Search PubMed⌕ Search

Biomedical subjects

S M Whitcup

Publications and source records attributed to S M Whitcup.

At least 109 records · Page 6Linked to original sources
PubMed1993

Treatment of autoimmune uveitis.

The number of effective drugs for the treatment of autoimmune uveitis has greatly increased over the past 40 years. Many patients previously condemned to blindness can now be successfully treated with new immunosuppressive agents. New targets of the immune system, such as cell adhesion molecules, may offer novel therapeutic approaches for the treatment of inflammatory disease. However, since the catholicon for uveitis is not yet available, the search for new antiinflammatory therapy continues.

Adrenal Cortex Hormones↗
PubMed1993

A masked, randomized, dose-response study between cyclosporine A and G in the treatment of sight-threatening uveitis of noninfectious origin.

Thirty-two patients with sight-threatening uveitis and a decrease in visual acuity requiring systemic therapy were randomly assigned to either cyclosporine A or G in a dose-escalation study. Groups received from 2.5 mg/kg of body weight/day to 10 mg/kg of body weight/day of either drug along with low-dose prednisone. More patients taking cyclosporine G had improved visual acuity and a decrease in macular edema, which occurred more rapidly than in the other group, even at the lower doses tested. No difference in renal function was noted between groups at any doses tested. Four patients receiving cyclosporine G had hepatic alterations, but only one required cessation of the drug. The study indicates the potential usefulness of cyclosporine G, particularly at lower doses (4 mg/kg of body weight/day), which could lower the potential for serious renal complications.

Adult↗
PubMed1993

Monoclonal antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) inhibit experimental autoimmune uveitis.

Cell adhesion molecules are surface proteins important for cell migration and adhesion and are strongly expressed in eyes with inflammation. We studied the expression of two cell adhesion molecules: intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) in mice with experimental autoimmune uveitis. B10.A mice were immunized with interphotoreceptor retinoid-binding protein and eyes were serially examined for expression of cell adhesion molecules using immunohistochemical staining. ICAM-1 was expressed on the vascular endothelium of the ciliary body and retina by 7 days after immunization, and LFA-1 was first expressed on some infiltrating inflammatory cells 9 days after immunization. Clear histologic evidence of ocular inflammation did not occur until 11 days after immunization. We then studied the effect of monoclonal antibodies against ICAM-1 and LFA-1 on the development of experimental autoimmune uveitis. Three groups of mice were immunized and treated for 21 days with daily intraperitoneal injections of rat monoclonal antibody against murine ICAM-1 or LFA-1 or with rat IgG as control. Ocular inflammation, graded clinically by examination of the fundus 14 and 21 days after immunization, was significantly decreased in animals treated with anti-ICAM-1 (P < 0.01 at Days 14 and 21) and with anti-LFA-1 antibody (P < 0.01 at Days 14 and 21). The intraocular inflammation graded histologically was also decreased in mice treated with anti-ICAM-1 and anti-LFA-1 antibody. This difference in the histologic grade of inflammation was statistically significant (P < 0.02) between mice treated with anti-ICAM-1 antibody and control mice and approached statistical significance (P < 0.10) in mice treated with anti-LFA-1 antibody compared to the control mice. Proliferative responses to lipopolysaccharide, PPD, and interphotoreceptor binding protein of lymphocytes obtained from the draining lymph nodes of mice treated with the antibodies were lower than those from the control mice, suggesting that cell-cell binding was impaired in treated mice. These data show that ICAM-1 is expressed in the eye before histologic evidence of inflammation, and that monoclonal antibodies against ICAM-1 and LFA-1 are effective in inhibiting experimental autoimmune uveitis in mice.

Animals↗
PubMed1993

Intraocular lymphoma. Clinical and histopathologic diagnosis.

BACKGROUND: Intraocular lymphoma is associated with significant morbidity and mortality, but early diagnosis and treatment may improve prognosis. METHODS: The diagnostic features of 12 cases of intraocular lymphoma diagnosed at the National Eye Institute between 1984 and 1992 were retrospectively reviewed. RESULTS: A pathologic diagnosis of large B-cell lymphoma was made on vitrectomy specimens in ten patients, cerebral spinal fluid in one, and on an enucleation specimen in one. The mean time from onset of symptoms to diagnosis was 21.4 months (range, 1-66 months). All 12 patients were given a final diagnosis of non-Hodgkin's lymphoma of the central nervous system (NHL-CNS), based on the epidemiology, pathology, and clinical course of their tumors. Although an initial vitrectomy was negative for malignant cells in three of ten patients, a repeat vitrectomy specimen subsequently showed intraocular lymphoma. Results of examination of the cerebrospinal fluid (CSF) showed malignant cells in 5 of 11 patients, although malignant cells were only identified after repeat examination of additional samples of CSF in three of these patients. Malignant cells often are difficult to identify, and an experienced cytopathologist was critical in making the correct diagnosis. In addition, corticosteroids are lympholytic to the lymphoma cells, and they appeared to decrease the viability of tumor cells obtained in samples of vitreous and CSF. CONCLUSION: The prompt, appropriate handling of specimens and review by an experienced cytopathologist are critical to the diagnosis of intraocular lymphoma. Malignant cells often are present in the cerebral spinal fluid at the time that ocular lymphoma is diagnosed. Nevertheless, multiple vitrectomies and lumbar punctures may be necessary before the correct diagnosis is made.

Adult↗
PubMed1993

The role of chorioretinal biopsy in the management of posterior uveitis.

BACKGROUND: The ideal management of intraocular inflammation may require a tissue diagnosis. Diagnostic vitrectomy is a well-established method for acquiring such tissue. However, in some patients, the diagnostic pathology is limited to the choroid and retina and vitrectomy may yield no useful information. In such cases, a more aggressive surgical approach to obtain tissue may be useful. METHODS: The authors performed chorioretinal biopsies on seven patients with progressive chorioretinal lesions of unknown etiology. Indications for biopsy included: (1) macular-threatening lesions unresponsive to therapy, (2) suspicion of malignancy, or (3) suspicion of an infectious etiology. In all cases, it was expected that the results would alter therapy or other aspects of clinical care. Preoperative visual acuity was 20/200 or worse in each eye biopsied with one or more peripheral chorioretinal lesions present. Biopsy specimens were divided into three parts and submitted for light and electron microscopy, immunohistochemistry, and tissue culture. RESULTS: On the basis of the biopsy findings, a diagnosis of multifocal choroiditis and subretinal fibrosis was rendered in three eyes, sarcoidosis in two eyes, and viral retinitis in two eyes. Therapy was changed in five patients. Final visual acuity was unchanged or improved in five eyes. Complications included the progression of lens opacity in all eyes and the development of phthisis in one eye that was extensively diseased preoperatively. CONCLUSION: Chorioretinal biopsy may provide useful information for determining the diagnosis and guiding the subsequent management of patients with progressive chorioretinal lesions of unknown etiology.

Adult↗
PubMed1993

A pilot study of sequential therapy with zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine in patients with severe human immunodeficiency virus infection.

A pilot study was initiated to explore a sequential combination antiretroviral regimen in 21 patients with AIDS or advanced human immunodeficiency virus (HIV) infection, who had received little or no prior anti-HIV therapy. The mean entry CD4 cell count was 184/mm3. Patients received 3-week cycles consisting of zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine for 1 week each. Overall, the regimen was well tolerated for up to 3 years. The principal toxicities were anemia, nausea, and vomiting; 1 patient developed retinal lesions. The mean CD4 cell count reached a peak of 64 cells/mm3 above baseline at week 8 (P = .005 compared to baseline) and remained above baseline for > 40 weeks. Patients also gained weight and had decreases in serum HIV p24 antigen. Eight patients developed opportunistic infections or tumors. Only 4 patients died during 3 years of follow-up. This regimen appears to be generally tolerable and to have anti-HIV activity. Additional studies will be needed, however, to learn how to best combine the available agents in patients with HIV infection.

AIDS-Related Complex↗
PubMed1993

Expression of cell adhesion molecules in corneal graft failure.

Corneal graft failure is frequently mediated by uncontrolled inflammatory disease. We studied the expression of cell adhesion molecules in seven penetrating keratoplasty specimens with graft failure and in a normal eye bank cornea using immunohistochemical staining and monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1, CD54), lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and major histocompatibility complex (MHC) class II antigen (HLA-DR). ICAM-1 and HLA-DR were expressed on keratocytes and the corneal endothelium in six of the seven specimens. ICAM-1 expression was strongest in the corneas with the most severe inflammation (corneal allograft rejection and severe intraocular inflammation). LFA-1 is a counter-receptor for ICAM-1, and infiltration with leukocytes expressing either the alpha or beta chain of LFA-1 was found in areas of ICAM-1 expression in four of the seven corneas. In contrast, E-selectin was expressed in the stroma in only two specimens, and VCAM-1 in one specimen. Expression of cell adhesion molecules or MHC class II antigen were not detected in the normal eye bank cornea. These data suggest that ICAM-1 expression may play an important role in the development of corneal graft failure. Furthermore, monoclonal antibodies to block ICAM-1 or its ligands may inhibit the development of corneal inflammation.

Antibodies, Monoclonal↗
PubMed1993

Monoclonal antibody against CD11b/CD18 inhibits endotoxin-induced uveitis.

PURPOSE: To examine the serial expression of cell adhesion molecules in C3H/HeN mice with endotoxin-induced uveitis, and to study the effect of treatment with a monoclonal antibody against Mac-1 on the development of endotoxin-induced uveitis. METHODS: Immunohistochemical staining was used to document the serial expression of Mac-1, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen-1 (LFA-1) in eyes of C3H/HeN mice with endotoxin-induced uveitis. Then, in two separate experiments, endotoxin-induced uveitis was produced in a total of 48 mice by injecting Salmonella typhimurium endotoxin into one hind footpad. At the time of endotoxin injection, 24 mice received an intraperitoneal injection of anti-Mac-1 antibody and 24 control mice received an intraperitoneal injection of rat IgG. Histopathologic sections of eyes taken 24 hours after endotoxin injection were graded by two masked observers on a scale of 0 to 4. RESULTS: Intercellular adhesion molecule-1 was first expressed on the ciliary body epithelium 6 hr after endotoxin injection and Mac-1 and LFA-1 were expressed on infiltrating inflammatory cells 12 hr after endotoxin injection. Treatment with anti-MAC-1 antibody significantly inhibited the development of ocular inflammation when compared with treatment with control IgG (P < 0.001). CONCLUSION: Intercellular adhesion molecule-1 is expressed in the eye before clinical or histologic signs of inflammation. Furthermore, treatment with antibody against Mac-1 significantly inhibits the development of endotoxin-induced uveitis in mice and suggests that anti-Mac-1 antibody may be useful for treating acute ocular inflammation.

Animals↗
PubMed1993

The paradoxical effect of tumor necrosis factor alpha (TNF-alpha) in endotoxin-induced uveitis.

PURPOSE: To investigate the role of TNF-alpha in endotoxin-induced uveitis (EIU) in mice. METHODS: To neutralize TNF-alpha activity, mice were pretreated with either repeated injections of this cytokine or a single injection of antibody against it. The mice were then injected intraperitoneally with 500 micrograms endotoxin, to induce lethal septic shock, or into the footpad with 200 micrograms to induce EIU. RESULTS: Although both pretreatments conferred protection against the systemic toxic effects of LPS, TNF-resistant mice and mice treated with anti-TNF-alpha antibody demonstrated an exacerbation of EIU when compared to control animals. CONCLUSIONS: Unlike its apparent participation in the systemic effect of endotoxin, TNF-alpha is not directly involved in the pathogenesis of EIU and may even protect against the inflammatory processes of this disease.

Acute Disease↗
PubMed1993

The role of mast cells in endotoxin-induced uveitis.

PURPOSE: To investigate the role of mast cells in the induction of endotoxin-induced uveitis (EIU). METHODS: We previously showed that the mean mast cell number in the anterior uvea was greatest for Lewis rats, lowest for Brown Norway (BN) rats, and intermediate for LBNF1 rats. In the current experiment, we assessed the time of onset and severity of EIU in these three rat strains. We then studied changes in mast cell numbers in the anterior uvea during the induction period of EIU. RESULTS: Time of onset and severity of EIU were related to the number of mast cells in the anterior uvea. EIU occurred earliest in the Lewis rats, and the maximum mean grade of ocular inflammation on a scale of 0 (no inflammation) to 4 (severe inflammation) +/- standard error of the mean was 3.87 +/- 0.13 for Lewis rats, 1.06 +/- 0.06 for BN rats, and 1.19 +/- 0.12 for LBNF1 rats. The difference between the mean grade of inflammation in the Lewis rats and the other two strains was highly statistically significant (P < .001). In the Lewis rats, mast cell numbers +/- SEM decreased from 68.9 +/- 10.8 at baseline to 49.6 +/- 5.9 4 hr after lipopolysaccharide (LPS) injection and to 27.6 +/- 8.4 8 hr after LPS injection, suggesting that mast cell degranulation occurs before the development of EIU. CONCLUSION: Mast cells in the anterior uvea appear to potentiate endotoxin-induced ocular inflammation.

Animals↗
PubMed1992

Combined use of cyclosporine and ketoconazole in the treatment of endogenous uveitis.

Ten patients with endogenous uveitis were in clinical remission attributable to treatment with cyclosporine and prednisone. After the cyclosporine dose was reduced by two thirds, these patients were randomly assigned to treatment with or without ketoconazole, a potent inhibitor of cytochrome P-450, in a double-masked placebo-controlled study. The dose was reduced over three days. During a three-month follow-up, no patients treated with ketoconazole had a relapse of uveitis, while four of six (66%) control subjects had a flare-up. Toxicity in the ketoconazole-treated group was limited to a transient decrease in glomerular filtration rate (20% from baseline) at one month in two of six (33%) patients. Renal function was stabilized by further reduction of the cyclosporine dose.

Autoimmune Diseases↗
PubMed1992

Retinal toxicity in human immunodeficiency virus-infected children treated with 2',3'-dideoxyinosine.

To assess the safety and antiretroviral activity of 2',3'-dideoxyinosine, we enrolled 43 children with symptomatic (Centers for Disease Control class P-2) human immunodeficiency virus infection in a Phase I-II study and monitored them prospectively for the development of ocular complications secondary to HIV infection or drug toxicity. Follow-up ranged from 12 to 103 weeks with a median follow-up of 71 weeks. Three of 43 children (7.0%) developed peripheral atrophy of the retinal pigment epithelium during treatment with 2',3'-dideoxyinosine. The two children with the most severe retinal atrophy were enrolled in the study at the highest dosage studied (540 mg/m2/day). In contrast to findings in children, no retinal atrophy in HIV-infected adults treated with 2',3'-dideoxyinosine has been evident to date.

Atrophy↗
PubMed1992

Expression of cell adhesion molecules in posterior uveitis.

Cells in the eye express surface molecules that direct leukocyte migration during ocular inflammation. We studied the expression of intercellular adhesion molecule-1, lymphocyte function-associated antigen-1, and endothelial leukocyte adhesion molecule-1 in six enucleated eyes from patients with uveitis and in seven normal control eyes. Lymphocyte function-associated antigen-1 was expressed on infiltrating lymphocytes and intercellular adhesion molecule-1 was expressed on endothelial cells of retinal and choroidal blood vessels and the retinal pigment epithelium in all uveitic eyes, but in none of the normal control eyes. Ocular inflammatory cells stained strongly positive for tumor necrosis factor alpha in all eyes with uveitis, but four of six uveitic eyes showed mild staining for tumor necrosis factor beta and interferon gamma. Cell adhesion molecules are expressed in eyes with posterior uveitis and may be regulated by cytokines such as tumor necrosis factor alpha.

Adult↗
PubMed1992

Pneumocystis carinii and Mycobacterium avium-intracellulare infection of the choroid.

It has been hypothesized that coinfection with mycobacteria occurs in patients with Pneumocystis carinii choroiditis, but cases demonstrating ocular infection by both organisms have not been reported. This study reports the case of a patient with P. carinii choroiditis who was treated with intravenous trimethoprim and sulfamethoxazole, followed by intravenous trimethoprim and dapsone. The choroidal lesions failed to resolve despite 6 weeks of treatment, and the patient died from massive pulmonary infection caused by P. carinii, Mycobacterium avium-intracellulare, and cytomegalovirus infections. Ocular histologic and electron microscopic examinations revealed choroidal infection by both P. carinii and M. avium-intracellulare. Serum levels of sulfamethoxazole were below the recommended therapeutic range for treating P. carinii infection during the first week of therapy, but adequate drug levels were subsequently obtained. Failure of choroidal lesions of P. carinii to resolve in some cases may suggest insufficient antimicrobial levels in the blood or raise the possibility of coexistent M. avium-intracellulare or other opportunistic infection.

AIDS-Related Opportunistic Infections↗
PubMed1992

Endothelial leukocyte adhesion molecule-1 in endotoxin-induced uveitis.

Expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells leads to the attachment of polymorphonuclear leukocytes. The sequential expression of ELAM-1 and major histocompatibility complex (MHC) class II antigen was examined in the eyes of 59 Lewis rats with endotoxin-induced uveitis (EIU) after the injection of Salmonella typhimurium endotoxin. The eyes were enucleated at 2-hr intervals. Hematoxylin and eosin-stained paraffin-embedded sections and immunohistochemically stained cryostat sections were graded by two masked observers. The MHC class II antigen was expressed on cells in the iris and ciliary body 4 hr after injection of endotoxin and on the corneal endothelium, 8 hr postinjection. It was found that ELAM-1 was expressed first on cells of the ciliary body and iris 10 hr after the injection of endotoxin and on the corneal endothelium, 22 hr postinjection. Clinical and histopathologic disease developed 16 hr postinjection. Adherence of polymorphonuclear cells to the corneal endothelium was observed at the time of ELAM-1 expression. In conclusion, expression of ELAM-1 on ocular tissue occurred in EIU and appeared to promote polymorphonuclear cell accumulation in the anterior segment of the eye.

Animals↗
PubMed1991

Immunohistochemistry of the inflammatory response in Propionibacterium acnes endophthalmitis.

Specimens were obtained from two patients with culture-proven Propionibacterium acnes endophthalmitis who had undergone vitrectomy. Wright's and Giemsa stains were performed using cytospin preparations of the dilute vitreous and revealed a predominance of polymorphonuclear leukocytes (80% to 90%). The remaining inflammatory cells in the vitreous were mostly macrophages (10% to 15%); very few lymphocytes were present (less than 5%). Immunohistochemical studies using monoclonal antibodies confirmed the paucity of lymphocytes. Most lymphocytes were CD4+ helper/inducer T cells. Almost no CD8+ suppressor/cytotoxic T lymphocytes or B lymphocytes were found. The inflammatory response in these two patients is most characteristic of acute inflammation and consistent with an underlying bacterial infection, despite a clinical picture of persistent, low-grade inflammation. Infection with P acnes has been shown to inhibit CD8+ T cells and may play a role in the persistent inflammation in cases of P acnes endophthalmitis.

Aged↗