Biomedical subjects

David Harrison

Publications and source records attributed to David Harrison.

23 records · Page 2Linked to original sources

PubMed2003

Automated image analysis of proliferating cells in carcinoma of the larynx.

OBJECTIVE: To determine the role of cell proliferation neoplastic progression in the larynx and possibly derive criteria of clinical significance using automated quantitative image analysis. MATERIAL AND METHODS: In a retrospective study involving archival material, the occurrence and location, size, shape and staining intensity of proliferating cell nuclear antigen (PCNA)-positive cells (12,538 cells in total) were analyzed in squamous cell carcinoma (SCC), as well as in pre- and non-neoplastic conditions, using computer-assisted morphometry with reproducibility and sensitivity exceeding 99%. RESULTS: Immunohistochemically detectable PCNA-positive cells were located in the basal layer in non-neoplastic states, in well-differentiated SCCs in layers adjacent to the basal membrane and in poorly differentiated neoplasms in the neoplastic epithelial islets. An increased degree of dysplasia was associated with an increased number of PCNA-immunoreactive cells of increased nuclear size and staining intensity. There was a significant difference between carcinomas and dysplasia in terms of altered nuclear shape. With increasing malignancy of SCCs, nuclear shape alterations and PCNA staining intensity increased, whilst nuclear size decreased. CONCLUSIONS: Automated image analysis of cell populations allowed the identification of populations of malignant cells and provided information on the severity of preneoplastic and neoplastic conditions of use in studies of tumor behavior and with potential clinical application.

Carcinoma, Squamous Cell↗

PubMed2002

Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation.

Laminin-1 is essential for early embryonic basement membrane assembly and differentiation. Several steps can be distinguished, i.e., the expression of laminin and companion matrix components, their accumulation on the cell surface and assembly into basement membrane between endoderm and inner cell mass, and the ensuing differentiation of epiblast. In this study, we used differentiating embryoid bodies derived from mouse embryonic stem cells null for gamma1-laminin, beta1-integrin and alpha/beta-dystroglycan to dissect the contributions of laminin domains and interacting receptors to this process. We found that (a) laminin enables beta1-integrin-null embryoid bodies to assemble basement membrane and achieve epiblast with beta1-integrin enabling expression of the laminin alpha1 subunit; (b) basement membrane assembly and differentiation require laminin polymerization in conjunction with cell anchorage, the latter critically dependent upon a heparin-binding locus within LG module-4; (c) dystroglycan is not uniquely required for basement membrane assembly or initial differentiation; (d) dystroglycan and integrin cooperate to sustain survival of the epiblast and regulate laminin expression; and (e) laminin, acting via beta1-integrin through LG1-3 and requiring polymerization, can regulate dystroglycan expression.

Animals↗

PubMed2002

Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation.

The receptors for the complement anaphylatoxins C3a and C5a are expressed by glial cells and neurons in normal and inflamed brain. Previous studies demonstrated modest elevations in mRNA expression of these receptors in a model of focal cerebral ischemia. Using a similar model system for both mice and rats, we report markedly different patterns of anaphylatoxin receptor mRNA expression in cerebral ischemia. C5a receptor expression was dramatically elevated within 3 h after middle cerebral artery occlusion, while C3aR expression was reduced to 25% of control animals. By 24 h post-occlusion, expression of both receptors was higher than at any other time point examined. This increased expression at late time points after occlusion is most likely the result of massive infiltration of leukocytes expressing the receptors. We also observed increased receptor mRNA expression in sham-operated animals, indicating that the procedures used for arterial occlusion affects mechanisms regulating receptor expression. This latter result highlights the importance of including this important control group in ischemic model systems for proper interpretation of changes in gene expression.

Animals↗

PubMed2002

WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis.

Glomerular disease is one of the most common causes of end-stage renal failure. Increasing evidence suggests that these glomerulopathies are frequently caused by primary lesions in the renal podocytes. One of the major consequences of podocyte lesions is the accumulation of mesangial matrix in the glomerular basement membrane, a process called glomerulosclerosis. Mesangial sclerosis is one of the most consistent findings in Denys-Drash patients and can be caused by dominant mutations in the Wilms' tumor 1 gene (WT1). The underlying mechanism, however, is poorly understood. WT1 is expressed in the podocytes throughout life, but its function in this cell type is unknown. Combining Wt1-knockout and inducible yeast artificial chromosome transgenic mouse models, we demonstrate that reduced expression levels of WT1 result in either crescentic glomerulonephritis or mesangial sclerosis depending on the gene dosage. Strikingly, the two podocyte-specific genes nphs1 and podocalyxin are dramatically downregulated in mice with decreased levels of Wt1, suggesting that these two genes act downstream of Wt1. Taken together, our data provide genetic evidence that reduced levels of Wt1 are responsible for the pathogenesis of two distinct renal diseases and offer a molecular explanation for the increased occurrence of glomerulosclerosis in patients with WAGR syndrome.

Animals↗

PubMedDate not supplied

Increasing awareness of services for people with multiple sclerosis.

Awareness of multiple sclerosis has been increasing in recent years. However, there are still many issues which the MS Society will be highlighting during MS Week. This year there are three main MS Week themes. These include funding for research, a volunteer recruitment drive, and promotion of the NICE guideline for MS.

Awareness↗