In order to investigate the generation and selection of hepatitis B virus mutants and the influence of interferon on their evolution, a longitudinal study including 22 patients was performed. The complete preS1/S2 open reading frame was analyzed by direct sequencing from serum samples obtained before and after seroconversion to anti-HBe in 11 children without alpha-interferon treatment. Furthermore, in 11 cases with therapy additional samples obtained during interferon therapy were investigated. The comparison of each patient's preS sequences analyzed before and during therapy did not show any nucleotide change, while in both groups numerous silent and missense mutations were found immediately after seroconversion. Surprisingly, in 7 cases the hepatitis B virus changed genotype from A to D (subtype adw to ayw) after seroconversion. Additional rearrangements were observed in 4 patients. In 3 cases the selection of preS2 start codon mutants was detected after seroconversion and in 1 individual a 183-nucleotide deletion was found during and after HBeAg positivity. In conclusion, the emergence of preS rearrangements and numerous base exchanges provide evidence for a strong selection process focused against the preS region. Moreover, the appearance of genotype changes after anti-HBe seroconversion reveales a thus far unrecognized event during the natural course of HBV infection in childhood.

Our data prove that TT virus is efficiently transmitted transplacentally. The increase of its prevalence in the group of newborns older than 1 week suggests that it may be furthermore transmitted postnatally. Therefore in our Caucasian population, vertical transmission, particularly in utero transmission, of TTV is likely to account for a major part of TTV infection in early childhood. However, no disease activity could be established for the novel virus by this infection route.

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Alveolar macrophages (AM) play a decisive role in the immunologic defense system of the lung and in inflammatory pulmonary pathomechanisms. AM and blood monocytes (BM) were exposed to chrysotile B, soot FR 101, and Printex 90 (P 90). We evaluated the reactive oxygen intermediate (ROI) release of AM and BM after particle exposure. ROI release was measured by chemiluminescence. Thirty-minute exposure caused a significant (up to 2.5-fold) increase in ROI release of AM (100 micrograms/10(6) cells) compared with control experiments (p < 0.01). Identical exposure conditions for BM resulted in a similar reaction pattern (maximum 2.2-fold increase in ROI release; p < 0.05). After a 90-min particle exposure at concentrations of 10 and 100 micrograms/10(6) cells, we investigated the steady-state level of p50/p105 mRNA encoding for the precursor protein of the p50 subunit of nuclear factor kappa B (NF-kappa B) by semiquantitative reverse transcription-polymerase chain reaction. One hundred micrograms Chrysotile B, FR 101, or P 90 induced a significant maximum 4.0-fold up-regulation of NF-kappa B gene expression in AM and a 3.3-fold up-regulation in BM (p < 0.05). The addition of superoxide dismutase (200 U/ml) to particle- and fiber-exposed macrophages resulted in inhibition of ROI release and a decrease in NF-kappa B mRNA expression (70%). NF-kappa B is an important transcription factor involved in the regulation of numerous genes (e.g., for inflammatory cytokines, and cytokine receptors). These cytokines are supposed to be involved in inflammatory pathomechanisms in bronchial epithelial cells, which result, for example, in chronic obstructive pulmonary disease. Our results suggest that particle-induced ROI release is associated with an increase in NF-kappa B (p50/p105) mRNA steady-state level.

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