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Biomedical subjects

D L Scott

Publications and source records attributed to D L Scott.

At least 19 recordsLinked to original sources
PubMed1992

Crystallographic and biochemical studies of the (inactive) Lys-49 phospholipase A2 from the venom of Agkistridon piscivorus piscivorus.

Chemical, genetic, and structural studies have defined a critical role for Asp-49 in the calcium-mediated activation of extracellular phospholipases A2 (PLA2). In 1984, a new class of PLA2 was isolated in which this invariant aspartate was replaced with a lysine (Maragnore, J.M., Merutka, G., Cho, W., Welches, W., Kezdy, F.J., and Heinrikson, R.L. (1984) J. Biol. Chem. 259, 13839-13843; Maragnore, J.M., and Heinrikson, R.L. (1986) J. Biol. Chem. 261, 4797-4804). The enzymatic activity of Lys-49 PLA2s has been questioned based on biochemical, mutational, and structural studies (van den Bergh, C.J., Slotboom, A.J., Verheij, H.M., and de Haas, G.H. (1988) Eur. J. Biochem. 176, 353-357). In this paper, we describe the structures of two crystal forms of the Lys-49 PLA2 isolated from the venom of Agkistridon piscivorus piscivorus. The refined models, along with complementary biochemical analysis, clarify the structural basis for the enzymatic inactivity of Lys-49 proteins.

Amino Acid Sequence↗
PubMed1992

Increased DNA strand breaks in mononuclear cells from patients with rheumatoid arthritis.

Immune dysfunction is linked with lymphocyte DNA metabolism. In particular, DNA damage may impair lymphocyte function and induce increased cell turnover; such changes are of relevance to the pathogenesis of rheumatoid arthritis. The rate of DNA unwinding in alkaline solution was used as a measure of the number of DNA strand breaks in mononuclear cells freshly isolated from peripheral blood. The rate of DNA unwinding was significantly increased in cells from patients with rheumatoid arthritis compared with those from healthy subjects and from patients with other autoimmune and connective tissue diseases. These findings support the hypothesis that DNA damage is increased in patients with rheumatoid arthritis and it is one factor contributing to immune dysfunction in this disease.

Adolescent↗
PubMed1992

Keratan sulphate in rheumatoid arthritis, osteoarthritis, and inflammatory diseases.

Serum concentrations of antigenic keratan sulphate determined by an enzyme linked immunosorbent assay (ELISA) with a monoclonal antibody were studied in patients with rheumatoid arthritis (RA), osteoarthritis, ankylosing spondylitis, other inflammatory diseases, and a large control group of women without arthritis. Mean keratan sulphate concentrations were low in 117 women with RA compared with 227 female control subjects matched for age drawn from a community survey. There were significant correlations between serum keratan sulphate concentrations in patients with RA and serum C reactive protein and the erythrocyte sedimentation rate. Serum keratan sulphate concentrations were also low in 29 men and women with ankylosing spondylitis and 29 patients with arthritis and high concentrations of C reactive protein. In 98 women undergoing an operation for benign breast disease there were decreases in serum keratan sulphate concentrations after the operation which correlated with doses in serum C reactive protein. No differences were found in keratan sulphate concentrations in 137 women with osteoarthritis compared with controls. Within the group with osteoarthritis there were no differences for the various joint groups and there was no obvious correlation with radiographic severity or progression. These findings suggest serum keratan sulphate is unlikely to be useful as a diagnostic marker in osteoarthritis or RA but indicate a role for inflammation in the regulation of cartilage loss.

Acute-Phase Reaction↗
PubMed1992

Localisation of fibronectin mRNA in the rheumatoid synovium by in situ hybridisation.

The distribution of fibronectin, an extracellular matrix glycoprotein which plays a part in fibrosis and tissue repair, has previously been described using immunohistochemical methods. These do not differentiate between locally synthesised and plasma derived fibronectin. In this work the distribution of cells actively synthesising fibronectin was assessed by in situ hybridisation using a radiolabelled antisense RNA probe in synovial biopsy samples from patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and control subjects without inflammatory disease. Large amounts of fibronectin mRNA were found specifically in synovial lining cells, providing evidence for the local production of fibronectin in the synovium. Levels of fibronectin mRNA were variable between patients. These differences were not related to the diagnosis or to the subintimal inflammatory cell infiltrate; where there was synovial lining cell hyperplasia there was a concomitant increase in the number of cells containing fibronectin mRNA, which was consistent with increased levels of immunoreactive fibronectin at this site. Increased levels of fibronectin in synovial fluid in patients with rheumatoid arthritis may be due to an increased number of lining cells secreting the protein, rather than upregulation of the gene by these cells.

Aged↗
PubMed1992

Angiogenesis and rheumatoid arthritis: pathogenic and therapeutic implications.

Rheumatoid arthritis can be considered as one of the family of 'angiogenesis dependent diseases'. Angiogenesis in rheumatoid arthritis is controlled by a variety of factors found in the synovial fluid and pannus tissue. Modulation of the angiogenic component of the disease may alter the pathogenesis of the condition, and subsequent cartilage and joint destruction, by reducing the area of the endothelium in the pannus and restricting pannus growth. Current therapeutic strategies exert, to varying extents, an inhibitory effect on the angiogenic process. In particular, the mode of action of the slow acting antirheumatic drugs may be due to their effect on the angiogenic response. The development of novel angiostatic treatments for chronic inflammatory joint disease may lead to a new therapeutic approach in controlling disease progression.

Arthritis, Rheumatoid↗
PubMed1992

Misoprostol in the prevention of gastroduodenal damage in rheumatology.

Patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) are at an increased risk of gastroduodenal erosions, ulcers, and the associated complications of haemorrhage, perforation, and death. Many NSAID associated ulcers that bleed or perforate have been asymptomatic until the time of presentation and conversely many patients with dyspepsia do not have ulcers. Symptoms are a poor guide to the presence of an ulcer. During continued treatment with NSAIDs misoprostol is the best choice for NSAID induced gastroduodenal damage; it achieves higher rates of healing than other drugs in these circumstances. Misoprostol is superior to other drugs in the prevention of gastric damage but misoprostol and H2 antagonists are of similar benefit in the duodenum. Prophylactic studies have all used endoscopic damage as an endpoint, and much larger studies will be needed to show an effect of misoprostol on the incidence of ulcer complications. There are no clear guidelines as to which patients should receive prophylactic treatment with misoprostol but those particularly at risk of ulcer complications--that is, those with previous peptic ulceration, the elderly, medically unfit, patients receiving large doses of NSAIDs, and those patients receiving steroids in addition to NSAIDs--should be considered.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Fibronectin synthesis in subretinal membranes of proliferative vitreoretinopathy.

In situ hybridisation and immunohistochemical studies were conducted on six surgically excised subretinal membranes of proliferative vitreoretinopathy to investigate whether displacement of retinal pigment epithelial and glial cells to subretinal membranes was associated with fibronectin production by the subretinal membrane cells. Fibronectin messenger RNA (mRNA) and fibronectin immunoreactivity were observed in some cells in all of the subretinal membranes studied and up to 30% of the cells in individual specimens showed intense labelling for fibronectin mRNA. The results support the concept that the cells in subretinal membranes produce fibronectin. Locally produced fibronectin may play a role in subretinal membrane cohesion, and displacement of retinal pigment epithelial and glial cells from their normal location may induce the cells to manufacture fibronectin. Fibronectin production may be more prominent in migrating subretinal cells.

Eye Diseases↗
PubMed1992

The outcome of arthritis: measures of function, X-rays damage, pain and patients' satisfaction.

The outcome of arthritis has several dimensions. These include mortality, morbidity, radiological measures of joint destruction, pain, and patients' satisfaction with therapy. Functional disability measured by health status questionnaires, is directly associated with long-term outcome and mortality. Long term clinical trials should incorporate functional indices as outcome measures. Studies measuring the outcome of arthritis should define clear end-points involving the determination of functional classes and this will allow standardised and sensitive end points. An example would be the time taken to reach a given functional class or increase from baseline by one functional class. Patients' satisfaction with treatment is a different dimension of response. There are considerable advantages in using an index of patients' satisfaction when determining the therapeutic efficacy in short term clinical trials. It gives a different indication of the response to treatment than conventional clinical and laboratory measures of disease activity. Alleviating pain and preservation of function remain the major therapeutic goals, and both reflect the outcome of arthritis. Outcome measures have shifted from laboratory markers and radiographic techniques to measures of health status, pain, and patients' satisfaction. These should become a routine part of patient assessment.

Arthritis↗
PubMed1992

Enteric coated naproxen; a double blind trial comparing the tolerance of enteric coated and standard formulations.

Enteric coated naproxen (Nycopren) was compared with standard naproxen in a double blind comparative trial of 348 patients with either rheumatoid or osteoarthritis. There were slightly fewer gastric side effects and slightly fewer withdrawals because of side effects in the enteric coated naproxen group but the differences did not reach statistical significance. There was no significant difference in the efficacy of the two formulations. A satisfaction index was used to assess the therapeutic ratio with visual analogue scales assigned to both efficacy and side effects. The scale performed as intended and is worthy of further exploration.

Adult↗
PubMed1992

Healthchoice: a managed health-care program for low-income uninsured workers.

The period in which we practice medicine is unprecedented in terms of the enormous changes that are taking place within the profession. Perhaps foremost among the changes is the manner in which the practice of medicine is organized. Historically, over the last 30 years we have witnessed the transition of substantial proportions of physicians as solo practitioners to professionals employed in one form or another by institutional management care systems. Further, from all indications, this change is continuing unabatedly. There are now more than 600 health maintenance organizations (HMOs), and their enrollment rates have been steadily increasing. More than 60 million Americans or about 30% of the insured population receive their medical care through HMOs and preferred provider organizations (PPOs). Moreover, it is estimated that in the year 2000, 90% of all Americans will be receiving their medical care from managed care systems. Clearly, the driving force behind these changes is the desire of third-party payers and the public at large to control health-care costs. We, of course, share this goal and are committed to working with the public and private sectors to accomplish this aim. Deborah L. Scott, director of the Wayne County Patient Care Management Systems, writes about HealthChoice, a model managed-care program in Detroit, Michigan. Ms Scott's article is being published in lieu of the President's Column.

Female↗
PubMed1991

Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate.

Phospholipase A2 (PLA2) participates in a wide range of cellular processes including inflammation and transmembrane signaling. A human nonpancreatic secretory PLA2 (hnps-PLA2) has been identified that is found in high concentrations in the synovial fluid of patients with rheumatoid arthritis and in the plasma of patients with septic shock. This enzyme is secreted from certain cell types in response to the proinflammatory cytokines, tumor necrosis factor or interleukin-1. The crystal structures of the calcium-bound form of this enzyme have been determined at physiological pH both in the presence [2.1 angstrom (A) resolution] and absence (2.2 A resolution) of a transition-state analogue. Although the critical features that suggest the chemistry of catalysis are identical to those inferred from the crystal structures of other extracellular PLA2s, the shape of the hydrophobic channel of hnps-PLA2 is uniquely modulated by substrate binding.

Amino Acid Sequence↗