Expression of O⁶-methylguanine-DNA methyltransferase in childhood medulloblastoma.

Medulloblastomas (MB) are the most common malignant brain tumors in childhood. Alkylator-based drugs are effective agents in the treatment of patients with MB. In several tumors, including malignant glioma, elevated O(6)-methylguanine-DNA methyltransferase (MGMT) expression levels or lack of MGMT promoter methylation have been found to be associated with resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ). In this study, we examined the MGMT status of MB and central nervous system primitive neuroectodermal tumor (PNET) cells and two large sets of primary MB. In seven MB/PNET cell lines investigated, MGMT promoter methylation was detected only in D425 human MB cells as assayed by the qualitative methylation-specific PCR and the more quantitative pyrosequencing assay. In D425 human MB cells, MGMT mRNA and protein expression was clearly lower when compared with the MGMT expression in the other MB/PNET cell lines. In MB/PNET cells, sensitivity towards TMZ and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) correlated with MGMT methylation and MGMT mRNA expression. Pyrosequencing in 67 primary MB samples revealed a mean percentage of MGMT methylation of 3.7-92% (mean: 13.25%, median: 10.67%). Percentage of MGMT methylation and MGMT mRNA expression as determined by quantitative RT-PCR correlated inversely (n = 46; Pearson correlation r (2) = 0.14, P = 0.01). We then analyzed MGMT mRNA expression in a second set of 47 formalin-fixed paraffin-embedded primary MB samples from clinically well-documented patients treated within the prospective randomized multicenter trial HIT'91. No association was found between MGMT mRNA expression and progression-free or overall survival. Therefore, it is not currently recommended to use MGMT mRNA expression analysis to determine who should receive alkylating agents and who should not.

Deficit in memory consolidation (abnormal forgetting rate) in childhood temporal lobe epilepsy. Pre and postoperative long-term observation.

Deficits in memory consolidation have been reported in adult patients with epilepsy but, not to our knowledge, in children. We report the long-term follow-up (9 y. o. to 18 y. o.) of a boy who suffered from temporal lobe epilepsy and underwent a left temporal lobectomy with amygdalo-hippocampal resection at the age of 10. He showed an abnormal forgetting rate when trying to encode new information and a significant deficit for retrieving remote episodic memories (when compared with his twin brother), both consistent with a consolidation disorder. His memory condition slightly improved after cessation of the epilepsy, nevertheless did not normalize. No standard memory assessment could pinpoint his memory problem, hence an adapted methodology was needed. We discuss the nature of the memory deficit, its possible causes and its clinical implications.

Intermittent ketoconazole therapy of chronic mucocutaneous candidiasis in childhood.

We report the clinical and laboratory findings in two children with chronic mucocutaneous candidiasis (CMC) treated successfully with intermittent long-term ketoconazole therapy. Both had chronic infection of the nails, skin and mucous membranes with positive cultures for candida. Both were resistant to multiple local and systemic antifungal agents. After institution of ketoconazole therapy there was a dramatic improvement with clearing of the oral (one week), skin (two months) and nail lesions (5 months). After 8 months the drug was stopped and clinical remission persisted for 10 and 7 months respectively. Relapse of oral candidiasis was treated with a short course of ketoconazole (4-16 weeks) leading to complete healing of the lesions. Clinical improvement was not related to an amelioration in lymphocyte transformation. There was no change in the progressive deterioration of the lymphocyte responses to candida antigen which was probably due to persisting candida cell wall components (e.g. mannan).

The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial.

The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.

Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia.

Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), <45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of the second remission, but not of the probability of 10-year event-free survival after relapse treatment. From 29 patients with non-classical cytogenetic aberrations, only 8 (28%) had been stratified to a high risk-arm on the first treatment protocol, suggesting that this subgroup might benefit from the identification of new prognostic markers in future studies.

Psychological distress in adult survivors of childhood cancer: the Swiss Childhood Cancer Survivor study.

PURPOSE: To evaluate the degree of psychological distress in adult childhood cancer survivors in Switzerland and to characterize survivors with significant distress. METHODS: Childhood cancer survivors who were age younger than 16 years when diagnosed between 1976 and 2003, had survived more than 5 years, and were currently age 20 years or older received a postal questionnaire. Psychological distress was assessed using the Brief Symptom Inventory (BSI). Raw scores were transformed into T scores according to the German norm sample, and the proportion of participants being at increased risk for psychological distress was calculated (case rule: T > or = 63). t tests and univariable and multivariable logistic regressions were used for statistical analyses. RESULTS: One thousand seventy-six survivors (63.% of eligible survivors, 71.9% of contacted survivors) returned the questionnaire, 987 with complete data on BSI. Comparison with the norm populations showed lower T scores (T < 50) in the Global Severity Index (GSI; T = 46.2), somatization (T = 47.6), obsessive-compulsive tendencies (T = 46.9), and anxiety (T = 48.4). However, more childhood cancer survivors (especially women) had increased distress for GSI (14.4%), interpersonal sensitivity (16.5%), depression (13.4%), aggression (16.9%), and psychotic tendencies (15.6%) than the expected 10% from the norm population. Caseness was associated with female sex, being a single child, older age at study, and self-reported late effects, especially psychological problems. CONCLUSION: Results show that childhood cancer survivors, on average, have less psychological distress than a norm population but that the proportion of survivors at risk for high psychological distress is disproportionally large. Monitoring psychological distress in childhood cancer survivors may be desirable during routine follow-up, and psychological support should be offered as needed.

The rise and fall of icons of 'stolen childhood' since the adoption of the UN Convention on the Rights of the Child

In the past two decades, the iconography of victimhood mobilized by child rights advocates has changed significantly. In particular, the child victim of violence has replaced the street child as the dominant icon on the international agenda. Based on data from more than 300 documents produced between 1989 and 2009 and interviews with leading advocates, this article explores the diverging trajectories of iconic child victims. It follows the traces of the successive translations of the idea of âeuro~stolen childhoodâeuro? and locates them against the backdrop of evolutions in the childrenâeuro?s rights field.

Exposure to radio-frequency electromagnetic fields from broadcast transmitters and risk of childhood cancer: a census-based cohort study.

We investigated the association between exposure to radio-frequency electromagnetic fields (RF-EMFs) from broadcast transmitters and childhood cancer. First, we conducted a time-to-event analysis including children under age 16 years living in Switzerland on December 5, 2000. Follow-up lasted until December 31, 2008. Second, all children living in Switzerland for some time between 1985 and 2008 were included in an incidence density cohort. RF-EMF exposure from broadcast transmitters was modeled. Based on 997 cancer cases, adjusted hazard ratios in the time-to-event analysis for the highest exposure category (>0.2 V/m) as compared with the reference category (<0.05 V/m) were 1.03 (95% confidence interval (CI): 0.74, 1.43) for all cancers, 0.55 (95% CI: 0.26, 1.19) for childhood leukemia, and 1.68 (95% CI: 0.98, 2.91) for childhood central nervous system (CNS) tumors. Results of the incidence density analysis, based on 4,246 cancer cases, were similar for all types of cancer and leukemia but did not indicate a CNS tumor risk (incidence rate ratio = 1.03, 95% CI: 0.73, 1.46). This large census-based cohort study did not suggest an association between predicted RF-EMF exposure from broadcasting and childhood leukemia. Results for CNS tumors were less consistent, but the most comprehensive analysis did not suggest an association.

Assessing the possible direct effect of birth weight on childhood blood pressure : a sensitivity analysis.

To estimate the possible direct effect of birth weight on blood pressure, it is conventional to condition on the mediator, current weight. Such conditioning can induce bias. Our aim was to assess the potential biasing effect of U, an unmeasured common cause of current weight and blood pressure, on the estimate of the controlled direct effect of birth weight on blood pressure, with the help of sensitivity analyses. We used data from a school-based study conducted in Switzerland in 2005-2006 (n = 3,762; mean age = 12.3 years). A small negative association was observed between birth weight and systolic blood pressure (linear regression coefficient βbw = -0.3 mmHg/kg, 95% confidence interval: -0.9, 0.3). The association was strengthened upon adjustment for current weight (βbw|C = -1.5 mmHg/kg, 95% confidence interval: -2.1, -0.9). Sensitivity analyses revealed that the negative conditional association was explained by U only if U was relatively strongly associated with blood pressure and if there was a large difference in the prevalence of U between low-birth weight and normal-birth weight children. This weakens the hypothesis that the negative relationship between birth weight and blood pressure arises only from collider-stratification bias induced by conditioning on current weight.

Parent-offspring similarity for childhood behaviorial inhibition and associations between inhibition and parental care

L'article constituant le présent travail de thèse décrit une recherche évaluant les similarités entre l'inhibition comportementale chez des enfants et leurs parents respectifs durant l'enfance, ainsi que l'association éventuelle entre l'inhibition et les attitudes parentales. L'inhibition comportementale - définie comme une prédisposition de l'enfant à réagir avec réticence et angoisse à des situations inhabituelles - est une caractéristique de tempérament qui apparaît tôt dans la vie et est relativement stable dans le temps. L'intérêt qui y est associé repose sur son association avec des conséquences développementales négatives pour l'individu: risque accentué chez les enfants d'inadaptation scolaire, de dysfonctionnement social et de sentiments de détresse; facteur de risque en ce qui concerne le développement ultérieur de troubles psychiatriques de l'adulte, dont les troubles anxieux en particulier. Nous avons dès lors investigué dans cette recherche 1) la présence d'une association entre l'inhibition comportementale actuelle des enfants et celle rétrospective de leurs parents, dans ses deux dimensions spécifiques, soit sociale (« peurs à l'école ») et non-sociale (« peurs générales »), et 2) si ces dimensions d'inhibition étaient associées au niveau de chaleur, d'affectivité et de soutien prodigués par les parents. C'est à partir de la récolte d'auto-questionnaires remplis dans le contexte d'une vaste étude initiée à Lausanne en 1994, que nous avons extrait un échantillon de 453 enfants scolarisés en 6/7ème années et 741 de leurs parents biologiques respectifs. Les analyses ont porté sur les auto-questionnaires évaluant, chez les enfants, leurs degrés d'inhibition comportementale, de symptomatologie psychiatrique actuelle et de perception de chaleur, d'affectivité et de soutien reçu de la part des parents, et, en ce qui concerne les parents, des auto¬questionnaires évaluant rétrospectivement leurs degrés d'inhibition comportementale durant l'enfance et de symptomatologie psychiatrique actuelle. La comparaison des scores des enfants avec ceux de leurs parents sur les échelles de l'inhibition comportementale (CSRCI-Child version of the Self-Report of Child Inhibition - et RSRI - Retrospective Self- Report of Inhibition -), montre la présence d'une similarité significative pour chacune des dimensions spécifiques, suggérant que les enfants de parents ayant présenté une inhibition comportementale dans l'enfance sont plus à risque d'en développer une à leur tour. Nous avons par ailleurs pu établir, au cours d'analyses complémentaires, que cette association se maintenait après l'ajustement des degrés de symptomatologie psychiatrique respectifs des enfants et de leurs parents, ce qui a permis d'écarter ce facteur confondant potentiel. Bien que la nature de cette association ne puisse être élucidée par cette recherche, le fait que la taille de l'effet soit modeste suggère qu'un rôle important dans le développement de l'inhibition soit joué par des facteurs environnementaux non partagés dans une famille. Un de ceux-ci semble suggéré par l'association négative qui apparaît dans cette étude entre le degré d'inhibition dans sa dimension « peurs à l'école » et l'attitude parentale: un bas niveau de chaleur, d'affectivité et de soutien perçu par l'enfant de la part de ses parents aurait ainsi une influence sur le développement de peurs en situations sociales en particulier. Alternativement, cette association négative pourrait suggérer que les peurs de l'enfant aient une influence négative sur le développement d'une attitude parentale de soutien ou, du moins, sur la perception de celle-ci par l'enfant. Il est aussi bien évidemment envisageable que ces processus interagissent dans une boucle de rétroaction. Seules des études longitudinales pourraient nous éclairer sur la nature de cette association. Quoi qu'il en soit, ce résultat présente un intérêt clinique pour orienter des interventions de prévention du développement de troubles psychiatriques chez des enfants inhibés, en proposant d'agir, soit directement sur les attitudes parentales, soit sur les peurs de l'enfant ainsi que sur les caractéristiques perçues par l'enfant de l'attitude parentale. Des études longitudinales sur les ressemblances entre les parents et leurs enfants concernant l'inhibition comportementale, incluant des études de jumeaux, d'enfants adoptés et de familles, sont nécessaires pour mieux comprendre les interactions entre les facteurs génétiques, familiaux et environnementaux dans le développement de l'inhibition comportementale des enfants.

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.

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis.

BACKGROUND: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. METHODS AND FINDINGS: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. CONCLUSIONS: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.