[Inframunicipality distribution of lung cancer in the urban area of Grenoble]. / Distribution infracommunale du cancer du poumon dans l'agglomération grenobloise.

BACKGROUND: Mapping a Cancer Atlas for the urban area of Grenoble revealed spatial distribution in the incidence of lung cancer among males at municipality level. Thus, our goal in this work was to use a new finer spatial scale to find out whether or not observed spatial variations might mask intramunicipality spatial variations. METHODS: The use of a Bayesian smoothing approach allowed us to overcome problems related to the very small inframunicipality scale and to take into account the spatial autocorrelation existing between neighbouring units. The relative risks were adjusted on different socioeconomic variables like the median income per consumption unit. RESULTS: After smoothing, areas with statistically significant 30 to 40% excess of cases and lack of cases were identified within the urban area of Grenoble. Median income per consumption unit appeared to be the most discriminating variable for characterizing the studied population. CONCLUSION: The inframunicipality scale enables the study of a health problem as the lung cancer within a context of strong demographic disparities.

The effect of Theiler's murine encephalomyelitis virus (TMEV) VP1 carboxyl region on the virus-induced central nervous system disease.

Members of the Theiler's murine encephalomyelitis virus GDVII subgroup, which includes GDVII strain, are highly neurovirulent and induce a rapidly fatal polioencephalomyelitis. By contrast, Theiler's original subgroup members, which includes DA strain, are not as neurovirulent, and produce a chronic, demyelinating disease with virus persistence. We investigated the importance of the carboxyl region of the capsid protein VP1 in TMEV-induced disease since a trypsin-cleavable immunodominant neutralization epitope is situated in the VP1 carboxyl region, and since this region is believed to lie adjacent to the putative receptor binding site. The present studies support the role of DA VP1 residue 268 (and the aligned GDVII VP1 270) in Theiler's murine encephalomyelitis virus-induced CNS disease; however, the effect of this residue varies depending on its context: mutation of DA VP1 268 attenuates demyelination; mutation of GDVII VP1 270 in a GDVII/DA recombinant virus has no effect on demyelination but reduces early deaths (neurovirulence); mutation of GDVII VP1 270 in GDVII virus has no effect on neurovirulence. These data suggest that DA VP1 268/GDVII VP1 270 are not functionally equivalent and that a residue in recombinant viruses can differ in function from the same residue situated in a parental strain. Additional mutagenesis studies suggest that: the trypsin cleavage site of TMEV, which affects virus viability, is located at the lysine at DA VP1 261 (GDVII VP1 263); GDVII VP1 276, the predicted carboxyl terminus of VP1, affects VP1/2A processing and virus infectivity.

A single amino acid change determines persistence of a chimeric Theiler's virus.

The DA strain of Theiler's virus persists in the central nervous system of mice and causes chronic inflammation and demyelination. On the other hand, the GDVII strain causes an acute encephalitis and does not persist in surviving animals. Series of recombinants between infectious cDNA clones of the genomes of DA and GDVII viruses have been constructed. The analysis of the phenotypes of the recombinant viruses has shown that determinants of persistence and demyelination are present in the capsid proteins of DA virus. Chimeric viruses constructed by the different research groups gave consistent results, with one exception. Chimeras GD1B-2A/DAFL3 and GD1B-2C/DAFL3, which contain part of capsid protein VP2, capsid proteins VP3 and VP1, and different portions of P2 of GDVII in a DA background, were able to persist and cause demyelination. Chimera R4, whose genetic map is identical to that of GD1B-2A/DAFL3, was not. After exchanging the viral chimeras between laboratories and verifying each other's observations, new chimeras were generated in order to explain this difference. Here we report that the discrepancy can be attributed to a single amino acid difference in the sequence of the capsid protein VP2 of the two parental DA strains. DAFL3 (University of Chicago) and the chimeras derived from it, GD1B-2A/DAFL3 and GD1B-2C/DAFL3, contain a Lys at position 141, while TMDA (Institut Pasteur) and R4, the chimera derived from it, contain an Asn in that position. This amino acid is located at the tip of the EF loop, on the rim of the depression spanning the twofold axis of the capsid. These results show that a single amino acid change can confer the ability to persist and demyelinate to a chimeric Theiler's virus, and they pinpoint a region of the viral capsid that is important for this phenotype.

Chimeric cDNA studies of Theiler's murine encephalomyelitis virus neurovirulence.

Strain GDVII and other members of the GDVII subgroup of Theiler's murine encephalomyelitis virus are highly neurovirulent and rapidly fatal, while strain DA and other members of the TO subgroup produce a chronic, demyelinating disease. GDVII/DA chimeric cDNA studies suggest that a major neurovirulence determinant is within the GDVII 1B through 1D capsid protein coding region, although the additional presence of upstream GDVII sequences, including the 5' untranslated region, contributes to full neurovirulence. Our studies indicate that there are limitations in precisely delineating neurovirulence determinants with chimeric cDNAs between evolutionarily diverged viruses, such as GDVII and DA.

Theiler's murine encephalomyelitis virus neutralization escape mutants have a change in disease phenotype.

DA strain of Theiler's murine encephalomyelitis virus produces a persistent demyelinating infection. We previously produced escape mutant viruses that are resistant to a neutralizing monoclonal antibody and have a mutation in VP1 amino acid residue 268 in a neutralization site (Y. Ohara, A. Senkowski, J. Fu, L. Klaman, J. Goodall, M. Toth, and R.P. Roos, J. Virol. 62:3527-3529, 1988). In contrast to wild-type DA strain, these escape mutants produce little if any demyelinating disease after inoculation into weanling mice.

Trypsin-sensitive neutralization site on VP1 of Theiler's murine encephalomyelitis viruses.

We generated Theiler's murine encephalomyelitis virus mutants resistant to several neutralizing monoclonal antibodies (MAbs) having their epitopes near a trypsin cleavage site of VP1. Neutralization and Western blot (immunoblot) studies suggest that two of the MAbs have identical epitopes that partly overlap the epitope of a third MAb. Sequencing of RNA of the mutants localized the epitopes to a site near the carboxyl end of VP1. The limited diversity of nucleotide changes seen in the mutants and the immunodominance of the site suggest that the carboxyl end of VP1 may have an important function.