Effect of long-term voluntary exercise wheel running on susceptibility to bacterial pulmonary infections in a mouse model

Regular moderate exercise has been suggested to exert anti-inflammatory effects and improve immune effector functions, resulting in reduced disease incidence and viral infection susceptibility. Whether regular exercise also affects bacterial infection susceptibility is unknown. The aim of this study was to investigate whether regular voluntary exercise wheel running prior to a pulmonary infection with bacteria (P. aeruginosa) affects lung bacteriology, sickness severity and phagocyte immune function in mice. Balb/c mice were randomly placed in a cage with or without a running wheel. After 28 days, mice were intranasally infected with P. aeruginosa. Our study showed that regular exercise resulted in a higher sickness severity score and bacterial (P. aeruginosa) loads in the lungs. The phagocytic capacity of monocytes and neutrophils from spleen and lungs was not affected. Although regular moderate exercise has many health benefits, healthy mice showed increased bacterial (P. aeruginosa) load and symptoms, after regular voluntary exercise, with perseverance of the phagocytic capacity of monocytes and neutrophils. Whether patients, suffering from bacterial infectious diseases, should be encouraged to engage in exercise and physical activities with caution requires further research

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

Early life antibiotic use and the risk of asthma and asthma exacerbations in children

Background: The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first three years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. Methods: Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7,393, the Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, the Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. Results: Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I2: 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I2: 0.0%). Conclusion: Children treated with antibiotic in the first three years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increase d risk of asthma exacerbations

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolininduced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-toexcellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner

Vitamin e intake, α-tocopherol levels and pulmonary function in children and adolescents with cystic fibrosis

Pancreatic insufficiency cystic fibrosis (CF) patients receive vitamin E supplementation according to CF-specific recommendations in order to prevent deficiencies. It has been suggested that higher serum α-tocopherol levels could have protective effects on pulmonary function (PF) in patients with CF. Whether current recommendations are indeed optimal for preventing deficiency and whether vitamin E has therapeutic benefits are subjects of debate. Therefore, we studied vitamin E intake as well as the long-term effects of vitamin E intake, the coefficient of fat absorption (CFA) and IgG on α-tocopherol levels. We also examined the long-term effects of serum α-tocopherol and serum IgG on forced expiratory volume in 1 s expressed as percentage of predicted (FEV1% pred.) in paediatric CF patients during a 7-year follow-up period. We found that CF patients failed to meet the CF-specific vitamin E recommendations, but serum α-tocopherol below the 2·5th percentile was found in only twenty-three of the 1022 measurements (2 %). Furthermore, no clear effect of vitamin E intake or the CFA on serum α-tocopherol was found (both P≥ 0·103). FEV1% pred. was longitudinally inversely associated with age (P< 0·001) and serum IgG (P= 0·003), but it was not related to serum α-tocopherol levels. We concluded that in the present large sample of children and adolescents with CF, vitamin E intake was lower than recommended, but serum α-tocopherol deficiency was rare. We found no evidence that higher serum α-tocopherol levels had protective effects on PF. Adjustment of the recommendations to the real-life intake of these patients may be considered

Asthma related medication use and exacerbations in children and adolescents with type 1 diabetes

ObjectivesTo investigate the use of asthma medication and occurrence of asthma exacerbations up to 5 years before and after the onset of type 1 diabetes mellitus (T1DM) in children and adolescents. MethodsChildren and adolescents younger than 19 years with at least 2 insulin prescriptions between 1999 and 2009 classified as T1DM cohort (n=915) and a 4 times larger reference cohort (n=3,590) with the same age and gender were identified from the Dutch PHARMO Record Linkage System. The date of first insulin dispensing was selected as the index date. ResultsThe 5-year prevalence rate of asthma medication use in the T1DM cohort (23.2%) was significantly higher than the reference cohort (18.3%) after the onset of diabetes. No statistically significant difference between the two cohorts was observed in the use of specific types of asthma medication except for short acting muscarinic antagonists that were significantly more used in the T1DM cohort (5.5%) compared with the reference cohort (0.62%) after the onset of diabetes. The incidence rate of asthma medication use declined over time with a peak in the T1DM cohort the 1st year after the onset of diabetes. Furthermore, 1 year after the index date there was a peak in incidence rate of asthma exacerbations in both T1DM (7.8 per 1,000 person year) and reference (6.8 per 1,000 person year) cohorts. ConclusionsT1DM is associated with statistically significantly higher asthma medication use after the onset of T1DM, especially in the 1st year after the onset of diabetes. Pediatr Pulmonol. 2016;51:1113-1121. (c) 2016 Wiley Periodicals, In

Vitamin A intake and serum retinol levels in children and adolescents with cystic fibrosis

BACKGROUND: Pancreatic insufficient cystic fibrosis (CF) patients receive vitamin A supplementation according to CF-specific recommendations to prevent deficiencies. Whether current recommendations are optimal for preventing both deficiency and toxicity is a subject of debate. We assessed the longitudinal relation between serum retinol levels and appropriate variables. METHODS: We studied vitamin A intake, and the long-term effects of vitamin A intake, coefficient of fat absorption (CFA) and immunoglobulin G (IgG) on serum retinol levels in 221 paediatrics CF patients during a seven-year follow up period. RESULTS: Total vitamin A intake, derived from 862 dietary assessments, exceeded the tolerable upper intake level in 30% of the assessments, mainly up to age six. Although CF patients failed to meet the CF-specific recommendations, serum retinol deficiency was found in only 17/862 (2%) of the measurements. Longitudinally, we observed no association to serum retinol levels for total vitamin A intake, CFA, gender or age but serum retinol levels were associated with serum IgG levels. Each g/L increase in serum IgG level would result in a 2.49% (95% CI -3.60 to -1.36%) reduction in serum retinol levels. CONCLUSION: In this large sample of children and adolescents with CF, serum retinol deficiency was rare despite lower than the CF-specific recommendations. However, the TUL was commonly exceeded. A reduction in CF-specific vitamin A supplementation recommendations should therefore be considered. Moreover, serum retinol levels were not associated with vitamin A intake, CFA, gender or age, although a decreased serum retinol was associated with an increased serum IgG

What Drives Prescribing of Asthma Medication to Children? A Multilevel Population-Based Study

PURPOSE Diagnosing asthma in children with asthmatic symptoms remains a challenge, particularly in preschool children. This challenge creates an opportunity for variability in prescribing. The aim of our study was to investigate how and to what degree patient, family, and physician characteristics influence prescribing of asthma medication in children

Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine

It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting β2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting β2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment