Veeze, H.J.

Genetic correlates of early accelerated infant growth associated with juvenile-onset type 1 diabetes (Article)

2011-10-06T00:00:00Z

Objective: We previously showed that accelerated growth predisposing to development of childhood-onset type 1 diabetes (T1D) is restricted to the first year after birth. We assessed whether this phenomenon of increased early growth is associated with variants of two genes, insulin-like growth factor-1 (IGF1) and insulin variable number of tandem repeats (INS-VNTR), whose products are components of the growth axis. Patients and methods: Patients and their siblings were genotyped for the INS-VNTR and for an IGF1 microsatellite. We tested for difference in first year growth, i.e., increased weight standard deviation score (SDS), a reliable measure of especially first year growth, between carriers and non-carriers of these gene variants, using a repeated measurement and regression analysis. Results: In patients, growth did not differ between carriers and non-carriers of the INS-VNTR*III allele, while carriership of this allele in siblings was positively associated with increased first year growth. In both patients and siblings, non-carriership of the IGF1*194 allele was positively associated with growth. Birth size was not associated with either variant. Conclusions/discussion: Non-carriership of the IGF1*194 allele was positively associated with accelerated first year growth in both patients and siblings, independent of disease. This IGF1 variant may therefore contribute to increased first year growth, but cannot explain the association of first year growth with diabetes. An effect on growth of the INS-VNTR was detected in healthy siblings, but not in patients, suggesting that disease supersedes a growth effect of INS-VNTR.

Passive immunisation against respiratory syncytial virus: A cost-effectiveness analysis (Article)

2010-07-01T00:00:00Z

Aim: The cost-effectiveness of passive immunisation against respiratory syncytial virus (RSV) in the Netherlands was studied by assessing incremental costs to prevent one hospitalisation in high-risk children using a novel individualised monthly approach. Methods: Cost-effectiveness analysis was performed by combining estimates of individual hospitalisation costs and monthly hospitalisation risks, with immunisation costs, parental costs and efficacy of passive immunisation for a reference case with the highest hospitalisation risks and costs of hospitalisation during the RSV season (male, gestational age ≤28 weeks, birth weight ≤2500 g, having bronchopulmonary dysplasia (BPD), aged 0 months at the beginning of the season (October)). Various sensitivity analyses and a cost-neutrality analysis were performed. Results: Cost-effectiveness of passive immunisation varied widely by child characteristics and seasonal month. For the reference case it was most cost effective in December at €13 190 per hospitalisation averted. Cost-effectiveness was most sensitive to changes in hospitalisation risk. For the reference case, cost neutrality was reached in December, if acquisition costs of passive immunisation decreased from €930 to €375, monthly hospitalisation risk increased from 7.6% to 17%, or hospitalisation costs increased from €10 250 to €23 250 per hospitalisation. Even if passive immunisation prevented all hospitalisations, costs per hospitalisation averted in December would still exceed €2645. Conclusions: Although cost-effectiveness of passive immunisation varied strongly by child characteristics and seasonal month, incremental costs per hospitalisation averted were always high. A restrictive immunisation policy only immunising children with BPD in high-risk months is therefore recommended. The costs of passive immunisation would have to be considerably reduced to achieve cost-effectiveness.

Revisiting infant growth prior to childhood onset type 1 diabetes (Article)

2010-05-01T00:00:00Z

Objective Accelerated early growth prior to childhood type 1 diabetes onset is associated with an increased risk for type 1 diabetes (T1D). We aimed to study early growth, correcting for the previously neglected confounder of familial effects. Design Infant growth was studied in a retrospective family case-control study of diabetic children in which siblings acted as matched familial controls allowing correction for confounders related to family particulars. Patients Weight and height data were collected from 213 juvenile onset type 1 diabetic children and their 255 healthy siblings. Growth in the first 4 years of life was studied using repeated measurement. The degree of early overgrowth was correlated with age of clinical onset. Results Birth weight and length did not differ between later diabetic children and their siblings. In the first year of life, weight standard deviation score (SDS) differed between patients and sibs (P = 0·0001). After the first year, both diabetic children and sibs showed parallel enhanced weight and height gain SDS until age 4 years. Earlier onset diabetes was associated with a higher weight SDS at 6 months of age. Conclusion In this family case-control study the association of increased growth with development of T1D is limited to the first year of life implying that increased growth beyond the first year can be attributed to familial growth patterns, rather than predisposition to T1D per se. Age at disease onset correlated with increased weight in the first 6 months of life, indicating importance of features very early in life on later development of T1D.

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings (Article)

2001-01-01T00:00:00Z

To investigate the impact of chloride (Cl(-)) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl(-) channels, on the manifestations of cystic fibrosis (CF), we determined Cl(-) transport properties of the respiratory and intestinal tracts in Delta F508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca(2+)-regulated Cl(-) conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl(-) conductance suggests that, in vivo, at least some Delta F508 CFTR can reach the plasma membrane and affect Cl(-) permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl(-) conductance, demonstrated by 30% of Delta F508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive (DIDS-insensitive) Cl(-) secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl(-) secretion was observed mainly in more severely affected patients. The more concordant Cl(-) secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.

The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data (Article)

1999-01-01T00:00:00Z

Congenital bilateral absence of the vas deferens (CBAVD) is found in 1-2% of infertile males and in most male cystic fibrosis (CF) patients. CF and some of the CBAVD cases were found to share the same genetic background. In this study, 21 males with CBAVD had extensive physical and laboratory testing for symptoms of CF. Possible defective cellular chloride transport was measured by interstitial current measurement of rectal suction biopsies. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis was performed for 10 common CFTR mutations. CF-related symptoms were found in six men. On laboratory testing slightly abnormal liver and pancreatic function was found in seven patients. The sweat test was found to be abnormal in four patients; interstitial current measurement showed defective chloride excretion in 11 patients. CFTR gene mutations were found in 66% of the patients: eight were compound heterozygotes; in six, only one common mutation could be detected. The 5T allele in one copy of intron 8 was found in four men. CBAVD appears to be a heterogeneous clinical and genetic condition. A CFTR gene mutation was found in both copies of the allele or interstitial current measurement showed defective chloride excretion in 14/21 cases. Genetic counselling is clearly indicated for couples seeking pregnancy through epididymal or testicular sperm aspiration and intracytoplasmic sperm injection.

Clinical presentation of exclusive cystic fibrosis lung disease (Article)

1999-01-01T00:00:00Z

The diagnosis of cystic fibrosis (CF) is based on the occurrence of two mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and on assays that measure the basic defect of abnormal chloride transport in the affected organs. However, in cases of atypical CF not all diagnostic tests may be positive. We present a patient with an atypical CF phenotype in whom the only presenting symptom was severe CF-like lung disease substantiated by an abnormal nasal potential difference. Genetic analysis showed that the patient was a symptomatic heterozygote, which suggests that one lesion in the CFTR gene may be sufficient to cause CF-like lung disease.

Pathophysiological aspects of cystic fibrosis : genotypes, phenotypes and intestinal current measurements (Doctoral Thesis)

1995-06-28T00:00:00Z

Cystic fibrosis (CF). is one of the commonest life-threatening autosomal recessive hereditary disease, predominantly affecting Caucasian populations. It is listed under number 219700 in McKusick's Mendelian Inheritance in Man and on Internet's Online Mendelian Inheritance in Man. In the Netherlands one in every 3600 newborns is affected by the disease. The disease is characterized by production of abnormally viscid secretions in epithelial tissues. The different organs involved such as lungs, pancreas, and liver are progressively damaged owing to obstructing mucoid plugs. The clinical manifestations of the disease and consequently the life expectancy range widely. The average life span has increased in the last decade to an age of almost 30 years. It is to be expected that newly diagnosed CF patients will have a better prognosis as a result of more aggressive therapy and preventive measures. Especially, improvement of treatment of meconium ileus, more effective antibiotic regimes, care for optimal nutritional status, and the formation of multidisciplinary teams of CF specialists have contributed in this respect.

Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype (Article)

1994-01-01T00:00:00Z

Previous Ussing chamber measurements of secretagogue-provoked changes in short circuit current in rectal suction biopsies of cystic fibrosis (CF) patients showed that in a minority of patients chloride secretion in response to cholinergic agonists is reduced but not completely absent. To assess a possible relationship between this phenomenon and both the genotype and the phenotype, we performed Ussing chamber experiments on rectal suction biopsies of 51 CF patients. The CF mutation was identified in 89 out of 102 CF alleles. No apparent chloride secretion was found in 30 CF patients (group I). Low residual chloride secretion was found in 11 CF patients (group II), while a relatively high residual secretion appeared in 10 CF patients (group III). Pancreatic function was preserved more frequently in CF patients displaying residual secretion: 0% in group I, 27% in group II, and 60% in group III (P < 0.001). The age at diagnosis (mean +/- SEM) in group III (18.4 +/- 6.6) was significantly different from group I (1.2 +/- 0.4, P < 0.01) and group II (3.5 +/- 1.4, P = 0.05). Residual chloride secretion was found in some of the 28 dF508 homozygous patients (three in group II, and one in group III), disclosing that other factors than the CF gene defect itself affect the transepithelial chloride transport. The age at diagnosis correlates significantly with the magnitude of the secretory response, even within the dF508 homozygous patients (r = 0.4, P < 0.05). We conclude that residual chloride secretion in CF is the pathophysiological basis of preserved pancreatic function and delayed presentation of the disease, which is not exclusively determined by the CF genotype.