The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

Practice parameters for the indications for polysomnography and related procedures: an update for 2005

These practice parameters are an update of the previously-published recommendations regarding the indications for polysomnography and related procedures in the diagnosis of sleep disorders. Diagnostic categories include the following: sleep related breathing disorders, other respiratory disorders, narcolepsy, parasomnias, sleep related seizure disorders, restless legs syndrome, periodic limb movement sleep disorder, depression with insomnia, and circadian rhythm sleep disorders. Polysomnography is routinely indicated for the diagnosis of sleep related breathing disorders; for continuous positive airway pressure (CPAP) titration in patients with sleep related breathing disorders; for the assessment of treatment results in some cases; with a multiple sleep latency test in the evaluation of suspected narcolepsy; in evaluating sleep related behaviors that are violent or otherwise potentially injurious to the patient or others; and in certain atypical or unusual parasomnias. Polysomnography may be indicated in patients with neuromuscular disorders and sleep related symptoms; to assist in the diagnosis of paroxysmal arousals or other sleep disruptions thought to be seizure related; in a presumed parasomnia or sleep related seizure disorder that does not respond to conventional therapy; or when there is a strong clinical suspicion of periodic limb movement sleep disorder. Polysomnography is not routinely indicated to diagnose chronic lung disease; in cases of typical, uncomplicated, and noninjurious parasomnias when the diagnosis is clearly delineated; for patients with seizures who have no specific complaints consistent with a sleep disorder; to diagnose or treat restless legs syndrome; for the diagnosis of circadian rhythm sleep disorders; or to establish a diagnosis of depression.     

Differential regulation of mast cell cytokines by both dexamethasone and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580

Activated mast cells generate multiple cytokines but it is not known if these can be differentially regulated by pharmacological agents. We report here that the glucocorticoid dexamethasone (DEX) preferentially inhibited Ag-induced expression of IL-4 and IL-6 mRNA relative to TNF-alpha mRNA in RBL-2H3 cells. Likewise, the drug more readily inhibited release of IL-4 than TNF-alpha protein. SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), enhanced Ag-induced TNF-alpha mRNA expression without affecting IL-4 or IL-6 mRNA. At the protein level, SB203580 exerted little effect on TNF-alpha release but inhibited IL-4 release; notably, the ratio of TNF-alpha : IL-4 increased markedly with the concentration of SB203580, confirming the differential regulation of these cytokines. PD98059, an inhibitor of MAPK kinase (MEK), a component of the p44/42 MAPK pathway, partially inhibited Ag-induced expression of mRNA for all three cytokines while cyclosporin A inhibited Ag-induced IL-4 and IL-6 mRNA more readily than TNF-alpha mRNA. Ag activation of the cells led to phosphorylation of p38 and p44/42 MAPK but this was not influenced by DEX. In conclusion, mast cell cytokines can be differentially regulated pre- and post-translationally by DEX and SB203580 but there does not appear to be a direct mechanistic link between the actions of these two drugs.     

Experimental analysis of the annotation of promoters in the public database

The ability to identify and examine promoter elements is important to researchers who wish to understand how gene expression is regulated in normal and pathological states. Unfortunately, the number of human promoters that have been directly experimentally defined is small. In order to determine if promoter sequences can be identified by simply aligning mRNA and genomic sequences, we have used a reporter gene assay to assess the promoter activity of the immediate 5' region flanking 38 mRNAs mapping to chromosome 21. For comparison, we have measured the activities of 19 sequences not thought to be promoters and 39 sequences taken from the Eukaryotic Promoter Database. Our results suggest that alignment of reference mRNAs to genomic sequence allows promoters to be identified for at least 75% of genes. These data provide the first empirical evidence that the current state of annotation of the genome is sufficient to allow molecular geneticists to correctly identify promoter sequences for most genes for which reference mRNA and genomic sequences are available.     

Immunopathologic Role of Proteoglycan Antigens in Rheumatoid Joint Disease

Cell-mediated immunity to proteoglycan antigens was assessed by leucocyte migration inhibition and by lymphocyte stimulation tests in patients with rheumatoid arthritis or with ankylosing spondylarthritis, in patients with relapsing synovitis after a single trauma to their knee joints, and in healthy donors. Both tests revealed a sensitization in most of the patients examined with various proteoglycan antigens derived from human cartilaginous tissues, rheumatoid synovial fluid, and species-common antigen of bovine nasal cartilage. Anybodies against proteoglycan antigens of human articular cartilage were detected by solid-phase radioimmunoassay in eleven out of twenty-nine sera from patients with rheumatoid arthritis and in four out of six rheumatoid synovial fluids. The results suggest that the cartilage antigenic components released by an inflammatory process or trauma may trigger a vicious circle of chronic inflammation and joint destruction.     

Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347-355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.