Attachment and temperament in early childhood; implications for later behavior problems.

In the context of a French validation study, the Child Behavior Checklist (CBCL) was administered to more than 3000 French speaking mothers of 5-year-old children. Scores were factor-analyzed. Principal components analysis revealed four dimensions: externalizing and internalizing behavior problems, immaturity and somatoform disorders. Another sample of 40 mothers participated in a longitudinal study, filling in the CBCL when their children were 5 years old. These children had been observed previously in the Strange Situation (SSP) at 21 months. Several dichotomous variables derived from the SSP (e.g. secure versus insecure, proximal versus distal interaction with the mother, avoidant behavior) have been used as predictors of the four dimensions extracted from the CBCL. Hierarchical regressions showed that proximal behaviors with the mother, which reflect temperamental characteristics independently of the quality of attachment, predicted internalizing problems, whereas avoidance of the mother, or insecure-avoidant attachment, predicted internalizing as well as externalizing problems at 5 years of age. These results show that attachment and temperament, as assessed by the SSP, may each have specific implications for later behavior problems.

Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood.

To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.

Early childhood caries in Switzerland: a marker of social inequalities.

BACKGROUND: Early childhood caries (ECC) is a marker of social inequalities worldwide because disadvantaged children are more likely to develop caries than their peers. This study aimed to define the ECC prevalence among children living in French-speaking Switzerland, where data on this topic were scarce, and to assess whether ECC was an early marker of social inequalities in this country. METHODS: The study took place between 2010 and 2012 in the primary care facility of Lausanne Children's Hospital. We clinically screened 856 children from 36 to 71 months old for ECC, and their caregivers (parents or legal guardians) filled in a questionnaire including items on socioeconomic background (education, occupation, income, literacy and immigration status), dental care and dietary habits. Prevalence rates, prevalence ratios and logistic regressions were calculated. RESULTS: The overall ECC prevalence was 24.8 %. ECC was less frequent among children from higher socioeconomic backgrounds than children from lower ones (prevalence ratios ≤ 0.58). CONCLUSIONS: This study reported a worrying prevalence rate of ECC among children from 36 to 71 months old, living in French-speaking Switzerland. ECC appears to be a good marker of social inequalities as disadvantaged children, whether from Swiss or immigrant backgrounds, were more likely to have caries than their less disadvantaged peers. Specific preventive interventions regarding ECC are needed for all disadvantaged children, whether immigrants or Swiss.

Early childhood constraint therapy for sensory/motor impairment in cerebral palsy: a randomised clinical trial protocol.

INTRODUCTION: Cerebral palsy (CP) is the most common physical disability in childhood. It is a disorder resulting from sensory and motor impairments due to perinatal brain injury, with lifetime consequences that range from poor adaptive and social function to communication and emotional disturbances. Infants with CP have a fundamental disadvantage in recovering motor function: they do not receive accurate sensory feedback from their movements, leading to developmental disregard. Constraint-induced movement therapy (CIMT) is one of the few effective neurorehabilitative strategies shown to improve upper extremity motor function in adults and older children with CP, potentially overcoming developmental disregard. METHODS AND ANALYSIS: This study is a randomised controlled trial of children 12-24 months corrected age studying the effectiveness of CIMT combined with motor and sensory-motor interventions. The study population will comprise 72 children with CP and 144 typically developing children for a total of N=216 children. All children with CP, regardless of group allocation will continue with their standard of care occupational and physical therapy throughout the study. The research material collected will be in the form of data from high-density array event-related potential scan, standardised assessment scores and motion analysis scores. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board. The findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT02567630.

Carie du biberon: un caillou dans la chaussure de la santé [The impact of childhood caries].

The early childhood caries affect primary dentition before the eruption of the permanent teeth. It is set to extended use of a bottle containing fermentable carbohydrates. The early childhood caries is not only a dental disease: it is a social, cultural and behavioral condition that reflects the practices and beliefs around the child. Swiss data indicate that in aged 2 children, one of for could be affected by this devastating oral disease, mainly in vulnerable populations. The primary care physician has an important role in the screening of preschool children, in determining the risk level of the child for early childhood caries. Physicians can advise families, especially pregnant women, about preventive measures and behavior, leading to a dramatic drop of early childhood caries prevalence.

Childhood epilepsy with neuropsychological regression and continuous spike waves during sleep: epilepsy surgery in a young adult.

We describe the case of a man with a history of complex partial seizures and severe language, cognitive and behavioural regression during early childhood (3.5 years), who underwent epilepsy surgery at the age of 25 years. His early epilepsy had clinical and electroencephalogram features of the syndromes of epilepsy with continuous spike waves during sleep and acquired epileptic aphasia (Landau-Kleffner syndrome), which we considered initially to be of idiopathic origin. Seizures recurred at 19 years and presurgical investigations at 25 years showed a lateral frontal epileptic focus with spread to Broca's area and the frontal orbital regions. Histopathology revealed a focal cortical dysplasia, not visible on magnetic resonance imaging. The prolonged but reversible early regression and the residual neuropsychological disorders during adulthood were probably the result of an active left frontal epilepsy, which interfered with language and behaviour during development. Our findings raise the question of the role of focal cortical dysplasia as an aetiology in the syndromes of epilepsy with continuous spike waves during sleep and acquired epileptic aphasia.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.

Conditioned polarized Caco-2 cell monolayers allow to discriminate for the ability of gut-derived microorganisms to modulate permeability and antigen-induced basophil degranulation.

BACKGROUND: Food allergy is a common allergic disorder--especially in early childhood. The avoidance of the allergenic food is the only available method to prevent further reactions in sensitized patients. A better understanding of the immunologic mechanisms involved in this reaction would help to develop therapeutic approaches applicable to the prevention of food allergy. OBJECTIVE: To establish a multi-cell in vitro model of sensitized intestinal epithelium that mimics the intestinal epithelial barrier to study the capacity of probiotic microorganisms to modulate permeability, translocation and immunoreactivity of ovalbumin (OVA) used as a model antigen. METHODS: Polarized Caco-2 cell monolayers were conditioned by basolateral basophils and used to examine apical to basolateral transport of OVA by ELISA. Activation of basophils with translocated OVA was measured by beta-hexosaminidase release assay. This experimental setting was used to assess how microorganisms added apically affected these parameters. Basolateral secretion of cytokine/chemokines by polarized Caco-2 cell monolayers was analysed by ELISA. RESULTS: Basophils loaded with OVA-specific IgE responded to OVA in a dose-dependent manner. OVA transported across polarized Caco-2 cell monolayers was found to trigger basolateral basophil activation. Microorganisms including lactobacilli and Escherichia coli increased transepithelial electrical resistance while promoting OVA passage capable to trigger basophil activation. Non-inflammatory levels of IL-8 and thymic stromal lymphopoietin were produced basolaterally by Caco-2 cells exposed to microorganisms. CONCLUSION: The complex model designed in here is adequate to learn about the consequence of the interaction between microorganisms and epithelial cells vis-a-vis the barrier function and antigen translocation, two parameters essential to mucosal homeostasis. It can further serve as a direct tool to search for microorganisms with anti-allergic and anti-inflammatory properties.

Development of allocentric spatial memory abilities in children from 18 months to 5 years of age.

Episodic memories for autobiographical events that happen in unique spatiotemporal contexts are central to defining who we are. Yet, before 2 years of age, children are unable to form or store episodic memories for recall later in life, a phenomenon known as infantile amnesia. Here, we studied the development of allocentric spatial memory, a fundamental component of episodic memory, in two versions of a real-world memory task requiring 18 month- to 5-year-old children to search for rewards hidden beneath cups distributed in an open-field arena. Whereas children 25-42-months-old were not capable of discriminating three reward locations among 18 possible locations in absence of local cues marking these locations, children older than 43 months found the reward locations reliably. These results support previous findings suggesting that allocentric spatial memory, if present, is only rudimentary in children under 3.5 years of age. However, when tested with only one reward location among four possible locations, children 25-39-months-old found the reward reliably in absence of local cues, whereas 18-23-month-olds did not. Our findings thus show that the ability to form a basic allocentric representation of the environment is present by 2 years of age, and its emergence coincides temporally with the offset of infantile amnesia. However, the ability of children to distinguish and remember closely related spatial locations improves from 2 to 3.5 years of age, a developmental period marked by persistent deficits in long-term episodic memory known as childhood amnesia. These findings support the hypothesis that the differential maturation of distinct hippocampal circuits contributes to the emergence of specific memory processes during early childhood.

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.

Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation.

Using quantitative fluorescence in situ hybridization and flow cytometry, the telomere length of telomere repeat sequences after stem cell transplantation (SCT) were measured. The study included the telomeres of peripheral blood monocytes that should reflect the length of telomeres in stem cells and the telomeres of T lymphocytes that could shorten as a result of peripheral expansion. The loss of telomeres in monocytes and in memory T cells, although accelerated initially, became comparable to the loss of telomeres in healthy controls from the second year after transplantation. In addition, the telomere length in the naive T cells that were produced by the thymus was comparable to the telomere length in the naive T cells of the donor. Compared to the total length of telomeres available, the loss of telomere repeats in leukocytes after SCT resembles the accelerated shortening seen in early childhood and remains, therefore, relatively insignificant.

The renal hemodynamic effects of ibuprofen in the newborn rabbit.

In early childhood, nonsteroidal anti-inflammatory drugs are mainly used to either prevent or treat premature labor of the mother and patent ductus arteriosus of the newborn infant. The most frequently used prostaglandin-synthesis inhibitor is indomethacin. Fetuses exposed to indomethacin in utero have been born with renal developmental defects, and in both the unborn child and the term and premature newborn this drug may compromise renal glomerular function. The latter has in the past also been observed when i.v. indomethacin or i.v. acetylsalicylic acid (aspirin) were administered to newborn rabbits. The present experiments were designed to evaluate whether ibuprofen has less renal side effects than indomethacin, as claimed. Three groups of anesthetized, ventilated, normoxemic neonatal rabbits were infused with increasing doses of ibuprofen (0.02, 0.2, 2.0 mg/kg body weight) and the following renal parameters were measured: urine volume, urinary sodium excretion, GFR, and renal plasma flow. Renal blood flow, filtration fraction, and the renal vascular resistance were calculated according to standard formulae. Intravenous ibuprofen caused a dose-dependent, significant reduction in urine volume, GFR, and renal blood flow with a fall in filtration fraction in the animals receiving the highest dose of ibuprofen (2 mg/kg body weight). There was a very steep rise in renal vascular resistance. Urinary sodium excretion decreased. These experiments in neonatal rabbits clearly show that acute i.v. doses of ibuprofen also have significant renal hemodynamic and functional side effects, not less than seen previously with indomethacin.