The effects of aminosalicylic acid derivatives on nitric oxide in a cell-free system

Aims and Methods: To determine the effect of aminosalicylic acid derivatives on the concentration of nitric oxide produced in a cell-free system, by the use of a sensitive and specific polarographic meter. Results: The aminosalicylic acid derivatives 3-ASA (IC₅₀ 100 μm ), 4-ASA (IC₅₀ 350 μm ) and 5-ASA (IC₅₀ 5 μm ) all decreased the nitric oxide signal. These drugs had a similar inhibitory effect on the formation in vitro of nitrite from sodium nitroprusside (IC₅₀ 200 μm , 500 μm and 100 μm , respectively). Sulphasalazine (31.1 ± 5% decrease in signal at 1 mm ) was less effective than 5-ASA, but sulphapyridine, N-acetyl 5-ASA, indomethacin and hydrocortisone produced no decrease in nitric oxide signal at all. Conclusions: Nitric oxide binding may be part of the mechanism by which ASA derivatives exert their therapeutic effect, and this work suggests that it may be an important factor in the pathogenesis of ulcerative colitis.     

Protecting persons with severe cognitive and mental disorders: An analysis of public conservatorship in Los Angeles County,California

The purpose of this article is to begin the identification of factors that place older adults at risk for conservatorship. This study, conducted on a sample of 2,151 adult public conservatees in Los Angeles, examines the characteristics of conservatees in the civil commitment (n 1,565) and Probate (n 566) programs. A subsample of conservatees aged 70 and above (n 623) was selected for comparison to a nationally representative sample of adults aged 70 and above (n 8,223). Findings show marked differences between the two types of conservatorship, with characteristics of young conservatees similar to those in the civil commitment program, and older conservatees similar to those in the Probate program. Compared to older adults nationwide, older public conservatees (70 ) are much older, more likely to suffer from dementia, to be physically impaired, and far less affluent than their nationwide counterparts. In addition, older conservatees are less likely to have available family members, implying social isolation as a risk factor for public conservatorship. A small number (n 10) of conservatees were identified who do not appear to have any risk factors for conservatorship. Rather, these conservatees (less than 0.5% of the sample) 'age in place' without documented need for conservatorship.     

Fmoc/solid-phase synthesis of Tyr(P)-containing peptides through t-butyl phosphate protection

The synthesis is of Tyr(P)-containing peptides by the use of Fmoc-Tyr(PO₃Me₂)-OH in Fmoc/solid phase synthesis is complicated since, firstly, piperidine causes cleavage of the methyl group from the -Tyr(PO₃ Me₂)-residue during peptide synthesis and, secondly, harsh conditions are needed for its final cleavage. A very simple method for the synthesis of Tyr(P)-containing peptides using t-butyl phosphate protection is described. The protected phosphotyrosine derivative, Fmoc-Tyr(PO₃^tBu₂)-OH was prepared in high yield from Fmoc-Tyr-OH by a one-step procedure which employed di-t-butyl N,N-diethyl-phosphoramidite as the phosphorylation reagent. The use of this derivative in Fmoc/solid phase peptide synthesis is demonstrated by the preparation of the Tyr(P)-containing peptides, Ala-Glu-Tyr(P)-Ser-Ala and Ser-Ser-Ser-Tyr(P)-Tyr(P).     

Distribution of matrix metalloproteinases and their inhibitor, TIMP-1, in developing human osteophytic bone

Connective tissues synthesise and secrete a family of matrix metalloproteinases (MMPs) which are capable of degrading most components of the extracellular matrix. Animal studies suggest that the MMPs play a role in bone turnover. Using specific polyclonal antisera, immunohistochemistry was used to determine the patterns of synthesis and distribution of collagenase (MMP-1), stromelysin (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) and of the tissue inhibitor of metalloproteinases-1 (TIMP-1) within developing human osteophytic bone. The different MMPs and TIMP showed distinct patterns of localisation. Collagenase expression was seen at sites of vascular invasion, in osteoblasts synthesising new matrix and in some osteoclasts at sites of resorption. Chondrocytes demonstrated variable levels of collagenase and stromelysin expression throughout the proliferative and hypertrophic regions, stromelysin showing both cell-associated and strong matrix staining. Intense gelatinase B expression was observed at sites of bone resorption in osteoclasts and mononuclear cells. Gelatinase A was only weakly expressed in the fibrocartilage adjacent to areas of endochondral ossification. There was widespread but variable expression of TIMP-1 throughout the fibrous tissue, cartilage and bone. These results indicate that MMPs play a role in the development of human bone from cartilage and fibrous tissue and are likely to have multiple functions.