Dissertationen zum Thema „Pediatric growth“

Orientadores: Maria Beatriz Rocha Ferreira, Antonio de Azevedo Barros Filho
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O objetivo desta pesquisa é investigar o crescimento, a atividade física, a performance e a ingestão alimentar em 277 crianças de 8 e 9 anos de idade, residentes em Terra Indígena, zona urbana e rural no município de Nova Laranjeiras, Paraná. Este estudo caracterizou-se por ser transversal e foram avaliados: peso, estatura, dobras cutâneas, diâmetros ósseos e circunferências; tipos e quantidade de atividades físicas; testes de performance: salto horizontal, shuttle run, sentar e alcançar, sentar e deitar; tipos de alimentos e ingestão energético protéica; renda domiciliar e escolaridade. Os procedimentos estatísticos foram freqüência e percentual, para os tipos de alimentos ingeridos e tipos de atividades realizadas e ANOVA e MANOVA com transformação em postos (ranks) para comparar as características antropométricas, testes de performance, quantidade de atividade física e ingestão energético-protéica em função do fator local. As crianças indígenas foram classificadas em dois grupos ( < -2 escore z) e (> - 2 escore z) de estatura para idade para realização dos procedimentos acima mencionados. Os resultados indicam que as crianças residentes nas zonas urbana e rural têm maior peso, estatura, diâmetros, circunferências e dobras cutâneas do que as residentes na Terra Indígena após serem controlados pela idade, quando controlados pela idade peso e estatura estas três últimas variáveis puderam explicar pouco as diferenças entre as crianças das três zonas, com exceção das meninas indígenas em que a área muscular do braço foi maior e a soma das dobras cutâneas foi menor quando comparadas com as demais meninas. Os resultados do escore z de peso, estatura e área gorda do braço foram maiores para as crianças das zonas urbana e rural, exceto na área muscular do braço para ambos os sexos. Os alimentos ingeridos pelas crianças da zona urbana e rural são mais diversificados e apresentam maior teor energético-protéico, contudo nas três regiões não atendem necessidades energéticas recomendadas. As atividades jogos e brincadeiras são variadas nas três regiões e as laborais realizadas em maior número na Terra Indígena, já iniciando o aprendizado daquelas atividades que farão na idade adulta. Nos testes de performance, quando controlados pela idade, peso e estatura as diferenças ocorrem apenas naqueles de flexibilidade, com melhores resultados para as crianças indígenas e no teste de sentar e deitar para os meninos das zonas urbana e rural. Existe uma tendência de maior quantidade de atividade física diária, medida pelo acelerômetro para as crianças indígenas. As possíveis influências dos fatores genéticos, associados ao estilo de vida podem ser fatores explicativos nas diferenças de crescimento encontradas nesta pesquisa. O contexto, com características rurais, em que as crianças vivem, parece estar influenciando os resultados dos testes de performance. Em se tratando de forma específica das crianças indígenas, verifica-se que aquelas com possível déficit de crescimento tendem a apresentar menores resultados nas características sócio-econômicas, de atividade física, de performance e ingestão nutricional, sendo apenas a ingestão energética estatisticamente significativa. As características do contexto sócio-cultural estudadas parecem ser menos favoráveis para as crianças com possível déficit de crescimento, contribuindo para um desenvolvimento menos favorável, quando comparadas com as demais crianças
Abstract: The aim of this study is to investigate the growth, physical activity, performance and food intake in 277 children aged 8 and 9, residing in Indigenous land, in the rural and in the urban area of Nova Laranjeiras, the State ofParaná, Brazil. This was a cross-section study where weight; height; skinfold; bone diameter and circurnference; types and amount of physical exerci se; performance tests such as horizontal jump, shuttle run, sitting and reaching, and sitting and lying; types of food and protein energetic intake; income; and level of schooling were evaluated. The statistical procedures were frequency and percentage for the type of food eaten and the type of activity carried out. ANOVA and MANOVA, transformed into ranks to compare the anthropometrics characteristics, performance tests, amount of physical exercise, and protein and energy intake based on local factor function were used. The Native Indian children were classified into two groups « -2 score z) and (> - 2 score z) height related to weight, canying out the procedures mentioned above. In terms of age factor, the results indicate that the children living in the rural and in the urban area are heavier, taller, have greater bone diameter and circumference and more skinfolds than those living on Indigenous lands. In terms of age, weight and height factors, these three variables could little explain the differences between the children from the three areas, except for the Native lndian girls whose arm muscle area was greater, and whose sum of the skin folds was less when compared to the girls from the other areas. The results of weight, height and arm fat area z score were greater for the children from the urban and rural areas, except for the arm muscle area for both sexes. The food intake of the children from urban and rural areas is more diversified and presents greater protein energetic proportion; however all three areas do not fulfill the recommended energetic necessities. The activities, games and entertainrnent are varied in the three areas with the work related ones being more carried out in the indigenous lands, where training in the activities the children will be canying out as adults, is already started. In the motor performance tests, in terms of age, weight and height, the differences only occur in the flexibility tests with the Native Indian children presenting better results and in the sitting and lying where the boys from both urban and rural areas present better results. The Native Indian children tend to do more daily physical activity, which is measured by the accelerometer. The possible influences of the genetic factors associated to life-style can be the explanation for factors such as the growth difference found in this research. The context with rural characteristics in which the children tive, seems to be influencing the results of the performance test. When dealing specifically with Native Indian children, it was verified that those with a possible growth deficit are inc1ined to present lower results in the following aspects: socio-economica1 level, physical activity, performance, and nutritional intake, where on1y the energetic intake is statistically significant. The characteristics of the socio-cultural context studied seem to be less favorable for the children with a possible growth deficit, thus contributing to a less favorable development when compared to other children
Doutorado
Saude da Criança e do Adolescente
Doutor em Saude da Criança e do Adolescente

In the absence of readily available physiological models of human growth, the effects of oestradiol on the human C28/I2 chondrocyte cell line were studied. The classical oestrogen receptors, ERα and ERβ, were shown to be expressed in both murine and human chondrocyte cell lines. Oestradiol and related chemicals, which alter the function of the oestrogen receptors (ER), were exploited to tease out the different functions of each ER in the growth plate. In the absence of foetal bovine serum, oestradiol had no effect on proliferation, differentiation or apoptosis of chondrocyte cells in monolayer culture or on the growth of the foetal metatarsal culture system. In addition, oestradiol did not convey a protective effect on chondrocytes exposed to the pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in monolayer culture. However, endogenous oestrogen appears to play an important role in maintaining chondrocyte proliferation in monolayer culture and mineralisation in metatarsal culture as reflected by the inhibitory effects of Faslodex, the non-specific ER antagonist, on chondrocytes and metatarsals in culture. In the presence of methyl-piperidino-pyrazole (MPP), a selective ERα antagonist, and raloxifene, a selective oestrogen receptor modulator with higher ERβ binding affinity, a reduction in chondrocyte proliferation and increase in apoptosis was observed in murine and human chondrocytes. Similarly, a marked reduction in linear growth occurred when foetal murine metatarsals were exposed to MPP and raloxifene in combination. A less marked reduction in growth was observed in MPP-treated metatarsals. These findings suggest that the oestrogen receptors may have opposing actions in the growth plate with ERβ acting like a brake on chondrocyte growth and ERα promoting growth. ERβ may regulate cell proliferation through control of cell cycle modulators affecting G1/S phase transition as MPP and raloxifene in combination reduced cyclin E and p53 levels on Western blot analysis. The aim of the second part of my thesis was to investigate the effect of oral oestrogen on linear growth in girls with primary ovarian insufficiency (POI). A retrospective review of girls with POI treated at a tertiary endocrinology clinic over an 11 year period was performed. As expected the majority of girls with POI had Turner syndrome (TS; 83.7%). Non-TS associated POI was rare and the leading cause was iatrogenic secondary to the effects of total body irradiation for bone marrow transplantation (12.8%). A significant proportion of these girls developed POI after full pubertal development so few cases were available to investigate the effect of oestrogen on growth. The oral oestrogen regime followed in individual patients with TS was highly variable so it was not possible to assess the effects of dose on height velocity or bone maturation in this retrospective audit. However, the second clinical study examined in detail the effect of oestrogen on growth in TS girls who received a standardised course of oral ethinylestradiol for pubertal induction and a standard dose of growth hormone (10 mg/m2/week). These girls participated in a prospective randomised double-blind placebo-controlled multi-centre study of growth promoting treatment in TS. The girls were initially randomised to oxandrolone or placebo at 9 years of age and further randomised to oral ethinylestradiol at 12 or 14 years of age. The results of this study are embargoed until published. The laboratory effects of oestradiol found in this thesis suggest that ERα may stimulate or maintain growth, and ERβ may inhibit growth. The obvious question is how these observations might be involved in the complex relationship between puberty, oestrogen and height velocity in humans. As affinity studies show that the half maximal effective concentration (EC50) of ERα is achieved at slightly lower concentrations of oestradiol than ERβ it is conceivable that the ERα effect could predominate at lower systemic oestradiol concentrations and that ERβ could become more important at higher concentrations for example in later puberty. Alternatively, it is possible that the expression of ERα reduces or ERβ increases in the growth plate after reaching peak height velocity.

Background. Premature infants are at risk for many complications. Among these, growth failure and intermittent hypoxia (IH) can independently impact the outcomes of other comorbidities. Recent data suggest that IH may directly affect postnatal growth. Our study aims to evaluate the impact of IH on growth velocity in preterm infants. Methods. This prospective cohort study utilized inpatient oximetry, nutrition, and growth data to evaluate the relationship between IH and growth velocity. Enrolled infants were dichotomized by high- versus low-exposure to IH. This relationship was explored in both unadjusted analyses and generalized linear models with repeated measures. Results. The study population included 19 preterm infants, with average birth gestational age of 29 weeks, each contributing one or more measures of weekly data. Infants in the high-exposure cohort had lower birth weight, higher rates of bronchopulmonary dysplasia, and longer duration of respiratory support and caffeine treatment. The unadjusted analysis revealed a marginally significant trend towards higher IH rates during weeks of slower growth. The logistic regression with repeated measures analysis also supported increased odds of slower growth associated with higher IH rates, but this relationship was also only marginally significant. Conclusion. Our study suggests a relationship between exposure to IH and slower growth velocity in preterm infants. The prospectively collected data allowed for accurate measures of IH, growth, and nutrition, but the small sample size likely contributed to the lack of significance of our results.

Background: Metabolomics is a science aimed to identify and interpret the metabolic profiles of a given biological system, namely the products of interaction between gene expression and environment. Among the "omic" sciences, it can be considered the closest one to phenotype. The impact of growth and nutrition in the very early stages of life is a topic of great interest, considering not only the immediate effect on development, but also on lifelong health. Ensuring an adequate nutritional intake and growth is even more crucial in preterm babies. Intrauterine growth restriction (IUGR) and extrauterine growth restriction (EUGR) are two conditions in which the fetus and the newborn respectively, are not able to achieve their genetically determined potential size. Nowadays reliable biomarker to assess the suitability of nutritional status and growth in preterm infants are lacking. Aim of the study: The aims of this study are to analyse and compare the metabolomic profile obtained by: 1) preterm infants diagnosed with IUGR during pregnancy versus preterm infants adequate for gestational age (AGA); 2) preterm infants who experienced EUGR and preterm infants who did not. Material and Methods: This prospective observational study has been conducted at the third level Neonatal Intensive Care Unit (NICU) of Padova. Premature neonates born between 23 and 32 weeks post-menstrual age (PMA) have been enrolled. For each subject urine samples have been collected at three time-point: within 72 hours of life, at 21 +/- 3 days of life and at 36 +/-1 weeks PMA. The urine samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra- performance liquid chromatography. For each enrolled subject all relevant clinical data during NICU stay have been captured. IUGR was diagnosed through review of obstetrical history of the mother; EUGR was diagnosed when weight at 36 weeks PMA was <10th %ile of the predicted value. The data obtained were analysed using multivariate and univariate statistical analysis tools. Results: 160 infants have been enrolled, with a median gestational age at birth of 195 days (interquantiles range: 185-207 days). Only urine samples collected within the first 48 hours of life were analysed (n=83). Among these 15 were collected from IUGR infants and were matched with 19 from AGA infants (controls). Untargeted metabolomic revealed evident clustering of the IUGR neonates versus the AGA ones. The metabolic derangements mainly involved were metabolism of tryptophan-serotonin and biosynthesis of steroid hormones. The comparison of urine samples collected from 9 infants with EUGR and 10 controls did not show any discriminant variables. Conclusions: Neonates with IUGR showed a distinctive urinary metabolic profile at birth. Although data are still preliminary, metabolomics is proving to be a promising tool to explore biochemical pathways involved in impaired fetal and neonatal growth.

Orientador: Maria Aparecida Affonso Moyses
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Com o objetivo de identificar e discutir sinais e sintomas de disfunção temporomandibular presentes em crianças e adolescentes durante importante fase do crescimento e desenvolvimento crânio facial, foram selecionados pacientes adultos que não receberam atenção terapêutica necessária e que certamente selaram seu presente, muito diferentemente do que se tivessem sido tratados na infância, de forma preventiva e/ou interceptadora. São casos que possuem características múltiplas de colapso orofacial presente em vários tecidos, identificados como problemas de origem dental, periodontal, das articulações temporomandibulares, assimetrias esqueletais dos ossos da face, alterações na postura da cabeça e do pescoço e compensações musculares e ligamentares de todo o sistema estomatognático, com consequências nas funções da fala, respiração, mastigação, deglutição, digestão e postura corporal. Sintomas de desconforto e dor crônica, algumas vezes de caráter incapacitante, são comuns e presentes nesses pacientes. Por outro lado, selecionamos alguns casos de crianças com problemas semelhantes aos encontrados nos adultos estudados, porém com sinais e sintomas não tão evidentes. Desta vez, foram diagnosticadas e tratadas. Visamos com esse trabalho, alertar todos os profissionais das áreas afins, da importância da identificação precoce de sinais e sintomas que possibilitem uma ação terapêutica mais econômica, previsível e estável, quando comparados aos casos que se apresentam na clínica, após muitos anos, sem diagnóstico ou com uma visão apenas focada na resolução dos problemas locais, sem dar a devida importância para a abrangência de seu significado.
Abstract: The objective of this work is to identify and discuss signs and symptoms of temporomandibular disorders present in children and adolescents during the intensive phase of growth and craniofacial development. Adult patients were selected for this work, who did not receive the necessary therapeutic attention and care that certainly defined their present, very differently than if they had been treated in childhood, in a preventive and / or intercepting form. These are cases that have multiple characteristics of oral facial collapse present in various tissues, identified as problems of dental and periodontal origin, temporomandibular joint, skeletal asymmetry of facial bones, changes in posture of the head and neck, and natural ligament and muscle compensation for all of the stomatognathic system, involving consequences on speech, breathing, chewing, swallowing and digestion functions and body posture. Symptoms of discomfort and chronic pain, sometimes of incapacitating character, are common in these patients. Moreover, some cases of children with problems similar to those found in adults studied were selected, but with signs and symptoms that are not so evident. This time they were diagnosed and treated. We aim with this work, to alert all professionals of related areas about the importance of early identification of signs and symptoms to enable a more economical, predictable and stable therapeutic action when compared to cases that are presented at the clinic, after many years without diagnosis or with a vision only focused on solving local problems, without giving due importance to the scope of its meaning.
Doutorado
Saude da Criança e do Adolescente
Doutor em Saude da Criança e do Adolescente

Research indicates that children with Human Immunodeficiency Virus (HIV) / Acquired Immune Deficiency Syndrome (AIDS) display a variety of neuro-developmental, cognitive, motor and nutritional deficiencies (Epstein el al., 1986:678; Davis-McFarland, 2000:20; Blanchette et al., 2001:50). Research also substantiates a need for additional intervention strategies such as improved nutrition and exercise programmes to improve the quality of life for HIV-infected children (Brady, 1994: 18; Stein et al., 1995:3 1 ; Parks & Danoff, 1999:527). The maintenance of motor skills in above-mentioned children is an important objective for intervention programmes, especially gross motor skills (Parks & Danoff, 1999:525). Literature indicates that growth retardation, exhaustion of fat storage and neuro-developmental deficiencies are related to HIV/AIDS (Aylward et al., 1992:218; Miller & Garg, 1998:368; Davis-McFarland, 2000:20; Miller et al., 200 1 : 1287). The monitoring of growth status is of outmost importance as children with serious stunting and wasting run the risk of early death. Growth retardation can also be an indication of infection or fast disease progression (Bobat et al, 200! :209). The aim of this study was firstly to determine the state of the motor development of 2, to 6-year old children infected with HIV and to compare it with that of affected (in that they are not infected with HIV, but have lost one or both parents to AIDS-related diseases) and non-affected children. Secondly the study aimed to determine the effect of a motor intervention programme for 2 to 6-year old children infected with and affected by HIV. A third aim was to determine the growth status of 2 to 6-year old children infected with HIV and to compare it with that of affected and non-affected children; and the last aim was to monitor the developmental tendencies of body composition and growth of 2 to 6-year old children infected with HIV in the course of nine months and to compare it with that of affected and non-affected children. The Peabody Developmental Motor Scales-:! (PDMS-2) (Folio & Fewell, 2000), which consist of six subtests, was used to determine the motor development of the children. Regarding the growth status the children were subjected to a series of anthropometric measurements of height, weight, circumference (upper arm - both tonic and relaxed), as well as skin folds (triceps, sub-scapular, calf), in accordance with standard procedures as prescribed by the International Society of Advanced Kinanthropometry (ISAK). The data was analysed using Statistica for Windows (Statsoft-, Inc S.A., 2001) and SAS (2000- 2003). Descriptive statistics were used to determine means (M), standard deviations (SD) and maximum and minimum values. One-way variance of analysis, forward stepwise discriminant analysis, independent T-testing, dependant T-testing and an ANCOVA, repeated measures ANOVA, and Bonferroni post hoc analysis were used to analyse the data in accordance with the above-mentioned aims. The level of statistic significance was set at p<0,05. Practical significance of differences (ES) between the testing sessions was calculated by dividing the mean difference (M) between the two testing sessions by the largest standard deviation (SD), as recommended by Cohen (1988) and Steyn (1999). Cohen (1988) set the following guidelines for interpreting practical significance, namely ES = 0,2 (small effect); ES = 0,5 (medium effect) and ES = 0,8 (large effect). Due to the small number of subjects it was considered practically significant if this effect size indicated a medium and larger effect. From the results of the study it seemed that the HIV-infected children performed the poorest of the groups regarding gross motor, fine motor and total motor skills. This group's gross motor skills showed larger deficits than their fine motor skills, while loco-motor skills contributed the most to the discrimination between the groups. The motor intervention programme led to a statistically significant improvement in loco-motor, fine motor, as well as total motor skills. The infected children showed better improvement compared to the affected children. The infected group displayed the poorest growth status of the three groups compared to the Centre for Disease Control (CDC) growth profiles, although they did not differ significantly from the affected children. The infected children differed significantly regarding height percentile, fat percentage and height-for-age 2-score (HAZ) from non-affected children. The infected group also displayed the least significant effects in the form of growth increases over the nine months monitoring period. It can be concluded from the results that motor deficiencies and growth impediments are part OF the life of HIV infected children. To address these problems, intervention strategies, such as motor intervention and nutrition programmes are needed.
Thesis (Ph.D. (Human Movement Science))--North-West University, Potchefstroom Campus, 2008.

Childhood onset growth hormone deficiency (CO-GHD) may contribute to low bone mass and alterations to body composition. This thesis consists of a series of studies utilising dual-energy X-ray absorptiometry (DXA), peripheral quantitative computerized tomography (pQCT) and biochemical assessment of bone health and body composition of CO-GHD. In addition, metabolic profiles, glucose metabolism as well as quality of life have been studied in these subjects. Furthermore, an interventional study of weight bearing exercise (WBE) was performed to explore its role in influencing the bone health of children and adolescents with CO-GHD. Chapter 1, relevant literature reviews explore: bone structure, growth, development and strength; GH/IGF-1 system and its actions; CO-GHD and its impacts during childhood and transition; and WBE and its mechanism and impacts on bone health. Chapter 2 presents the rationale and specific aims of this thesis. Chapter 3, a retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005-2013 were reviewed. Of the 130, 74/130(57%) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74(82%) remained GHD with 51/74(69%) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Despite clinical guidelines, there was significant variation in the management of CO-GHD in young adulthood across Scotland. Chapter 4, a cross-sectional control study of bone DXA measurements in (n=21) subjects with CO-GHD treated with rhGH and had attained final height from 2005 to 2013 in a single tertiary paediatric centre compared to (n= 21) heights/age matched healthy controls. By applying different models of DXA adjustment, our analysis revealed lower TB-BMC for bone area in males with CO-GHD and lower LS-BMAD SDS in females with CO-GHD compared to matched controls. In addition, subjects with CO-GHD had lower LM for height and higher FM for height compared to controls, and this was more pronounced in males than females (p=0.04). The time of onset and aetiology of CO-GHD have a larger influence on accrual of bone mass in these patients. These findings indicate that adolescents with CO-GHD have a low bone mass, despite prior long term rhGH replacement therapy. In chapter 5, we investigated bone health of subjects with CO-GHD at time of initial evaluation and retesting at final height. A total of 25 children (first time assessment group) undergoing GH stimulation tests for investigation of short stature (naive GHD-15, normal-10), and 11adolescents with CO-GHD (retesting group) undergoing biochemical re-evaluation at final height after withdrawal of rhGH therapy (persistent GHD-7, GH-sufficient-4) were recruited from Royal Hospital for Children between 2012-2013. By using further bone health assessment methods in addition to DXA (including p.QCT, mechanography, bone profiles and biomarkers), the bone density and body composition did not differ when we compared GHD to matched height but normal GH at initial evaluation and retesting. However, naive GHD had lower muscle force as assessed by mechanography compared to the normal. In addition, bone resorption biomarker CTX was significantly higher in naive GHD vs. normal and that was significantly correlated to PTH levels in both first time assessment and retesting groups. Our results suggest that muscle force and serum PTH may be important determinants of bone health in subjects with CO-GHD. Chapter 6 investigates lipids, adipokines (leptin- adiponectin- resistin) and glucose homeostasis and their relationship with bone and body composition in children and adolescents with CO-GHD at times of initial evaluation and retesting at final height (same population as chapter 5). Lipid profiles, adipokines and glucose homeostasis were not different between those with GHD and those who had normal GH levels across the groups of first time assessment and retesting. In the retesting group, those who were older at the time of diagnosis of CO-GHD with a shorter duration of rhGH therapy were more likely to have higher cholesterol(r=0.9, p<0.001), leptin (r=0.8, p<0.001), and lower osteoclacin (r=-0.7, p=0.01) at final height. Leptin levels correlated positively with osteocalcin at diagnosis (r=0.51, p=0.01) but inversely at retesting (r=-0.91, p<0.01). The conclusion was that the timing and duration of childhood rhGH therapy might influence adiposity parameters and bone metabolism in subjects with CO-GHD. In chapter 7 the study participants of chapter 5 were asked to complete either Short Form-36 (SF-36) or Adult Growth Hormone Deficiency Assessment (AGHDA) quality of life (QoL) questionnaires at the time of assessment of their GH axis. Our analysis showed that the overall QoL was not altered in children with naive GHD with a total score of SF-36 [93 (77, 96) naive GHD vs. 90 (84, 93) normal, P=0.56] (higher scores reflect better QoL). However, naive GHD had less energy and vitality scores compared with normal (75 (65, 100) vs. 95 (65,100) respectively, p=0.04), when the normal scored lower in the subscale of emotional well-being compared to those with naive GHD (78 (55, 84) vs. 90 (68, 96) respectively, p<0.001). In the retesting group, those with persistent GHD scored better in the AGHDA than GH sufficient (6 points (2, 8) vs. 9 points (7, 17) respectively, though not significant (p= 0.10) (higher scores reflect poorer QoL). Unexpectedly, subscale analysis showed that GH-sufficient subjects significantly lacked energy and complained of tiredness compared to those who were confirmed to have persistent GHD (5 points (3, 6) vs. 1 point (0, 1) respectively, p= 0.03). Further studies to validate QoL specific instruments in this population are needed with greater insight to elucidate factors that modify the relationship between GH status and QoL in children and adolescents. Chapter 8 was a prospective intervention, randomised controlled study of 14 subjects among the first time assessment group (GHD-10, normal-4) and five subjects with CO-GHD among retesting group (persistent GHD-4, GH-sufficent-1). Subjects were randomised into either an exercise intervention group (EX) (25 jumps off 25 cm platform step/three days/week for six months) or a control, in addition to rhGH being prescribed. The results of this study were limited by the small sample size and poor compliance. Therefore, there were insufficient data to recommend the use of weight bearing exercise in the absence of rhGH in children and adolescents with CO-GHD. Further studies with adequate sample size that can more rigorously exam the optimal exercise interventions are needed. Chapter 9 discusses the main findings of each chapter in this thesis and outlines potential limitations of the thesis methodology, and some important and interesting areas for future research in children and adolescents with CO-GHD.

Resumo: Introdução: A Retinopatia da Prematuridade (ROP) é uma doença que ocorre na retina incompletamente vascularizada de recém-nascidos prematuros e que constitui causa importante de cegueira na infância. Recentemente foi demonstrado que os baixos níveis séricos de insulin-like growth factor I (IGF-I) estão associados à ROP ao interferir com o desenvolvimento vascular da retina humana. Objetivos: (a) caracterizar a ROP em recém-nascidos de muito baixo peso quanto à prevalência e fatores de risco; (b) determinar os níveis séricos de IGF-I nestes recém-nascidos e (c) avaliar a influência dos níveis séricos de IGF-I sobre a ocorrência de ROP. Métodos: Estudo longitudinal, observacional e prospectivo, que incluiu recém-nascidos com peso de nascimento < 1500 g e idade gestacional < 34 semanas, admitidos nas primeiras 24 horas de vida. Amostras de sangue foram obtidas a partir do cordão umbilical ao nascimento e do material excedente nas coletas para outros exames laboratoriais durante a internação hospitalar. Resultados: Entre março/2004 e agosto/2005 foram incluídos 60 recém-nascidos, cuja média de idade gestacional foi de 29,15 + 1,87 semanas e de peso de nascimento de 1087,08 + 197,62 g. Treze (21,67%) pacientes receberam o diagnóstico de ROP. Na análise univariada, mostraram-se associados ao risco de ROP: a menor idade gestacional e peso ao nascimento; a menor freqüência de acompanhamento pré-natal; a maior freqüência do diagnóstico de SDR, de asfixia perinatal, de 5 ou mais episódios de infecção e de HPIV; os maiores tempos totais de oxigenioterapia e suporte ventilatório; o uso mais freqüente de surfactante e de dexametasona; a idade mais precoce da primeira e mais tardia da última hemotransfusão; a permanência mais prolongada em NPT e o menor ganho ponderal pós-natal. Destes, apenas a idade gestacional ao nascimento mostrouse significativa para o risco de ROP após análise de regressão logística multivariada (OR = 0,32 IC 95% = 0,10 - 0,92, p = 0,04). Os níveis séricos de IGF-I apresentaram uma diminuição significativa após o nascimento, atingindo valores mínimos na 1ª semana de vida, com elevação progressiva após a 2a semana de vida. As concentrações de IGF-I foram significativamente maiores na 4a semana de vida no grupo sem ROP (16,00 g/L), quando comparado ao grupo com ROP (8,00 g/L, p = 0,01). No grupo com ROP não se observou elevação significativa dos níveis de IGF-I após o nascimento, com medianas de IGF-I de 8,00 g/L, 13,50 g/L, 10,00 g/L, 8,00 g/L e 13,00 g/L, respectivamente na 1ª, 2ª, 3ª e 4ª semanas de vida e após o 28º dia de vida. Já no grupo sem ROP houve elevação significativa dos níveis de IGF-I ( 7,50 g/L, 10,00 g/L, 13,50 g/L, 16,00 g/L e 19,00 g/L, respectivamente, p = 0,001). A concentração sérica de IGF-I na 4ª semana de vida mostrou-se significativa para o risco de ROP na análise de regressão logística multivariada (OR = 0,78 IC 95% = 0,61 a 0,97, p = 0,04). O risco relativo de ROP quando as concentrações séricas de IGF-I na 4a semana de vida eram < 13 g/L foi de 2,70 (IC 95% = 1,11 a 6,59). Conclusões: A prevalência de ROP em recém-nascidos de muito baixo peso foi de 21,67%. A idade gestacional ao nascimento e a concentração sérica de IGF-I na 4a semana de vida foram os fatores de risco mais importantes para ROP. Os níveis séricos de IGF-I aumentaram nas primeiras semanas de vida nos recém-nascidos sem ROP, o que não ocorreu nos recém-nascidos com ROP. Menores concentrações séricas de IGF-I e a ausência de aumento destas após o nascimento parecem estar relacionadas à ROP.

Down syndrome (DS) is associated with psychomotor retardation, short stature and endocrine dysfunction. Statural growth is a well-known indicator of health. The growth in DS differs markedly from that of other children and there is a 20 cm reduction of final height as compared to target height. We developed growth charts specific for Swedish children with DS, in order to facilitate early diagnosis of concomitant diseases that influence growth. The growth charts are available for paediatricians and child health care professionals in Sweden. The mechanism underlying the impaired growth in DS is unknown. Height is influenced by parental factors, energy intake, hormone balance and general health. In DS, genetic factors deriving from the extra chromosome 21 further affect growth. Children with DS seem to have reasonable levels of growth hormone (GH), even though GH treatment for limited periods of time improves growth velocity. Within the present project, the subjects of a previous study on early GH therapy in DS were followed up regarding late effects. We found a larger adult head circumference and better psychomotor abilities in the previously treated subjects despite a lack of effect on final height. In adult life, GH has effects on psychological well-being and metabolism. The clinical features in adults with DS might indicate impaired GH secretion. Ten young adults with DS were studied and compared with ten healthy controls. The GH secretion in the DS subjects did not differ from that in the controls. The fat body mass percentage was increased in DS, in line with the high prevalence of overweight/obesity. The finding of an increased HOMA index as well as a high relative rate of hepatic glucose production in DS indicates reduced insulin sensitivity both peripherally and in the liver. Thyroid dysfunction is common in DS. There is a 30-fold increase in congenital hypothyroidism, and acquired hypothyroidism has been reported to be present in up to 50% of adults with DS. We collected neonatal screening results and hospital records for the first ten years of life of 68 children with DS. The mean TSH concentration was increased neonatally, indicating marginal hypothyroidism early in life in DS. However, the neonatal TSH level did not predict development of manifest hypothyroidism later in life.
Downs syndrom (DS) är en vanlig kromosomavvikelse. Kortvuxenhet och psykomotorisk utvecklingsstörning är kardinaltecken vid DS. Endokrina avvikelser är också frekvent förekommande. Tillväxt är en bra indikator på barns hälsa. Nyfödda barn med DS är kortare än andra nyfödda, och skillnaden i längd ökar under barndomen. Sjukdomar som påverkar tillväxten upptäcks ofta via ett förändrat tillväxtmönster. Detta kan lätt förbises vid DS eftersom tillväxten redan är avvikande. Användning av syndromspecifika tillväxtkurvor ökar möjligheterna till diagnostik av sjukdomar som stör längdtillväxten. Vi har framställt tillväxtkurvor för barn med DS, vilka finns tillgängliga inom svensk barnsjukvård och barnhälsovård. Längdtillväxt styrs av nedärvda faktorer från föräldrarna liksom av nutrition, hälsa och hormoner. Genetiska faktorer, kopplade till kromosom 21, kan påverka tillväxten vid DS, men tillväxtstörningens exakta bakgrund är inte känd. I vuxen ålder är personer med DS ungefär 20 cm kortare än förväntat med hänsyn till föräldralängder. Trots att barn med DS har relativt normala nivåer av tillväxthormon (STH eller GH) förbättras deras tillväxt vid STH-behandling. Inom avhandlingsarbetet följde vi upp ungdomar med DS, vilka behandlats med STH i tidig barndom. Vi kunde påvisa större huvudomfång samt förbättrad kognitiv och motorisk förmåga, trots avsaknad av effekt på slutlängden. Tillväxthormon har i vuxen ålder effekt både på ämnesomsättning och psykologiskt välbefinnande. Vuxna individer med DS uppvisar flera tecken förenliga med STH-brist. Vi jämförde tio unga vuxna med DS med tio friska kontrollindivider avseende förmågan att insöndra STH. STH-insöndringen hos individerna med DS skiljde sig inte från den hos kontrollerna. Vid samtidig undersökning av kroppssammansättning påvisades en ökad andel kroppsfett hos individerna med DS, resultat i linje med den frekventa förekomsten av övervikt/fetma. Individerna med DS hade en förhöjd glukosproduktion, som tillsammans med ett ökat HOMA-index talar för förekomst av minskad insulinkänslighet både på levernivå och perifert. Brist på sköldkörtelhormon är mycket vanligt vid DS och upp till hälften av vuxna med DS kan ha hypotyreos. Vi studerade 68 barn med DS avseende nivåer av tyroideastimulerande hormon (TSH) vid PKU-provtagning. Vi följde också barnens journalhandlingar från de tio första levnadsåren i syfte att undersöka om den neonatala TSH-nivån kan prediktera framtida underfunktion av sköldkörteln. Resultaten visade att barn med DS har en förhöjd nivå av TSH neonatalt, vilket indikerar en brist på sköldkörtelhormon redan i nyföddhetsperioden, men nivån förutsäger inte utveckling av manifest hypotyreos senare under barndomen.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma in childhood and arises as a consequence of regulatory disruption of the growth and differentiation pathways of myogenic precursor cells. RMS are divided in two main subgroups on the basis of histology: alveolar (ARMS) and embryonal (ERMS). ARMS, which is associated with a relatively high frequency of metastatic disease and needs an intensive therapeutic regimen, is the rhabdomyosarcoma subtype that carries the poorest prognosis. It comprises the 20% of patients and is characterized by specific chromosomal translocations, t(2;13)(q35;q14) and t(1;13)(p36;q14), that originate abnormally regulated fusion protein PAX3- and PAX7-FKHR, respectively. In contrast to ARMS, ERMS occurs at younger age, has a better prognosis and it is associated with an 11p15.5 loss of heterozygosity (LOH) and it comprises 80% of all RMS. Nowadays, the detection of genetic imbalances is used for a correct and rapid diagnosis of RMS subtypes, but prognostic biomarkers and factors that increase patient’s survival are not known. Recently, expression of Anaplastic Lymphoma Kinase (ALK) has been observed in RMS, but its role has not been investigated. ALK is a receptor tyrosine kinase (RTK) described as the constitutively active fusion protein in different tumors and, as membrane protein, in neurons of the central and peripheral nervous system at late embryonic stages. Recently ALK was also found in other malignant cancers, such as glioblastomas and neuroblastomas, associated to genetic aberrations, such as amplifications or point mutations. ALK has an extracellular ligand-binding region, a transmembrane-spanning domain and a kinase catalytic region. ALK is known to be activated through autoactivation in vitro, as the other RTK, in which ligands induce dimerization that results from conformational changes in the active site and lead to autophosphorylation with activated downstream signalling pathways, critical for cell proliferation and survival. However, the growth factor to enforce ALK dimerization and activation is still unknown, althought recently pleiotrophin (PTN) and midkine (MK) were proposed to be the physiological ligands. In this study we evaluated the biological and preclinical relevance of ALK in RMS, given that ALK has been originally described in RMS cell lines, but its function has not been studied. ALK expression was evaluated in 9 RMS cell lines, 4 ERMS and 5 ARMS, by Real Time PCR and western blotting, and we found that ALK expression level is higher in alveolar RMS cells having PAX-FKHR gene. Furthermore no basal self-activation of ALK was detected, suggesting that ALK is constitutively inactive differently from the fusion protein NPM-ALK in ALCL or EML4-ALK in NSCLC, therefore its dimerization is ligand-dependent. Our data suggest that PTN and MK failed to activate ALK in RMS cell lines, indicating different regulatory mechanisms. In fact we do not observe neither tyrosine phosphorylation in kinasic domain of ALK or activation of the signalling pathways downstream of the receptor. To elucidate the role of ALK in RMS, we used an agonist monoclonal antibody (mAb16-39) against the extracellular domain to induce dimerization. Stimulation of RMS cells markedly induces the phosphorylation of ALK and of proteins involved in cell proliferation and survival (MAPK; PI3K/AKT). ALK inhibition decreased tyrosine phosphorylation of ALK and of signalling pathways, which increased programmed cell death (apoptosis) and cell cycle arrest. In conclusion, ALK function is still unknown in RMS, althought our data suggest an important role in RMS tumorigenesis.
Il rabdomiosarcoma (RMS) è il più comune sarcoma pediatrico dei tessuti molli che si sviluppa come conseguenza dell’alterazione dei pathways che controllano la crescita e la differenziazione dei precursori del tessuto muscolare striato. Il RMS presenta due principali sottotipi istologici: il rabdomiosarcoma alveolare (ARMS) ed embrionale (ERMS). Il RMS alveolare è associato ad una più spiccata tendenza alla disseminazione, necessita di un regime terapeutico più aggressivo e presenta una prognosi sfavorevole. Comprende circa il 20% dei casi ed è caratterizzato da traslocazioni cromosomiche specifiche, t(2;13)(q35;q14) e t(1;13)(p36;q14), le quali danno origine alle proteine di fusione PAX3-FKHR e PAX7-FKHR, rispettivamente. A differenza degli ARMS, i RMS embrionali costituiscono l’80% dei casi, sono più frequenti nei bambini più piccoli, sono associati a perdita di eterozigosi al locus 11p15.5, ma hanno una prognosi migliore. Attualmente, l’analisi di alterazioni genetiche è usata per una corretta e rapida diagnosi dei RMS, anche se non sono ancora stati trovati fattori e biomarkers prognostici che possano essere utilizzati per incrementare la sopravvivenza dei pazienti. Recentemente è stata descritta l’espressione delle chinasi ALK nei RMS, ma il suo ruolo rimane sconosciuto. ALK è un recettore tirosin-chinasico (RTK) descritto come proteina di fusione costitutivamente attiva NPM-ALK nei linfomi anaplastici (ALCL) e come proteina di membrana è espressa nei neuroni del sistema nervoso centrale e periferico durante lo sviluppo embrionale. Recentemente ALK è stato descritto anche in diversi tumori maligni, come nel glioblastoma e nel neuroblastoma frequentemente associato ad aberrazioni geniche quali amplificazioni o mutazioni puntiformi. ALK è costituito da una regione extracellulare in cui si legano i substrati, un dominio trans-membrana e un dominio chinasico catalitico. Come per altri RTK, l’attivazione di ALK necessita di una dimerizzazione ligando-dipendente, in cui i domini chinasici si fosforilano a vicenda e attivano vie di segnale critiche per la proliferazione e sopravvivenza cellulare, come MAPK ERK1/2 e PI3K AKT. I fattori di crescita che determinano la dimerizzazione e l’attivazione di ALK sono ancora sconosciuti, anche se recentemente sono stati proposti pleiotropina (PTN) e midkine (MK) come possibili ligandi. In questo studio, abbiamo valutato la rilevanza biologica e pre-clinica di ALK nei RMS, dal momento che è stato descritto per la prima volta in linee cellulari di RMS, ma la sua funzione non è mai stata studiata. L’espressione di ALK è stata valutata in 9 linee cellulari di RMS, 4 ERMS e 5 ARMS, mediante Real Time PCR e western blotting, osservando che ALK è maggiormente espresso nelle linee di RMS alveolare che esprimono l’oncogene PAX-FKHR. Tuttavia, ALK risulta inattivo nelle cellule di RMS, a differenza di NPM-ALK negli ALCL o di EML4-ALK in NSCLC, e per la sua attivazione necessita di una dimerizzazione ligando-dipendente. I risultati ottenuti nel nostro laboratorio indicano però che PTN e MK non sono in grado di attivare ALK nelle linee cellulari di rabdomiosarcoma suggerendo meccanismi di regolazione diversi da quelli finora descritti. Infatti non si osservano né la fosforilazione a livello delle tirosine presenti nel sito chinasico né l’attivazione delle vie di segnale. Per capire il ruolo di ALK, è stato quindi utilizzato un anticorpo monoclonale agonista (mAb16-39) in grado di legarsi al dominio extracellulare di ALK e stimolarne la dimerizzazione. In queste condizioni, è stato possibile osservare un aumento della fosforilazione di ALK e di proteine implicate nei fenomeni di proliferazione e sopravvivenza cellulare tumorale (MAPK; PI3K/AKT). L’inibizione di ALK determina una diminuzione della fosforilazione di ALK, e della trasduzione del segnale che risulta in un aumento della morte cellulare programmata (apoptosi). In conclusione il ruolo di ALK nei RMS rimane ancora largamente sconosciuto, anche se i nostri dati sembrano suggerire un ruolo importante di ALK nella tumorigenesi del RMS.

Background: Extensively hydrolyzed formula (eHF) is the first-line therapy in cow’s milk protein allergy. Aims of the study: We studied growth and plasmatic protein profile, depending on the different formula employed. Materials and methods: We selected 40 children with cow’s milk protein allergy. Diagnosis was made by skin prick test and double-blind placebo-controlled food challenge. Children were fed with soya protein-based or hydrolyzed rice protein-based or extensively hydrolyzed casein formula. The sample was analyzed at the 6th (t0) and 12th (t1) months of life: anthropometric parameters, plasmatic levels of total proteins, albumin, prealbumin, and retinol binding protein were collected. Results: The comparison among the groups fed with the different formulas didn’t show a gap of weight z-score, length z-score and BMI z- score at t0 and t1. We found a positive trend of growth in children fed with rice protein-based formula. The plasmatic protein profiles among the three groups weren’t statistically different (p<0,05). The mean of plasmatic level of pre-albumin of the two groups fed with eHF is higher than the one of the group fed with soya protein-based formula, especially rice protein-based formula at t0. Conclusions: Children fed with eHF show a positive trend of weight z-score rise. So hydrolyzed proteins could give a nutritional qualitative benefit. Each formula ensures a good growth, but no one is the best, in spite of a positive trend of eHF, especially the rice-based one.

Background: Infants of diabetic mothers (IDM) are at increased risk for the development of obesity and metabolic syndrome (MS) in childhood. Maternal obesity, fetal macrosomy and early acceleration of postnatal growth may be additional risk factors. Objective: Aim of present study is to assess whether an increased weight gain can be detected in IDM and to define which biochemical markers of metabolism in the newborn and anthropometric parameters in the first year of life can be used to identify those IDM that are most subject to growth acceleration. Design/Methods: 56 infants of daibetic mothers both non insulin-treated (NIT-GDM) and insulin-treated (IT-GDM) have been recruited. Each newborn has been assessed for metabolic and nutritional status (Glycaemia, Electrolytes, Blood Urea Nitrogen, Retinol Binding Protein [RBP], Cholesterol, Triglycerides Total Fatty Acids) at 4+1 days of life. Anthropometric measurements (weight, length, head circumference, waist circumference, tricep skinfold) have been taken in the first year of life (at birth, 1, 3, 6 and 12 months). The most well known risk factors for obesity and MS in childhood and most frequent morbidities of GDM on fetus and newborn have been studied. Results: Premature NIT-GDM, at term NIT-GDM, premature IT-GDM and at term IT-GDM have been compared. Growth pattern has shown to be consistent with normal growth curves of the paediatric population. A greater weight gain in IT-GDM compared to NIT-GDM infants has been found. A reduced incidence of short term most frequent complications of ODM has been found in our sample, compared to literature reports. Greater values of RBP have been detected in IT-GDM infants (p=0.049). Also, RBP values appear to be positively correlated with parameters of waist circumference at 6 and 12 months and weight at 6 and 12 months (p=0.004; R2 0.19). Lipid metabolism was not found to be modified by insulin treatment, and it was not related to growth parameters at any age. Conclusions: The normality of growth parameters and the low incidence of complications in the short term are likely due to effective implementation of monitoring protocols and prevention in pregnancy and early neonatal period. The laboratory data support other findings according to which RBP can be used to identify those subjects that are at increased risk of developing MS in childhood and that are especially in need for an early nutritional intervention.

L’os est un matériau dont les propriétés évoluent tout au long de la vie en fonction des contraintes environnementales. Aujourd’hui, les modalités d’imagerie permettent aux cliniciens d’évaluer la qualité osseuse chez l’adulte. Malheureusement, ces outils diagnostics ne sont pas adaptés pour l’enfant (nocivité des radiations, anesthésie ou sédation nécessaire), et le développement d’un outil clinique nécessite une bonne connaissance des propriétés du tissu osseux pédiatrique.Peu d’études ont analysé les propriétés du tissu osseux au cours de la croissance. Cette pénurie de données de référence s’explique par la faible quantité d’échantillons disponible pour les essais en laboratoire et par la qualité même de ces échantillons pour la plupart «prélevés» et associés à une pathologie de l’enfant.Les objectifs de ce travail de thèse s’inscrivent dans une logique de compréhension des mécanismes et des propriétés de l’os en croissance. L’intérêt majeur de ce travail est donc d’apporter de nouvelles connaissances sur l’os cortical pédiatrique. Les propriétés mécaniques et tissulaires ont été étudiées via l’utilisation de diverses techniques: la microtomographie, la microradiographie, la FTIRM, la biochimie, la compression, la caractérisation ultrasonore et la nanoindentation. Ce travail a permis de mettre en avant l’évolution de l’os cortical pédiatrique vers un état mature: la structure des fibres de collagène se hiérarchise, le tissu se minéralise. Ces changements dans la structure du tissu osseux lui permettent de se rigidifier. Ces travaux de thèse ont permis de mieux comprendre cette évolution, et vont permettre d’avoir une 1ère base de données sur la fibula infantile
Bone is a material whose properties change throughout life depending on environmental constraints. Today, imaging modalities allow clinicians to assess bone quality in adults. Unfortunately, these diagnostic tools are not suitable for children (harmful radiation, anesthesia or sedation required). Development of a clinical tool requires a good knowledge of pediatric bone tissue properties.Few studies have analyzed the properties of bone tissue during growth. This lack of reference data is due to the small amount of samples available for laboratory testings and the quality of these samples for the most taken and associated with a child's illness.The aims of this thesis are to understand the growing bone. The major interest of this work is to provide new knowledge on pediatric cortical bone. Mechanical, structural and chemical properties have been studied by the use of various techniques: tomography, microradiography, FTIRM, biochemistry, compression, ultrasonic characterization and nanoindentation.This work allowed to highlight that pediatric cortical bone evolves into a mature state: maturation of collagen cross-links, mineralization of bone tissue. These changes in the structure of the bone allows it to stiffen. This work allows to understand this evolution and will enable to have a first database on child fibula

Les données de la littérature concernant la tolérance à long terme du traitement par hormone de croissance (GH) recombinante sont très réduites. L’objectif du travail rapporté dans cette thèse porte sur l’analyse de la morbidité chez 6874 patients de l’étude SAGhE traités en France dans le cadre d’un déficit idiopathique en GH ou d’une petite taille constitutionnelle, avec les 3 axes de travail suivants : Risque neurovasculaire : Utilisant des données de référence issues de 2 registres de population, nous avons montré une augmentation du risque d’accident vasculaire cérébral (SIR à 3.5 ou 4.4 selon le registre considéré), et plus particulièrement d’hémorragies sous-arachnoïdiennes (SIR 5.7 ou 6.3). Risque de diabète : Utilisant les prescriptions d’antidiabétiques fournies par le SNIIRAM au sein de notre cohorte, nous n’avons pas mis en évidence d’augmentation de la prévalence du diabète traité (SPR 1.0). Risque de cancer : En comparaison au registre de référence du réseau FRANCIM, il n’y a pas de différence significative dans le risque de survenue d’un cancer (SIR 0.7). En revanche, le risque de développer une tumeur osseuse est 3.5 fois plus élevé chez les sujets exposés à l’hormone de croissance dans l’enfance. Les évènements ont été identifiés à partir de trois sources : a) RNIPP et CépiDC pour la connaissance du statut vital et les causes de décès si le sujet est décédé, b) Questionnaire de santé envoyé aux sujets non décédés, c) Données SNIIRAM à partir d’une extraction spécifique basée sur les identifiants des sujets de notre cohorte, permettant d’obtenir les codes CIM-10 des déclarations d’Affection Longue Durée, les codages PMSI entre 2008 et 2010 correspondant aux hospitalisations, et les prescriptions d’antidiabétiques
The literature is scarce regarding the long term effect of synthetic growth hormone (GH) treatment. The objective of this thesis was to analyse the morbidity of 6874 patients from the French SAGhE study treated by GH for short stature, focusing on three themes: Neurovascular risk: Using two population-based registries, we showed an increase in the risk of stroke (SIR 3.5 to 4.4 according the registry used), more specifically for the subarachnoid hemorrhage (SIR 5.7 or 6.3). Risk of diabetes : Using the antidiabetic drugs deliveries obtained from the French national health insurance database, no difference in the risk of treated diabetes was found (SPR 1.0). Risk of cancer : Compared with the French population-based registries of cancer, no significant difference in the risk of cancer was found (SIR 0.7), but the excess risk for bone tumor is 3.5 . Events were identified from three sources : a) Information on vital status collected from the Répertoire National d’Identification des Personnes Physiques and cause of death as indicated on death certificate, b) Health questionnaire sent to all living patients, c) Data extracted from the French national health insurance information, including the French hospital discharge database, also called Programme de Médicalisation des Systèmes d’Information from 2008 to December 2010, long-lasting affection statements, and antidiabetics drugs deliveries

Le nombre d'adultes porteurs de cardiopathies congénitales, de plus en plus sévères est constante progression. A moyen voire long terme certain d’entre eux posent des problèmes d’insuffisance cardiaque et de troubles du rythme parfois létaux. La physiologie de ces complications est multi factorielle et s’écarte souvent des schémas habituels. L’asynchronisme ventriculaire présentent chez un nombre important d’entre eux est connu pour favoriser un remodelage ventriculaire conduisant à l’insuffisance cardiaque sur cœur sain.Dans ce travail en couplant données expérimentales animales et études cliniques, nous avons étudié : 1) l’impact aigu puis chronique de la resynchronisation biventriculaire sur un modèle animal d’insuffisance cardiaque droite mimant la tétralogie de Fallot et sur une population de patients ; 2) le rôle et la conséquence d’une stimulation conventionnelle sur une physiologie de ventricule droit systémique ; 3) l’effet délétère de la stimulation VD prolongée sur un modèle de cœur animal en cours de développement.Nous avons appris que 1) la resynchronisation biventriculaire permet un bénéfice hémodynamique significatif chez l’animal mais aussi sur une population de Fallot implantées ; 2) que l’asynchronisme généré par la stimulation conventionnelle est délétère pour la fonction du ventricule systémique mais aussi pour le cœur de l’enfant en cours développement. La resynchronisation est un traitement prometteur pour traiter l’insuffisance cardiaque mais pourrait aussi l’être pour en prévenir sa survenue. De nouvelles techniques d’implantation nous permettent aujourd’hui d’implanter des patients qui présentent beaucoup d’obstacles anatomiques et d’éviter nombre de complications grave de la stimulation
The number of adults with severe congenital heart disease is constantly growing. At medium to long-term follow up, these patients may present with heart failure or conduction disorders, which may lead to death. The pathophysiology and clinical course of these complications is multi-factorial and may be different from that in patients without congenital heart disease. In normal hearts, electromechanical dyssynchrony is known to induce ventricular remodeling and heart failure. Ventricular asynchrony is also present in a substantial number of adults with congenital heart disease. In this study, we combined animal experiments and clinical studies to investigate: 1) the acute and chronic effect of biventricular resynchronization therapy on cardiac function in an animal model mimicking right ventricular heart failure in Tetralogy of Fallot, as well as in patients with Tetralogy of Fallot; 2) the consequences of conventional ventricular pacing in patients with ‘systemic right ventricle physiology’; 3) the effects of chronic right ventricular pacing in an animal model of the developing heart.We found that: 1) biventricular resynchronization induces significant hemodynamic benefit in the animal model of Tetralogy of Fallot as well as in Fallot patients; 2) ventricular asynchrony induced by conventional ventricular pacing is deleterious to the function of the systemic right ventricle; 3) chronic right ventricular pacing is harmful to the developing (pediatric) heart with normal biventricular anatomy. Cardiac resynchronization therapy is promising as a treatment for heart failure, but may also prevent heart failure. Nowadays, new implantation techniques allow us to implant pacing devices in patients with limited anatomical access due to prior surgery and help to avoid numerous severe complications of conventional pacing therapy

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2021
Introdução: O atraso estaturo-ponderal é umas das principais complicações da doença renal crónica em idade pediátrica. Contudo, mesmo após o transplante renal, cerca de 50% das crianças não atingem a estatura esperada na idade adulta. Os objetivos deste estudo foram avaliar o crescimento após transplante e identificar fatores que o possam influenciar. Métodos: Foi realizado um estudo observacional retrospetivo. Foram analisados os processos clínicos de todos os doentes submetidos a transplante renal nos últimos 25 anos (n=149) e foram realizadas chamadas telefónicas para obtenção de dados em falta. Os z-scores de estatura e índice de massa corporal (IMC) foram examinados à altura do transplante, 3 meses, 6 meses, 1 ano e 5 anos após o transplante renal e a estatura final na idade adulta, através das curvas e tabelas de crescimento da OMS. Ademais, dados relativos à duração da doença previamente ao transplante, técnica de substituição da função renal, administração de hormona de crescimento, suporte nutricional, estatura alvo, função renal e dose cumulativa de corticosteroides foram obtidos. Resultados: A análise dos z-scores revelou uma recuperação da estatura estatisticamente significativa aos 6 meses (p=0,006), 1 ano (p<0,001), 5 anos após transplante (p<0,001) e na idade adulta (p=0,012). Houve também uma recuperação significativa do IMC em todos os momentos avaliados (p<0,001). A taxa de filtração glomerular correlacionou-se de forma positiva e significativa com a estatura (p=0,006) e o IMC (p=0,006). O tratamento com hormona do crescimento não teve impacto na estatura à data do transplante (p=0,182). A utilização de gastrostomia não teve impacto significativo na estatura (p=0,167) nem no IMC (p=0,086) à data do transplante. A duração da doença renal até ao transplante não demonstrou influenciar a estatura (r=- 0,087, p=0,464) e o IMC (r=-0,144, p=0,225) na idade adulta. Ademais, a dose cumulativa de corticosteroides a que são sujeitos não demonstrou impacto na estatura (r=-0,080, p=0,538) e IMC (r=-0,155, p=0,229) na idade adulta. A evidenciar, temos o facto de que, em média, a estatura destas crianças na idade adulta foi 8,82 cm mais baixa do que a estatura-alvo.Conclusão: Apesar dos resultados encorajadores do nosso trabalho relativamente à recuperação da estatura após o transplante renal, os resultados permanecem longe do que seria desejável. Desta forma, estratégias devem ser estudadas e aplicadas, nomeadamente, a utilização sistemática de gastrostomia. Ademais, deve ser feito um controlo regrado do IMC de modo a evitar um excessivo ganho ponderal, que se associa a um aumento do risco cardiovascular.
Background: Growth failure is one of the major complications of pediatric chronic kidney disease (CKD). However, even after KT, up to 50% of patients fail to attain expected final height by the time they transition to adult services. The aims of this project were to assess longitudinal growth after KT and to identify factors that influence it. Methods: A retrospective observational study was performed. We reviewed the clinical records of all patients who underwent KT in the last 25 years in a single center (n=149) and performed phone interviews in order to obtain further data. Height-for-age and sex and BMI-for-age and sex were examined at transplant, 3 months, 6 months, 1 year and 5 years post-transplant and at final adult height, using WHO growth standards. Data regarding duration of disease prior to transplant, type of dialysis, administration of pretransplant recombinant human growth hormone (rhGH), nutritional support, target height, glomerular filtration rate (GFR) and cumulative corticosteroid dose were obtained as well. Results: Height z-scores showed catch-up growth at 6 months (p=.006), 1 year (p<.001), 5 years after transplantation (p<.001) and on transition to adult care (p=.012). Regarding BMI z-scores, a significant increase was also detected at all time-point assessments (p<.001). GFR was significantly associated with height z-score (p=.006) and BMI z-score (p=.006). In our cohort, treatment with rhGH had no impact on height zscore at transplant (p=.182). Use of gastrostomy feeding tube had no statistically significant impact on height z-score (p=.167) and BMI z-score (p=.086) at transplantation, although only 6% (n=6) of our patients used gastrostomy feeding tube. Disease duration until transplantation had, also, no influence on height z-score (r=-.087, p=.464) or BMI z-score (r=-.144, p=.225) at adult care transition. Furthermore, cumulative corticosteroid dose had no influence on height z-score (r=-.080, p=.538) or BMI z-score (r=-.155, p=.229) at transition to adult care. Importantly, in our cohort height in adulthood was 8.82 cm lower, on average, than the target height.Conclusion: Although the encouraging results regarding catch-up growth after KT presented in this cohort, results remain far from optimum. Therefore, strategies must be thought, including systematic use of gastrostomy tube feeding. Furthermore, closely monitoring of BMI is important in order to avoid excessive weight gain as it is associated with a greater cardiovascular risk.

Vitamin D is known to benefit skeletal bone health and prevent rickets in children. Limited evidence exists to support a role of vitamin D in linear growth and stunting, especially in children at high risk for growth faltering, e.g. undernourished low socio-economic status children <5 years. Also, it is unclear if the immunomodulatory benefits of vitamin D impact childhood pneumonia. It is critical to determine whether vitamin D ameliorates stunting and pneumonia, as these conditions are responsible for a high burden of child mortality and morbidity. A secondary analysis of two studies in Ecuador was undertaken to determine the prevalence of vitamin D deficiency and the effect of vitamin D status on growth (height-for-age (HAZ) and weight-for-age (WAZ) z-scores) (n=516) and illness duration in children hospitalized for severe pneumonia (n=348). Serum 25-hydroxyvitamin D (25(OH)D) concentrations of children who participated in a community-based trial (ages 6-36 months) and hospital-based trial (ages 2-59 months) were determined at baseline. Overall, 18.6% of children had serum 25(OH)D levels <17 ng/ml (n=516), 62.2% were stunted (HAZ≤-2), and 65.5% were underweight (WAZ≤-1). Children with 25(OH)D concentrations <17 ng/ml had a higher risk of stunting (HAZ≤-2) than those with concentrations ≥17 ng/ml (ORadj: 2.8; 95%CI: 1.6, 4.7) in logistic regression models. Underweight (WAZ≤-1) children were twice as likely to have 25(OH)D concentrations <17 ng/ml than normal weight children (WAZ>-1) (ORadj: 2.0; 95%CI: 1.2,3.3). Vitamin D deficiency (≤20 ng/ml) did not affect pneumonia duration among hospitalized children in Cox proportional hazard models (HRadj: 1.2; 95% CI: 0.93,1.5). Younger children (2-12 months), underweight children (WAZ≤-2), and children with higher respiratory rates had a longer duration of illness (HRadj: 0.61; 95% CI: 0.43,0.86; HRadj: 0.78; 95% CI: 0.59,1.0; HRadj: 0.97; 95% CI: 0.96,0.99, respectively). Underweight Ecuadorian children are at increased risk for lower serum 25(OH)D concentrations. Low vitamin D status is associated with stunting among undernourished children but not with the duration of pneumonia illness. This indicates that vitamin D may be a modifiable risk factor for stunting, which, if validated in further research, can potentially impart beneficial effects on growth among stunted children in resource limited settings.
2020-06-30T00:00:00Z

碩士
國防醫學院
藥學研究所
105
Background: Pediatric dosing information is not routinely acquired during the drug development process, and empirical rules based on body weight or age are often used for estimating doses in pediatric patients. However, “children are not small adults”the difference between children and adults cannot be realized by a simple linear function of body weight or age. Recently, more complex mathematical models have been proposed to describe the changes of drug clearance at different ages from birth to adulthood. These models account for growth and maturation in child development, and have been applied successfully to a wide variety of drugs. Since drugs have diverse pharmacokinetic properties, with varied dependence on hepatic metabolism and renal excretion, the maturation model often includes drug-specific parameter values for a particular drug; and generalizability is difficult, or not impossible. Objectives: The objectives of the present study are (1) to investigate whether a general model can be used for predicting the clearance values of mainly renally excreted drugs based on the assumption that GFR maturation may account for the maturation of renal drug-eliminating ability; (2) to compare the prediction performance among various prediction models; and (3) to investigate the relationship between the maturation of renal function indices (e.g. GFR, renal blood flow rate, and active tubular secretion rate) and the maturation of drug elimination in the human body. Methods: Four GFR maturation models and two allometric scaling models (size models) were included to predict drug clearance (CL) at different child ages. Real, observed CL values were obtained from published studies through a PubMed-based text-mining procedure. Besides, simulations were conducted to generate simulated CL values (based on the WHO/CDC growth chart). Predictive performance was evaluated using various precision and accuracy measures (e.g. RMSE, AFE, and AAFE). Besides, two specific models (Hayton GFR vs. Mahmood GFR) were used to describe the relationship between maturation of renal function and that of drug elimination. Results: A total of 868 exact and 1628 simulated CL values were included for analysis. The exact CL values are from 39 drugs, spanning various therapeutic categories. The maturation models generally have better predictive performance than the size models in younger ages; however, at 2 years of age and above, the prediction accuracy seems to be similar, suggesting that the size model alone can be used for the prediction of drug clearance at ages above 2 years. Remarkably, among all the maturation models, the Hayton equation provides the best predictions. The advantage and attractiveness of using a GFR maturation model based on the Hayton equation is that a general equation with a limited number of parameters can be used in predicting drug CL values for a wide variety of drugs at different human developmental stages. Besides, we found that among the three indicators of renal function (GFR, tubular active secretion, renal blood flow), GFR maybe the best parameter to describe the development of drug-eliminating ability. Conclusions: The study demonstrates that the GFR maturation models may be used as a general model for predicting the total clearance of drugs that are mainly excreted from the kidneys. The study further shows that the development of human drug elimination capability is closely related to the maturation process of GFR.

Indiana University-Purdue University Indianapolis (IUPUI)
This investigation served as a follow-up of the unilateral and bilateral cleft lip and palate patients who underwent primary alveolar bone grafting at James Whitcomb Riley Hospital of the Indiana University Medical Center. The sample consisted of 18 patients, 15 males and three females, who received primary alveolar grafts between September 7, 1983 and March 5, 1985. Thirteen had complete unilateral clefts, and five had complete bilateral clefts of the lip and palate. The mean age of the group was 8 years, and none had received orthodontic treatment. The statistical analysis of the lateral cephalometric radiographs revealed significant differences in maxillofacial growth between the Riley sample population and the non-cleft, age-matched patients in the University of Michigan Growth Study. The Riley data were, overall, statistically and proportionately smaller than the normal population. These findings are due to the smaller skeletal size of the Riley group. Arch symmetry measurements indicated that at 8 years of age there were significant differences from ideal or perfect symmetry. Due to existent dental development and scarring from the palatal procedure, these findings were expected. Ideal symmetry may not be a realistic achievement for the cleft patients. Palatal surface area values were visually analyzed through graphs. The growth patterns of the Riley population were similar to those of the normal and non-grafted cleft groups in a study from the University of Miami. The data supports the theory that primary alveolar bone grafting, as performed at James Whitcomb Riley Hospital, does not result in growth attenuation.

OBJECTIVE: Prior studies suggested rapid weight gain in infancy as a risk factor for the development of obesity. Our aim was to determine if early-childhood treatment for malnutrition is associated with the development of obesity in later-childhood. METHODS: This was a retrospective chart review of 194 children who had been treated and discharged from the Growth and Nutrition Program (GNP) from 1/1/2000 to 7/30/2014, with at least one height and weight recorded after discharge. Subjects predisposed to obesity due to medical conditions or medications were excluded. Obesity was defined using WHO and CDC growth charts, body mass index ≥95th percentile for age and sex, and compared to published prevalence rates. Potential predictors of obesity prevalence were also examined. RESULTS: None of the 194 subjects were obese at time of discharge from GNP. Over the 20-year follow-up period, 7% became obese (well below the national obesity prevalence of 18.5%1. 3 of 11 (27.3%) patients prescribed preterm infant formula became obese in contrast to 10 of 173 (5.8%) who were not prescribed (p=0.007). 6 of 27 (22.2%) subjects identified as African American became obese in contrast to 7 of 157 (4.5%) who did not identify (p=0.001). CONCLUSION: While overall prevalence of obesity was lower than that of the general population, children requiring preterm infant formula and/or identified as African American were more likely to develop obesity in childhood. Findings support the need for more anticipatory guidance regarding preterm infant formula and aggressive weight management and planning prior to GNP discharge.
2022-06-07T00:00:00Z

INTRODUCTION: Feeding difficulties are commonly multifactorial in nature, and no uniformly agreed-upon classification system for feeding difficulties currently exists. The Diagnostic and Statistical Manual of Mental Disorders (DSM)-V included a new diagnosis called Avoidant/Restrictive Food Intake Disorder (ARFID), created in order to address the weaknesses of the DSM-IV-text revision (TR) classification system by better capturing the range of feeding difficulties typically found in clinical practice. Little is known about the clinical characteristics associated with meeting the ARFID criteria, and no studies have investigated ARFID prevalence and associated clinical characteristics in patients below the age of 8 years. AIM: To describe the clinical characteristics of a sample of patients referred to Boston Children Hospital’s Growth and Nutrition Program, including the prevalence of ARFID, and identify clinical characteristics associated with meeting the criteria for ARFID. METHODS: We examined prospectively collected data from 69 subjects, age 9 months to 7 years, referred to the Growth and Nutrition Program for feeding difficulties and/or malnutrition between November 2013 and April 2016. Data was collected from caregiver-completed questionnaires, including the Behavioral Pediatrics Assessment Scale (BPFAS), and each patient’s electronic medical record. RESULTS: Premature birth (32.3%), digestive conditions (69.2%), developmental conditions (56.9%), food allergy (20.3%), and meal duration of over 30 minutes (36.2%) were common. Problematic feeding behaviors such as refusing to eat (62.1%) and gagging or vomiting when given new foods (29.2%) were also common. Strategies caregivers used to increase food and liquid consumption included offering only foods the child likes (60.9%) and feeding in front of the television or electronic devices (30.4%). 90.8% had a BPFAS score above threshold. 83.1% of the sample met criteria for ARFID. No statistically significant relationship was found between meeting ARFID criteria and having a BPFAS score above threshold, and there was no statistically significant relationship between meeting ARFID criteria and having a food allergy, having a first-degree relative with a food allergy, or with any of the feeding behaviors or strategies we investigated. CONCLUSION: This study suggests that the majority of patients between the ages of 9 months to 7 years with feeding difficulties referred to the Growth and Nutrition Program meet the criteria for ARFID. While no statistically significant relationship was found between ARFID and the investigated clinical characteristics, further analysis involving a larger sample of patients will be useful for better understanding the clinical characteristics associated with ARFID, and assessing ARFID’s clinical utility.
2019-07-11T00:00:00Z

He, Qiqiang.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2009.
Includes bibliographical references (leaves 142-154).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.