Objective. To test whether the G-to-A polymorphism at position-308 in the promoter of the tumor necrosis factor ␣ (TNF␣) gene influences response to infliximab therapy in patients with rheumatoid arthritis (RA). Methods. We genotyped 59 RA patients by polymerase chain reaction and subdivided them into two groups: those with the A/A or A/G genotype and those with the G/G genotype. We compared the groups' clinical responses to infliximab treatment after 22 weeks, using the Disease Activity Score in 28 joints (DAS28). Results. We found that 42% of patients in the A/A and A/G group and 81% of patients in the G/G group had improvement of at least 1.2 in the DAS28 score (P ؍ 0.0086). The average improvement in the DAS28 score was 1.24 in the A/A and A/G patients and 2.29 in the G/G patients (P ؍ 0.029). Conclusion. These data suggest that patients with a TNF␣-308G/G genotype are better infliximab responders than are patients with A/A or A/G genotypes. TNF␣ ؊308 genotyping may be a useful tool for predicting response to infliximab treatment. PATIENTS AND METHODS Patients. Fifty-nine consecutive RA patients requiring infliximab therapy were included in this prospective study. All of them were enrolled in the Department of Rheumatology at La Conception Hospital in Marseille from September 2000 to January 2002. All patients fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 revised criteria for RA (8), and all had evidence of active disease, as indicated by a Disease Activity Score in 28 joints (DAS28) (9) of Ͼ3.2 despite methotrexate (MTX)
Objective. To determine whether patients with rheumatoid arthritis (RA) have elevated Epstein-Barr virus (EBV) load in their peripheral blood mononuclear cells (PBMCs) and whether it is correlated with the HLA-DR genes they express, we developed an accurate EBV DNA quantitative assay using real-time polymerase chain reaction (PCR) with fluorescent probes.Methods. We studied the EBV DNA load in the PBMCs of 84 patients with RA, 69 normal controls, and 22 patients with rheumatic conditions other than RA. A 214-bp segment from the long internal repeat of EBV was amplified from 500 ng of PBMC DNA (150,000 cells) and quantified by real-time PCR with fluorescent probes.Results. We demonstrated that in patients with RA, the EBV DNA load in PBMCs is increased almost 10-fold compared with that in normal controls. The EBV load is stable over time and is not obviously influenced by disease-modifying antirheumatic drugs or HLA-DR.Conclusion. Patients with RA have elevated EBV load in their peripheral blood.
The Salmonella dublin plasmid gene vsdC is essential for virulence. We have constructed a vsdC-lacZ translational fusion to demonstrate that vsdC is selectively expressed during the stationary phase of bacterial cell growth. This pattern of expression has been confirmed by mRNA hybridization studies. Carbon starvation is able to induce vsdC expression by limiting bacterial growth. The expression of vsdC is dependent upon an upstream gene, vsdA, whose gene product possesses significant amino-terminus homology with the LysR family of transcriptional activator proteins. We have further demonstrated that vsdC expression is not dependent upon the known Salmonella chromosomal virulence regulatory loci ompR, phoP, and cya-crp and that vsdC can be expressed in a range of nontyphoidal Salmonella serovars, including some serovars in which introduction of the virulence plasmid does not confer mouse virulence. The vsd system provides a model for the study of transcriptional activation, a basis for the development of new expression vectors, and a novel mechanism of virulence gene regulation. Bacterial growth limitation within the phagosomes of host phagocytic cells may be the environmental signal inducing plasmid-mediated virulence gene expression in salmonellae.
The virulence properties of various non-typhoid Salmonella serotypes depend on the presence of large plasmids 60-100 kb in size. We have shown previously that the virulence region on the 80 kb plasmid pSDL2 of Salmonella dublin Lane maps within a 14kb SalI fragment. In this report we show that an 8.2 kb region within this fragment is sufficient to express lethal disease in BALB/c mice. Sequence analysis of this segment revealed six sequential open reading frames designated vsdA-F, which encode putative proteins of 13-65kDa. Deletion analysis and location of Tn5-oriT inserts which abolish virulence suggest that vsdA, vsdC, vsdD and vsdE are essential for virulence expression. Downstream of vsdF we discovered a locus involved in stable plasmid maintenance. Deletion of that region resulted in plasmid multimerization and instability.
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