A population-based nested case control study on recurrent pneumonias in children with severe generalized cerebral palsy: ethical considerations of the design and representativeness of the study sample

BACKGROUND: In children with severe generalized cerebral palsy, pneumonias are a major health issue. Malnutrition, dysphagia, gastro-oesophageal reflux, impaired respiratory function and constipation are hypothesized risk factors. Still, no data are available on the relative contribution of these possible risk factors in the described population. This paper describes the initiation of a study in 194 children with severe generalized cerebral palsy, on the prevalence and on the impact of these hypothesized risk factors of recurrent pneumonias. METHODS/DESIGN: A nested case-control design with 18 months follow-up was chosen. Dysphagia, respiratory function and constipation will be assessed at baseline, malnutrition and gastro-oesophageal reflux at the end of the follow-up. The study population consists of a representative population sample of children with severe generalized cerebral palsy. Inclusion was done through care-centres in a predefined geographical area and not through hospitals. All measurements will be done on-site which sets high demands on all measurements. If these demands were not met in "gold standard" methods, other methods were chosen. Although the inclusion period was prolonged, the desired sample size of 300 children was not met. With a consent rate of 33%, nearly 10% of all eligible children in The Netherlands are included (n = 194). The study population is subtly different from the non-participants with regard to severity of dysphagia and prevalence rates of pneumonias and gastro-oesophageal reflux. DISCUSSION: Ethical issues complicated the study design. Assessment of malnutrition and gastro-oesophageal reflux at baseline was considered unethical, since these conditions can be easily treated. Therefore, we postponed these diagnostics until the end of the follow-up. In order to include a representative sample, all eligible children in a predefined geographical area had to be contacted. To increase the consent rate, on-site measurements are of first choice, but timely inclusion is jeopardized. The initiation of this first study among children with severe neurological impairment led to specific, unexpected problems. Despite small differences between participants and non-participating children, our sample is as representative as can be expected from any population-based study and will provide important, new information to bring us further towards effective interventions to prevent pneumonias in this population

The asthma epidemic and our artificial habitats

BACKGROUND: The recent increase in childhood asthma has been a puzzling one. Recent views focus on the role of infection in the education of the immune system of young children. However, this so called hygiene hypothesis fails to answer some important questions about the current trends in asthma or to account for environmental influences that bear little relation to infection. DISCUSSION: The multi-factorial nature of asthma, reflecting the different ways we tend to interact with our environment, mandates that we look at the asthma epidemic from a broader perspective. Seemingly modern affluent lifestyles are placing us increasingly in static, artificial, microenvironments very different from the conditions prevailed for most part of our evolution and shaped our organisms. Changes that occurred during the second half of the 20th century in industrialized nations with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance). Asthma according to this view is a manifestation of our respiratory maladaptation to modern lifestyles, or in other words to our increasingly artificial habitats. The basis of the artificial habitat notion may lie in reduced exposure of innate immunity to a variety of environmental stimuli, infectious and non-infectious, leading to reduced formulation of regulatory cells/cytokines as well as inscribed regulatory pathways. This could contribute to a faulty checking mechanism of non-functional Th2 (and likely Th1) responses, resulting in asthma and other immuno-dysregulation disorders. SUMMARY: In this piece I discuss the artificial habitat concept, its correspondence with epidemiological data of asthma and allergy, and provide possible immunological underpinning for it from an evolutionary perspective of health and disease

Early life patterns of common infection: a latent class analysis

Early life infection has been implicated in the aetiology of many chronic diseases, most often through proxy measures. Data on ten infectious symptoms were collected by parental questionnaire when children were 6 months old as part of the Avon Longitudinal Study of Parents and Children, United Kingdom. A latent class analysis was used to identify patterns of infection and their relationship to five factors commonly used as proxies: sex, other children in the home, maternal smoking, breastfeeding and maternal education. A total of 10,032 singleton children were included in the analysis. Five classes were identified with differing infectious disease patterns and children were assigned to the class for which they had a highest probability of membership based on their infectious symptom profile: ‘general infection’ (n = 1,252, 12.5%), ‘gastrointestinal’ (n = 1,902, 19.0%), ‘mild respiratory’ (n = 3,560, 35.5%), ‘colds/ear ache’ (n = 462, 4.6%) and ‘healthy’ (n = 2,856, 28.5%). Females had a reduced risk of being in all infectious classes, other children in the home were associated with an increased risk of being in the ‘general infection’, ‘mild respiratory’ or ‘colds/ear ache’ class. Breastfeeding reduced the risk of being in the ‘general infection’ and ‘gastrointestinal’ classes whereas maternal smoking increased the risk of membership. Higher maternal education was associated with an increased risk of being in the ‘mild respiratory’ group. Other children in the home had the greatest association with infectious class membership. Latent class analysis provided a flexible method of investigating the relationship between multiple symptoms and demographic and lifestyle factors

Multiple mechanisms underlie defective recognition of melanoma cells cultured in three-dimensional architectures by antigen-specific cytotoxic T lymphocytes

Cancer cells` growth in three-dimensional (3D) architectures promotes resistance to drugs, cytokines, or irradiation. We investigated effects of 3D culture as compared to monolayers (2D) on melanoma cells` recognition by tumour-associated antigen (TAA)-specific HLA-A*0201-restricted cytotoxic T-lymphocytes (CTL). Culture of HBL, D10 (both HLA-A*0201+, TAA+) and NA8 (HLA-A* 0201+, TAA-) melanoma cells on polyHEMA-coated plates, resulted in generation of 3D multicellular tumour spheroids (MCTS). Interferon-gamma (IFN-gamma) production by HLA-A*0201-restricted Melan-A/MART-1(27-35) or gp100(280-288)-specific CTL clones served as immunorecognition marker. Co-culture with melanoma MCTS, resulted in defective TAA recognition by CTL as compared to 2D as witnessed by decreased IFN-gamma production and decreased Fas Ligand, perforin and granzyme B gene expression. A multiplicity of mechanisms were potentially involved. First, MCTS per se limit CTL capacity of recognising HLA class I restricted antigens by reducing exposed cell surfaces. Second, expression of melanoma differentiation antigens is downregulated in MCTS. Third, expression of HLA class I molecules can be downregulated in melanoma MCTS, possibly due to decreased interferonregulating factor-1 gene expression. Fourth, lactic acid production is increased in MCTS, as compared to 2D. These data suggest that melanoma cells growing in 3D, even in the absence of immune selection, feature characteristics capable of dramatically inhibiting TAA recognition by specific CTL

Birth order modifies the effect of IL13 gene polymorphisms on serum IgE at age 10 and skin prick test at ages 4, 10 and 18: a prospective birth cohort study

Background:Susceptibility to atopy originates from effects of the environment on genes. Birth order has been identified as a risk factor for atopy and evidence for some candidate genes has been accumulated; however no study has yet assessed a birth order-gene interaction.Objective:To investigate the interaction of IL13 polymorphisms with birth order on allergic sensitization at ages 4, 10 and 18 years.Methods:Mother-infant dyads were recruited antenatally and followed prospectively to age 18 years. Questionnaire data (at birth, age 4, 10, 18); skin prick test (SPT) at ages 4, 10, 18; total serum IgE and specific inhalant screen at age 10; and genotyping for IL13 were collected. Three SNPs were selected from IL13: rs20541 (exon 4, nonsynonymous SNP), rs1800925 (promoter region) and rs2066960 (intron 1). Analysis included multivariable log-linear regression analyses using repeated measurements to estimate prevalence ratios (PRs).Results:Of the 1456 participants, birth order information was available for 83.2% (1212/1456); SPT was performed on 67.4% at age 4, 71.2% at age 10 and 58.0% at age 18. The prevalence of atopy (sensitization to one or more food or aeroallergens) increased from 19.7% at age 4, to 26.7% at 10 and 41.1% at age 18. Repeated measurement analysis indicated interaction between rs20541 and birth order on SPT. The stratified analyses demonstrated that the effect of IL13 on SPT was restricted only to first-born children (p = 0.007; adjusted PR = 1.35; 95%CI = 1.09, 1.69). Similar findings were noted for firstborns regarding elevated total serum IgE at age 10 (p = 0.007; PR = 1.73; 1.16, 2.57) and specific inhalant screen (p = 0.034; PR = 1.48; 1.03, 2.13).Conclusions:This is the first study to show an interaction between birth order and IL13 polymorphisms on allergic sensitization. Future functional genetic research need to determine whether or not birth order is related to altered expression and methylation of the IL13 gene