Thyroid hormone (T3)-modification of polyethyleneglycol (PEG)-polyethyleneimine (PEI) graft copolymers for improved gene delivery to hepatocytes.

Targeting of gene vectors to liver hepatocytes could offer the opportunity to cure various acquired and inherited diseases. Efficient gene delivery to the liver parenchyma has been obscured from efficient targeting of hepatocytes. Here we show that the thyroid hormone, triiodothyronine (T3), can be used to improve the gene transfer efficiency of nonviral gene vectors to hepatocytes in vitro and to the liver of mice in vivo. T3 conjugated to the distal ends of fluorescent labeled PEG-g-dextran resulted in T3-specific cellular endosomal uptake into the hepatocellular cell line HepG2. PEG-g-PEI graft copolymers with increasing molar PEG-ratios were synthesized, complexed with plasmid DNA, and transfected into HepG2 or HeLa cells. Gene transfer efficiency decreased as the number of PEG blocks increased. T3 conjugation to PEI and the distal ends of PEG blocks resulted in T3 specific gene transfer in HepG2 cells as evidenced by reduction of gene transfer efficiency after pre-incubation of cells with excess of T3. In vivo application of T3-PEG-g-PEI based gene vectors in mice after tail vein injection resulted in a significantly 7-fold increase of gene expression in the liver compared with PEG-g-PEI based gene vectors.

Towards improving the accuracy of diagnosing asthma in early childhood.

OBJECTIVES: Early and correct diagnosis of asthma in wheezing children is essential for early treatment and prevention of under- or over-treatment. The aim was to study whether combining frequency and age of onset of wheezing illness with respiratory and atopic morbidity at age 0-6 years and sociodemographic parameters for asthma might be helpful for the general practitioner to diagnose asthma early and accurately. METHODS: Birth cohort, mean follow-up 20 years (SD 4.8) in general practice. The outcome, adolescent asthma, was analysed in relation to wheezing and non-wheezing respiratory and personal and familial atopic morbidity. All diagnoses were from the Continuous Morbidity Registration of the Department of General Practice of the University of Nijmegen, the Netherlands. RESULTS: 1586 (64%) of the children could be followed. Adolescent asthma occurred in 6.4%. There were indications for under- and over-diagnosis of asthma at age 0-6 years. Non-recurrent wheezing (only one episode) and recurrent wheezing (>or =2 episodes) in the first three years of life, and recurrent wheezing at age 4-6 increased the risk with odds ratios (95% confidence interval) of 3.3 (1.9-5.6), 4.7 (2.8-8.2) and 15.4 (7.1-33.7), respectively. The risk additionally increased independently with a family history for asthma, (2.0 [1.1-3.6]), atopic dermatitis (1.7 [1.1-2.7]) and sinusitis (2.9 [1.3-6.4]) and decreased for > or =2nd born children (0.38 [0.19-0.47]) and those with a low social-economic status (0.61 [0.39-0.94]). CONCLUSION: Easily available history and clinical data may facilitate the early diagnosis of asthma in children with wheezing illness.

Environmental exposure reduction in high-risk newborns: where do we start?

BACKGROUND: When analyzing the effect of environmental exposure reduction measures on asthma in high-risk children, one must know how far asthmatic families already have applied such measures, because this would affect the effectiveness and efficiency of interventions aimed at reducing environmental exposure. OBJECTIVE: To describe the room for improvement by asthmatic families in mite, pet, and food allergen reducing measures and in parental passive smoking and to determine the resulting levels of mite and pet allergens by the applied sanitation measures. METHODS: Data were sampled by observation, weekly diary entries, and questionnaire when the infant was 6 months old and 1 year old. Dust samples were collected by vacuuming the living room floor and the parental and infant mattresses. Multiple logistic regression analyses were applied with the use of mattress encasing, having a smooth floor covering, having pets, exclusive breast-feeding and/or hypoallergenic formula during the infant's first 6 months, and passive smoking as the dependent variables. RESULTS: Frequencies of applied measures were as follows: having a smooth floor covering, 36%; daily house cleaning, 27%; use of parental and infant antimite mattress encasings, 13% and 9%, respectively; keeping no pets, 66%; no cow's milk-based regular formula, 13%; no solid foods in the first 6 months of life, 28%; and abstinence of smoking by the mother prenatally, 89%; by the mother postnatally, 85%; and by her partner, 76%. Having a smooth floor covering and daily cleaning but not use of antimite mattress encasings resulted in significantly lower mite and pet allergen levels. CONCLUSIONS: There is (still) enough room for improvement to reduce exposure to inhalant and food allergens, especially by application of mattress encasings, exclusive breast-feeding and/or hypoallergenic formula feeding, and postponing the time until first solids are given.