ABSTRACT
We report on a measles outbreak originating in an anthroposophic community in Austria, 2008. A total of 394 (94.9%) cases fulfilled the outbreak case definition including 168 cases affiliated to the anthroposophic community. The source case was a school pupil from Switzerland. The Austrian outbreak strain was genotype D5, indistinguishable from the Swiss outbreak strain. A school-based retrospective cohort study in the anthroposophic school demonstrated a vaccine effectiveness of 97.3% in pupils who had received a single dose of measles-containing vaccine and 100% in those who had received two doses. The vaccination coverage of the cases in the anthroposophic community was 0.6%. Of the 226 outbreak cases not belonging to the anthroposophic community, the 10-24 years age group was the most affected. Our findings underline the epidemiological significance of suboptimal vaccination coverage in anthroposophic communities and in older age groups of the general population in facilitating measles virus circulation. The findings of this outbreak investigation suggest that the WHO European Region is unlikely to achieve its 2010 target for measles and rubella elimination.
Subject(s)
Disease Outbreaks , Measles/epidemiology , Adolescent , Adult , Age Distribution , Austria/epidemiology , Child , Child, Preschool , Humans , Infant , Middle Aged , Minority Groups , Retrospective Studies , Schools , Young AdultABSTRACT
Recent evidence has shown that missense mutations in the p53 tetramerisation domain can inactivate the protein. However, most of these studies have been done only in vitro or concern proteins whose physico-chemical properties have not been fully investigated. Alanine mutants of the beta-strand 326-333 from the tetramerisation domain have been characterized in vitro and studied for their thermodynamic stability. They therefore offer a unique opportunity to establish a correlation between in vitro and cellular activities of proteins with a mutated tetramerisation domain. The eight mutant proteins resulting from the mutation of the eight residues of the beta-strand 326-333 to alanine were analysed for their ability to stimulate transcription, to inhibit the growth of Saos-2 cells and to repress the promoter of the multidrug resistance gene 1. The experimental results show a perfect correlation between in vitro and cellular data. The Leu330Ala and Ile332Ala proteins are inactive, the Phe328Ala protein has a moderate activity. The Glu326Ala, Tyr327Ala, Thr329Ala, Gln331Ala and Arg333Ala proteins show activity similar to that of wild-type protein. This work is based on an exhaustive analysis of p53 mutants both in vitro and in cells and shows that mutations in the tetramerisation domain might be of importance in cancer development since they inactivate the p53 protein.
Subject(s)
Genes, p53/genetics , Genes, p53/physiology , Mutation, Missense , Cell Division/genetics , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , Genes, MDR/genetics , Humans , Models, Molecular , Protein Structure, Secondary , Thermodynamics , Transcription, GeneticABSTRACT
p53 is altered in about 50 % of cancers. Most of the p53 mutants have lost the wild-type tumour suppressor activity but show oncogenic properties. The majority of the p53 alterations are missense mutations of residues located in its DNA binding domain (DBD). Only a few mutations concern residues in its tetramerisation domain (TD). However, the study of mutant proteins identified in tumors that do not form tetramers has shown that they have lost the wild-type activity like most of the p53 DBD mutants. Here, we show that two of such mutant proteins, Arg342Pro and Leu344Pro are not dominant negative and do not stimulate the expression of a reporter gene under the control of the multi-drug resistance gene-1 (MDR-1). This suggests that to be oncogenic, p53 mutants need to form tetramers. Accordingly, the dominant negative effect and the ability of a tetrameric mutant protein, Asp281Gly, to stimulate the MDR-1 promoter are abolished when its TD is rendered non-functional by the mutation of leucine 344 to a proline residue. These results suggest that mutations in the TD, are less selected in tumors than mutations in the DBD because they do not lead to oncogenic proteins.
Subject(s)
Genes, p53 , Mutation , Neoplasms/genetics , Tumor Suppressor Protein p53/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Amino Acid Substitution , Genes, Dominant/genetics , Humans , Neoplasms/etiology , Oligodeoxyribonucleotides/genetics , Oligodeoxyribonucleotides/metabolism , Osteosarcoma , Phenotype , Precipitin Tests , Promoter Regions, Genetic/genetics , Protein Binding , Protein Biosynthesis , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Response Elements/genetics , Transfection , Tumor Cells, Cultured , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/geneticsABSTRACT
Following a brief presentation of a few significant data and specifications in respect of the structure and organisation of the Austrian Public Health administration, general basic rules for across-the-border cooperation in the region of Lake Constance are outlined. The following subjects for such cooperation are listed: epidemiology and how to fight spring-summer meningoencephalitis, rabies, echinococcosis, AIDS/HIV. Other areas of cooperation are, for example. Health protection within the framework of prostitution, drugs and drug substitution, states of emergency (natural or other catastrophes), incidents or cases or topics concerning pharmaceuticals, pharmacology or pharmacies in general, and especially environmental protection and protection of natural resources in connection with the large drinking water reservoir Lake Constance. Future perspectives are roughly sketched in respect of possible closer cooperation and communication if occasion arises.
