Blockade of antigen nonspecific costimulatory signals is a promising approach for the treatment of autoimmune diseases including systemic lupus erythematosus (SLE). CTLA4Ig, an antagonist of the CD28/B7 costimulatory interaction, effectively prevents SLE onset in several murine models and, when used in combination with cyclophosphamide, can induce remission of active SLE nephritis. In this review we describe the known mechanisms of action of CTLA4Ig both in normal immunity and in autoimmune disease models and address issues about its activity that still need to be resolved. We discuss the preclinical use of CTLA4Ig in murine SLE models and the rationale for a clinical trial in SLE patients.

Clinical trials show that hormone therapy (HT) is an effective treatment for vasomotor symptoms and vaginal dryness. HT improves other symptoms including sleep and quality of life in women who have menopause symptoms. In the Women's Health Initiative controlled clinical trials, both estrogen therapy (ET) and estrogen plus progestin therapy (EPT) reduced fracture risk, neither reduced the risk of heart disease, and both increased the risk of stroke, deep vein thrombosis, and dementia. EPT, but not ET, increased breast cancer risk and reduced colon cancer risk. Differences between EPT and ET may reflect chance, baseline differences between the EPT and ET cohorts, or a progestin effect. Studies of younger women and lower HT doses with intermediate endpoints are beginning.

We here report the cDNA sequences of 11 new rat Ly49 genes with full and three with incomplete open reading frames. Although obtained from different inbred rat strains, these as well as six previously published cDNA represent non-allelic genes matching different loci in the Brown Norway (BN) rat genome, which is predicted to contain 34 Ly49 loci distributed over the distal part of the NK cell gene complex. Some of the cloned genes appear to be mutated to non-function in the BN genome, which harbors additional genes with full open reading frames, suggesting at least 26 non-allelic functional Ly49 genes in the rat. Of the encoded receptors, 13 are predicted to be inhibitory, eight to be activating, whereas five may be both ('bifunctional'). Phylogenetic analysis bears evidence of a highly dynamic genetic region, in which only the most distally localized Ly49 gene has a clear-cut mouse ortholog. In phylograms, the majority of the genes cluster into three subgroups with the genes mapping together, defining three chromosomal regions that seem to have undergone recent expansions. When comparing the lectin-like domains, the receptors form smaller subgroups, most containing at least one inhibitory and one activating or 'bifunctional' receptor, where close sequence similarities suggest recent homogenization events.

BACKGROUND

The usefulness of currently available colon imaging tests, including air contrast barium enema (ACBE), computed tomographic colonography (CTC), and colonoscopy, to detect colon polyps and cancers is uncertain. We aimed to assess the sensitivity of these three imaging tests.

METHODS

Patients with faecal occult blood, haematochezia, iron-deficiency anaemia, or a family history of colon cancer underwent three separate colon-imaging studies--ACBE, followed 7-14 days later by CTC and colonoscopy on the same day. The primary outcome was detection of colonic polyps and cancers. Outcomes were assessed by building an aggregate view of the colon, taking into account results of all three tests.

FINDINGS

614 patients completed all three imaging tests. When analysed on a per-patient basis, for lesions 10 mm or larger in size (n=63), the sensitivity of ACBE was 48% (95% CI 35-61), CTC 59% (46-71, p=0.1083 for CTC vs ACBE), and colonoscopy 98% (91-100, p<0.0001 for colonoscopy vs CTC). For lesions 6-9 mm in size (n=116), sensitivity was 35% for ACBE (27-45), 51% for CTC (41-60, p=0.0080 for CTC vs ACBE), and 99% for colonoscopy (95-100, p<0.0001 for colonoscopy vs CTC). For lesions of 10 mm or larger in size, the specificity was greater for colonoscopy (0.996) than for either ACBE (0.90) or CTC (0.96) and declined for ACBE and CTC when smaller lesions were considered.

INTERPRETATION

Colonoscopy was more sensitive than other tests, as currently undertaken, for detection of colonic polyps and cancers. These data have important implications for diagnostic use of colon imaging tests.