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Biomedical subjects

D M MacDonald

Publications and source records attributed to D M MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed1995

Detection of circulating adhesion molecules in erythrodermic skin disease.

BACKGROUND: Diagnosis of the underlying dermatosis in erythroderma is often difficult. The cause of increased mortality in erythroderma, particularly in relation to infection, is incompletely understood. OBJECTIVE: We investigated the potential diagnostic use of circulating intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and E-selectin (cE-selectin) levels in erythroderma. METHODS: cICAM-1, cVCAM-1, and cE-selectin were measured by enzyme-linked immunosorbent assay in 14 patients with erythroderma of known cause and in 17 control subjects. Levels were correlated with other markers of the inflammatory response. RESULTS: In erythroderma median cICAM-1, cVCAM-1, and cE-selectin levels were significantly elevated, but no difference was found between values in patients with eczema and values in those with psoriasis. Circulating adhesion molecule levels did not correlate with erythrocyte sedimentation rate or total white blood cell count. CONCLUSION: cICAM-1, cVCAM-1, and cE-selectin were detectable in patients with erythroderma but were not differential diagnostic use in this study. Because in vitro these molecules may interfere with normal cell adhesion mechanisms, we speculate that they may contribute to the immunosuppressive state in these patients.

Adult↗
PubMed1995

Tumour necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression.

Tumour necrosis factor alpha (TNF-alpha) is a potent immunoregulatory cytokine produced by many cutaneous cells, including keratinocytes, mast cells and Langerhans cells. To explore its potential role in inflammatory skin disease, we have studied immunohistochemically the effects of intradermal recombinant human TNF-alpha (rHuTNF-alpha) on cutaneous inflammatory cells, adhesion molecules and Langerhans cells in normal human skin. Volunteers receive rHuTNF-alpha 100 U (group A), 5000 U (group B), or 100 U daily for 5 days (group C), and biopsies were taken at 6 h (groups A and B), or 6 h after the final injection (group C). An inflammatory cell infiltrate developed in all cases: following single injections of either 100 or 5000 U rHuTNF-alpha this was predominantly neutrophilic, whereas following multiple injections of 100 U few neutrophils were seen, although many lymphocytes (CD3+, CD4+) were present. In all groups there was an increase in cells of monocyte/macrophage lineage (CD36+). TNF-alpha induced a dose- and time-dependent decrease in CD1a+ epidermal Langerhans cell numbers and an increase in dermal CD1a+ cells, suggesting migration of Langerhans cells away from the epidermis. TNF-alpha induced endothelial E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in all groups, and adhesion molecule expression by interstitial dermal dendritic cells (ICAM-1 and VCAM-1) and keratinocytes (ICAM-1) was observed. These findings indicate that TNF-alpha is a potent modulator of cutaneous immune function in vivo, and this central role in the cutaneous immune response suggests that TNF-alpha may be an attractive target for therapeutic inhibition.

Antigens, CD↗
PubMed1995

p53 immunoreactivity is uncommon in primary cutaneous lymphoma.

p53 gene mutation appears to play an important role in the development of systemic lymphoma, and may be associated with tumour progression. Its role in cutaneous lymphoma is currently unknown. We examined p53 expression in 55 biopsies of cutaneous lymphoma, including patch-, plaque- and tumour-stage mycosis fungoides (MF), T- and B-cell lymphoma and lymphomatoid papulosis. Strong, homogeneous p53 expression, thought to correlate most closely with p53 gene mutation, was seen in only three cases; in a plaque and tumour from a patient with tumour-stage MF, in plaque-stage MF in a patient without tumours, and in one case of CD30+ large-cell anaplastic lymphoma. These data suggest that p53 gene mutation is not a critical step in the development of the majority of primary cutaneous lymphomas.

Humans↗
PubMed1995

Mast cells and T lymphocytes in chronic urticaria.

Mast cells are considered to be the primary effector cells in urticaria but it is possible that lymphocytes contribute to the formation of weals by secreting histamine releasing factors. The aim of this study was to examine the population of mast cells and to quantify the T cell subsets and their activation status in delayed pressure urticaria (DPU), chronic idiopathic urticaria and normal controls. Three biopsies were obtained from each of four patients with chronic idiopathic urticaria but not DPU. Three biopsies were taken from each of 13 patients with DPU, from a combination of unchallenged skin and at 0, 2, 6, 24, 48, and 120 h after weighted steel rods (diameter 1.5 cm) had been applied to the thighs. Three biopsies were similarly obtained from each of four normal controls before an identical pressure challenge and at 6, 24 and 48 h afterwards. The chloracetate esterase stain was used to demonstrate mast cells and an alkaline phosphatase anti-alkaline phosphatase immunohistochemical technique to assess the phenotypic and activation characteristics of the T cell infiltrate. The mast cell count did not differ significantly between unchallenged skin from DPU patients and normal controls. Following a pressure challenge to the DPU patients, the number of stainable mast cells decreased significantly to a level comparable with that in spontaneous weals of chronic idiopathic urticaria. Investigation of T cell subsets showed a preponderance of CD4+ cells over CD8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Posttransplant skin cancer: a possible role for p53 gene mutation but not for oncogenic human papillomaviruses.

BACKGROUND: Loss of p53 tumor suppressor function is a critical step in the development of diverse malignancies, including skin cancers in nonimmunosuppressed patients where UV-specific p53 gene mutations have been identified. In tumors associated with human papillomavirus (HPV), such as cervical carcinoma, p53 may be inactivated instead by binding to a viral oncoprotein. OBJECTIVE: Our purpose was to examine the hypothesis that HPV may play an analogous role in the development of posttransplant skin cancer. METHODS: p53 Immunoreactivity, suggestive of p53 gene mutation, was examined by immunocytochemistry. Oncogenic HPV DNA was detected by polymerase chain reaction. RESULTS: Comparable p53 immunoreactivity was seen in skin tumors from both transplant and nontransplant patients. HPV DNA was not demonstrated in any tumor specimen. CONCLUSION: Our data do not implicate oncogenic HPV in posttransplant skin cancer. p53 Gene mutation, rather than HPV-induced p53 degradation, may be more significant in the development of these tumors.

Basal Cell Carcinoma↗
PubMed1994

Langerhans' cell expression of the selectin ligand, sialyl Lewis x.

Cellular adhesion molecules play a central role in leucocyte migration through peripheral blood and tissues. A crucial stage in these events in selectin-mediated adhesion involving E-selectin expressed on activated endothelium interacting with a range of carbohydrate ligands expressed by specific subpopulations of leucocytes. As such mechanisms may be relevant to bone marrow-derived dendritic epidermal Langerhans' cell (LC) migration, expression of these carbohydrate ligands was assessed immunocytochemically in whole skin biopsies and in epidermal cell suspensions obtained from adult humans. Double-labelling experiments revealed that sialyl Lewis x, recognized by the monoclonal antibody CSLEX1, was expressed on epidermal LC (n = 9). Furthermore, expression was enhanced at 24 hr following epicutaneous application of antigen and in the inflammatory disorder psoriasis (n = 10). E-selectin was concomitantly strongly expressed on dermal endothelium in psoriasis and allergic contact dermatitis. Intradermal injection of the T-cell-derived cytokine interferon-gamma (IFN-gamma) led to increased LC expression of sialyl Lewis x. In epidermal cell suspensions, in contrast to keratinocytes, CD1a+ cells expressed sialyl Lewis x, intensity of which was enhanced after 4 days in culture. CSLEX1 staining could be abolished and CD15 (non-sialated Lewis x) expression induced by saponification and treatment with neuraminidase. Expression of other selectin ligands was also examined. While the cutaneous lymphocyte antigen defined by the monoclonal antibody HECA-452 reacted with a small minority of LC, sialyl Lewis a and sulphatide were not expressed under any experimental conditions. These studies indicate that E-selectin-sialyl Lewis x interactions are potentially important in LC migration, both into and out of skin.

Adult↗
PubMed1993

Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin.

Inflammatory cell infiltrates and cell adhesion molecule expression have been examined in normal human skin after intradermal injection of sensory neuropeptides substance P (n = 6), vasoactive intestinal polypeptide (n = 6), and calcitonin gene-related peptide (n = 6) together with PBS as control (n = 4). Each neuropeptide induced rapid, time-dependent neutrophil influx into dermis, which was initially observed at 15 min and persisted for 8 h after injection. Increases in numbers of neutrophils with time after substance P, vasoactive intestinal polypeptide and calcitonin gene-related peptide were highly significant when compared with controls p < 0.005, p < 0.005, p < 0.005, respectively (analysis of variance). Substance P additionally induced marked eosinophilic accumulation at 4 and 8 h in four of six subjects. These changes paralleled rapid translocation of P-selectin from cytoplasmic Weibel-Palade granules to luminal membranes by 15 min, and significant up-regulation of E-selectin expression at 4 and 8 h. Increases in percentage of E-selectin positive vessels with respect to time after each neuropeptide were highly significant when compared with controls, p < 0.005, p < 0.005, p < 0.005 (ANOVA), respectively, and were significantly correlated with neutrophil infiltrates, r = 0.55, p < 0.001. VCAM-1 was not expressed, and constitutive ICAM-1 expression on dermal endothelium was unchanged at all time points examined (0-8 h). Induction of endothelial adhesion molecule expression by neuropeptides provides a mechanism for neutrophil accumulation in neurogenic inflammation. Substance P-induced eosinophil accumulation in the absence of VCAM-1 expression suggests that mechanisms distinct from VCAM-1/very late antigen-4 binding mediate selective tissue eosinophilia.

Adult↗
PubMed1993

Excess melanocytic nevi in children with renal allografts.

BACKGROUND: Renal allograft transplantation is associated with an increased incidence of malignant melanoma. The development of excess melanocytic nevi may be an indicator of this risk. OBJECTIVE: This study determines the prevalence of melanocytic nevi in children who have received renal allografts. METHODS: Total and regional melanocytic nevi counts were made in 38 children (27 boys, 11 girls) with a renal allograft and in 38 individually age- and sex-matched healthy controls; counts were related to age, sex, skin type, and duration of immunosuppression. RESULTS: There was a significant increase in the total number of nevi in the renal transplant group compared with the control group (p < 0.05), with most marked increases occurring on the back and at acral sites. A strong positive correlation between nevi count and duration of immunosuppression independent of age was observed (p < 0.005). CONCLUSION: Excess numbers of melanocytic nevi occur in children with renal allografts. These patients constitute a risk group for malignant melanoma and require continued assessment.

Adolescent↗
PubMed1993

Vascular cell adhesion molecule-1: expression in normal and diseased skin and regulation in vivo by interferon gamma.

BACKGROUND: Vascular cell adhesion molecule-1 (VCAM-1) is an endothelial protein with adhesive properties for inflammatory cells including lymphocytes. Its role in skin disease and regulation in vivo are uncertain. OBJECTIVE: Our purpose was to determine expression of VCAM-1 in normal and inflamed skin and the effect on this of the T-cell-derived cytokine interferon gamma (IFN-gamma). METHODS: VCAM-1 was detected immunohistochemically in frozen-section biopsy specimens of inflammatory dermatoses and skin tumors. Volunteers received intradermal IFN-gamma and underwent biopsy 2 hours to 6 days later. RESULTS: In normal skin, VCAM-1 was present on perivascular dendritic cells and some follicular keratinocytes. In allergic contact dermatitis, atopic dermatitis, and psoriasis, VCAM-1 was variably upregulated on dermal endothelium and dendritic cells, but was most pronounced in lichen planus. IFN-gamma led to marked upregulation of endothelial and dermal dendritic cell VCAM-1. CONCLUSION: VCAM-1 may be involved in the pathogenesis of various skin diseases and in vivo, IFN-gamma is a potent modulator of its expression.

Cell Adhesion Molecules↗
PubMed1993

Posttransplant cutaneous lymphoma.

BACKGROUND: Posttransplant lymphoma is closely associated with Epstein-Barr virus (EBV) infection and appears to have a predilection for extranodal sites. We describe four cases of primary cutaneous posttransplant lymphoma. OBJECTIVE: Our aim was to determine cell lineage and any possible association with EBV in each case of cutaneous lymphoma. METHODS: Tumor tissue was examined by light microscopy, immunohistochemistry, nonisotopic in situ hybridization and polymerase chain reaction. RESULTS: The data were consistent with a diagnosis of EBV-associated cutaneous B-cell lymphoma in three cases and cutaneous T-cell lymphoma not associated with EBV in one case. No patient with B-cell lymphoma had extracutaneous involvement during a mean follow-up of 3.9 years. The patient with cutaneous T-cell lymphoma died of cerebral involvement 9 months after initial presentation. CONCLUSION: These data suggest a possible role for EBV infection in the origin of cutaneous B-cell lymphoma in immunosuppressed patients.

Aged↗
PubMed1993

p53 immunoreactivity in human malignant melanoma and dysplastic naevi.

Expression of the tumour suppressor protein, p53, was determined in 77 cutaneous melanocytic lesions, and in five lymph node metastases from malignant melanoma, in an immunohistochemical study employing CM-1, an antiserum raised against recombinant human p53 protein. Because wild-type p53 protein is rapidly degraded in normal cells, p53 immunoreactivity suggests the presence of an abnormally stable p53 protein. This may occur through either post-translational mechanisms or gene mutation. A highly significant correlation was found between p53 immunoreactivity and malignancy in melanocytic lesions (P < 0.0001). Overall, p53 immunoreactivity was observed in 63% of tumour specimens examined, but not in benign melanocytic naevi, although occasional foci of weak nuclear p53 immunoreactivity were observed in a minority of dysplastic naevi and a solitary Spitz naevus. A significant correlation was also found between strong p53 immunoreactivity and malignant melanomas associated with a poor prognosis (P = 0.008). These data suggest an important role for p53 tumour suppressor protein in the biology of human cutaneous malignant melanoma.

Dysplastic Nevus Syndrome↗
PubMed1993

Sunlight exposure, antioxidant status, and cataract in Hong Kong fishermen.

STUDY OBJECTIVES: The aim was to test whether cataract is associated with higher lifetime exposure to sunlight, and whether antioxidants protect against cataract. DESIGN: This was a cross sectional survey of eye disease, with assessment of antioxidant status in a subgroup. SETTING: Hong Kong fishing communities in 1989. PARTICIPANTS: 685 men and women aged 55 to 74 years old were included in the study, of whom 367 (54%) attended hospital for detailed examination. MEASUREMENTS AND MAIN RESULTS: At a mobile clinic visual acuity and lens opacities were assessed, and using a questionnaire, occupational history and lifetime exposure to sunlight. At hospital ophthalmic measurements were repeated and blood was taken for measurement of plasma vitamin C, vitamin E, and total carotenoids, and red cell activities of glucose-6-phosphate dehydrogenase, glutathione peroxidase, superoxide dismutase, and catalase. Higher grades of cataract (particularly nuclear cataract) tended to be more common in subjects with the most sun exposure, although not to the point of statistical significance. In contrast to earlier studies, no association was found with antioxidant status. CONCLUSIONS: The findings give some support to the hypothesis that sunlight causes cataract. The absence of a relation to antioxidant status may be because blood levels of antioxidants at one point in time do not adequately reflect a subject's past metabolic state, and particularly the past activity of antioxidants in the lens.

Aged↗
PubMed1993

Increased epidermal cell proliferation in normal human skin in vivo following local administration of interferon-gamma.

Recombinant human interferon-gamma was administered intradermally (10 micrograms in 0.1 ml) to healthy adult human volunteers from day 1 to day 3, and epidermal cell proliferation was measured on whole skin biopsies at day 6. Three independent parameters were assessed, namely, a) epidermal keratin-16 expression, b) keratinocyte proliferating cell nuclear antigen expression, and c) keratinocyte silver nucleolar organizer region counts. Significantly increased scores for each parameter were observed after interferon-gamma injection (P < 0.01 in each case) compared to site-matched controls. Keratin-16 expression was confined to suprabasal epidermis, whereas proliferating cell nuclear antigen and silver nucleolar organizer region counts were particularly elevated in the basal epidermis. Taken together with previous findings, these studies indicate both proinflammatory and growth regulatory roles for interferon-gamma in human skin. These data are likely to be of particular importance to pathophysiological mechanisms of psoriasis and related cutaneous inflammatory diseases.

Adult↗
PubMed1993

Expression of selectin ligands by cutaneous squamous cell carcinoma.

Recent evidence suggests that interactions between endothelial selectins and tumor surface selectin ligands may be of importance in cancer metastasis. To investigate the role of such mechanisms in cutaneous tumors, whole skin biopsies were examined immunohistochemically for a variety of selectin ligands including sialyl-Lewis-X, sialyl-Lewis-A (S-Le(a)), sulfatides, and CD15. In 12 of 12 squamous cell carcinomas (SCCs), there was expression of sialyl-Lewis-X and CD15, but no tumor expressed S-Le(a). Occasional keratinocytes in eight of 12 SCCs expressed sulfatides. All selectin ligands were absent on keratinocytes in basal cell carcinomas (BCCs, n = 8) and normal skin (n = 8), with the exception of one BCC that expressed S-Le(a). E-selectin was not present in normal skin, but was strongly expressed by dermal endothelium in both SCC and BCC. Keratinocyte cell lines A431, HaCaT, and SVK14 were investigated by flow cytometry, which demonstrated sialyl-Lewis-X and S-Le(a) expression by all three, whereas normal human keratinocytes did not express these molecules. These findings suggest a potential role for selectin-mediated events in early and late metastasis, and differential expression of these ligands by BCC and SCC may explain the relatively low metastatic potential of the former.

Basal Cell Carcinoma↗
PubMed1992

Epidermal dendritic cells in psoriasis possess a phenotype associated with antigen presentation: in situ expression of beta 2-integrins.

BACKGROUND: Epidermal dendritic cells (DCs) isolated from psoriasis possess greatly enhanced T lymphocyte-activating properties compared with DCs from normal skin, suggesting that DCs in psoriasis express surface antigens crucial for antigen presentation. These include beta 2-integrins and intercellular adhesion molecule (ICAM)-1. OBJECTIVE: Our purpose was to determine DC phenotype in psoriatic compared with normal epidermis with respect to these molecules. METHODS: Tissue sections were single labeled with a peroxidase antiperoxidase (PAP) immunohistochemical technique and double labeled where necessary with a combination of a PAP and an alkaline phosphatase-anti-alkaline phosphatase technique. RESULTS: In psoriatic compared with normal skin, decreased numbers of DCs expressed CD1a (p less than 0.05), whereas increased numbers of DCs expressed class II major histocompatibility antigens (p less than 0.05). In normal skin positive staining for CD18 was not observed, whereas in psoriasis both CD1a+ and CD1a- DCs expressed beta 2-integrins, LFA-1 (CD11a/CD18), and gp 150/95 (CD11c/CD18). DCs in atopic dermatitis and lichen planus were also found to express beta 2-integrins. Neither MAC 1 (CD11b/CD18) nor ICAM-1 was observed on DCs. CONCLUSION: These data are consistent with either migration of dendritic antigen-presenting cells into the epidermis or in situ cytokine modulation of Langerhans cell phenotype in inflamed skin. Furthermore, they indicate that epidermal DCs in psoriasis and other cutaneous inflammatory diseases express molecules that are known to be crucial for Langerhans cell-driven T-cell activation in vitro.

Cell Adhesion Molecules↗
PubMed1992

Effect of in vivo interleukin-1 on adhesion molecule expression in normal human skin.

We have examined the expression of three endothelial adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], endothelial leukocyte adhesion molecule-1 [ELAM-1], and vascular cell adhesion molecule-1 [VCAM-1]) in normal human skin following intradermal injection of stratum corneum-derived interleukin-1 alpha (SCIL-1 alpha). In control skin, constitutive expression of ICAM-1 was found on endothelial cells and at low levels on dermal dendritic cells but not on keratinocytes. ELAM-1 and VCAM-1 were present in low levels on endothelium and perivascular dendritic cells, respectively. SCIL-1 alpha injection produced marked endothelial ELAM-1 upregulation. Double staining with neutrophil elastase demonstrated that many ELAM-1-positive vessels contained marginating neutrophils and that interstitial neutrophils were clustered around ELAM-1-positive vessels. An increase in dermal dendritic cell ICAM-1 expression occurred and in two of three biopsies there was keratinocyte expression of ICAM-1 in the SCIL-1 alpha-injected tissue. Also, there was upregulation of VCAM-1 on vascular endothelium and an increase in the dermal dendritic cell expression of this molecule. These results give in vivo confirmation that SCIL-1 alpha modulated endothelial and dermal dendritic cell adhesion molecule expression, and show that endothelial VCAM-1 is regulated in vivo by SCIL-1 alpha, thus providing a regulatable ICAM-1-independent means of mononuclear cell recruitment.

Adult↗