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Biomedical subjects

P Hiscott

Publications and source records attributed to P Hiscott.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hepatocyte growth factor/scatter factor in the eye.

Hepatocyte growth factor, also known as scatter factor (HGF/SF) is a multipotential cytokine which can produce a range of responses in target cells and its influence in the eye in health and disease is just beginning to be appreciated. Usually HGF/SF is synthesised by mesenchymally derived cells and targets and signals epithelial cells in a paracrine manner via their c-Met surface receptor. However, there is growing evidence for the existence of autocrine loops in a number of cell systems prominent among which are ocular cells such as the corneal endothelium, the lens epithelium, the retinal pigment epithelium (RPE) and others. Marked cellular proliferation is stimulated when activated HGF/SF is exposed to hepatocytes, renal epithelium, melanocytes and vascular endothelial cells but it is often a poor mitogen for other cell types. In target cells the cytokine promotes other bioactions such as junctional breakdown, shape change, cell scattering, directional and nondirectional migration, cell survival, invasive behaviour and/or tubule formation. These activities seem to depend on HGF/SF linking with the c-Met receptor and pathways to stimulate the various types of cytokine/receptor response are being unravelled at the present time. In corneal wound healing, HGF/SF is produced by stromal keratocytes and targets the repairing epithelium. HGF/SF is a constituent of tears, aqueous humour and vitreous humour at levels above that found in plasma although it is not clear how much is activated. Aqueous HGF/SF may well influence lens epithelial, corneal endothelial and trabecular meshwork cell survival. Vitreous levels of HGF/SF are elevated in proliferative vitreoretinopathy (PVR), where a target cell is the RPE and in proliferative diabetic retinopathy (PDR) where HGF/SF has been shown to be a major angiogenesis factor. Finally HGF/SF may be involved in the metastatic spread of tumour cells from uveal melanomata and in the formation of vascular channels in these tumours.

Animals↗
PubMed2000

Challenges in ophthalmic pathology: the vitreoretinal membrane biopsy.

The introduction of vitreoretinal microsurgery has produced a new type of biopsy; that of the vitreoretinal membrane. This review investigates methods by which these scar-like tissues are handled in the laboratory and explores the implications of the results of such evaluations. The study of vitreoretinal membrane biopsies has provided much information concerning the pathobiology of the various conditions which may give rise to the tissue as well as insights into how membranes themselves develop. Moreover, the application of new laboratory techniques is expected to enhance our understanding of the formation of vitreoretinal membranes, and lead to further advances in their surgical and medical management.

Biopsy↗
PubMed2000

Ligneous conjunctivitis: a local manifestation of a systemic disorder?

Ligneous conjunctivitis is a descriptive term. It refers to the "woody" consistency of the pseudomembrane that usually forms on the palpebral conjunctiva of those affected. It is rare and probably only one manifestation of a multiorgan, pseudomembranous disease. (1-4) We report a case of ligneous conjunctivitis in which investigation revealed a plasminogen deficiency in the heterozygous range (previously reported only in association with a homozygous plasminogen deficiency). We suggest a strategy for investigating known and new cases of ligneous conjunctivitis and/or pseudomembranous disease.

Biopsy↗
PubMed2000

Active scatter factor (HGF/SF) in proliferative vitreoretinal disease.

PURPOSE: Hepatocyte growth factor/scatter factor (HGF/SF) possesses mitogenic, motogenic, and morphogenic properties and has recently been implicated in various retinal diseases. The role of HGF/SF in proliferative vitreoretinal disease was investigated. METHODS: Sections of epiretinal membranes were stained immunohistochemically for cytokeratins, to identify HRPE cells, and for HGF/SF receptor (c-Met). Cultured HRPE cells were stained for c-Met and investigated for shape change in response to HGF/SF, by using image analysis. The dose-response relationship for HRPE cells to HGF/SF was investigated by a cell migration assay and the specificity of this response evaluated by a neutralization experiment. Subretinal fluid (SRF) and vitreous from patients with retinal detachment and proliferative vitreoretinopathy (PVR) plus vitreous from eyes obtained after death, eyes with macular hole, and eyes with proliferative diabetic retinopathy (PDR) were investigated for the presence of HGF/SF using an enzyme-linked immunosorbent assay (ELISA). HGF/SF activity was measured using an MDCK cell scatter assay. RESULTS: HRPE cells in epiretinal membranes and in culture expressed c-Met. Cultured HRPE cells responded to HGF/SF by an epithelial-to-mesenchymal shape change and by cell migration, a response that increased with increasing concentrations of HGF/SF. This response was reduced in the presence of neutralizing antibody. There was evidence of HGF/SF in increasing concentrations in more severe PVR and in PDR when measured by ELISA, and, conversely, there was evidence of correspondingly decreasing HGF/SF activity when measured by MDCK cell scatter assay in these diseases. CONCLUSIONS: HGF/SF is present in normal and pathologic vitreous. HRPE cells respond by shape change and cell migration to HGF/SF. Concentrations of HGF/SF increase in proliferative vitreoretinal disease and increase in turn with increased severity of the disease, but HGF/SF bioactivity decreases (consistent with activator depletion). These findings are consistent with the hypothesis that HGF/SF may play a role in the HRPE mesenchymal transformation that typifies PVR.

Adult↗
PubMed1999

A choroidal amyloid-rich neuroendocrine tumor: initial manifestation of Cushing syndrome.

A 57-year-old man with a history of hepatic adenocarcinoma was referred 3 years after his diagnosis with a choroidal tumor in the right eye. Results of a transscleral excision biopsy revealed the tumor to be an amyloid-rich neuroendocrine metastasis. The patient subsequently developed cushingoid features and investigations revealed ectopic corticotropin syndrome, an elevated urinary 5-hydroxyindoleacetic acid level, and neuroendocrine metastasis in several locations. The choroidal neuroendocrine metastasis stained negative for serotonin and corticotropin. The source of the ectopic corticotropin and the location of the primary tumor have not been found. This case demonstrates that disseminated neuroendocrine tumors may rarely cause ocular lesions before systemic endocrine sequelae arise.

Amyloidosis↗
PubMed1999

Matrix and the retinal pigment epithelium in proliferative retinal disease.

In their normal state, RPE cell are strongly adherent to Bruch's membrane. Certain pathological conditions such as retinal detachment cause an injury-type response (probably augmented or induced by the local accumulation of a variety of substances which modulate cell behaviour) in which RPE begin to dissociate from the membrane. This RPE-Bruch's membrane separation may be mediated by proteins with counter-adhesive properties and proteolytic enzymes, partly derived from the RPE themselves. Concomitant with the RPE disassociation, the cells begin to lose tertiary differentiation characteristics and gain macrophage-like features. When the "free" RPE arrive at the surface of the neuroretina, they may attach to or create a provisional matrix. Some of the cells adopt a fibroblast-like phenotype. This phenotype is similar to that of the dermal fibroblast during cutaneous wound repair and the fibroblastic RPE synthesise the types of matrix components found in healing skin wounds. Many of these molecules in turn further modulate the activities of the cells via several families of cell surface receptors, while the RPE continue to remodel the new matrix with a range of proteolytic enzymes. The resulting tissue (or membrane) has many of the features of a contractile scar and is the hallmark of the condition known as proliferative vitreoretinopathy (PVR). Thus the development of PVR, and the resulting tractional distortion of the neuroretina, appears to be dependent on RPE-matrix interactions. The interactions present a number of potential therapeutic targets for the management of the disorder.

Animals↗
PubMed1999

Repair in avascular tissues: fibrosis in the transparent structures of the eye and thrombospondin 1.

Wound repair is a process which is normally dependent on the vasculature of the damaged tissue. However, the transparent structures of the eye (e.g. central cornea, lens, vitreous) are avascular and yet are still subject to repair and fibrosis. Moreover, the resulting ophthalmic scars often remain avascular. Since this type of ocular scarring may result in blindness, it is the subject of intense research. An aspect of avascular ophthalmic fibrosis which has attracted attention is the question concerning early wound healing components that are usually derived from blood constituents. One such molecule is the glycoprotein thrombospondin 1. Thrombospondin 1 is thought to be a key regulator of cell behaviour in early wound repair and appears to be derived totally from platelet alpha-granules during repair of incisional skin wounds. It has been shown that the ocular cells involved in avascular repair processes, and which are thus responsible for healing in the absence of platelet-derived thrombospondin 1, are capable of synthesizing the protein themselves. It is suggested that cells involved in ophthalmic repair processes produce thrombospondin 1 in the absence of the platelet-derived molecule. Local synthesis of thrombospondin 1 may represent a therapeutic target in the management of ophthalmic fibrosis.

Animals↗
PubMed1999

Modulation of retinal pigment epithelial cell behavior by Agaricus bisporus lectin.

PURPOSE: To determine whether Agaricus bisporus lectin (ABL) binds retinal pigment epithelial cells (RPEs), to conduct a preliminary viability study of RPEs exposed to ABL, and to evaluate the effects of ABL on RPE proliferation and RPE-mediated matrix contraction in vitro. METHODS: Using cultured bovine RPEs, immunohistochemistry was used to study ABL binding. Morphologic and trypan blue exclusion techniques were used for toxicity studies. The effect of ABL on RPE proliferation was investigated by [methyl-3H]-thymidine incorporation. The effect of ABL on RPE-mediated matrix contraction was evaluated with RPE-populated three-dimensional collagen matrices. RESULTS: ABL bound to RPE cells. This binding was inhibited by asialomucin. No change in RPE morphology or trypan blue exclusion compared with controls was observed in RPEs incubated with 5 to 60 microg/ml ABL for 3 days. Twenty-four-hour incubations of RPEs with ABL significantly inhibited RPE proliferation in a dose-dependent way, 40 microg/ml ABL inhibited proliferation by 83% (SE 14, P<0.05). ABL showed a dose-dependent significant inhibition of RPE-mediated collagen matrix contraction over 3 days, with 93% inhibition compared with controls by 40 microg/ml lectin (P<0.05). The inhibitory effect of ABL on proliferation and gel contraction was partly reversible after eliminating ABL from the culture medium. CONCLUSIONS: Bovine RPE cells bind ABL, and preliminary evaluations suggest that levels of ABL that are nontoxic to the cells potently inhibit RPE proliferation and RPE-mediated matrix contraction. ABL deserves further investigation as a potential inhibitor of RPE proliferation and cell-mediated matrix contraction in anomalous reparative processes such as proliferative vitreoretinopathy and as a laboratory tool for RPE behavioral studies.

Animals↗
PubMed1998

Epithelioid cell Spitz nevus of the eyelid.

PURPOSE: To report a 20-month-old child with a rapidly growing dome-shaped red nodule on the left lower eyelid. The lesion was diagnosed clinically as an hemangioma, but microscopy disclosed an epithelioid Spitz nevus. METHOD: Case report. RESULT: Histopathologic examination of the excised lesion disclosed a Spitz nevus (benign juvenile melanoma) of a chiefly epithelioid cell type. CONCLUSIONS: The differential diagnosis of eyelid skin nodules in children should include Spitz nevus. This uncommon nevus has many cytologic features in common with nodular malignant melanoma. Histologically, it may be difficult to distinguish between nodular malignant melanoma and Spitz nevus.

Diagnosis, Differential↗
PubMed1997

Immunolocalisation of thrombospondin 1 in human, bovine and rabbit cornea.

Light- and electron-microscopic immunohistochemical techniques were used to investigate the distribution of the matricellular protein thrombospondin 1 in normal human, bovine and rabbit cornea. Light-microscopic immunoreactivity for thrombospondin 1 was observed in the epithelial basement membrane, posterior Descemet's membrane and endothelium of human and bovine cornea. The bulk of the stroma, the stromal cells (keratocytes) and the anterior part of Descemet's membrane in human and bovine cornea were devoid of detectable thrombospondin 1 and the protein could not be demonstrated in any of the layers of the rabbit cornea. Electron-microscopic immunogold studies of human and bovine cornea revealed that thrombospondin 1 labelling of corneal endothelial (and basal epithelial) cells included focal deposits at cell membranes. It is postulated that thrombospondin 1 regulates interactions between cells and their basement membrane, and perhaps cell-to-cell interactions, in the normal human and bovine corneal endothelium and basal epithelium.

Adult↗
PubMed1997

Clinical and morphological response to UV-B irradiation after excimer laser photorefractive keratectomy.

This paper represents an update on a study that has been reported elsewhere (Nagy ZZ et al: Ophthalmology 104:375-380, 1997). The aim of the study was to evaluate the clinical and light- and electron-microscopic effects of ultraviolet-B (UV-B) exposure on the outcome of photorefractive keratectomy (PRK). A total of 42 pigmented rabbits were used in the study. One eye from each of 12 rabbits received a 193 nm 45-microm deep (-5.0 diopters [D]) excimer laser PRK, one eye from each of 12 rabbits received a 135-microm deep (-15.0 D) excimer laser PRK, and one eye from each of 12 rabbits received a 270 microm deep (-30.0 D) excimer laser PRK. Twenty-one days after PRK, six of the laser-treated eyes from each group were exposed to 100 mJ/cm2 UV-B (280-320 nm). The other six rabbits from the PRK groups received no further treatment. One eye from each of six rabbits received only UV-B irradiation, serving as control. Subepithelial haze was evaluated before and after UV-B irradiation. Clinical changes were followed by laser tyndallometry, confocal corneal biomicroscopy, ultrasound biomicroscopy, and endothelial specular microscopy. Corneal morphology was assessed 4, 8, and 12 weeks after UV-B exposure, employing light microscopic and transmission electron-microscopic techniques (TEM). Eyes only exposed to 100 mJ/cm2 UV-B exhibited keratitis for 2 days, but showed no haze and were histologically normal at all time intervals. The PRK-UV-B-irradiated rabbit eyes exhibited a significant increase of stromal haze compared to the eyes receiving PRK alone; this phenomenon correlated with the depth of photoablation. The severity of clinical findings also correlated with the previously attempted photoablation depth; in PRK-UV-B-irradiated eyes the symptoms were much more serious than in eyes treated with PRK alone. Histologically, the main difference between the UV-B-irradiated and nonirradiated-post-PRK eyes was the presence of anterior stromal extracellular vacuolization in the UV-B-exposed eyes. The vacuolated foci were confined to the PRK treatment area, contained increased numbers of keratocytes and showed a disorganization of normal collagen lamellae. Transmission electron microscopy revealed activated keratocytes containing abundant rough endoplasmic reticulum, prominent Golgi zones, and extracellular vacuoles filled with amorphous material. The haze and morphological changes showed a tendency to incomplete resolution over a period of 12 weeks. Ultraviolet-B exposure during post-PRK stromal healing exacerbates and prolongs clinical symptoms and the stromal healing response, which is manifest biomicroscopically by augmentation of subepithelial haze. The findings suggest that excessive ocular UV-B exposure should be avoided during the period of post-PRK stromal repair and that UV-B may modulate the response of tissues to excimer 193 nm, and perhaps, other laser energy in general.

Animals↗
PubMed1997

Intermediate filament expression by normal and diseased human corneal epithelium.

Cicatricial conjunctivitis may be a sequel to systemic disorders (eg, Stevens-Johnson syndrome, cicatricial pemphigoid) or local disorders such as chemical burns. The cicatrisation is often associated with corneal epithelial changes that cause visual loss. These have been attributed to encroachment of the conjunctival epithelium over the cornea. However, the epithelial anomalies are poorly understood. We investigated the corneal epithelial changes in cicatricial conjunctivitis with an immunohistochemical study of intermediate filaments in normal and pathological specimens. Our results show that the normal corneal epithelium is immunoreactive for cytokeratin 3 (CK 3) but not cytokeratin 19 (CK 19), whereas normal conjunctival epithelium is CK 3 negative and CK 19 positive. Conjunctiva artificially transposed over the cornea (after therapeutic conjunctival flap reconstruction) retained the normal pattern of conjunctival cytokeratin expression (CK 3 negative, CK 19 positive). Conversely, the entire corneal epithelium exhibited the normal cytokeratin pattern (CK 3 positive, CK 19 negative) in 82% of Stevens-Johnson, 80% of cicatricial pemphigoid, and 69% of chemical burns specimens. The findings suggest that conjunctival encroachment is not responsible for the changes at the corneal surface in cicatricial conjunctivitis and that the abnormal corneal epithelium is derived from native corneal cells in these diseases.

Adult↗
PubMed1997

Ultraviolet-B enhances corneal stromal response to 193-nm excimer laser treatment.

PURPOSE: The purpose of the study was to evaluate the biomicroscopic, light microscopic, and electron microscopic effects of ultraviolet-B (UV-B) exposure on the outcome of photorefractive keratectomy (PRK). METHODS: A total of 24 pigmented rabbits were used in the study. One eye of 16 rabbits received a 193-nm, 45-micron deep (-5.0 diopter) excimer laser PRK. Twenty-one days after PRK, eight of the laser-treated eyes were exposed to 100 mJ/cm2 UV-B (280-315 nm) UV radiation by placing the rabbits in a standard clinically used dermatologic chamber for 7 minutes. Eight PRK-treated rabbits received no further treatment. The remaining eight non-PRK-treated rabbits received 100 mJ/cm2 UV-B only to one eye. Subepithelial haze was assessed before and after UV irradiation. Corneal morphology was assessed 4, 8, 12, and 16 weeks after UV-B exposure, using light microscopic and transmission electron microscopic (TEM) techniques. RESULTS: Untreated eyes exposed to 100 mJ/cm2 UV-B only exhibited photokeratitis for 2 days, but showed no haze and were normal histologically at all intervals. The PRK-treated UV-B irradiated eyes exhibited a significant increase of stromal haze compared to eyes receiving PRK alone. Histologically, the main difference between the UV-B irradiated and nonirradiated post-PRK eyes was the presence of anterior stromal extracellular vacuolization in the UV-B-exposed eyes. The vacuolated foci were confined to the PRK treatment area and showed increased keratocyte density and disorganization of normal collagen lamellae. TEM showed activated keratocytes containing abundant rough endoplasmic reticulum, prominent Golgi zones, and extracellular vacuoles filled with amorphous material. The haze and morphologic changes showed a tendency to incomplete resolution over the period of 16 weeks. CONCLUSIONS: The UV-B exposure during post-PRK stromal healing exacerbates and prolongs the stromal healing response and is manifest biomicroscopically by augmentation of subepithelial haze. The findings suggest that excessive ocular UV-B exposure should be avoided during the period of post-PRK stromal repair and that UV-B may modulate the response of tissues to 193-nm excimer laser and perhaps other laser energy in general.

Animals↗
PubMed1996

Keratocytes produce thrombospondin 1: evidence for cell phenotype-associated synthesis.

Immunochemical techniques were used to determine whether cells of the avascular corneal stroma (keratocytes) have the ability to synthesize thrombo- spondin 1 (TSP1), a glycoprotein originally described in platelets and more recently implicated in regulating cell behavior (e.g., migration) during wound repair in vascular tissue. Immunoprecipitation experiments with metabolically labeled cells showed that bovine keratocytes in preconfluent cultures produced TSP1, but de novo TSP1 production could not be detected in confluent keratocyte cultures. Immunofluorescence studies of the preconfluent cells revealed that the keratocyte TSP1 was distributed in perinuclear granules and peripheral foci. TSP1 expression also was observed in keratocytes cultured in a collagen matrix model of stromal wound healing and, in this model, immunogold labeling revealed TSP1 foci on keratocyte surfaces adjacent to collagen fibers in the matrices. TSP1 expression was not observed in the syncytial keratocytes of normal bovine cornea. The results indicate that keratocytes have the ability to synthesize TSP1, and do so in vitro under conditions which simulate corneal stroma repair, but suggest that keratocytes in a syncytial arrangement (as in the normal cornea) do not make TSP1. TSP1 may play a role in corneal pathologies which induce keratocytes to change from a syncytial to a wound repair phenotype, such as mechanical damage to the stroma. Local production of TSP1 might provide an alternative source to platelet-derived TSP1 during nonvascularized stromal tissue repair.

Animals↗
PubMed1996

Unexpected expression of thrombospondin 1 by corneal and iris fibroblasts in the pseudoexfoliation syndrome.

Pseudoexfoliation (PEX) syndrome is a common, but little known, systemic degenerative condition manifest by the extracellular deposition of a distinctive fibrillar material (PEX material) in various organs. In the eye, PEX material is characteristically found on the surfaces of structures that line the anterior and posterior chambers, and it is associated with cataract and glaucoma. Although PEX material contains several elements normally present in basement membranes, its precise composition remains obscure. Because the glycoprotein thrombospondin 1 (TSP1) can be shown in some basement membranes, we attempted to define its involvement in the composition of PEX material by immunohistochemical analysis of ocular tissues from patients with PEX syndrome. Although we were unable to detect TSP1 in PEX material, we were surprised to find that iris and corneal stromal fibroblasts expressed TSP1. In age-matched normal eyes, iris and corneal fibroblasts did not contain demonstrable TSP1. These observations indicate that TSP1 is not a significant component of PEX material but suggest that, in PEX syndrome, stromal fibroblasts remote from the principal sites of PEX material deposition are altered at the molecular level. The findings add evidence to the theory that PEX syndrome represents a disorder of connective tissue metabolism and intimate that the syndrome involves anomalous production of proteins other than those found in PEX material.

Aged↗