Hepatitis B vaccination strategies tailored to different endemicity levels: some considerations.

Hepatitis B is a serious public health problem. Worldwide three different levels of hepatitis B endemicity (high, intermediate and low) can be distinguished. Areas with different levels of endemicity require tailored vaccination strategies to fit the needs for individuals at risk and/or countries, depending on the infection risk per age group, vaccination rate, duration of protection after vaccination, cost effectiveness of vaccination strategies and ease of implementation in the national immunization schedules.This opinion paper evaluates these factors and proposes a combination of infant risk group and universal adolescent vaccination for low endemic countries thus targeting the different groups at risk. A universal infant vaccination schedule starting with a newborn vaccination within 24h after birth is more appropriate in intermediate- and high-endemic regions.

Expression of proteins correlated with the unique cisplatin-sensitivity of testicular cancer.

Cisplatin (CDDP) has a curative effect in approximately 80%, of patients with testicular cancer, in contrast to the frequent development of resistance in patients with small cell lung cancer and ovarian cancer, and to the natural resistance of colon cancer. At present it is unknown which factors explain the unique curability of testicular cancer. Since it is very likely that the absence or presence of specific proteins plays an important role in cellular sensitivity towards CDDP, we have screened the protein patterns of various human CDDP-sensitive cell lines and cell lines with acquired or intrinsic resistance to CDDP of testicular, lung and colon origin. The expression of several proteins appeared to correlate with in vitro CDDP sensitivity. The most striking difference found was a relative increase in expression lactate dehydrogenase (LDH) H-subunit expression in the germ cell lines. In testis and colon tumour samples some of these proteins, LDH-H included, also appeared to correlate with in vivo CDDP sensitivity. In the analysis of the mechanisms of drug-resistance, screening of the protein patterns of intrinsic sensitive and resistant cell lines could be a valuable approach.

Effects of low dose methotrexate therapy on the concentration and the glycosylation of alpha 1-acid glycoprotein in the serum of patients with rheumatoid arthritis: a longitudinal study.

OBJECTIVE: The concentration, and the degree of fucosylation and sialylation of human serum alpha 1-acid glycoprotein (AGP) were investigated for changes during 24-week low-dose methotrexate (MTX) or azathioprine treatment (AZA) in rheumatoid arthritis (RA) patients. METHODS: Serum samples from a longitudinal study were analyzed by crossed affinoimmunoelectrophoresis with the fucose specific Aleuria aurantia lectin. RESULTS: In general, the degree of fucosylation of AGP in RA sera was higher than in control sera, but decreased markedly under the influence of successful therapy with MTX. Concomitantly, the degree of sialylation of AGP increased and the concentration decreased. For alpha 1-protease inhibitor and haptoglobin similar results were obtained. In AZA responders less pronounced changes than in MTX responders were observed. In MTX nonresponders no significant trends were found. As in control sera, large interindividual differences in the AGP values were found. CONCLUSION: The heavy fucosylation of AGP in RA sera reflects disease activity rather than an intrinsic characteristic of people genetically predisposed to RA, since it was found to decrease upon disease improvement. The differences in effects on AGP of MTX and AZA suggest either a gradual difference in a similar mechanism of action, or a different mechanism of action of the drugs. Fucosylated and sialylated AGP could be important in the etiopathogenesis of RA, because these molecules potentially can bind to adhesion receptors (selectins), which could prevent the extravasation of leukocytes into inflamed joints.

Antimetabolite-induced increases in the invasive capacity of murine leukaemia L1210 cells.

Pretreatment of murine leukaemia L1210 cells with non-lethal concentrations of various antimetabolites increased the in vitro invasive capacity of these cells into monolayers of rat embryo fibroblasts. The increase in invasive capacity was partly correlated with the induced cell cycle arrest. The concomitant increase in cell surface fucosylation and inhibition of invasion with sulphate indicate a role for glycoproteins in this process. Our results suggest that treatment with antimetabolites may lead to a more aggressive phenotype by altering cell surface properties.

Inflammation-induced expression of sialyl Lewis X-containing glycan structures on alpha 1-acid glycoprotein (orosomucoid) in human sera.

The glycosylation of the acute phase glycoprotein alpha 1-acid glycoprotein (AGP) in human sera is subject to marked changes during acute inflammation as a result of the cytokine-induced hepatic acute phase reaction. The changes described thus far comprise alterations in the type of branching of the carbohydrate structures as revealed by increased reactivity of AGP with concanavalin A. We now report on acute inflammation-induced increases in alpha 1-->3-fucosylated AGP molecules, as detected by the reactivity of AGP towards the fucose-binding Aleuria aurantia lectin (AAL) in crossed affino-immunoelectrophoresis of human sera. Laparotomy of women, for the removal of benign tumors of the uterus, was used as a model for the development of the hepatic acute phase response. Hugh increases were detected in the amounts of strongly AAL-reactive fractions of AGP, presumably containing three or more fucosylated N-acetyllactosamine units. At least part of these Lewis X-type glycans (Gal beta 1-->[Fuc alpha 1-->3]GlcNAc-R) appeared to be substituted also with an alpha 2-->3-linked sialic acid residue. This was revealed by the laparotomy-induced abundant staining of AGP with an antisialyl Lewis X monoclonal antibody (CSLEX-1) on blots of sodium dodecyl sulfate-polyacrylamide gels containing AGP isolated from the sera of a patient at various days after operation. It is concluded that acute inflammation induces a strong increase in sialyl Lewis X-substituted AGP molecules that persists at a high level throughout the inflammatory period. We postulate that these changes represent a physiological feedback response on the interaction between leukocytes and inflamed endothelium, which is mediated via sialylated Lewis X structures and the selectin endothelial-leukocyte adhesion molecule 1.

Changes in glycosylation of L1210 cells after exposure to various antimetabolites.

This study establishes that antimetabolites do have the potency to change cellular glycosylation, as was suggested in our previous review (Eur J Cancer 1990, 26, 516-523). Murine leukaemia L1210 cells were exposed to various antimetabolites under non-lethal conditions. The antimetabolites 5-fluorouracil (5FU), arabinofuranosylcytosine (AraC), methotrexate (MTX) and 6-mercaptopurine (6MP), but not 6-thioguanine, induced considerable changes in the metabolic incorporation of radioactively labelled monosaccharides. Each antimetabolite exhibited a different effect. Significant differences were found between the radioactivity incorporated from the monosaccharides glucosamine, fucose, mannose and galactose, relative to control values. Polyacrylamide gel electrophoresis indicated that changes were induced in the glycosylation of individual glycoproteins. 5FU, AraC, MTX and 6MP all influenced both pyrimidine- and purine-mediated sugar incorporation. This excludes, therefore, direct effects of the antimetabolites on their analogue nucleotide-sugars. The antimetabolite-induced changes in glycosylation did not directly correlate with the observed cell-cycle effects of the antimetabolites.