Biomedical subjects
C S Foster
Publications and source records attributed to C S Foster.
Human basement membrane components of keratoconus and normal corneas.
Using immunofluorescence techniques, we analyzed the distribution of glycoproteins in normal and keratoconus corneas of humans. Laminin, bullous pemphigoid antigen, fibronectin, and fibrin/fibrinogen were all found in the epithelial basement membrane of normal corneas. Keratoconus corneas produced similar results, except that staining for fibrin/fibrinogen was weak. Fibrin/fibrinogen was absent from normal corneal basement membrane in animal models studied previously. Keratoconus may be the result of the lysis of fibrin or may involve impeded elaboration of fibrin.
Ascorbic acid therapy in a thermal burn model of corneal ulceration in rabbits.
We studied the effect of topical and systemic ascorbic acid on a rabbit model of corneal ulceration produced by thermal burn. Central stromal ulceration occurred in 77% to 100% of eyes in all treatment groups. The rate of ulceration was accelerated in animals treated with systemic ascorbic acid. Ulceration began after 5.80 +/- 2.14 days in control eyes and 2.75 +/- 1.26 days in the eyes of rabbits treated with both topical and systemic ascorbic acid (P less than .02). Subconjunctival ascorbic acid alone did not affect the rate of ulceration (average onset, 6 +/- 1 days). Once ulceration occurred in animals treated with both topical and systemic ascorbic acid, the incidence of perforation and descemetocele formation was increased and that of healing was decreased. The time required for healing was not significantly altered by treatment (9.50 +/- 2.28 days for control eyes vs 5.75 +/- 2.78 days for treated eyes) (P greater than .05).
Systemic immunosuppressive therapy for progressive bilateral Mooren's ulcer.
Nine patients with progressive bilateral Mooren's ulcer unresponsive to conventional ocular and systemic therapy were treated with methotrexate or with cyclophosphamide. The progressively destructive inflammatory process was arrested, and ocular anatomy and function were preserved, in eight patients who were adequately treated with immunosuppressive doses of the cytotoxic drugs for 6 to 24 months. The inflammatory process eventually destroyed both eyes of one patient who received inadequate therapy and follow-up care. Used properly, cytotoxic immunosuppressive therapy may offer a reasonable option in the care of patients with bilateral progressive Mooren's ulcer.
Autoimmune reactions in the eye.
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Ocular cicatricial pemphigoid associated with hyperproliferation of the conjunctival epithelium.
We determined the mitotic rate, measured by evaluating uptake of tritiated thymidine autoradiographically, and the frequency of goblet cells in conjunctival epithelial biopsy specimens from nine normal subjects and from 11 patients (seven women and four men ranging in age from 50 to 80 years) with ocular cicatricial pemphigoid. The mitotic rate of patients with the disease was significantly higher than that of normal subjects, 7.2 +/- 2.2 vs 1.6 +/- 0.2 labeled cells per 100 basal epithelial cells (P less than .01). The goblet cell frequency, however, was significantly less in patients than in normal subjects. This suggests that ocular cicatricial pemphigoid is associated with hyperproliferation of the conjunctival epithelium, with a concurrent failure of normal conjunctival differentiation.
Immunoglobulin deposition in localized conjunctival amyloidosis.
Immunofluorescent studies were performed on tarsus and tarsal conjunctiva from a 30-year-old woman with blepharoptosis secondary to localized nonfamilial amyloidosis. Both kappa and lambda light chains were identified in abundance in the resected tissue. There was no evidence of any systemic disease or of amyloid deposition elsewhere. Six months after the patient underwent surgery, there was no sign of recurrence. The antigenic determinants of the amyloid suggested that the pathogenesis of localized nonfamilial ocular amyloidosis involves the accumulation of proteins similar to immunoglobulin.
Antiviral medications and corneal wound healing.
Masked controlled rabbit studies were done to determine the toxic effects on corneal wound healing of the antiviral ointments 0.5% idoxuridine, 3% Ara A, and 3% acyclovir, and the antiviral drops 0.1% idoxuridine, 3% Ara AMP, and 1% trifluridine. Ara A, acyclovir, trifluridine and idoxuridine drops had no significant effects on the rate of closure of epithelial wounds. Idoxuridine ointment given 5 times a day significantly retarded the rate of epithelial wound closure, but not when given 4 times a day. Only Ara AMP caused a retardation of epithelial healing and an actual increase in the defect after 4 days of treatment. Histopathologically all drugs, except acyclovir, showed a toxic effect on the regenerating epithelium. All drugs, except acyclovir, showed retarded stromal wound healing with reduced bursting strength and collagen content. Ara AMP had increased bursting strength and collagen content possibly because of greater inflammation. Acyclovir, in comparison to all the other medications studied, appeared to have minimal to no toxic effects on experimental epithelial and stromal wound healing, and on this basis is the agent of choice for use in herpes simplex stromal keratitis with ulceration and as a prophylactic agent for long-term use after penetrating keratoplasty.
Monoclonal antibodies to the human mammary gland: III. Monoclonal antibody LICR-LON-M18 identifies impaired expression and excess sialylation of the I(Ma) cell-surface antigen by primary breast carcinoma cells.
Monoclonal antibody LICR -LON- M18 identifies the immunodominant oligosaccharide sequence of the I(Ma) blood-group antigen: Gal beta 1----4GlcNAc beta 1----6--. In primary breast cancers this structure is almost totally cryptic, due to "masking" by sialic acid, but can be revealed by digestion with the specific glycosidase neuraminidase. Following desialylation, light microscopic immunohistochemical examination has revealed the epitope identified by LICR -LON- M18 to be heterogeneously distributed throughout the population of breast carcinoma cells. These tumor cells express the antigen as both a cytoplasmic and a surface membrane determinant. In the normal human breast, this structure is expressed exclusively along the luminal plasma membranes of the duct and alveolar littoral epithelial cells. Desialylation of tissue sections of normal resting and lactating breast epithelium with neuraminidase virtually abolishes the heterogeneous intercellular distribution of the I(Ma) determinant. In desialylated nonneoplastic breast tissues, the expression of this antigen is observed within the cytoplasm of some myoepithelial cells, but not in the littoral epithelial cells. The expression of the I(Ma) antigen by neoplastic and normal breast epithelial cells has also been compared with that of the oligosaccharide sequence Gal beta 1----3GalNAc. This structure, recognized by peanut agglutinin, forms the dominant portion of the Thomsen-Friedenreich antigen. With respect to normal and lactating breast epithelial cells, both oligosaccharide structures are sialylated and appear to be similarly misprocessed by breast carcinomas. The masking of surface carbohydrate determinants and the faulty processing of structures usually expressed on the surface of non-neoplastic breast epithelial cells may be important phenomena in the pathobiology of breast carcinomas.
Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression.
We performed a nonrandomized clinical trial comparing the ocular and systemic efficacy of cytotoxic immunosuppression with steroidal and nonsteroidal anti-inflammatory therapy in the care of 34 patients with rheumatoid arthritis who developed peripheral ulcerative keratitis and/or necrotizing scleritis. Nine of the 17 patients managed with conventional therapy died of a vascular-related event during the ten-year period of the study. In 13 of the 17 patients, the ocular inflammatory process progressed, and in 5 patients extraocular, although nonlethal, vasculitic lesions developed. One of 17 patients treated with long-term immunosuppressive therapy died during the ten-year follow-up period, and this death occurred after cytotoxic therapy was withdrawn. None of the patients on immunosuppressive regimens developed extraocular vasculitis while taking the drug, and none had progression of the ocular destructive lesion. The results of this study emphasize that the eye is a sensitive indicator for potentially lethal occult systemic vasculitis in patients with rheumatoid arthritis who develop peripheral ulcerative keratitis or necrotizing scleritis. Our mortality data strongly suggest that the use of cytotoxic drugs may alter favorably the general as well as the ocular prognosis in these patients.
Basement membrane components in healing rabbit corneal epithelial wounds: immunofluorescence and ultrastructural studies.
The nature of the substrate that supports epithelial migration in vivo is of interest, particularly with respect to mechanisms of wound healing. Immunofluorescence and electron microscopy were used to search for common substrate components in prototype rabbit corneal wounds: epithelial scrape wounds, in which the corneal or conjunctival epithelium migrated over the denuded lamina densa of the corneal basement membrane (CBM), and superficial keratectomy, in which the corneal epithelium migrated over a bare stroma without CBM. The corneal epithelium moved rapidly over the CBM or stroma to cover the defect within 2-3 d, whereas the conjunctival epithelium required 1-2 wk. In all wounds, fibronectin and fibrin/fibrinogen were deposited onto the bare surface within 8 h after wounding and persisted under the migrating epithelium until migration was complete. Bullous pemphigoid antigen (BPA), a normal component of the CBM, was removed with the epithelium upon scrape wounding and reappeared in the CBM after migration was completed. In contrast, the conjunctival epithelium had a continuous subepithelial band of BPA out to the migrating tip. Laminin, also a normal component of the CBM, was not removed in the scrape wounds, indicating that the region of least resistance to shear stress was between the BPA and laminin layers. Laminin was removed by superficial keratectomy and was not detectable under the leading edge of the migrating cells. Laminin and BPA were restored in the CBM by 2-4 wk. Type IV collagen could not be detected in normal CBM, but was conspicuously present in conjunctival basement membrane and in blood vessels. Focal bands of type IV collagen did appear in the newly synthesized CBM 2-4 wk after keratectomy. These results argue that BPA, laminin, and type IV collagen are not essential for the migration of corneal epithelium during wound healing and support the hypothesis that fibronectin and fibrin/fibrinogen are the common, perhaps the essential, components of the provisional matrix that serves as a substrate until the permanent attachment components are regenerated.
Fibronectin in developing rabbit cornea.
Fibronectin is believed to be important in tissue morphogenesis. We examined the distribution of fibronectin in developing rabbit cornea by immunohistofluorescence. Cryostat sections of cornea from 13, 15, and 20-day-old fetuses, 3-day neonates, and adults were incubated with affinity-purified fluoresceinated guinea pig anti-rabbit fibronectin antiserum (aFN). aFN bound to components within the presumptive stromal region and along the basal surfaces of corneal and lens epithelia during early stages of mesenchymal invasion. At 15 days of gestation, fluorescence was associated with the stromal extracellular matrix of the cornea, the subepithelial zone, and the lens capsule. In the 20-day fetus an intense aFN fluorescence was present along the inner corneal stromal border coincident with the formation of Descemet's membrane. Fluorescence within the corneal stroma appeared as fine lines, restricted to the collagen lamellae, remaining through birth and disappearing in the adult. Although stromal fluorescence disappeared in the adult, Descemet's membrane continued to fluoresce, albeit to a lesser extent. The results of our studies indicate the presence of fibronectin in developing rabbit cornea. Because fibronectin is important to cell adhesion in vitro, and because intercellular and cell-extracellular matrix interactions, including adhesion, are necessary for tissue morphogenesis, our observation suggests that fibronectin plays an important role in corneal morphogenesis.
Two mouse hybridoma antibodies against human milk-fat globules recognise the I(Ma) antigenic determinant beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 6).
Two mouse hybridoma antibodies (LICR-LON-M39 and LICR-LON-M18) against the human-milk-fat globules were found to resemble human autoantibodies of anti-I type in their cold agglutinating property and their preferential reactions with erythrocytes of I- rather than i-type. From inhibition of binding assays with glycoproteins having known A, B, H, Lea, Leb, I, and i activities, and oligosaccharides of the Type 1 and Type 2 lacto-N-glycosyl series, it was established that these antibodies are directed at Type 2 structures, and that the I(Ma) determinant, beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 6), which is usually found on branched oligosaccharides, is the preferred sequence. The hybridoma antibodies as well as anti-I Ma were shown to react well with the beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 6)-D-Gal or -D-Man sequence. Studies of the reactions of these antibodies with glycolipids on thin-layer plates showed that the two hybridoma antibodies differ from anti-I Ma in reacting weakly with the unbranched i-type sequence beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 3)-beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 3)-beta-D-galp-(1 leads to 4) as found on lacto-N-norhexasylceramide. Furthermore, they differ from anti-I Ma but resemble anti-I Woj and Sti, and a hybridoma antibody 1B2 in their failure to react with their determinant in the presence of alpha-D-(1 leads to 3)-linked galactosyl groups. From their lack of reactions with blood-group-A and -H active glycoproteins, and their reactions with neuraminidase-treated erythrocytes, it was deduced that the determinants recognised by the two hybridoma antibodies are also masked in the presence of alpha-L-(1 leads to 2)-linked fucosyl groups and sialic acid.
Human mammary gland morphogenesis in vitro: the growth and differentiation of normal breast epithelium in collagen gel cultures defined by electron microscopy, monoclonal antibodies, and autoradiography.
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The effect of donor cornea epithelium removal on the incidence of allograft rejection reactions.
The most frequent cause of human corneal transplant failure is immunologic rejection. Surface antigenic determinants on nucleated cells are thought to prime the host's immune system for rejection. Greater than 90% of the nucleated cells of the cornea reside in the epithelium; therefore, one might expect that host sensitization and subsequent graft rejection could be modified by epithelium removal prior to transplantation. The major objective of this two-institution combined prospective and retrospective clinical study was to determine the effect of epithelium removal on the incidence of human corneal allograft rejection reaction. A retrospective study of 152 patients showed an incidence of 24.7% rejection reactions in patients with epithelium transplanted compared to 7.2% in the epithelium-removed group (P = 0.008). In the prospective study of 55 patients, there was a rejection incidence of 30% in the epithelium-on group versus 8.0% with epithelium removed (P = 0.04). The decision to remove graft epithelium, however, must be tempered by anticipation of postoperative healing problems.
Corneoscleral manifestations of Graves' disease, the acquired connective tissue disorders, and systemic vasculitis.
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Immunomodulation in ophthalmology.
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Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies.
Perineural spread has been demonstrated histologically in 65/180 (36%) major surgical resections for squamous carcinomas of the head and neck; the incidence in a smaller necropsy series was 18/20 (90%). Perineural infiltration was observed most commonly in the vicinity of carcinomas arising in the buccal cavity (31/63, 50%) and, at all sites, it was most commonly encountered near tumours less than or equal to 2.5 cm in diameter. Perineural spread near cervical node metastases was, by contrast, uncommon in the surgical series. Tumour within perineural spaces tends to be concentrated at the margin of the nerve and shows only limited extension inwards, but cells may track upwards and downwards within the spaces. Distant spread for greater than 2 cm is unusual, and interval sampling of involved nerves in necropsy material indicates that most perineural tumour cells are confined to the distal 1 cm of the affected nerve. Infiltrated nerves regularly show varying degrees of myelin and axonal degeneration, probably anoxic in origin, and segmental infarction of nerve trunks was observed in three patients. Fine changes in axons and myelin have been regularly demonstrated with two monoclonal antibodies, and the use of these new reagents is described.