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Biomedical subjects

G A Scott

Publications and source records attributed to G A Scott.

At least 19 recordsLinked to original sources
PubMed2001

Anti-arrhythmic and electrophysiological effects of the endothelin receptor antagonists, BQ-123 and PD161721.

The effects of the endothelin ET(A), (BQ-123) and endothelin ET(A/B) (PD161721) receptor antagonists were investigated on ischaemia-induced arrhythmias and on the maximum following frequency. The study was carried out in Langendorff perfused rat hearts subjected to coronary artery occlusion in which the severity of arrhythmias, coronary perfusion pressure and heart rate were measured. The % incidence of ischaemia-induced irreversible ventricular fibrillation (ventricular fibrillation) was reduced significantly from 58%, in control rat hearts, to 0% (at 10(-7) and 10(-6) M PD161721 and 10(-6) M BQ-123 P<0.05). Maximum following frequency was measured in guinea-pig isolated atria. In the presence of normal extracellular [K(+)], BQ-123 and PD161721, at 10(-6) M, significantly decreased the maximum following frequency from 9.0+/-0.7 to 7.2+/-0.4 and from 8.3+/-0.4 to 6.7+/-0.3 Hz, respectively (P<0.05). These effects were not potentiated by raising the extracellular [K(+)] with the exception of 10(-9) M PD161721. In contrast, lignocaine's ability to reduce the maximum following frequency was greater in elevated (e.g. at 1.7x10(-4) M from 8.4+/-0.3 to 2.5+/-0.6 Hz) than in normal [K(+)] (from 9.0+/-0.3 to 4.9+/-0.5 Hz). In conclusion, both BQ-123 and PD161721 had an anti-fibrillatory effect in isolated rat hearts that may be due, at least in part, to an ability to reduce the maximum following frequency. This latter effect is unlikely to be due to Na(+) channel blockade since it was not markedly potentiated by elevation of extracellular [K(+)].

Animals↗
PubMed1999

Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition.

UV light is a complete carcinogen, inducing both basal and squamous cell skin cancers. The work described uses the selective COX-2 inhibitor celecoxib to examine the efficacy of COX-2 inhibition in the reduction of UV light-induced skin tumor formation in hairless mice. UVA-340 sun lamps were chosen as a light source that effectively mimics the solar UVA and UVB spectrum. Hairless mice were irradiated for 5 days a week for a total dose of 2.62 J/cm(2). When 90% of the animals had at least one tumor, the mice were divided into two groups so that the tumor number and multiplicity were the same (P < 0.31). Half of the mice were then fed a diet containing 1500 p.p.m. celecoxib. Tumor number, multiplicity and size were then observed for the next 10 weeks. Ninety-five percent of the tumors formed were histopathologically evaluated as squamous cell carcinoma. COX-2 expression and activity were increased in tumors. After 10 weeks, the difference in tumor number and multiplicity in the drug-treated group was 56% of UV controls (P < 0.001). The results show that the orally administered selective COX-2 inhibitor celecoxib prevents new tumor formation after the onset of photocarcinogenesis and suggest that treatment with celecoxib may be very useful in preventing UV-induced skin tumors in humans.

Animals↗
PubMed1999

Melanocytes adhere to and synthesize laminin-5 in vitro.

Melanocytes arise from the neural crest, migrate to the skin, and can be detected in the basal layer of the epidermis in skin biopsies of human fetuses as early as 11 weeks gestational age. During post-natal life, melanocytes reside at the basal layer of the epidermis, but the ligands to which they attach are unknown. Laminin-5 is a component of anchoring filaments of the lamina lucida of the epidermal basement membrane. In this report we show that human melanocytes adhere to purified laminin-5 to a level comparable with normal human keratinocytes. Blocking antibodies to the 165 kDa subunit of laminin-5 significantly inhibited fetal and neonatal melanocyte attachment to the surface of salt-split skin, which exposes laminin-5 on its surface, suggesting that laminin-5 is a ligand for melanocyte attachment to the basement membrane in vivo. Western blotting of concentrated culture supernatant of fetal and neonatal melanocytes with anti-laminin-5 antibodies demonstrated a single immunoreactive band of the expected size of laminin-5. In contrast, 3 human metastatic melanoma cell lines did not produce laminin-5. Immunofluorescence microscopy with antibodies to each of the three chains of laminin-5 confirmed the presence of laminin-5 in a peri-cellular distribution around melanocytes, but not melanoma cells. Our results suggest that laminin-5 may be a ligand for normal human melanocytes in the basement membrane, and that loss of laminin-5 production by melanoma cells may be a marker for malignant transformation.

Cell Adhesion↗
PubMed1998

Malignant fibrous tumors.

Dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and malignant fibrous histiocytoma (MFH) are rare soft tissue sarcomas of intermediate to high-grade malignancy that the dermatologist must evaluate and treat. DFSP is a fibrohistiocytic tumor of intermediate malignancy characterized by aggressive local growth and propensity to recur after surgical excision. AFX is a superficial malignant tumor that arises on sun-exposed surfaces and is characterized by local aggressive behavior. MFH is the most aggressive of the fibrohistiocytic tumors with a high local recurrence rate and significant metastatic rate usually associated with a poor prognosis. This article reviews the epidemiology, pathogenesis, clinical presentation, histology, management, prognosis, and follow-up of these malignant tumors.

Chemotherapy, Adjuvant↗
PubMed1998

Rac1 mediates dendrite formation in response to melanocyte stimulating hormone and ultraviolet light in a murine melanoma model.

Melanocytes are pigment producing cells that reside in the basal layer of the epidermis, and form multiple long dendritic processes that transport melanosomes from the melanocyte cell body to the dendritic tips, and then to keratinocytes. Dendrite formation requires actin polymerization in the newly forming dendrite, and dendrite formation in melanocytes is stimulated by hormones and ultraviolet light. The rho-subfamily of monomeric guanosine triphosphate-binding proteins is implicated in remodeling the cellular actin cytoskeleton, resulting in the formation of filopodia, lamellipodia, and stress fibers, as well as in oncogenesis and activation of the Jun/p38 mitogen activated kinase cascade. In this paper we show that rac1 induces the formation of dendrite-like structures when activated mutants are transiently expressed in B16F1 murine melanoma cells and in four human melanoma cell lines. Activated mutants of cdc42 and rhoA induced the formation of filopodia and stress fibers, respectively, in B16F1 cells, but not dendrites. A dominant negative inhibitor of rac1 abrogated the ability of alpha-melanocyte stimulating hormone, a peptide hormone known to stimulate melanocyte dendrite formation, and ultraviolet light, to induce dendrite formation in B16F1 cells, and alpha-melanocyte stimulating hormone and ultraviolet light stimulated the localization of rac1 to dendrite cell membranes. These results suggest that rac1 is an important signaling intermediate in dendrite formation in B16F1 cells, and that rac1 mediates the well-known ability of alpha-melanocyte stimulating hormone and ultraviolet light to induce dendrite formation.

Actins↗
PubMed1996

Multiple chemical sensitivities, including iatrogenic allergic contact dermatitis, in a patient with chronic actinic dermatitis: implications for management.

BACKGROUND: Chronic actinic dermatitis represents a spectrum of photosensitive dermatoses. Phototesting and photopatch testing are necessary to elucidate the specific subtype. Such patients may have multiple cutaneous allergies and photoallergies. OBJECTIVE: This is a case report of a patient with chronic actinic dermatitis whose condition was worsened by certain sunscreens and corticosteroids. Our purpose was to identify the specific subtype of chronic actinic dermatitis and cutaneous allergens. METHODS: Phototesting to UVB and UVA was performed. Photopatch testings to standard photoallergens and to Photoplex sunscreen ingredients was performed. Patch testing to standard allergens and proprietary corticosteroids was performed. RESULTS: Positive photoallergies to Photoplex sunscreen and the UVA screen within Photoplex, Parsol 1789 (4-tert-butyl-4'-methoxydibenzoyl-methane), were identified. Positive allergies to Aclovate (alclometasone dipropionate) cream and ointment and Locoid (hydrocortisone butyrate) ointment were identified. The patient showed increased UVB sensitivity. CONCLUSION: This is a case report of a patient with chronic actinic dermatitis. A relevant photoallergy to Parsol 1789 and corticosteroid sensitivities to aclometasone and hydrocortisone butyrate were identified. Multiple cutaneous allergens may be identified in patients with chronic actinic dermatoses, and avoidance of known allergens may result in significant improvement of the chronic dermatitis.

Adrenal Cortex Hormones↗
PubMed1995

Report of three cases of cutaneous reactions to granulocyte macrophage-colony-stimulating factor and a review of the literature.

Granulocyte macrophage-colony-stimulating factor (GM-CSF) is a cytokine used to stimulate the growth and maturation of granulocytes and macrophages in a variety of clinical settings. Reported cutaneous side effects of GM-CSF therapy include both local reactions at the site of injection and diffuse eruptions. In this report we describe the clinical and histologic features of three patients who had a widespread macular-papular eruption after GM-CSF therapy to stimulate bone marrow recovery. In all three patients the eruptions occurred within 3 days of starting GM-CSF therapy and resolved after the infusion ended. Histologic features of the eruptions included a mixed infiltrate of lymphocytes, eosinophils, and neutrophils, primarily in the papillary dermis. In all three cases there was an increase in the number of dermal macrophages, and in two cases there was a striking increase in the size of dermal macrophages, many of which contained ingested elastin. We report these cases to alert the reader that alteration in number or size of dermal macrophages is a clue to the diagnosis of GM-CSF-induced dermatoses. A review of the literature of cutaneous side effects of GM-CSF is included.

Aged↗
PubMed1995

Developmental regulation of focal contact protein expression in human melanocytes.

Focal contacts are transmembrane links between the extracellular matrix and the actin cytoskeleton that play a critical role in directed cell migration, adhesion, and normal growth. Several different component proteins of the focal contact show developmentally dependent changes in expression, suggesting that this is an important mechanism by which focal contact formation is controlled during embryogenesis. In this report we examine the expression of focal contact-associated proteins in human fetal and neonatal melanocytes using Western blotting. We show that expression of paxillin, a 69-kDa vinculin binding protein, is fourfold higher in neonatal melanocytes than in fetal melanocytes. Further, we show that talin, a high molecular weight structural protein that links integrins to the actin cytoskeleton, is proteolytically cleaved in fetal, but not in neonatal melanocytes. Immunofluorescence microscopy of cells grown on fibronectin confirmed the presence of paxillin, talin, and vinculin at the ends of actin stress fibers at presumptive focal contacts in melanocytes. Adhesion experiments to extracellular matrix ligands revealed significant differences in adhesion of fetal and neonatal melanocytes to fibronectin. The developmentally specific changes in focal contact protein expression observed suggest that this may be an important mechanism by which focal contact assembly is controlled in human melanocytes during development.

Actinin↗
PubMed1994

Defects of the first branchial cleft.

Four cases of first branchial arch defects are presented. The literature relating to such defects is reviewed and a possible embryogenic mechanism is proposed with particular reference to the disposition of the facial nerve. The classification of these defects into Types I and II by Work (1972) is supported.

Branchial Region↗
PubMed1993

Clear cell sarcoma of tendons and aponeuroses and malignant blue nevus arising in prepubescent children. Report of two cases and review of the literature.

The low incidence of malignant melanoma in children makes the diagnosis of this disease problematic for clinicians and pathologists. The diagnosis becomes especially difficult when the melanoma is a rare variant of conventional melanoma, such as clear cell sarcoma of tendons and aponeuroses (CCSTA), and malignant blue nevus (MBN). In this report we describe two prepubescent children, one with a MBN, and one with CCSTA. The patient with MBN also developed acute lymphoblastic leukemia, and died of metastatic malignant melanoma within 1 year of diagnosis. We present the histological and clinical features of these cases and review the literature on these rare tumors arising in prepubescent children.

Cell Nucleolus↗
PubMed1993

Homeobox genes and skin development: a review.

Homeobox (HOX) genes are a gene family that encode information critical for the normal embryologic development of many different organisms, including vertebrates. HOX genes encode transcriptional regulatory factors that bind to multiple different genes and thereby determine the developmental fate of a cell. The role of HOX genes in the development of skin is undetermined but, based on information from other organisms and recent experimental data from skin models, it is likely that this class of genes is important for the normal development of skin adnexae, pigmentary system, and stratified epidermis during embryogenesis. The purpose of this review is to briefly summarize what is known about HOX genes and to familiarize the reader with recent insights into how HOX genes may function in skin development.

Animals↗
PubMed1991

Diagnosis of cutaneous cytomegalovirus infection: a review and report of a case.

Cytomegalovirus infections are a major source of morbidity and mortality in immunocompromised patients. We report a case of cutaneous cytomegalovirus in a patient with the acquired immunodeficiency syndrome, in which routine light microscopy was suggestive but not diagnostic of cytomegalovirus. Immunohistochemical studies of the specimen for cytomegalovirus antigens revealed numerous intracytoplasmic and intranuclear viral inclusions. This case illustrates the utility of immunoperoxidase techniques to diagnose cytomegalovirus infection of the skin rapidly. Immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction have been added to the more routine methods of viral culture and light microscopy to diagnose cytomegalovirus. In this report we review the cases of cutaneous cytomegalovirus in the literature and the laboratory detection methods available to establish this diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Keratinocytes regulate melanocyte number in human fetal and neonatal skin equivalents.

To determine if keratinocytes influence melanocyte number and position in the developing epidermis we have experimentally recombined keratinocytes and melanocytes from epidermis of different stages of differentiation in the skin equivalent (SE) system. Previously we showed that developmental differences in the position and number of melanocytes characteristic of the epidermis in vivo were preserved in fetal and neonatal skin equivalents. In the present study we have combined cultured fetal or neonatal keratinocytes with age-matched or non-age-matched cultured melanocytes on the dermal equivalent. The ratio of basal keratinocytes to melanocytes (BK/M) present in multiple high-power fields was determined after localization of melanocytes by staining with the melanocyte-specific monoclonal antibody, HMB-45. The BK/M ratio in SE composed of neonatal keratinocytes and either fetal (n = 4) or neonatal (n = 5) melanocytes was 26.2 and 21.5, respectively. The BK/M ratio in SE composed of fetal keratinocytes and either fetal (n = 8) or neonatal (n = 5) melanocytes was 9.2 and 7.7, respectively. In each case, the BK/M ratio was dependent on the keratinocytes rather than the melanocytes. With either type of melanocyte, ratios in SE composed of neonatal keratinocytes were significantly greater than those with fetal keratinocytes. These results establish that keratinocytes regulate the BK/M ratio in this model and suggest that developmental differences between fetal and neonatal keratinocytes may be responsible for determining melanocyte numbers in the epidermal-melanin unit in vivo. The precise mechanisms that control the organization and number of melanocytes in the epidermis are unknown although keratinocytes may interact with melanocytes via growth factors, cell surface molecules, or other factors related to proliferation and differentiation of the epidermis.

Cell Communication↗
PubMed1991

Physiologic distribution and differentiation of melanocytes in human fetal and neonatal skin equivalents.

There is evidence that epidermal keratinocytes play a critical role in melanocyte position and differentiation in the epidermis, although little is known about the molecular mechanisms involved. We have used an in vitro skin equivalent as a model system in which to study keratinocyte/melanocyte interactions in both fetal and neonatal skin. Because the skin equivalent model has been shown to closely simulate the morphologic and biochemical features of differentiated epidermis we hypothesized that the factors that influence melanocyte position and differnetiation would also function in this system. Localization of melanocytes in skin equivalents, using the monoclonal antibody HMB-45, established that melanocytes in fetal skin equivalents are grouped and distributed both basally and suprabasally, whereas melanocytes in neonatal skin equivalents are singly distributed among basal epidermal keratinocytes, similar to the distributions of fetal and neonatal melanocytes, respectively, in vivo. Similarly, in fetal and neonatal skin equivalents the patterns of expression of a number of melanoma/melanocyte-associated antigens closely parallels that seen in vivo. These results suggest that the skin equivalent model is an excellent system in which to study the dynamic factors that regulate melanocyte migration, proliferation, and differentiation during ontogeny and post-natal differentiation of the skin.

Cell Differentiation↗
PubMed1991

Characterization of keratocalmin, a calmodulin-binding protein from human epidermis.

Using affinity-purified calmodulin-binding proteins from human epidermis we have developed a monoclonal IgM antibody, ROC 129.1, to a human desmosomal calcmodulin-binding protein. This antibody reacts with a submembranous 250-kD protein from human keratinocytes and stains human epidermis in a "cell-surface pattern". Permeability studies indicated that the epitope with which this monoclonal reacts is on the inner surface of the cell membrane. Immunoelectronmicroscopy localized the antigen to the desmosome. The epitope is restricted to stratified squamous epithelia and arises between 8-12 wk of fetal development. This desmosomal calmodulin-binding protein, which we have termed keratocalmin, may be involved in the calcium-regulated assembly of desmosomes.

Animals↗