Kindergeneeskunde in ontwikkeling

Rede, uitgesproken bij de aanvaarding van het ambt van hoogleraar in de Kindergeneeskunde aan de Erasmus Universiteit te Rotterdam, op 3 juni 198

Bronchial responsiveness in children

The aim of the research described in this thesis is to get more insight into various aspects of bronchial responsiveness. The literature is reviewed and discussed in the first part of this thesis (chapters 2-5) and emphasis is placed on recent developments. In the review results from studies in animals and in humans are correlated as much as possible. Our own studies are designed to analyse various aspects of the mechanisms in bronchial responsiveness in children, as well as the role of bronchial responsiveness in the occurrence of symptoms. These studies, started in 1976, are divided into three groups: a. Dose- and time-response relationships using inhaled histamine. These are analysed and the methods for the measurement of bronchial responsiveness considered (chapter 6). b. Studies on mechanisms of: 1. The relative contribution of the autonomic and the mast cell system in the pathogenesis of bronchial responsiveness using exercise is studied by means of protective agents (paragraph 7.1). 2. The pattern of bronchial obstruction after exercise is evaluated with flowvolume curves using air and helium/oxygen mixtures (paragraph 7.2). 3. The feasibility of leucocytes as a model for hyperresponsiveness at a cellular level are performed by measuring the release of mediators (paragraphs 7.3 and 7.4). c. The clinical significance of the relationship between bronchial responsiveness and the occurrence of bronchial obstruction after contact with allergens and after exercise (chapter 8)

Bacterial meningitis: Mechanisms of disease and therapy

Bacterial meningitis continues to be a serious infectious disease with a high morbidity and mortality in young children. Early recognition and initiation of adequate treatment are the major determinants for a good outcome. Recent advances in our understanding of the host inflammatory response by cytokines may result in the use of new therapeutic strategies. Such modulation of the inflammatory response may reduce the incidence of sequelae and death. The use of steroids as adjunctive therapy in children with bacterial meningitis probably has beneficial effects although the available data are still controversial. Additionally, studies in experimental meningitis models indicate that non-steroidal anti-inflammatory drugs and monoclonal antibodies against bacterial products, cytokines and CD18 on leucocytes reduce the extent of the meningeal inflammation. Human studies to evaluate the efficacy of these immune modulators are expected to start soon. However, prevention of bacterial meningitis by conjugate vaccines againstStreptococcus pneumoniae andNeisseria meningitidis will be the most promising development in the next decade

The cystic fibrosis defect approached from different angles - New perspectives on the gene, the chloride channel, diagnosis and therapy

Abstract The search for the basic defect in cystic fibrosis (CF) has reached a decisive stage since the recent identification of the responsible gene. Electrophysiological and biochemical research had defined the CF defect as a dysregulation of epithelial chloride channels. The putative protein product of the now identified gene shares properties with other known transport proteins, but it is not necessarily itself a chloride channel protein. Elucidation of the primary cellular defect will certainly have important aetiological and hopefully therapeutic implications. The identification of the major gene mutation already has significant consequences for genetic counselling and prenatal diagnosis. Heterozygote detection at the population level awaits identification of the probably heterogenous mutations on about 30% of the CF chromosomes. At present, about 50% of CF patients are homozygous for the recently identified major CF mutation

Relation between cytokines and routine laboratory data in children with septic shock and purpura

Objective To establish the relation between routine laboratory data (lactate, fibrinogen, CRP) and cytokines (TNF,IL-1 and-6) and to estimate their prognostic value in pediatric patients with severe infectious purpura on admission. Design Prospective study. Setting Pediatric intensive care unit (PICU). Patients 17 children aged 5–172 months (median 46) were hospitalized in our PICU in 1989–90 with severe infectious purpura.Neisseria meningitidis was isolated in 15 children andHaemophilus influenzae in two. The patients were divided into 3 groups: non-shock, shock and severe shock leading to death. Shock was defined by standard criteria. Measurements Arterial blood was sampled for lactate, CRP, fibrinogen, TNF, and IL-1 and-6 on admission. The PRISM (pediatric risk of morality)-score was recorded. Methods Statistical analysis was performed with the Student'st-test using the logarithmic values of the cytokine concentration, and Spearman correlation analysis. Results According to the shock criteria, 9 patients were in shock of whom 4 did not survive. Significant differences existed between the 3 groups concerning lactate, TNF, and IL-6. Fibrinogen, CRP, IL-1, and PRISM-score discriminated only between survivors and non-survivors. A highly significant correlation existed between cytokines, the PRISM-score and lactate (TNF:r=0.69, IL-1:r=0.56, IL-6:r=0.65, PRISM:r=0.65). A significant inverse correlation existed between cytokines and CRP (TNF:r=−0.55, IL-1:r=−0.64, and IL-6:r=−0.56), and IL-6 and fibrinogen (r=−0.65). Conclusion These results show a significant correlation between cytokines and lactate, and lactate, TNF and IL-6 are closely associated with the severity of septic shock with purpura in children

Once-daily versus twice-daily administration of ceftazidime in the preterm infant

Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life. Patients with suspected septicemia were randomized on day 1 of life in two groups. One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily. Both groups also received 25 mg of amoxicillin per kg twice daily. Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection. An additional blood sample was taken at 24 h from the group dosed once a day. High-performance liquid chromatography was used to determine serum ceftazidime concentrations. The pharmacokinetics of ceftazidime were best described by using a one-compartment model. The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups. The ceftazidime/inulin clearance ratio was 0.72 for both groups. However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter). The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens. We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily

Early respiratory and skin symptoms in relation to ethnic background: the importance of socioeconomic status; the PIAMA study

AIMS: To evaluate ethnic differences in the prevalence of respiratory and skin symptoms in the first two years of life. METHODS: A total of 4146 children participated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Parents completed questionnaires on respirato

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive