The association between spastic Cerebral Palsy, intellectual impairment, and gestational age: results from the Northern Ireland Cerebral Palsy Register

Background
Studies suggest a complex relationship between Cerebral Palsy sub-types, severity of impairment, and risk factors such as gestational age. To investigate these relationships, we conducted analyses on over 1,100 children included in the Northern Ireland Cerebral Palsy Register (NICPR) whose clinical CP subtype was Bilateral Spastic or Spastic Hemiplegia, and for whom information was available on the relevant variables.
Methods
We tested for the association between Bilateral and Hemiplegia subtypes, severe intellectual impairment, and gestational age (term; moderately preterm; very or extremely preterm) while controlling for gender, socio-economic deprivation, year of birth, and birth weight (using a standardized birth-weight score based on deviance from the birth weight average within each gestational age band). Severity of intellectual impairment was dichotomised (severe intellectual delay vs. moderate or no delay).
Results
Logistic regressions indicated a good fit of the model, and the predictors included explained approximately 19% of variability in the outcome. The results indicated a strong association between the Bilateral subtype and severe intellectual impairment: compared to children with the Hemiplegia subtype, those with Bilateral Spastic CP displayed a 10-fold increase in the odds of severe intellectual impairment. The results revealed a significant interaction between CP subtype and gestational age: for the Bilateral CP subtype, being born at term was associated with increased probability of severe intellectual impairment.
Discussion
Results are consistent with other studies (Hemming et al., 2008) in indicating that the likelihood of cognitive impairments increases with increasing gestational age at delivery of Bilateral Spastic CP children. The results are discussed in light of hypotheses that suggest the brain might be able to reorganise and compensate the effects of lesions and injuries when it is still less developed.

Occupational exposure to asthmagens and adult onset wheeze and lung function in people who did not have childhood wheeze : A 50-year cohort study

Acknowledgements Funding: Chest, Heart and Stroke Scotland, grant ref. R13/A148. The funder had no role in study design, data collection, analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication. All authors had full access to all the data in the study. The corresponding author had final responsibility for the decision to submit for publication.

Psychopathology during childhood and adolescence predicts delusional-like experiences in adults : a 21-year birth cohort study

Objective: Community surveys have shown that many otherwise well individuals report delusional-like experiences. The authors examined psychopathology during childhood and adolescence as a predictor of delusional-like experiences in young adulthood. ---------- Method: The authors analyzed prospective data from the Mater-University of Queensland Study of Pregnancy, a birth cohort of 3,617 young adults born between 1981 and 1983. Psychopathology was measured at ages 5 and 14 using the Child Behavior Checklist (CBCL) and at age 14 using the Youth Self-Report (YSR). Delusional-like experiences were measured at age 21 using the Peters Delusional Inventory. The association between childhood and adolescent symptoms and later delusional-like experiences was examined using logistic regression. ---------- Results: High CBCL scores at ages 5 and 14 predicted high levels of delusional-like experiences at age 21 (odds ratios for the highest versus the other quartiles combined were 1.25 and 1.85, respectively). Those with YSR scores in the highest quartile at age 14 were nearly four times as likely to have high levels of delusional-like experiences at age 21 (odds ratio=3.71). Adolescent-onset psychopathology and continuous psychopathology through both childhood and adolescence strongly predicted delusional-like experiences at age 21. Hallucinations at age 14 were significantly associated with delusional-like experiences at age 21. The general pattern of associations persisted when adjusted for previous drug use or the presence of nonaffective psychoses at age 21. ---------- Conclusion: Psychopathology during childhood and adolescence predicts adult delusional-like experiences. Understanding the biological and psychosocial factors that influence this developmental trajectory may provide clues to the pathogenesis of psychotic-like experiences.

Are there any true adult-onset offenders?

In the extant literature, adult-onset offending has usually been identified using official sources. It is possible, however, that many of the individuals identified would have had unofficial histories of prior offending. To investigate this issue, the men from the Cambridge Study in Delinquent Development (CSDD) were examined. The CSDD is a prospective longitudinal study of men from inner-city London, followed from age 8 to age 48. Onset of offending was identified using official records and then the self-reported offending of the adult-onset offender group (with a first conviction at age 21 or later) was compared to others. All the adult-onset offenders self-reported some previous offending in childhood and adolescence but most of this offending was not sufficiently frequent or serious to lead to a conviction in practice. About one-third of adult-onset offenders were considered to be self-reported delinquents who were realistically in danger of being convicted because of the frequency of their offending. For some, the adjudication by the criminal justice system was simply the first time that their ongoing pattern of offending had been detected. Their lack of detection was because the types of offences they were committing had lower detection rates.

Defining a developmental subtype of bipolar disorder in a sample of nonreferred adults by age at onset

Objective To test the hypothesis that the age at onset of bipolar disorder would identify a developmental subtype of bipolar disorder in adults characterized by increased levels of irritability, chronic course, rapid cycling, and comorbidity with attention deficit hyperactivity disorder. Methods Forty-four adult subjects diagnosed with bipolar disorder were selected from large family studies of youth with and without attention deficit hyperactivity disorder. These subjects were stratified by the age at onset in childhood (younger than 13 years; n = 8, 18%), adolescence (13–18 years; n = 12, 27%, or adulthood (older than 19 years; n = 24, 55%). All subjects were administered structure diagnostic interviews and a brief cognitive battery. Results In contrast with adult-onset bipolar disorder, child-onset bipolar disorder was associated with a longer duration of illness, more irritability than euphoria, a mixed presentation, a more chronic or rapid-cycling course, and increased comorbidity with childhood disruptive behavior disorders and anxiety disorders. Conclusion Stratification by age at onset of bipolar disorder identified subgroups of adult subjects with differing clinical correlates. This pattern of correlates is consistent with findings documented in children with pediatric bipolar disorder and supports the hypothesis that child-onset bipolar disorder may represent a developmental subtype of the disorder.

Novel ANKH amino terminus mutation (Pro5Ser) associated with early-onset calcium pyrophosphate disease with associated phosphaturia

This report describes a 32-year-old woman presenting since childhood with progressive calcium pyrophosphate disease (CPPD), characterized by severe arthropathy and chondrocalcinosis involving multiple peripheral joints and intervertebral disks. Because ANKH mutations have been previously described in familial CPPD, the proband's DNA was assessed at this locus by direct sequencing of promoter and coding regions and revealed 3 sequence variants in ANKH. Sequences of exon 1 revealed a novel isolated nonsynonymous mutation (c.13 C>T), altering amino acid in codon 5 from proline to serine (CCG>TCG). Sequencing of parental DNA revealed an identical mutation in the proband's father but not the mother. Subsequent clinical evaluation demonstrated extensive chondrocalcinosis and degenerative arthropathy in the proband's father. In summary, we report a novel mutation, not previously described, in ANKH exon 1, wherein serine replaces proline, in a case of early-onset severe CPPD associated with metabolic abnormalities, with similar findings in the proband's father.

Mitochondrial helicase Twinkle in mtDNA copy number regulation and a late-onset disease model

Mitochondrial diseases are caused by disturbances of the energy metabolism. The disorders range from severe childhood neurological diseases to muscle diseases of adults. Recently, mitochondrial dysfunction has also been found in Parkinson s disease, diabetes, certain types of cancer and premature aging. Mitochondria are the power plants of the cell but they also participate in the regulation of cell growth, signaling and cell death. Mitochondria have their own genetic material, mtDNA, which contains the genetic instructions for cellular respiration. Single cell may host thousands of mitochondria and several mtDNA molecules may reside inside single mitochondrion. All proteins needed for mtDNA maintenance are, however, encoded by the nuclear genome, and therefore, mutations of the corresponding genes can also cause mitochondrial disease. We have here studied the function of mitochondrial helicase Twinkle. Our research group has previously identified nuclear Twinkle gene mutations underlying an inherited adult-onset disorder, progressive external ophthalmoplegia (PEO). Characteristic for the PEO disease is the accumulation of multiple mtDNA deletions in tissues such as the muscle and brain. In this study, we have shown that Twinkle helicase is essential for mtDNA maintenance and that it is capable of regulating mtDNA copy number. Our results support the role of Twinkle as the mtDNA replication helicase. No cure is available for mitochondrial disease. Good disease models are needed for studies of the cause of disease and its progression and for treatment trials. Such disease model, which replicates the key features of the PEO disease, has been generated in this study. The model allows for careful inspection of how Twinkle mutations lead to mtDNA deletions and further causes the PEO disease. This model will be utilized in a range of studies addressing the delay of the disease onset and progression and in subsequent treatment trials. In conclusion, in this thesis fundamental knowledge of the function of the mitochondrial helicase Twinkle was gained. In addition, the first model for adult-onset mitochondrial disease was generated.

Does airways inflammation pre-exist before late onset wheeze in children?

Epidemiological studies show that some children develop wheezing after 3 yr of age which tends to persist. It is unknown how this starts or whether there is a period of asymptomatic inflammation. The aim of this study is to determine whether lower airway allergic inflammation pre-exists in late onset childhood wheeze (LOCW). Follow-up study of children below 5 yr who had a non-bronchoscopic bronchoalveolar lavage (BAL) performed during elective surgery. The children had acted as normal controls. A modified ISAAC questionnaire was sent out at least 7 yr following the initial BAL, and this was used to ascertain whether any children had subsequently developed wheezing or other atopic disease (eczema, allergic rhinitis). Cellular and cytokine data from the original BAL were compared between those who never wheezed (NW) and those who had developed LOCW. Eighty-one normal non-asthmatic children were recruited with a median age of 3.2 . Of the 65 children contactable, 9 (16.7%) had developed wheeze, 11 (18.5%) developed eczema and 14 (22.2%) developed hay fever. In five patients, wheeze symptoms developed mean 3.3- yr (range: 2–5 yr) post-BAL. Serum IgE and blood eosinophils were not different in the LOCW and NW, although the blood white cell count was lower in the LOCW group. The median BAL eosinophil % was significantly increased in the patients with LOCW (1.55%, IQR: 0.33 to 3.92) compared to the children who never wheezed, NW (0.1, IQR: 0.0 to 0.3, p = 0.01). No differences were detected for other cell types. There are no significant differences in BAL cytokine concentrations between children with LOCW and NW children. Before late onset childhood wheezing developed, we found evidence of elevated eosinophils in the airways. These data suggest pre-existent airways inflammation in childhood asthma some years before clinical presentation.

Behavioural and cognitive-behavioural group-based parenting programmes for early-onset conduct problems in children aged 3 to 12 years.

Early-onset child conduct problems are common and costly. A large number of studies and some previous reviews have focused on behavioural and cognitive-behavioural group-based parenting interventions, but methodological limitations are commonplace and evidence for the effectiveness and cost-effectiveness of these programmes has been unclear. To assess the effectiveness and cost-effectiveness of behavioural and cognitive-behavioural group-based parenting programmes for improving child conduct problems, parental mental health and parenting skills. We searched the following databases between 23 and 31 January 2011: CENTRAL (2011, Issue 1), MEDLINE (1950 to current), EMBASE (1980 to current), CINAHL (1982 to current), PsycINFO (1872 to current), Social Science Citation Index (1956 to current), ASSIA (1987 to current), ERIC (1966 to current), Sociological Abstracts (1963 to current), Academic Search Premier (1970 to current), Econlit (1969 to current), PEDE (1980 to current), Dissertations and Theses Abstracts (1980 to present), NHS EED (searched 31 January 2011), HEED (searched 31 January 2011), DARE (searched 31 January 2011), HTA (searched 31 January 2011), mRCT (searched 29 January 2011). We searched the following parent training websites on 31 January 2011: Triple P Library, Incredible Years Library and Parent Management Training. We also searched the reference lists of studies and reviews. We included studies if: (1) they involved randomised controlled trials (RCTs) or quasi-randomised controlled trials of behavioural and cognitive-behavioural group-based parenting interventions for parents of children aged 3 to 12 years with conduct problems, and (2) incorporated an intervention group versus a waiting list, no treatment or standard treatment control group. We only included studies that used at least one standardised instrument to measure child conduct problems. Two authors independently assessed the risk of bias in the trials and the methodological quality of health economic studies. Two authors also independently extracted data. We contacted study authors for additional information. This review includes 13 trials (10 RCTs and three quasi-randomised trials), as well as two economic evaluations based on two of the trials. Overall, there were 1078 participants (646 in the intervention group; 432 in the control group). The results indicate that parent training produced a statistically significant reduction in child conduct problems, whether assessed by parents (standardised mean difference (SMD) -0.53; 95% confidence interval (CI) -0.72 to -0.34) or independently assessed (SMD -0.44; 95% CI -0.77 to -0.11). The intervention led to statistically significant improvements in parental mental health (SMD -0.36; 95% CI -0.52 to -0.20) and positive parenting skills, based on both parent reports (SMD -0.53; 95% CI -0.90 to -0.16) and independent reports (SMD -0.47; 95% CI -0.65 to -0.29). Parent training also produced a statistically significant reduction in negative or harsh parenting practices according to both parent reports (SMD -0.77; 95% CI -0.96 to -0.59) and independent assessments (SMD -0.42; 95% CI -0.67 to -0.16). Moreover, the intervention demonstrated evidence of cost-effectiveness. When compared to a waiting list control group, there was a cost of approximately $2500 (GBP 1712; EUR 2217) per family to bring the average child with clinical levels of conduct problems into the non-clinical range. These costs of programme delivery are modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Behavioural and cognitive-behavioural group-based parenting interventions are effective and cost-effective for improving child conduct problems, parental mental health and parenting skills in the short term. The cost of programme delivery was modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Further research is needed on the long-term assessment of outcomes.

In danger of jammed minds: A deconstructive discourse analysis of the criteria for early onset schizophrenia and imagination in children's literature

The purpose of this research is to expose and complicate those discourses of childhood imagination as demonstrated in the diagnostic criteria for early onset schizophrenia by using an antipsychiatry perspective. This will be done by evaluating those discourses alongside those found in popular children’s literature, specifically, Harry Potter and The Philosopher’s Stone, Bridge to Terabithia, and A Wrinkle in Time. Once uncovered, the underlying power discourses were then exposed. This research will then employ a minor reading as provided by Deleuze and Guattari’s (1987) approach to minor literature to demonstrate the ways in which the child can subvert those dominant discourses. The potential of literature is evaluated for its ability to provide alternative modes of experience and lines of flight for the child subjected to the diagnostic criteria of schizophrenia.

Alternative strategies for deciphering the genetic architecture of childhood Pre-B acute lymphoblastic leukemia

La leucémie lymphoblastique aigüe (LLA) est une maladie génétique complexe. Malgré que cette maladie hématologique soit le cancer pédiatrique le plus fréquent, ses causes demeurent inconnues. Des études antérieures ont démontrées que le risque à la LLA chez l’enfant pourrait être influencé par des gènes agissant dans le métabolisme des xénobiotiques, dans le maintient de l’intégrité génomique et dans la réponse au stress oxydatif, ainsi que par des facteurs environnementaux. Au cours de mes études doctorales, j’ai tenté de disséquer davantage les bases génétiques de la LLA de l’enfant en postulant que la susceptibilité à cette maladie serait modulée, au moins en partie, par des variants génétiques agissant dans deux voies biologiques fondamentales : le point de contrôle G1/S du cycle cellulaire et la réparation des cassures double-brin de l’ADN. En utilisant une approche unique reposant sur l’analyse d’une cohorte cas-contrôles jumelée à une cohorte de trios enfants-parents, j’ai effectué une étude d’association de type gènes/voies biologiques candidats. Ainsi, j’ai évaluer le rôle de variants provenant de la séquence promotrice de 12 gènes du cycle cellulaire et de 7 gènes de la voie de réparation de l’ADN, dans la susceptibilité à la LLA. De tels polymorphismes dans la région promotrice (pSNPs) pourraient perturber la liaison de facteurs de transcription et mener à des différences dans les niveaux d’expression des gènes pouvant influencer le risque à la maladie. En combinant différentes méthodes analytiques, j’ai évalué le rôle de différents mécanismes génétiques dans le développement de la LLA chez l’enfant. J’ai tout d’abord étudié les associations avec gènes/variants indépendants, et des essaies fonctionnels ont été effectués afin d’évaluer l’impact des pSNPs sur la liaison de facteurs de transcription et l’activité promotrice allèle-spécifique. Ces analyses ont mené à quatre publications. Il est peu probable que ces gènes de susceptibilité agissent seuls; j’ai donc utilisé une approche intégrative afin d’explorer la possibilité que plusieurs variants d’une même voie biologique ou de voies connexes puissent moduler le risque de la maladie; ces travaux ont été soumis pour publication. En outre, le développement précoce de la LLA, voir même in utero, suggère que les parents, et plus particulièrement la mère, pourraient jouer un rôle important dans le développement de cette maladie chez l’enfant. Dans une étude par simulations, j’ai évalué la performance des méthodes d’analyse existantes de détecter des effets fœto-maternels sous un design hybride trios/cas-contrôles. J’ai également investigué l’impact des effets génétiques agissant via la mère sur la susceptibilité à la LLA. Cette étude, récemment publiée, fût la première à démontrer que le risque de la leucémie chez l’enfant peut être modulé par le génotype de sa mère. En conclusions, mes études doctorales ont permis d’identifier des nouveaux gènes de susceptibilité pour la LLA pédiatrique et de mettre en évidence le rôle du cycle cellulaire et de la voie de la réparation de l’ADN dans la leucémogenèse. À terme, ces travaux permettront de mieux comprendre les bases génétiques de la LLA, et conduiront au développement d’outils cliniques qui amélioreront la détection, le diagnostique et le traitement de la leucémie chez l’enfant.

A longitudinal study of overweight during childhood : etiology, mental health outcomes and mediating factors

Au cours des 30 dernières années, l’embonpoint et l’obésité infantile sont devenus de véritables défis pour la santé publique. Bien que l’obésité soit, à la base, un problème physiologique (i.e. balance calorique positive) une série de facteurs psychosociaux sont reliés à son développement. Dans cette thèse, nous avons étudié le rôle des facteurs périnataux et de la petite enfance dans le développement du surpoids, ainsi que la relation entre le surpoids et les troubles internalisés au cours de l’enfance et au début de l’adolescence. Nous avions trois objectifs généraux: 1) Modéliser le développement de l’indice de masse corporelle (IMC) ou du statut pondéral (le fait d’être en surpoids ou non) durant l’enfance, ainsi qu’estimer l’hétérogénéité dans la population au cours du temps (i.e. identification de trajectoires développementales de l’IMC). 2) Identifier les facteurs périnataux et de la petite enfance pouvant accroitre le risque qu’un enfant suive une trajectoire menant au surpoids adolescente. 3) Tester la possibilité que le surpoids durant l’enfance soit associé avec des problèmes de santé mentale internalisés à l’adolescence, et vérifier la possibilité qu’une telle association soit médiatisée par l’expérience de victimisation par les pairs et l’insatisfaction corporelle. Ce travail est mené dans une perspective de développement au cours de la vie (life span perspective), considérant l’accumulation des facteurs de risques au cours du temps ainsi que les facteurs qui se manifestent durant certaines périodes critiques de développement.1,2 Nous avons utilisé les données provenant de l’Étude Longitudinale du Développement des Enfants du Québec (ELDEQ), une cohorte de naissances de la province de Québec, Canada. L’échantillon initial était composé de 2120 familles avec un bébé de 5 mois nés au Québec en 1997. Ces familles ont été suivies annuellement ou à tous les deux ans jusqu’à ce que les enfants atteignent l’âge de 13 ans. En ce qui concerne le premier objectif de recherche, nous avons utilisé la méthode des trajectoires développementales fondée sur des groupes pour modéliser l’IMC en continu et en catégories (surpoids vs poids normal). Pour notre deuxième objectif, nous avons effectué des modèles de régression multinomiale afin d’identifier les facteurs périnataux et de la petite enfance associés aux différents groupes développementaux du statut pondéral. Les facteurs de risques putatifs ont été choisis parmi les facteurs identifiés dans la littérature et représentent l’environnement périnatal, les caractéristiques de l’enfant, ainsi que l’environnement familial. Ces facteurs ont été analysés longitudinalement dans la mesure du possible, et les facteurs pouvant servir de levier potentiel d’intervention, tels que l’usage de tabac chez la mère durant la grossesse, le sommeil de l’enfant ou le temps d’écoute de télévision, ont été sélectionnés pour l’analyse. Pour notre troisième objectif, nous avons examiné les associations longitudinales (de 6 à 12 ans) entre les scores-z d’IMC (selon la référence CDC 2000) et les problèmes internalisés avec les modèles d’équations structurales de type « cross-lagged ». Nous avons ensuite examiné comment la victimisation par les pairs et l’insatisfaction corporelle durant l’enfance peuvent médiatiser un lien potentiel entre le surpoids et les troubles internalisés au début de l’adolescence. Les contributions scientifiques de la présente thèse incluent l’identification de trajectoires distinctes du statut pondérale durant l’enfance (précoce, tardive, jamais en surpoids), ainsi que les facteurs de risques précoces et les profils de santé mentale pouvant différer selon la trajectoire d’un enfant. De plus, nous avons identifié des mécanismes importants qui expliquent une partie de l’association entre les trajectoires de surpoids et les troubles internalisés: la victimisation par les pairs et l’insatisfaction corporelle.

How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs), these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1D), Sjögren's syndrome, and autoimmune thyroiditis (AITD). Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D), while for others it does not have a significant influence on the course of disease (i.e., SS) or no unanimous consensus exists (i.e., RA and MS).

The aetiology and treatment of developmental stammering in childhood

Developmental stammering (DS, also known as idiopathic stammering or stuttering) is a disorder of speech fluency that affects approximately 0.75% to 1% of the populations of Great Britain, Australia and America,(1-4) although a recent study puts the point prevalence figure at between 1% and 3% in the UK.(5) Prevalence is generally thought to be similar amongst communities worldwide, although there have been occasional suggestions that this figure might be lower in countries where there is less pressure on verbal acuity.(6) DS may be distinguished from neurogenic stammering, which can occur subsequent to neurological damage of various aetiologies (for example, stroke, tumour, degenerative disease) and psychogenic stammering, whose onset can be related to a significant psychological event such as bereavement. While a diagnosis of neurogenic stammering might be made in early childhood and adolescence, both neurogenic and psychogenic types are typically associated with an adult onset. DS is by far the most common form of stammering and usually develops in the pre-school years. The mean age at onset is 4 2, with 75% of cases beginning before the age of 6.(1) However, occasionally, stammering onset may be seen as late as 12 or 13 years of age.