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S Dawson

Publications and source records attributed to S Dawson.

At least 127 records · Page 7Linked to original sources
PubMed1992

The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review.

Plasminogen activator inhibitor-1 (PAI-1) is a rapid inhibitor of tissue plasminogen (tPA) in vivo. Evidence suggests that the level of plasma PAI-1 activity is responsible for the regulation of the whole fibrinolytic process through this tPA/PAI-1 interaction. Levels of PAI-1 have therefore emerged as a candidate for a thrombotic risk factor. Recent epidemiological data supports the view that high plasma levels of PAI-1 may be important in the pathogenesis of arterial and thrombotic disease. These data are reviewed and their significance discussed. PAI-1 expression has been shown to be regulated by many different factors in vitro and the relevance of these data to in vivo physiology is addressed. The current knowledge of the biochemistry, expression and genetics of PAI-1 is also presented and the significance of this to disease pathogenesis is discussed.

Arteriosclerosis↗
PubMed1992

Genetic factors determining thrombosis and fibrinolysis.

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Factor VIII↗
PubMed1992

Radiographic patterns and associations of osteoarthritis of the hip.

A number of patterns of osteoarthritis of the hip are described, though studies are conflicting with respect to the frequency of such patterns and their associations. Two hundred and eleven patients (133 women, 78 men; mean age 66 years, range 29-86) referred to hospital with osteoarthritis of the hip were studied. Involvement was unilateral in 108 (51%) and bilateral in 89 (42%); 14 (7%) had undergone arthroplasty and were presenting with osteoarthritis hips). Sixty one per cent of hips had severe, 28% moderate, and 11% mild changes (Kellgren grade). Superior pole migration occurred in 82% (46% superolateral, 25% intermediate, 11% superomedial), medial/axial migration occurred in only 8%, and in 10% the pattern was indeterminate. In bilateral osteoarthritis of the hip the pattern was generally symmetrical. Superomedial and medial/axial patterns were proportionately more common in women, whereas superlateral osteoarthritis predominated in men. No association was found between multiple clinical nodes, radiographic polyarticular interphalangeal or first carpometacarpal osteoarthritis and any migration pattern. Any interphalangeal osteoarthritis was negatively associated with medial migration. Only 40% of hips could be categorised as hypertrophic or atrophic; chondrocalcinosis at any site was associated with atrophic osteoarthritis; no associations were seen with Forestier's disease. This large survey confirms the association between chondrocalcinosis and atrophic osteoarthritis of the hip. Importantly it suggests that gender, rather than associated osteoarthritis at other sites, is a major determinant of the pattern of osteoarthritis of the hip.

Adult↗
PubMed1992

The study of gene-environment interactions that influence thrombosis and fibrinolysis. Genetic variation at the loci for factor VII and plasminogen activator inhibitor-1.

We describe studies on variation in the genes coding for factor VII (FVII) and plasminogen activator inhibitor-1 (PAI-1) that influence levels of these proteins in the blood. For FVII, we have identified a genetic polymorphism that results in the substitution of arginine at residue 353 to glutamine. The frequency of the glutamine allele is approximately 0.1 in samples of individuals from the United Kingdom (n = 777) and the United States (n = 140) and in Afro-Caribbeans (n = 49), and is significantly higher in a sample of individuals from the Indian subcontinent (n = 53). In all samples, carriers of the glutamine allele had levels of FVII coagulant activity 20% to 25% lower than those with only the arginine allele. These differences were highly statistically significant in the United Kingdom sample. This effect was consistent in healthy men and women and in those with coronary artery disease. In individuals homozygous for the glutamine allele, both FVII coagulant activity and antigen are low, and the mechanism of the association appears likely to be due to an effect on secretion from the liver or stability in the plasma. In individuals in the general population FVII coagulant activity is positively correlated with levels of plasma triglycerides, due to the effect of such lipoproteins on activation of FVII. This relationship appears weaker in individuals carrying the glutamine allele, and since elevated FVII coagulant antibody is associated with risk of thrombosis, this is an example of how environmental factors may interact with an individual's genotype to determine his or her thrombotic risk. Roughly 20% of the general population are carriers of the glutamine allele and are likely to be genetically protected from such risk. For PAI-1, we have recently shown that variation at the PAI gene locus, detected as DNA polymorphisms, is associated with between-individual differences in levels of PAI-1. We have now detected a common sequence change in the promoter region of the gene that explains part of this effect. The sequence change is at position 675, where a fifth guanine (5G allele) has been inserted into a run of four guanines (4G allele) when compared with published sequences. In a sample of both 83 healthy individuals and 105 young patients with coronary artery disease from Sweden, the frequency of the 4G allele is roughly 0.5, and those individuals homozygous for the 4G allele have higher levels of PAI-1 than those with other genotypes (29% higher). Preliminary data show that the 5G allele binds a hepatic nuclear protein that the 4G allele does not, suggesting that the mechanism of the effect may be due to a direct effect of the sequence change on transcription of the PAI-1 gene.(ABSTRACT TRUNCATED AT 400 WORDS)

Arginine↗
PubMed1991

Studies on the role of feline calicivirus in chronic stomatitis in cats.

Two groups of cats were inoculated oro-nasally with one of two isolates of feline calicivirus (FCV) from clinical cases of chronic stomatitis. All cats developed signs typical of acute FCV infection; namely, ocular and nasal discharge, conjunctivitis, and marked oral ulceration. None of the cats shed virus beyond 28 days. Seronegative control cats were then infected with a lower dose of one isolate, but again only acute signs were seen and no carriers produced. The original cats were then re-infected with the heterologous isolate. As before, only signs of acute disease were seen, but the range of clinical signs and severity was reduced. Virus shedding patterns in one group were similar to those seen originally, but in the other the duration was reduced. No chronic stomatitis developed over the 10 months of the study. Serum virus neutralising and serum and salivary class specific immunoglobulin responses were investigated. Although long-term carriers were not induced, no relationship between cessation of virus shedding in an individual animal and systemic and local antibody responses was seen.

Acute Disease↗
PubMed1991

Effect of primary-stage feline immunodeficiency virus infection on subsequent feline calicivirus vaccination and challenge in cats.

The effect of experimental primary-stage feline immunodeficiency virus (FIV) infection on feline calicivirus (FCV) vaccination and challenge in cats was studied. Clinical signs of acute FCV disease were more widespread in the cats which were infected with FIV than in those which were not. FIV infection also prolonged shedding of FCV, with more of the FIV-infected cats becoming chronic carriers. Although vaccination induced protection against acute FCV disease, this was to a lesser degree in FIV-infected cats. Vaccination by itself also appeared to enhance long-term virus shedding. There was evidence of an impaired anamnestic FCV-neutralizing antibody response in FIV-infected cats following FCV challenge.

Animals↗
PubMed1991

Bacterial colonization of tunneled right atrial catheters in pediatric oncology: a comparison of sterile saline and bacteriostatic saline flush solutions.

In a double-blind, randomized controlled trial, children with malignant diseases had their tunneled right atrial catheters flushed with either sterile saline or bacteriostatic saline, once per week for 26 weeks. There was no significant difference in the rates of catheter colonization between the two groups, which did differ, however, in terms of the time from entry into the study to the first infective event (64 +/- 34 days vs. 146 +/- 27 days; p less than 0.001). This was strongly suggestive of a seasonal effect, as all of the colonizations in the bacteriostatic saline group were delayed until the summer months. We conclude that the use of a bacteriostatic saline flush solution for tunneled right atrial catheters is beneficial in efforts to prevent catheter colonization.

Bacterial Infections↗
PubMed1991

Maintenance of the patency of indwelling central venous catheters: is heparin necessary?

The use of indwelling central venous catheters for the ambulatory management of children with cancer has been well described. There remains uncertainty as to the best method for maintaining the patency of these catheters. The standard approach at our institution is to flush the catheter twice daily with a solution containing heparin. This is both costly and inconvenient for most families. We describe a randomized cross-over study designed to compare the standard approach to a less intense program using an isotonic saline flush once a week. Evaluation continued for approximately 1,515 days in each study arm. The catheters were monitored for blockage, clot formation, and infection. One catheter blocked in a patient receiving the experimental method of care. Two episodes of thrombus formation were demonstrated at the end of the study (one in each of the study arms). The incidence of infection, while in keeping with our overall experience, was higher in the experimental arm. This led to a subsequent study, reported separately in this symposium. The results indicate that there is no significant difference, in the incidence of blocked catheters or other complications, between the two forms of care.

Adolescent↗
PubMed1991

Evaluation of a home intravenous antibiotic program in pediatric oncology.

We conducted a pilot program of home intravenous antibiotic therapy for the management of febrile neutropenic episodes in a population of children with cancer. During a 6-month period, 13 children/families participated in the successful treatment of 22 episodes of infection. A cost analysis of the program indicates that home therapy is considerably cheaper than in-hospital treatment. Although the program represents an incremental cost to the hospital, it does provide for more efficient health care delivery. Feedback from parents who participated was highly favorable. We believe that home intravenous antibiotic therapy is a safe and efficacious alternative to hospital management of children with malignant diseases admitted with fever and neutropenia.

Anti-Bacterial Agents↗