Improving outcome of childhood bacterial meningitis by simplified treatment : Experience from Angola

Background Acute bacterial meningitis (BM) continues to be an important cause of childhood mortality and morbidity, especially in developing countries. Prognostic scales and the identification of risk factors for adverse outcome both aid in assessing disease severity. New antimicrobial agents or adjunctive treatments - except for oral glycerol - have essentially failed to improve BM prognosis. A retrospective observational analysis found paracetamol beneficial in adult bacteraemic patients, and some experts recommend slow β-lactam infusion. We examined these treatments in a prospective, double-blind, placebo-controlled clinical trial. Patients and methods A retrospective analysis included 555 children treated for BM in 2004 in the infectious disease ward of the Paediatric Hospital of Luanda, Angola. Our prospective study randomised 723 children into four groups, to receive a combination of cefotaxime infusion or boluses every 6 hours for the first 24 hours and oral paracetamol or placebo for 48 hours. The primary endpoints were 1) death or severe neurological sequelae (SeNeSe), and 2) deafness. Results In the retrospective study, the mortality of children with blood transfusion was 23% (30 of 128) vs. without blood transfusion 39% (109 of 282; p=0.004). In the prospective study, 272 (38%) of the children died. Of those 451 surviving, 68 (15%) showed SeNeSe, and 12% (45 of 374) were deaf. Whereas no difference between treatment groups was observable in primary endpoints, the early mortality in the infusion-paracetamol group was lower, with the difference (Fisher s exact test) from the other groups at 24, 48, and 72 hours being significant (p=0.041, 0.0005, and 0.005, respectively). Prognostic factors for adverse outcomes were impaired consciousness, dyspnoea, seizures, delayed presentation, and absence of electricity at home (Simple Luanda Scale, SLS); the Bayesian Luanda Scale (BLS) also included abnormally low or high blood glucose. Conclusions New studies concerning the possible beneficial effect of blood transfusion, and concerning longer treatment with cefotaxime infusion and oral paracetamol, and a study to validate our simple prognostic scales are warranted.

Dissection of the genetic background of childhood onset progressive myoclonic epilepsies

The progressive myoclonic epilepsies (PMEs) are a clinically and etiologically heterogeneous group of symptomatic epilepsies characterized by myoclonus, tonic-clonic seizures, psychomotor regression and ataxia. Different disorders have been classified as PMEs. Of these, the group of neuronal ceroid lipofuscinoses (NCLs) comprise an entity that has onset in childhood, being the most common cause of neurodegeneration in children. The primary aim of this thesis was to dissect the molecular genetic background of patients with childhood onset PME by studying candidate genes and attempting to identify novel PME-associated genes. Another specific aim was to study the primary protein properties of the most recently identified member of the NCL-causing proteins, MFSD8. To dissect the genetic background of a cohort of Turkish patients with childhood onset PME, a screen of the NCL-associated genes PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8 and CTSD was performed. Altogether 49 novel mutations were identified, which together with 56 mutations found by collaborators raised the total number of known NCL mutations to 364. Fourteen of the novel mutations affect the recently identified MFSD8 gene, which had originally been identified in a subset of mainly Turkish patients as the underlying cause of CLN7 disease. To investigate the distribution of MFSD8 defects, a total of 211 patients of different ethnic origins were evaluated for mutations in the gene. Altogether 45 patients from nine different countries were provided with a CLN7 molecular diagnosis, denoting the wide geographical occurrence of MFSD8 defects. The mutations are private with only one having been established by a founder-effect in the Roma population from the former Czechoslovakia. All mutations identified except one are associated with the typical clinical picture of variant late-infantile NCL. To address the trafficking properties of MFSD8, lysosomal targeting of the protein was confirmed in both neuronal and non-neuronal cells. The major determinant for this lysosomal sorting was identified to be an N-terminal dileucine based signal (9-EQEPLL-14), recognized by heterotetrameric AP-1 adaptor proteins, suggesting that MFSD8 takes the direct trafficking pathway en route to the lysosomes. Expression studies revealed the neurons as the primary cell-type and the hippocampus and cerebellar granular cell layer as the predominant regions in which MFSD8 is expressed. To identify novel genes associated with childhood onset PME, a single nucleotide polymorphism (SNP) genomewide scan was performed in three small families and 18 sporadic patients followed by homozygosity mapping to determine the candidate loci. One of the families and a sporadic patient were positive for mutations in PLA2G6, a gene that had previously been shown to cause infantile neuroaxonal dystrophy. Application of next-generation sequencing of candidate regions in the remaining two families led to identification of a homozygous missense mutation in USP19 for the first and TXNDC6 for the second family. Analysis of the 18 sporadic cases mapped the best candidate interval in a 1.5 Mb region on chromosome 7q21. Screening of the positional candidate KCTD7 revealed six mutations in seven unrelated families. All patients with mutations in KCTD7 were reported to have early onset PME, rapid disease progression leading to dementia and no pathologic hallmarks. The identification of KCTD7 mutations in nine patients and the clinical delineation of their phenotype establish KCTD7 as a gene for early onset PME. The findings presented in this thesis denote MFSD8 and KCTD7 as genes commonly associated with childhood onset symptomatic epilepsy. The disease-associated role of TXNDC6 awaits verification through identification of additional mutations in patients with similar phenotypes. Completion of the genetic spectrum underlying childhood onset PMEs and understanding of the gene products functions will comprise important steps towards understanding the underlying pathogenetic mechanisms, and will possibly shed light on the general processes of neurodegeneration and nervous system regulation, facilitating the diagnosis, classification and possibly treatment of the affected cases.

Stability of the factorial structure of metabolic syndrome from childhood to adolescence : a 6-year follow-up study

Background: Metabolic syndrome (MS) is a clustering of cardiometabolic risk factors that is considered a predictor of cardiovascular disease, type 2 diabetes and mortality. There is no consistent evidence on whether the MS construct works in the same way in different populations and at different stages in life. Methods: We used confirmatory factor analysis to examine if a single-factor-model including waist circumference, triglycerides/HDL-c, insulin and mean arterial pressure underlies metabolic syndrome from the childhood to adolescence in a 6-years follow-up study in 174 Swedish and 460 Estonian children aged 9 years at baseline. Indeed, we analyze the tracking of a previously validated MS index over this 6-years period. Results: The estimates of goodness-of-fit for the single-factor-model underlying MS were acceptable both in children and adolescents. The construct stability of a new model including the differences from baseline to the end of the follow-up in the components of the proposed model displayed good fit indexes for the change, supporting the hypothesis of a single factor underlying MS component trends. Conclusions: A single-factor-model underlying MS is stable across the puberty in both Estonian and Swedish young people. The MS index tracks acceptably from childhood to adolescence.

Objectively Measured Physical Activity and Sedentary Time during Childhood, Adolescence and Young Adulthood: A Cohort Study

Background: To know how moderate-to-vigorous physical activity (MVPA) and sedentary time change across lifespan periods is needed for designing successful lifestyle interventions. We aimed to study changes in objectively measured (accelerometry) MVPA and sedentary time from childhood to adolescence and from adolescence to young adulthood. Methods: Estonian and Swedish participants from the European Youth Heart Study aged 9 and 15 years at baseline (N = 2312) were asked to participate in a second examination 6 (Sweden) to 9/10 (Estonia) years later. 1800 participants with valid accelerometer data were analyzed. Results: MVPA decreased from childhood to adolescence (21 to 22.5 min/d per year of follow-up, P = 0.01 and ,0.001, for girls and boys respectively) and also from adolescence to young adulthood (20.8 to 22.2 min/d per year, P = 0.02 and ,0.001 for girls and boys, respectively). Sedentary time increased from childhood to adolescence (+15 and +20 min/d per year, for girls and boys respectively, P,0.001), with no substantial change from adolescence to young adulthood. Changes in both MVPA and sedentary time were greater in Swedish than in Estonian participants and in boys than in girls. The magnitude of the change observed in sedentary time was 3–6 time larger than the change observed in MVPA. Conclusions: The decline in MVPA (overall change = 30 min/d) and increase sedentary time (overall change = 2:45 h/d)observed from childhood to adolescence are of concern and might increase the risk of developing obesity and other chronic diseases later in life. These findings substantially contribute to understand how key health-related behaviors (physical activity and sedentary) change across important periods of life.

Environmental judgment in early childhood and its relationship with the understanding of the concept of living beings

The evidence collected concerning the biocentric judgment that young children express when evaluating human actions on the environment leads some scholars to suggest that an essential understanding of the notion of living beings should appear earlier than previously believed. This research project aims to study that assumption. To this end, young children’s choice when they are put in situation of having to compare and choose the most negative option between environmentally harmful actions and the breaking of social conventions are examined. Afterwards, the results are categorized in relation to those obtained from the study of children’s grasp of the distinction between living beings and inanimate entities. The data is analysed according to the individuals’ age and overall, it suggests a lack of relationship between environmental judgment and the understanding of the concept of living beings. The final results are discussed in keeping with recent research in the field of moral development that underscores the role that unconscious emotional processing plays in the individual’s normative judgment.

El arte como mediador entre el artista y el trauma. Acercamientos al arte desde el psicoanalisis y la escultura de Louise Bourgeois

411 p. : il., col.

Prevalência de transtorno do estresse pós-traumático no período pós-parto entre mulheres atendidas em maternidade de referência para agravos perinatais no município do Rio de Janeiro

O Transtorno do estresse pós-traumático (TEPT) é um transtorno mental que ocorre em resposta a um evento traumático que coloca em risco a vida do indivíduo ou de outras pessoas. O TEPT no período pós-parto foi documentado pela primeira vez em 1978. Porém, há poucos estudos sobre o tema, principalmente em gestantes de alto risco materno e fetal. Visando preencher essa lacuna, essa dissertação tem por objetivo estimar a magnitude de TEPT no período pós-parto em uma maternidade de alto risco fetal no município do Rio de Janeiro e identificar subgrupos vulneráveis ao transtorno. Trata-se de um estudo transversal, cuja população de estudo foi composta por 456 mulheres que tiveram o parto no Instituto Fernandes Figueira e realizaram a consulta de revisão pós-parto entre fevereiro e julho de 2011. Casos suspeitos de TEPT foram identificados por meio de dois instrumentos: Trauma History Questionnaire (THQ) utilizado para a captação de situações potencialmente traumáticas ao longo da vida e Post-Traumatic Stress Disorder Checklist (PCL-C) para rastreio de sintomas de TEPT. A prevalência agregada de TEPT no período pós-parto foi de 9,4%. Subgrupos considerados vulneráveis foram: mulheres com três ou mais partos anteriores (15,1%), com o recém-nascido com APGAR menor ou igual a 7 no primeiro minuto (13,6%), com histórico de psicopatologia anterior (29,0%) ou concomitante à gestação (36,7%), com depressão pós-parto (31,5%), mulheres que sofreram violência física (19,8%) e psicológica (11,6%) perpetrada por parceiro íntimo durante a gestação, mulheres que sofreram abuso sexual na infância (25,7%) e com histórico de 5 ou mais situações traumáticas anteriores (25,9%). A elevada prevalência de TEPT encontrada entre as mulheres entrevistadas pode ser, em parte, atribuída às particularidades da população assistida nessa instituição, de reconhecido risco materno e fetal. A alta prevalência de casos suspeitos de depressão pós-parto entre as mulheres com suspeição de TEPT é um fator de preocupação adicional, já que dificulta o manejo clínico dos casos e afasta a mulher e a criança dos serviços de saúde. TEPT no período pós-parto não é um evento raro e merece atenção. Rápido diagnóstico e tratamento são fundamentais para a melhor qualidade de vida da mãe tornando-a apta aos cuidados do recém-nascido.

Sociologia do trauma: elementos sociogenéticos e psicogenéticos

O presente trabalho investiga os diferentes processos sociais relacionados ao surgimento do transtorno de estresse pós-traumático (TEPT) no contexto brasileiro. Categoria diagnóstica norte-americana instituída na década de 1980 pela terceira edição do Manual Diagnóstico e Estatístico de Transtornos Mentais (Diagnostic and Statistical Manual of Mental Disorders DSM-III) uma publicação da Associação Americana de Psiquiatria (American Psychiatric Association APA) o TEPT tornou-se, desde a sua aparição, uma das categorias nosológicas mais difundidas, estudadas e diagnosticadas da psiquiatria contemporânea. A partir do cotidiano de um laboratório de pesquisa e tratamento do TEPT, de análises conversacionais dos atendimentos médicos, de um estudo das diferentes escalas psiquiátricas utilizadas no acompanhamento dos pacientes e de pesquisas sobre a mídia relacionada às experiências traumáticas buscou-se entender os entrelaçamentos entre os processos de difusão e a construção da legitimidade da categoria diagnóstica do TEPT. A abordagem aqui proposta pretende ir além do aparente dilema entre uma concepção medicalizada que assumem a existência o TEPT como um fenômeno natural e as abordagens sócio-antropológicas que veem o TEPT como uma experiência culturalmente construída. Por fim, pretendo mostrar, pela investigação dos alicerces políticos e culturais dos denominados transtornos mentais, que o estatuto social dos diagnósticos e dos tratamentos da moderna psiquiatria só pode ser compreendido tendo como referência as dinâmicas de longo prazo nas sociedades contemporâneas.

Frequência cardíaca peritraumática após exposição ao trauma como preditor de transtorno de estresse pós-traumático em adultos: revisão sistemática e metanálise.

O transtorno de estresse pós-traumático (TEPT) é um transtorno de ansiedade que pode ser desenvolvido após a ocorrência de um evento traumático, e que costuma vir acompanhado de um significativo comprometimento da qualidade de vida. Indivíduos diagnosticados com o TEPT apresentam níveis de frequência cardíaca mais elevados em situações de exposição a eventos estressores, como sons e imagens que relembram a experiência traumática. No entanto, estudos que avaliaram a frequência cardíaca no momento do trauma como preditor do desenvolvimento de TEPT não apresentam resultados consistentes. Os objetivos deste trabalho foram: verificar se frequência cardíaca (FC) peritraumática de repouso, após exposição ao trauma, é um fator preditor para o desenvolvimento do TEPT e para a gravidade dos sintomas de TEPT em adultos. Foi realizada uma revisão sistemática, seguida de metanálise, utilizando-se as bases eletrônicas PUBMED, LILACS, PILOTS, PsycoINFO e Web of Science. Foram incluídos 17 estudos nesta revisão sistemática. Os resultados de dez estudos foram utilizados para a metanálise das diferenças de médias de FC combinada. Oito estudos foram utilizados para a metanálise das correlações entre a FC e a gravidade dos sintomas de TEPT. Modelos de meta-regressão foram ajustados para identificar variáveis que pudessem explicar a heterogeneidade entre os estudos. A FC peritraumática no grupo de pacientes com TEPT é, em média, 3,98 batimento por mimuto (bpm) (p=0,04) maior em comparação com aqueles sem o transtorno, e o coeficiente de correlação de Pearson combinado foi de 0,14 (p=0,05).Consistente com a hipótese levantada, a frequência cardíaca peritraumática de repouso foi maior em indivíduos que desenvolveram o TEPT. Contudo, mensuração mais próxima do evento traumático e a exclusão de casos dissociativos poderão ampliar a magnitude do efeito encontrado, tornando este biomarcador simples e facilmente obtido um preditor clinicamente útil do desenvolvimento de TEPT.

FB1, an E2A fusion partner in childhood leukemia, interacts with U19/EAF2 and inhibits its transcriptional activity

Background: U19/EAF2 is a potential tumor suppressor exhibiting frequent down-regulation and allelic loss in advanced human prostate cancer specimens. U 19/EAF2 has also been identified as ELL-associated factor 2 (EAF2) based on its binding to ELL, a fusion partner of MLL in acute myeloid leukemia. U19/EAF2 is a putative transcription factor with a transactivation domain and capability of sequence-specific DNA binding. Methods: Yeast-two-hybrid-screening was used to identify U19/EAF2-binding partners. Co-immunoprecipitation and mammalian 1-hybrid assay were used to characterize a U19/EAF2-binding partner. Results: FB1, an E2A fusion partner in childhood leukemia, was identified as a binding-partner of U19/EAF2. FB1 also binds to EAF1, the only homologue of U19/EAF2. FB1 also interacts and co-localizes with ELL in the nucleus. Interestingly, FB1 inhibited the transcriptional activity of U19/EAF2 but not EAF1. Conclusions: FB1 is an important binding partner and a functional regulator of U19/EAF2, EAF1, and/or ELL. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Age-dependence of urinary normal and modified nucleosides in childhood as determined by reversed-phase high-performance liquid chromatography

Modified nucleosides have been characterized as tumor markers for a number of malignant diseases. In order to use these markers in children, the age-dependence of the nucleoside levels in healthy children has to be established and taken into account in diagnostic decisions. In this study, the levels of 12 normal and modified nucleosides in urine of 166 healthy children and adolescents with an age between 1 day and 19 years are determined by reversed-phase HPLC, and age-dependent reference ranges are defined. The urinary nucleoside concentrations are related to the creatinine concentrations, which allows the use of randomly collected urine samples. All nucleoside levels in urine of children decrease with age, most pronounced during the first 4 years of life, and the age-dependence of the reference values of the individual nucleosides can be approximated by a mathematical function y = b(0) + b(1) (1/x) with the regression coefficients b(0) and b(1), the nucleoside levels y and the age x between 1 year and 19 years. In the very young children, the shifts in the nucleoside concentrations are more differentiated. Starting with low levels on the first day of life, the concentrations of all studied nucleosides rise up to an age of 1-2 months, when they reach their absolute maximum for all age periods, and then decrease. (C) 2004 Elsevier B.V. All rights reserved.

Trauma and the Memory of Politics

Edkins, Jenny, Trauma and the Memory of Politics (Cambridge: Cambridge University Press, 2003), pp.xvii+265 RAE2008

Growing up in a mainstream world: a retrospective enquiry into the childhood experiences of young adults with a physical disability.

Children with disabilities are at greater risk of developing mental health problems than their peers, yet the emotional well-being of this group is largely overlooked and there is scant literature about children with a mobility disability. This study examined the retrospective experiences of growing up with mobility disability. The sample comprised of 16-25 year olds with mobility disability. A thematic analysis, informed by grounded theory was used. Themes identified included a common socio educational journey, conflict between care and independence in school and the impact of being singled out because of disability out side school. The result was a range of psycho-social issues that affected participants view of themselves and the world around them. The study also looked at what the participants found helpful in dealing with the emotional impact of their disability. Whilst some sought help through talking therapies, others found involvement in disability sport was helpful.

Can population-level variation in early childhood development be measured in a manner that supports service planning and intervention?

Background: The Early Development Instrument (EDI) is a population-level measure of five developmental domains at school-entry age. The overall aim of this thesis was to explore the potential of the EDI as an indicator of early development in Ireland. Methods: A cross-sectional study was conducted in 47 primary schools in 2011 using the EDI and a linked parental questionnaire. EDI (teacher completed) scores were calculated for 1,344 children in their first year of full-time education. Those scoring in the lowest 10% of the sample population in one or more domains were deemed to be 'developmentally vulnerable'. Scores were correlated with contextual data from the parental questionnaire and with indicators of area and school-level deprivation. Rasch analysis was used to determine the validity of the EDI. Results: Over one quarter (27.5%) of all children in the study were developmentally vulnerable. Individual characteristics associated with increased risk of vulnerability were being male; under 5 years old; and having English as a second language. Adjusted for these demographics, low birth weight, poor parent/child interaction and mother’s lower level of education showed the most significant odds ratios for developmental vulnerability. Vulnerability did not follow the area-level deprivation gradient as measured by a composite index of material deprivation. Children considered by the teacher to be in need of assessment also had lower scores, which were not significantly different from those of children with a clinical diagnosis of special needs. all domains showed at least reasonable fit to the Rasch model supporting the validity of the instrument. However, there was a need for further refinement of the instrument in the Irish context. Conclusion: This thesis provides a unique snapshot of early development in Ireland. The EDI and linked parental questionnaires are promising indicators of the extent, distribution and determinants of developmental vulnerability.