souris Nkx2.1Cre+/NSE-DTA+/- a indiqué que les neurones dérivés de Nkx2.1 n'étaient pas impliqués dans ce processus. Finalement, afin de discriminer entre les deux populations de cellules gliales dérivées de Nkx2.1, les astroglies et les polydendrocytes, nous avons croisé une lignée de souris NG2-Cre avec des souris Rosa-DTA+/-. Dans ce dernier mutant, le réseau de vaisseaux sanguins du cortex ainsi que la distribution des erythrocytes étaient affectés de la même manière que dans le cortex des souris Nkx2.1Cre+/Rosa-DTA+/-. Par conséquent, ce résultat indique que très probablement, les polydendrocytes NG2+ sont impliqués dans la mise en place du réseau de vaisseaux dans le cerveau. Prises dans leur ensemble, ces observations montrent que durant le développement embryonnaire du cerveau, des sous-populations de glies régulées par Nkx2.1 jouent un rôle de cellules « guidepost » dans le guidage des axones, ainsi que des vaisseaux. Les polydendrocytes sont impliquées dans la régulation de l'angiogenèse tandis que, autant les neurones GABAergiques que les astrocytes collaborent dans le guidage des axones commissuraux en croissance.

Government and the distribution of skills

Individuals' life chances in the future will very much depend on how we invest in our children now. An optimal human capital model would combine a high mean with minimal variance of skills. It is well-established that early childhood learning is key to adult success. The impact of social origins on child outcomes remains strong, and the new role of women poses additional challenges to our conventional nurturing approach to child development. This paper focuses on skill development in the early years, examining how we might best combine family inputs and public policy to invest optimally in our future human capital. I emphasize three issues: one, the uneven capacity of parents to invest in children; two, the impact of mothers' employment on child outcomes; and three, the potential benefits of early pre-school programmes. I conclude that mothers' intra-family bargaining power is decisive for family investments and that universal child care is key if our goal is to arrive at a strong mean with minimal variance.

Influence of a lifestyle intervention in preschool children on physiological and psychological parameters (Ballabeina): study design of a cluster randomized controlled trial.

Childhood obesity and physical inactivity are increasing dramatically worldwide. Children of low socioeconomic status and/or children of migrant background are especially at risk. In general, the overall effectiveness of school-based programs on health-related outcomes has been disappointing. A special gap exists for younger children and in high risk groups. This paper describes the rationale, design, curriculum, and evaluation of a multicenter preschool randomized intervention study conducted in areas with a high migrant population in two out of 26 Swiss cantons. Twenty preschool classes in the German (canton St. Gallen) and another 20 in the French (canton Vaud) part of Switzerland were separately selected and randomized to an intervention and a control arm by the use of opaque envelopes. The multidisciplinary lifestyle intervention aimed to increase physical activity and sleep duration, to reinforce healthy nutrition and eating behaviour, and to reduce media use. According to the ecological model, it included children, their parents and the teachers. The regular teachers performed the majority of the intervention and were supported by a local health promoter. The intervention included physical activity lessons, adaptation of the built infrastructure; promotion of regional extracurricular physical activity; playful lessons about nutrition, media use and sleep, funny homework cards and information materials for teachers and parents. It lasted one school year. Baseline and post-intervention evaluations were performed in both arms. Primary outcome measures included BMI and aerobic fitness (20 m shuttle run test). Secondary outcomes included total (skinfolds, bioelectrical impedance) and central (waist circumference) body fat, motor abilities (obstacle course, static and dynamic balance), physical activity and sleep duration (accelerometry and questionnaires), nutritional behaviour and food intake, media use, quality of life and signs of hyperactivity (questionnaires), attention and spatial working memory ability (two validated tests). Researchers were blinded to group allocation. The purpose of this paper is to outline the design of a school-based multicenter cluster randomized, controlled trial aiming to reduce body mass index and to increase aerobic fitness in preschool children in culturally different parts of Switzerland with a high migrant population. Trial Registration: (clinicaltrials.gov) NCT00674544.

Late Early Triassic climate change: Insights from carbonate carbon isotopes, sedimentary evolution and ammonoid paleobiogeography

The late Early Triassic sedimentary-facies evolution and carbonate carbon-isotope marine record (delta(13)C(carb)) of ammonoid-rich, outer platform settings show striking similarities between the South ChinaBlock (SCB) and the widely distant Northern Indian Margin (NIM). The studied sections are located within the Triassic Tethys Himalayan belt (Losar section, Himachal Pradesh, India) and the Nanpanjiang Basin in the South China Block (Jinya section, Guangxi Province), respectively. Carbon isotopes from the studied sections confirm the previously observed carbon cycle perturbations at a time of major paleoceanographic changes in the wake of the end-Permian biotic crisis. This study documents the coincidence between a sharp increase in the carbon isotope composition and the worldwide ammonoid evolutionary turnover (extinction followed by a radiation) occurring around the Smithian-Spathian boundary. Based on recent modeling studies on ammonoid paleobiogeography and taxonomic diversity, we demonstrate that the late Early Triassic (Smithian and Spathian) was a time of a major climate change. More precisely, the end Smithian climate can be characterized by a warm and equable climate underlined by a flat, pole-to-equator, sea surface temperature (SST) gradient, while the steep Spathian SST gradient suggests latitudinally differentiated climatic conditions. Moreover, sedimentary evidence suggests a transition from a humid and hot climate during the Smithian to a dryer climate from the Spathian onwards. By analogy with comparable carbon isotope perturbations in the Late Devonian, Jurassic and Cretaceous we propose that high atmospheric CO(2) levels could have been responsible for the observed carbon cycle disturbance at the Smithian-Spathian boundary. We suggest that the end Smithian ammonoid extinction has been essentially caused by a warm and equable climate related to an increased CO(2) flux possibly originating from a short eruptive event of the Siberian igneous province. This increase in atmospheric CO(2) concentrations could have additionally reduced the marine calcium carbonate oversaturation and weakened the calcification potential of marine organisms, including ammonoids, in late Smithian oceans. (c) 2006 Elsevier B.V. All rights reserved.