Treatment of rheumatoid corneal ulcers.
Explore the source record for details and available documents.
Arthritis, Rheumatoid↗
Biomedical subjects
R J Epstein
Publications and source records attributed to R J Epstein.
Subepithelial infiltrates in Acanthamoeba keratitis.
Six patients had Acanthamoeba keratitis that manifested an unusual type of subepithelial corneal infiltrate late in the course of the disease. These infiltrates occurred in the anterior corneal stroma, often in a location removed from the site of infection. In four of these patients the infiltrates occurred with no other clinical signs of inflammation. Two patients had mild foreign-body sensation that resolved despite the persistence of the subepithelial infiltrates. The infiltrates resolved with topical corticosteroid therapy in three patients; however, in two of these three patients the infiltrates recurred when corticosteroid therapy was tapered or discontinued. The subepithelial infiltrates appeared and behaved similarly to those associated with viral and chlamydial corneal infections. An immunologic mechanism may be responsible for these unusual delayed-in-onset infiltrates.
Acanthamoeba↗
Use of the disposable contact lens as a bandage contact lens.
Explore the source record for details and available documents.
Bandages↗
Photodynamic therapy for corneal neovascularization.
We have previously described corneal neovascularization (CNV) induced by the intrastromal injection of interleukin-2 (IL-2) in inbred mice. Photodynamic therapy (PDT), administered by a deeply penetrating 630 nm fiberoptic laser, can destroy neoplasms and their associated neovascularization with some selectivity, but can damage neighboring tissues when used for CNV. We performed PDT with a 514 nm ophthalmic argon laser in an attempt to induce regression of CNV and reduce the associated toxicity. Eight weeks following IL-2 injection, mice with CNV were injected i.v. with dihematoporphyrin ether (DHE). Seventy-two hours later, 11 eyes (group I) were irradiated with eight 800 mW, 1000 mu, 2 s spots. Controls included 11 vascularized corneas from mice that received DHE but no laser (group II), 11 that received laser but no DHE (group III), and 35 untreated vascularized corneas (group IV). Comparison of the mean areas of CNV in groups I through IV pretreatment (6.0, 6.5, 6.7, and 7.6 mm2) and 12 weeks posttreatment (4.3, 6.3, 5.6, and 7.5 mm2) revealed that a significant decrease was seen in group I only (p less than 0.04, ANOVA). Complications in group I included blepharitis (9%) and iris damage (18%). Histologic studies revealed no evidence of posterior segment damage. PDT with the 514 nm laser is safe and efficacious for the treatment of IL-2-induced CNV in this model.
Analysis of Variance↗
Contact lenses for the correction of pediatric aphakia.
Explore the source record for details and available documents.
Animals↗
A reproducible method for injecting the mouse corneal stroma.
An improved delivery system for injecting the mouse corneal stroma was developed. This system incorporates the following features: a repeating dispenser that eliminates inaccuracies in depressing a syringe plunger, foot activation which frees both hands for manipulating the needle and permits constant observation of the injection site, and a flexible 30-cm, 32-gauge stainless steel needle with a 30 degrees bevel and a locking hub that resists pulsation due to back pressure while permitting freedom of motion by the operator. These injections were done while observing the cornea with a vertically mounted slit lamp, ideally suited for examining and photographing the eyes of laboratory animals. The reproducibility of the new delivery system, expressed in terms of the signal-to-noise ratio, was estimated and compared with that of a hand-held microsyringe by injecting a solution of radioactive chromium into the corneal stroma of A/J mice. The eyes were removed within 1 hr of injection, and the amount of chromium in each eye was determined in a gamma counter. The new delivery system had significantly (P less than 0.05) greater reproducibility than the hand-held syringe and could be calibrated to deliver up to 0.65 microliter to the mouse cornea.
Animals↗
Modulation of a Mr 175,000 c-neu receptor isoform in G8/DHFR cells by serum starvation.
The neu proto-oncogene product has been found to exist in two interconvertible forms in G8/DHFR mouse fibroblasts. The 185-kilodalton form (p185) present in growing cells is replaced by a 175-kilodalton form (p175) under conditions of serum starvation. This low molecular weight form accounts almost exclusively for the phosphotyrosine content of the receptor and is associated with increased tyrosine kinase activity. Addition of serum, platelet-derived growth factor or tumor promoter induces conversion of p175 to p185 within minutes, and this increase in molecular weight is associated with phosphorylation of serine and threonine; removal of serum growth factors is followed by replacement of p185 with p175 over several hours. Unlike G8/DHFR cells, the human breast cancer cell line SK-Br-3 expresses a high molecular weight neu/HER2 receptor with unchanged phosphotyrosine content in both serum-starved and serum-stimulated cultures. These findings indicate that activation of the neu proto-oncogene product in G8/DHFR cells may be regulated in part by protein kinase C-mediated receptor transmodulation rather than by ligand availability alone.
Animals↗
Drug-induced DNA damage and tumor chemosensitivity.
Cytotoxic drugs act principally by damaging tumor-cell DNA. Quantitative analysis of this interaction provides a basis for understanding the biology of therapeutic cell kill as well as a rational strategy for optimizing and predicting tumor response. Recent advances have made it possible to correlate assayed DNA lesions with cytotoxicity in tumor cell lines, in animal models, and in patients with malignant disease. In addition, many of the complex interrelationships between DNA damage, DNA repair, and alterations of gene expression in response to DNA damage have been defined. Techniques for modulating DNA damage and cytotoxicity using schedule-specific cytotoxic combinations, DNA repair inhibitors, cell-cycle manipulations, and adjunctive noncytotoxic drug therapy are being developed, and critical therapeutic targets have been identified within tumor-cell subpopulations and genomic DNA alike. Most importantly, methods for predicting clinical response to cytotoxic therapy using both in vitro markers of tumor-cell sensitivity and in vivo measurements of drug-induced DNA damage are now becoming a reality. These advances can be expected to provide a strong foundation for the development of innovative cytotoxic drug strategies over the next decade.
DNA Damage↗
Interleukin-2 induces corneal neovascularization in A/J mice.
Mitogen-stimulated lymphocytes induce a highly reproducible form of corneal neovascularization (CNV) in inbred mice. To determine if supernatants derived from stimulated lymphocytes and their constituent mediators were also angiogenic, we injected conditioned medium (CM) from mitogen-stimulated lymphocytes, control non-conditioned medium, recombinant interleukin-2 (rIL-2), or control bovine serum albumin (BSA), a component of rIL-2, into the corneas of syngeneic A/J mice. Control, nonconditioned medium was not angiogenic. While the other injections all induced some CNV, the CM and rIL-2 both induced a significantly greater area of CNV than BSA (p less than 0.05). The area of CNV induced by the CM was greater than that induced by IL-2 (p = 0.03). These data show that IL-2, which stimulates vascular endothelial cells in vitro and is elaborated during corneal immune reactions in vivo, is one of the potential mediators of immunologically mediated CNV.
Animals↗
The effect of flurbiprofen on herpes simplex virus type 1 stromal keratitis in mice.
The use of steroidal compounds to reduce the inflammation and scarring associated with herpes simplex virus type 1 (HSV-1) stromal keratitis can result in severe exacerbation of the corneal disease. We compared the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen sodium with dexamethasone for the treatment of HSV-1 induced corneal stromal disease in an inbred mouse model. Stromal disease was induced by the direct intrastromal injection of HSV-1. A stromal opacity and corneal neovascularization (CNV) developed in 100% of the injected eyes, with no epithelial involvement until late in the course, when the stromal disease was quite severe, such that it was possible to test the effectiveness of drugs in animals with an intact epithelium. Dexamethasone treatment had a variable effect on the severity of disease, ranging from a significant reduction in severity to significant exacerbation of disease, compared with placebo-treated controls. The most frequent effect of dexamethasone treatment was a worsening of corneal stromal opacities and CNV. In contrast, treatment with the NSAID did not exacerbate HSV-1 stromal disease. Flurbiprofen treatment resulted in a significant reduction of the maximum intensity of stromal opacity in some experiments, whereas in other experiments the effect was not statistically significant. In vitro studies of the effect of the anti-inflammatory drugs on HSV-1 replication in Vero cells revealed that both dexamethasone and flurbiprofen inhibited HSV-1 replication in a dose-dependent manner. Flurbiprofen had a greater inhibitory effect, which appears to be due, at least in part, to a direct virucidal effect. Dexamethasone did not exhibit virucidal activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Drug wars in the United States.
Explore the source record for details and available documents.
Drug and Narcotic Control↗
Oestrogen potentiates topoisomerase-II-mediated cytotoxicity in an activated subpopulation of human breast cancer cells: implications for cytotoxic drug resistance in solid tumours.
Primary resistance to chemotherapeutic agents is a major problem in the management of advanced cancer. By using oestrogen to modulate the topoisomerase II content of T-47D human breast cancer cells, we show here that cell subpopulations resistant to the topoisomerase-II-interactive drug VPI6 (etoposide) can be identified and quantified using single-cell analytical techniques. Immunohistochemical studies reveal topoisomerase II to be present in approximately 10% of control cells compared with 30% of oestrogen-stimulated cells, and this difference is reflected in the proportions of cells exhibiting VPI6-induced cell-cycle delay. This moderate increase in overall cell sensitivity is accompanied by massive enhancement of clonogenic cell kill, suggesting that oestrogen enhances VPI6 cytotoxicity by recruiting a clonogenic cell subpopulation characterized by increased topoisomerase II content. Flow cytometry confirms that the increase in topoisomerase II is localized to an activated G1-phase cell subset. We conclude that (i) single-cell analysis of cellular topoisomerase II content is predictive of VPI6 chemosensitivity; (ii) the existence of resistant tumour-cell subpopulations does not necessarily indicate the presence of phenotypically divergent subclones; and (iii) rational strategies for eliminating tumour resistance may be based on biological manipulation of specific cytotoxic drug targets.
Breast Neoplasms↗
Mitogen-induced topoisomerase II synthesis precedes DNA synthesis in human breast cancer cells.
Cells released from quiescence exhibit increased levels of the DNA-modifying enzyme topoisomerase II, a nuclear protein which is also a target for antitumour drugs such as VP-16 (etoposide) and m-AMSA (4',9'-acridinylamino-methanesulfon-m-anisidide). By using Western blotting, DNA-protein crosslinking and drug-induced DNA cleavage to detect topoisomerase II, we show here that oestrogen stimulation of T-47D human breast cancer cells results in increased cellular enzyme content at least 4hr prior to enhancement of DNA synthesis. Taken in conjunction with previous findings, these results suggest that oestrogen enhances topoisomerase II synthesis within a G1-phase cell subset.
Amsacrine↗
The effect of cellular immune tolerance to HSV-1 antigens on the immunopathology of HSV-1 keratitis.
Previous studies have revealed that herpes simplex virus type 1 (HSV-1) corneal stromal lesions do not develop in the absence of a cell-mediated immune (CMI) response to HSV-1 antigens. HSV-1 glycoprotein C (gC) has been shown to play an important role in the induction of the cytotoxic T lymphocyte (CTL) response to HSV-1 infections at anatomical sites other than the eye. Here we report that a deletion mutant lacking gC (gC-39) when used to infect the corneas of A/J mice was a poor inducer of both CTL and delayed type hypersensitivity (DTH) responses. We have also followed histologically and immunohistochemically the course of HSV-1 stromal disease in A/J mice following topical corneal (TC) infection with wild type (WT) HSV-1, TC infection with gC-39 HSV-1, and simultaneous TC and anterior chamber (TC + AC) infection with WT HSV-1. The latter type of infection has been shown to induce a profound state of DTH and CTL tolerance of HSV-1 antigens. Following TC infection with WT HSV-1, stromal disease progressed to severe ulcerative keratitis with neovascularization by day 21. Histologic and immunohistochemical analysis revealed a predominantly mononuclear infiltrate consisting of numerous plasma cells as well as L3T4+ (T helper/inducer) and Lyt-2+ (T suppressor/cytotoxic) T lymphocytes. Following TC infection with gC-39, or simultaneous TC + AC infection with WT HSV-1, the severity of stromal disease did not progress beyond day 7. On day 21, there was at most a mild stromal cellular infiltrate consisting predominantly of polymorphonuclear neutrophils. These findings indicate that early stromal disease consists of a nonspecific inflammatory response, but severe stromal disease involves a CMI response to HSV-1. AC injection of HSV-1 inhibits the CMI response, thereby halting the progression of stromal disease. Similarly, gC-39, a poor inducer of CMI responses, is also a poor inducer of stromal disease.
Animals↗
Removing the stableflex intraocular lens during penetrating keratoplasty.
Closed-loop, semiflexible anterior chamber intraocular lenses, particularly the Stableflex lens, have been increasingly associated with corneal decompensation. Due to the formation of synechiae around the haptics in the angle, such lenses can be difficult to remove during penetrating keratoplasty. We describe a technique for the safe removal of the Stableflex intraocular lens.
Corneal Transplantation↗
Topoisomerases in human disease.
Topoisomerases are DNA-modifying enzymes that are becoming increasingly important in clinical practice. These enzymes form a target for antibiotics, autoantibodies, and antitumour drugs, and may also be involved in the pathogenesis of certain genetic disorders. Strategies for clinical manipulation of these nuclear enzyme targets are discussed.
Anti-Bacterial Agents↗
Estrogen-induced potentiation of DNA damage and cytotoxicity in human breast cancer cells treated with topoisomerase II-interactive antitumor drugs.
Hormone stimulation of responsive neoplasms is a potential strategy for improving the target selectivity of cancer chemotherapy. Using an alkaline DNA-unwinding technique to detect drug-induced DNA strand breakage, we have shown that estrogen stimulation of T-47D human breast cancer cells enhances induction of DNA cleavage by etoposide (VP-16), 4',9-acridinylaminomethanesulfon-m-anisidide (m-AMSA), mitoxantrone, and doxorubicin, drugs known to interact with the DNA-modifying enzyme topoisomerase II. No enhancement of DNA cleavage or cytotoxicity was seen in estrogen-treated cells exposed to X-rays or bleomycin. Novobiocin (an inhibitor of topoisomerase II) markedly antagonized the enhancing effect of estrogen on VP-16-induced DNA cleavage, while neutral nucleoid sedimentation detected less than 10% of such strand breaks revealed in estrogen-treated cells by alkaline unwinding. Estrogen did not affect DNA repair of lesions induced by X-rays, VP-16, or ultraviolet radiation. Enhancement of DNA cleavage was accompanied by a corresponding enhancement of cytotoxicity in cells treated with VP-16 or m-AMSA, but only minimal enhancement of cytotoxicity was seen following treatment with mitoxantrone or doxorubicin. Estrogen-treated and control cells treated with VP-16 and m-AMSA sustained similar levels of DNA cleavage for equivalent levels of cytotoxicity. These findings suggest that estrogen potentiates the cytotoxicity of VP-16 and m-AMSA by enhancing topoisomerase II-mediated DNA damage but that such "damage" does not contribute significantly to cytotoxicity induced by mitoxantrone or doxorubicin. Estrogen stimulation of receptor-positive breast cancer may prove to be a clinically relevant strategy for improving the selectivity and cytotoxicity of some, but not all, topoisomerase II-interactive drugs.
Amsacrine↗