Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium.

OBJECTIVE: Rituximab displays therapeutic benefits in the treatment of patients with rheumatoid arthritis (RA) resistant to tumor necrosis factor (TNF) blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. We undertook this study to investigate the global molecular effects of rituximab in synovial biopsy samples obtained from anti-TNF-resistant RA patients before and after administration of the drug. METHODS: Paired synovial biopsy samples were obtained from the affected knee of anti-TNF-resistant RA patients before (time 0) and 12 weeks after (time 12) initiation of rituximab therapy. Total RNA was extracted, labeled according to standard Affymetrix procedures, and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction experiments were performed to confirm the differential expression of selected transcripts. RESULTS: According to Student's paired t-tests, 549 of 54,675 investigated probe sets were differentially expressed between time 0 and time 12. Pathway analysis revealed that genes down-regulated between time 0 and time 12 were significantly enriched in immunoglobulin genes and genes involved in chemotaxis, leukocyte activation, and immune responses (Gene Ontology annotations). In contrast, genes up-regulated between time 0 and time 12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (Gene Set Enrichment Analysis). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy. CONCLUSION: Rituximab displays unique effects on global gene expression profiles in the synovial tissue of RA patients. These observations open new perspectives in the understanding of the biologic effects of the drug and in the selection of patients likely to benefit from this therapy.

[Assessment of pelvic floor muscle training programs and urinary incontinence in women: A literature Review]. / Évaluation des programmes d'entraînement musculaire du plancher pelvien et incontinence urinaire chez la femme : revue de la littérature.

OBJECTIVES: Pelvic floor rehabilitation is efficient for the first line treatment of urinary incontinence in women. However, several questions remain as regards the best pelvic floor muscle training program to recommend. The objective was perform a literature review regarding the muscular strengthening program to recommend to treat stress or mixed urinary incontinence in women. METHODS: We performed a systematic review of studies on the topic using Medline's database covering the 10 last years. Among the 1130 articles that were identified, we retained 6 for our analysis. RESULTS: Given the heterogeneity of the exercise programs, it was impossible to exhaustively and comparatively analyze their efficacies. However, a significant improvement is noted when the exercises are based on the muscular training principles of the American College of Sports Medicine. They combine long and short contractions with the practice of the knack in situations of pressure exertion and are part of a self-rehabilitation program based on the needs of the patient and the individual's progression. CONCLUSION: Current knowledge does not allow us to recommend an optimal muscle training program to treat female urinary incontinence. Research must be conducted to evaluate different muscular training regimens but also their integration into a program based on personal needs as well as factors of adherence to the treatment of patients.

High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival.

We have identified an antigen recognized by autologous CTL on the lung carcinoma cells of a patient who enjoyed a favorable clinical evolution, being alive 10 years after partial resection of the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts malate to pyruvate. In the tumor cell line derived from the patient, only the mutated malic enzyme allele is expressed, because of a loss of heterozygosity in the region of chromosome 6 that contains this locus. Tetramers of soluble HLA-A2 molecules loaded with the antigenic peptide stained approximately 0.4% of the patient's blood CD8 T cells. When these cells were stimulated in clonal conditions, 25% of them proliferated, and the resulting clones were lytic and specific for the mutated malic enzyme peptide. T-cell receptor analysis indicated that almost all of these antimalic CTLs shared the same receptor. Antimalic T cells were consistently found in blood samples collected from the patient between 1990 and 1999, at frequencies ranging from 0.1 to 0.4% of the CD8 cells. Their frequency appeared to double within 2 weeks after intradermal inoculation of lethally irradiated autologous tumor cells. These results indicate that nonmelanoma cancer patients may also have a high frequency of blood CTLs directed against a tumor-specific antigen.

Age-specific modulation of light production potential, and alkaline phosphatase and protein tyrosine kinase activities in various age mutants of Caenorhabditis elegans.

Previous work has shown that reduction-of-function mutations in the genes daf-2 and age-1 can increase adult life (Age phenotype) of Caenorhabditis elegans and that certain daf-12 alleles considerably amplify this effect in daf-2; daf-12 doubles. We have measured the light production potential (LPP) and alkaline phosphatase (ALP) and protein tyrosine kinase (PTK) activity levels as suitable biochemical markers to further investigate genetic interactions between these genes. The light production assay measures superoxide anion production by freeze-thawed worms in assay medium containing sufficient amounts of nicotineamide adenine dinucleotide, reduced form (NADH) and nicotineamide adenine dinucleotide phosphate, reduced form (NADPH) to drive the chemiluminescent reaction at maximal speed, and 5 mM cyanide to fully repress cytosolic superoxide dismutase (SOD). This assay thus provides an estimate of the maximum output of the metabolic pathways involved at the instant of freeze-fixation, and under the condition of the assay. LPP and PTK activities decreased similarly in daf-12(m20), and a control strain that had wild-type alleles of daf-12, age-1, and daf-2. The age-dependent decrease of LPP and PTK was reduced in age-1(hx542) and age-1(hx542); daf-2(e1370), and virtually absent in daf-2(e1370) and daf-2(e1370); daf-12(m20) mutant worms. ALP activity increased with age in non-Age genotypes and showed little, if any, age-dependent alteration in daf-2(e1370) and daf-2(e1370); daf-12(m20) mutant worms. Mutation in both age-1 and daf-2 caused no stronger phenotype than a single mutation as estimated by LPP, PTK, and ALP. We propose that (a) daf-2 is the major effector of metabolic activity during adult life, (b) daf-2 downregulates metabolic activity with increasing age, and (c) daf-12 stimulates oxygen consumption independently of daf-2.