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Biomedical subjects

C Lawson

Publications and source records attributed to C Lawson.

At least 19 recordsLinked to original sources
PubMed2005

Expression of human ecto 5' nucleotidase in pig endothelial cells and its implication for adenosine production and xenotransplantation.

Human endothelial activity of ecto-5'-nucleotidase (E5'N) is several times higher than in pig endothelial cells. This may have implication for xenotransplantation due to the role this enzyme plays in conversion of pro-inflammatory and pro-aggreggatory nucleotides into anti-inflammatory and antiaggregatory adenosine. We have shown in this study that human E5'N can be functionally expressed in pig endothelial cells leading to increased adenosine production from both extracellular AMP and ATP. We suggest that E5'N expression in transgenic pigs for xenotransplantation may help to prolong graft survival.

5'-Nucleotidase↗
PubMed2001

Effects of cross-linking ICAM-1 on the surface of human vascular smooth muscle cells: induction of VCAM-1 but no proliferation.

OBJECTIVE: Intercellular adhesion molecule (ICAM)-1 is an immunoglobulin-like cell adhesion molecule expressed by several cell types, including proliferating vascular smooth muscle cells (VSMC). Cross-linking ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. Here, our objective was to examine events following ligation of ICAM-1 on the surface of human VSMC. METHODS: VSMC were isolated by explant from human pulmonary arteries or aortic tissue from cardiac transplant donors. ICAM-1 was ligated with monoclonal antibodies, followed by cross-linking with a secondary antibody. Activation of signalling pathways, proliferation and expression of a second adhesion molecule, vascular cell adhesion molecule (VCAM)-1 were investigated. RESULTS: ICAM-1 cross-linking caused an increase in activation of extracellular regulated kinase (Erk)-1/-2 and Jun N-terminal kinase (JNK)-1/-2. mRNA and protein for VCAM-1 was observed after ICAM-1 cross-linking, and this was abrogated by addition of an upstream inhibitor of Erk-1/-2, PD98059. No increase in cell proliferation was observed. CONCLUSIONS: Ligation of ICAM-1 on the surface of vascular smooth muscle cells in vitro, leads to the expression of adhesion molecules associated with monocyte infiltration, but does not contribute to smooth muscle cell proliferation. In vivo, this might lead to prolongation of the inflammatory response within diseased blood vessels, by arresting monocytes within atherosclerotic plaques.

Cell Communication↗
PubMed2001

Ectopic endometrial cells express high concentrations of interleukin (IL)-8 in vivo regardless of the menstrual cycle phase and respond to oestradiol by up-regulating IL-1-induced IL-8 expression in vitro.

Endometriosis, an oestrogen-dependent disorder affecting women of reproductive age, is associated with active angiogenesis and an increased recruitment of leukocyte into the peritoneal cavity where the implants often develop. The role of oestrogens in the development of endometriosis has been clearly established, but the biochemical mechanisms of their action are still not clearly elucidated. The present study shows that interleukin-1 (IL-1) induces interleukin-8 (IL-8) secretion by endometriotic cells and that oestradiol enhances endometriotic cell responsiveness to IL-1. In contrast, no significant cell responsiveness to progesterone either alone in the culture medium or in combination with oestradiol was noted. Positive immunostaining for IL-8 was observed throughout endometriotic tissue, and no perceptible difference in the intensity of staining regarding the menstrual cycle phase was observed. Together with the in-vitro data, this suggests that IL-8 expression in endometriotic tissue is not subject to cyclic variation. Furthermore, this study provides evidence that oestradiol indirectly up-regulates the expression by ectopic endometrial cells of IL-8, a cytokine endowed with neutrophil chemotactic and angiogenic properties. This may contribute to peritoneal leukocyte recruitment and to the growth of endometriotic implants, and may be a new mechanism for oestradiol action in endometriosis.

Adolescent↗
PubMed2001

Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer.

OBJECTIVE: Despite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model. METHODS: The release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery. RESULTS: The in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102.4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean +/- standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment were observed. CONCLUSION: The diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.

Animals↗
PubMed2001

Protecting genetic materials and genetic information: a case study of Guthrie Cards in Victoria.

The authors are privileged to have been provided with correspondence about a dispute over the ongoing storage of genetic material (as Guthrie Cards) in Victoria. The correspondence details confusion over the roles of government and the private sector service provider in accounting for the storage, use and destruction of these stored genetic materials collected as part of a government public health program. The purpose in publishing this account is to highlight the present inadequacies in current practices and the ongoing potential for a crisis in the management of collected genetic materials through a lack of appropriate regulation, transparency and accountability. The article suggests measures to remedy some of the existing inadequacies in contractual arrangements and recommends that the government retain ownership and control of both the genetic materials and the derived information to ensure some accountability in the present legal environment.

Contract Services↗
PubMed2000

An epithelial cell line that can stimulate alloproliferation of resting CD4+ T cells, but not after IFN-gamma stimulation.

It has previously been shown that IFN-gamma-induced up-regulation of HLA class II on the surface of epithelial cells is not sufficient to induce proliferation of allospecific CD4+ T cells in vitro. To further investigate this phenomenon, a human epithelial bladder carcinoma, T24, was induced to constitutively express HLA class II without IFN-gamma stimulation, by permanent transfection with the full-length class II transactivator (CIITA) gene. Proliferation of allospecific T cells to transfected and wild-type cells with and without prior activation with saturating levels of IFN-gamma for 4 days was examined. IFN-gamma-activated T24 did not induce any response from CD4+ T cells. However, T24.CIITA induced significant levels of alloproliferation, which could be abrogated by pretreatment of T24.CIITA with a mAb to LFA-3. Prestimulation of T24. CIITA with saturating levels of IFN-gamma for 4 days also prevented allospecific CD4+ T cell proliferation. These findings suggest that epithelial cells may be intrinsically able to process and present alloantigen and provide adequate costimulation. We propose that IFN-gamma has a secondary, as yet unidentified, effect that acts to negatively regulate this response, at least in some epithelial cells.

CD4-Positive T-Lymphocytes↗
PubMed2000

Activation of NF-kappa B in human endothelial cells induced by monoclonal and allospecific HLA antibodies.

Chronic graft rejection, characterized by a gradual occlusion of grafted vessels, is the most serious complication following heart and kidney transplantation. Although often associated with chronic production of anti-HLA and anti-endothelial antibodies, the precise role of antibodies in chronic rejection remains uncertain. Here we have investigated whether HLA-specific antibodies, either monoclonal or derived from patients, cause endothelial cell activation. Thus we investigated tyrosine phosphorlyation, NF-kappaB activation and cell proliferation in human umbilical vein endothelial cells (HUVEC) or microvascular endothelial cells from adult human heart (CMEC). Ligation of monomorphic determinants of MHC class I molecules (using the mAb W6/32) on the surface of HUVEC caused an increase in tyrosine phosphorylation of proteins of mol. wt approximately 75-80 kDa. Similarly, ligation of monomorphic determinants on both CMEC and HUVEC resulted in increased NF-kappaB binding compared to controls (by 74.4 and 52.5%, P = 0.001) and this was enhanced by addition of secondary antibody. Two HLA-specific mAb resulted in a 277 and 170% increase in NF-kappaB-binding activity compared to controls. Four patient samples containing HLA antibodies were used against HLA-specific HUVEC and four samples were incubated with HUVEC bearing irrelevant antigens. Patient sera alone enhanced NF-kappaB binding by 27-186%, but only when added to HUVEC bearing relevant antigens. W6/32 and allospecific antibodies from patients significantly enhanced HUVEC proliferation, measured by uptake of [(3)H]thymidine. In conclusion, activation of NF-kappaB by human anti-HLA antibodies demonstrates their potential role in pathogenesis of chronic vascular occlusive disease following transplantation.

Adult↗
PubMed1999

Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism.

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Depression and the interpretation of ambiguity.

A number of studies have produced findings consistent with the possibility that depressives display a negative bias in interpretation. However, the results of such studies can equally well be explained by the operation of a depression-linked response bias, reflecting an elevated tendency for depressives to emit or endorse negatively-toned response options. The present experiment compares the patterns of interpretative processing displayed by subjects who differ in their BDI scores, using a priming methodology developed by anxiety researchers to eliminate the contaminating influence of emotional response bias. The pattern of priming effects obtained provides no evidence to support the existence of a negative interpretative bias in the more depressive individuals. Indeed, quite the reverse conclusion is sustained by the findings, which indicate that high BDI subjects showed an attenuated tendency to activate the more negative interpretations of the ambiguous textual stimuli. The conceptual and methodological implications of these findings are discussed, together with some specific suggestions for future research on this topic.

Adult↗
PubMed1999

Review article: evaluation of drugs in experimental gut distension models.

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristics of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT3 receptor antagonist, alosetron.

Abdominal Pain↗
PubMed1997

The effect of caloric load and nutrient composition on induction of small intestinal satiety in dogs.

The influence of caloric load and nutrient composition on small intestinal satiety was investigated in six dogs with chronic esophageal fistulas. Dogs received small bowel infusion of a mixed nutrient liquid meal, a fat, carbohydrate, and a protein solution over two hours. Each infusion was given over a range of caloric densities which represented between 0 to 20% of the total 24 h caloric requirement for each animal. Satiety was measured by sham feeding at the end of the infusion. Infusion of 0.25 cal/ml (equivalent to 5% of the 24 h caloric requirement) of a liquid mixed nutrient meal (Isocal) significantly suppressed sham feeding (volume sham fed: control 265 +/- 28 ml/min; Isocal 0.25 cal/ml 218 +/- 52 ml/min, p < 0.05). Oleate and dextrose polymer also significantly reduced sham feeding at a caloric concentration of 0.25 cal/ml (volume sham fed: control 265 +/- 28 ml/min; oleate 112 +/- 28 ml/min; oleate 112 +/- 9 ml/min; dextrose polymer 190 +/- 11 ml/min), whereas peptone did not significantly suppress sham feeding until a solution with 0.5 cal/ml was given. These studies demonstrate that caloric load of intestinal nutrients must reach a threshold to produce satiety in sham feeding dogs. The threshold caloric load is different for the three nutrient groups, with fats requiring the lowest caloric load to produce satiety. These provide insight into the mechanisms by which small intestinal signals might contribute to regulation of the inter-meal interval.

Animals↗
PubMed1996

Contaminant migration from food packaging laminates used for heat and eat meals.

EU legislation requires that components from food contact plastics should not migrate significantly into the food. The nature and extent of species migrating from laminated materials used for packaging 'heat and eat' meals have been investigated. Selected target analytes included additives incorporated into the polyolefin, e.g. the Irganox and Irgafos antioxidants, the diisocyanate and polyol residues from the adhesive and oligomeric material from the nylon. The results identified a wide range of migrants arising from each of the individual components of the laminate. Some of the migrants have been identified as precursors of the principal components of the laminate as well as those anticipated from a knowledge of the laminate construction. The levels of migration for those components identified and quantified has been well below the legal limits. Some significant migrant species have been however left unidentified by this investigation.

Journal Article↗