Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene but the association between mutation (genotype) and disease presentation (phenotype) is not straightforward. We have been investigating whether variants in the CFTR gene that alter splicing efficiency of exon 9 can affect the phenotype produced by a mutation. A missense mutation, R117H, which has been observed in three phenotypes, was found to occur on two chromosome backgrounds with intron 8 variants that have profoundly different effects upon splicing efficiency. A close association is shown between chromosome background of the R117H mutation and phenotype. These findings demonstrate that the genetic context in which a mutation occurs can play a significant role in determining the type of illness produced.

The adenovirus E1A proteins form complexes with a group of cellular proteins, including a protein of 130 kD. EIA-associated p130 was purified through coimmunoprecipitation with EIA, and sequence data from four tryptic peptides was obtained. Oligonucleotides derived from the peptide sequences were used to clone a 4.85-kb eDNA. The eDNA contained an 1139-amino-acid open reading frame with homology to the retinoblastoma protein and E1A-associated p107 but was more closely related to p107. In vitro-translated p130 bound to E1A, and anti-p130 antibodies detected p130 in immunoblots of EIA immunoprecipitates, p130 was also detected in immunoprecipitates of cyclins A and E and was an efficient substrate in vitro for kinase activities associated with these eyclins. The p130 gene mapped to chromosome 16q12.2-13, a region that undergoes allelic loss in several types of tumors, including hepatocellular, prostate, and breast carcinomas.

No abstract

Dyspnea is a common symptom in ED patients contributing substantially to ED, hospital, and ICU workload. It is also associated with significant mortality. There are a wide variety of causes however chronic disease accounts for a large proportion.