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Biomedical subjects

S M Whitcup

Publications and source records attributed to S M Whitcup.

At least 55 records · Page 3Linked to original sources
PubMed1999

Uveitis induced by lymphocytes sensitized against a transgenically expressed lens protein.

PURPOSE: Previously established experimental models for lens-associated uveitis (LAU) are all mediated by antibodies. The present study analyzed the features of a novel experimental intraocular inflammatory eye disease that is mediated by lymphocytes targeted at a lens antigen. METHODS: Conventional technologies were used to generate three lines of transgenic (Tg) mice, expressing hen egg lysozyme (HEL) under the control of the alphaA-crystallin promoter. To induce intraocular inflammation, these Tg mice were injected with lymphocytes from syngeneic wild-type donors sensitized against HEL. Before their injection, the cells were stimulated in culture with HEL. To release lenticular material, some eyes were capsulotomized. Ocular histopathologic changes were examined by routine methods. Levels of HEL antibody were measured by enzyme-linked immunosorbent assay, whereas cellular immunity was determined by the lymphocyte proliferation assay. RESULTS: Intraocular inflammation developed in HEL-Tg mice injected with syngeneic lymphocytes sensitized against HEL. The severity of inflammation was directly related to the number of injected cells, as well as to the accessibility of HEL. The most intense inflammation was seen in Tg mice in which the lens was disintegrated due to high production of HEL. In mice with no apparent lenticular changes the inflammation was enhanced by capsulotomy. The inflammation affected all segments of the eye and persisted for at least 39 days after adoptive transfer of cells. Four days after cell injection, the inflammation consisted of subacute infiltration, with both mononuclear and polymorphonuclear leukocytes, whereas more chronic infiltration was seen at later times. Vigorous cellular immunity but no antibody to HEL was found in recipient mice, thus demonstrating the exclusive participation of cellular immunity in the pathogenesis of this experimental disease. CONCLUSIONS: Transgenic mice expressing HEL in their lenses develop intraocular inflammation after injection of syngeneic lymphocytes sensitized against HEL. This experimental disease is a novel cell-mediated model for LAU.

Adoptive Transfer↗
PubMed1998

Phakic patients with cystoid macular edema, retinal periphlebitis, and vitreous inflammation.

OBJECTIVE: To characterize a group of phakic patients with idiopathic intermediate uveitis as defined by vitritis, cystoid macular edema, and retinal periphlebitis. DESIGN: Cross-sectional study. PARTICIPANTS: Nineteen phakic patients (35 eyes) with vitreous inflammation, cystoid macular edema, and/or retinal periphlebitis of unknown cause. INTERVENTION: None. MAIN OUTCOME MEASURES: Best-corrected final visual acuities, standardized clinical examinations, photographic and fluorescein angiographic evaluations, and class I and II HLA analysis on all 19 patients. RESULTS: Fifteen of the 19 patients were women. The mean age was 38 years, the mean follow-up was 104 months, and the mean duration of symptoms was 154 months. All 35 affected eyes had significant vitritis; 21 eyes (60%) had cystoid macular edema, 21 eyes (60%) had retinal periphlebitis. The median initial visual acuity was 20/30. The median final visual acuity was 20/20 with 32 (91%) of 35 eyes having 20/40 or better visual acuity at the final visit. No patient developed "snow-banks" or evidence of systemic disease, including multiple sclerosis or sarcoidosis, during the follow-up period. There were no statistically significant HLA associations in these patients compared with controls from another study from Iowa, but the Iowa phakic patients with cystoid macular edema did differ from the Iowa patients with pars-planitis at loci HLA-B8, HLA-B51, and HLA-DR2. CONCLUSIONS: We describe a disease entity of idiopathic intermediate uveitis that affects primarily young to middle-aged women and usually causes bilateral vitritis, cystoid macular edema, and retinal periphlebitis. Most patients retained good vision over a prolonged follow-up period. Multiple sequential examinations and HLA associations suggest that these conditions are distinct from other syndromes of intermediate uveitis, particularly parsplanitis.

Adolescent↗
PubMed1998

A novel murine model of allergic conjunctivitis.

Allergic conjunctivitis affects over 40 million patients per year in the United States. Here we present the first murine model that incorporates the clinical, cellular, and humoral parameters of allergic conjunctivitis, including a ragweed-induced Th2-type cytokine production by lymphocytes. SWR/J mice were immunized with short ragweed pollen in aluminum hydroxide. Ten days after immunization, allergic conjunctivitis was induced by one topical application of ragweed pollen onto the eye. Immediate response was characterized by chemosis, redness of the conjuctiva, and lid edema. Histopathology and immunohistochemistry showed dense conjunctival infiltration with polymorphonuclear leukocytes, macrophages, and CD4+ T lymphocytes. In addition, ragweed-specific IgG1 and IgE serum levels were significantly higher in immunized animals, and high levels of IL-4 and IL-5 were detected in supernatants from ragweed-activated lymphocytes. This reproducible model is a well-suited instrument for testing the pathophysiology and future therapies of allergic conjunctivitis.

Allergens↗
PubMed1998

Recoverin-associated retinopathy: a clinically and immunologically distinctive disease.

PURPOSE: To compare the immune response to retinal antigens in a patient with a clinical condition resembling cancer-associated retinopathy with the immune responses of patients with other retinal degenerations or uveitis. METHODS: Cellular and humoral immune responses to retinal S-antigen and recoverin were determined in one patient with disease resembling cancer-associated retinopathy, three patients with other retinal degenerations, and eight patients with uveitis. RESULTS: A cellular immune response against recoverin was found only in the patient with the condition resembling cancer-associated retinopathy. Elevated levels of antibody against recoverin were found in this patient and in one of the three patients with a retinal degeneration, but in none of the eight patients with uveitis. In contrast, moderate lymphocyte responses to retinal S-antigen were found in most of the patients studied, and this response did not distinguish among the patient groups. Levels of serum antibodies against retinal S-antigen were also similar in all patients tested. Serum from the patient with disease resembling cancer-associated retinopathy produced strong immunostaining of the rods, cones, outer plexiform layer, and some cone bipolar cells, but serum from the patients with uveitis or other retinal degenerations did not show specific reactivity with the retina. CONCLUSIONS: We propose that this immunologically and clinically distinctive condition be termed recoverin-associated retinopathy, and we suggest that a cellular immune response against recoverin may be a distinguishing feature of the disorder.

Adenolymphoma↗
PubMed1998

Cyclosporine therapy for severe sight-threatening uveitis in children and adolescents.

OBJECTIVE: To review the safety and efficacy of cyclosporine in the treatment of children with severe bilateral sight-threatening intermediate uveitis or panuveitis. DESIGN/PARTICIPANTS: A retrospective chart review was performed on all children younger than 18 years of age with chronic bilateral sight-threatening uveitis who were treated with cyclosporine. MAIN OUTCOME MEASURES: Assessment of the therapeutic efficacy and development of adverse effects of cyclosporine after 6 months, 2 years, and 4 years of therapy was performed. RESULTS: Between 1983 and 1992, 15 children and adolescents were treated with cyclosporine. After 6 months, visual acuity improved or stabilized in 82.1% of eyes, while median vitreous inflammation decreased from 2.0 to 0.5. After 2 and 4 years, visual acuity improved or stabilized in 64% and 75% of eyes, respectively. Median vitreous inflammation remained 0.5 after 2 and 4 years of therapy. Mean creatinine clearance and hemoglobin values decreased and serum creatinine increased after 6 months. After 2 years, only mean hemoglobin values remained decreased. After 4 years, no significant differences were noted in any of the laboratory studies. The most frequently noted side effects included transient increases in serum creatinine in 53%, gingival hyperplasia in 40%, and hirsutism in 20% of patients. CONCLUSIONS: The authors' results suggest that cyclosporine is a safe and effective therapy for the treatment of children with severe bilateral sight-threatening intermediate uveitis or panuveitis.

Adolescent↗
PubMed1998

Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts.

OBJECTIVE: To determine whether maintenance therapy can be discontinued safety in patients with quiescent cytomegalovirus retinitis (CMVR) and increased CD4+ counts after treatment with highly active antiretroviral therapy (HAART). DESIGN: A prospective observational case series. PARTICIPANTS: Eight human immunodeficiency virus (HIV)-positive patients with quiescent CMVR who were taking HAART and had CD4+ counts above 100 cells/microliter elected to discontinue anti-CMV maintenance treatment. INTERVENTION: Biweekly-to-monthly indirect ophthalmoscopy and fundus photographs, monthly-to-quarterly CD4+ counts, and quarterly HIV viral loads were ordered. MAIN OUTCOME MEASURES: Twelve previously affected eyes were examined for evidence of recurrent retinitis, which was defined as any retinal whitening, border opacification, or expansion of areas of retinal pigment epithelial (RPE) atrophy greater than 750 microns. Four previously unaffected fellow eyes were observed for new CMVR. RESULTS: There was no reactivation or progression of retinitis in any patient during the mean follow-up interval of 11.4 months (range, 3-16 months). No previously unaffected eye developed CMVR. CD4+ remained elevated in all patients (range, 70-725; mean, 255). The HIV viral load ranged from undetectable to 139,000 copies. CONCLUSION: Discontinuation of maintenance therapy may be considered in patients with HAART-induced elevated CD4+ counts above 100 cells/microliter, prolonged relapse-free intervals during the reconstitution period before CD4+ counts rise above 100 cells/microliter, and completely quiescent retinitis characterized by RPE scarring only. Reduced risks of drug toxicity and drug-resistant organisms are potential benefits. Close observation for evidence of recurrent retinitis is indicated.

AIDS-Related Opportunistic Infections↗
PubMed1998

Topical liposome-encapsulated FK506 for the treatment of endotoxin-induced uveitis.

PURPOSE: Liposome preparations of FK506 improve the penetration of topically administered drug into the aqueous humor. The purpose of the experiment was to compare topically administered highdose oil-dissolved FK506 (OD-FK506) and low-dose liposome-bound FK506 (LB-506) for the treatment of endotoxin-induced uveitis (EIU). METHODS: Endotoxin-induced uveitis was produced in female Lewis rats with Salmonella typhimurium endotoxin. Four hours prior to endotoxin injection, one eye received 20 mul eyedrops every four hours containing either high-dose OD-FK506 at 3 mg/ml (N = 20), low-dose LB-FK506 at 0.16 mg/ml (N = 19), prednisolone acetate 1% (N = 20), or empty liposomes (N = 20). Eyes were enucleated 24 hours after endotoxin injection and inflammatory cells were counted on histologic sections by two masked observers. RESULTS: The mean number of infiltrating inflammatory cells per section +/- S.E.M. was 127.8 +/- 20.1, 76.8 +/- 16.7, 75.0 +/- 19.1, and 3.6 +/- 0.4 for animals treated with empty liposomes, LB-FK506, OD-FK506, and prednisolone acetate, respectively. The difference in inflammation between the empty liposome controls and the LB-FK506- and OD-FK506-treated animals was statistically significant (p = 0.03 and p = 0.02, respectively). The difference in inflammation between the high-dose OD-FK506- and low-dose LB-FK506-treated animals was not statistically significant (0 = 0.94). CONCLUSION: In this study, low-dose LB-FK506 and high-dose (OD-FK506) were both effective in inhibiting EIU. Higher concentrations of LB-FK506 are being developed and should augment the therapeutic effect of topical FK506.

Administration, Topical↗
PubMed1998

A comparison of self-reported utilization of ophthalmic care for diabetes in managed care versus fee-for-service.

PURPOSE: To assess the association between structural factors in the health care delivery system and self-reported utilization of ophthalmic services by patients with diabetes in the Medical Outcomes Study (MOS). METHODS: Self-reported utilization of ophthalmic services within the 6 months preceding enrollment into the MOS among 522 of 567 individuals with diabetes in the MOS longitudinal panel was measured. Use of eye care services was regressed (logistic model) on patient demographics, geographic location, physician specialty, type of practice, and finance plan (prepaid or fee-for-service). RESULTS: None of the variables was significantly associated with a higher or lower likelihood of having used ophthalmic services in the preceding 6 months. Thus, no difference between prepaid or fee-for-service plans or among solo practice, large multispecialty groups, or HMOs were identified. Having seen an internist, family practitioner, or diabetes specialist for diabetes care was not related to use of ophthalmic services. CONCLUSIONS: Despite a presumed greater interest in preventive health, prepaid health plans were no more or less likely than the fee-for-service sector to have patients with diabetes reporting an eye examination within the prior 6 months. Thus, steps to improve the rate of eye examinations of diabetics may need to focus beyond the structural elements of the health care delivery system.

Diabetes Mellitus↗
PubMed1998

Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone. PATIENTS AND METHODS: Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity. RESULTS: The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting. CONCLUSION: The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.

Adult↗
PubMed1998

A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection.

BACKGROUND: Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. METHODS: HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (</=2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. RESULTS: A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period. CONCLUSIONS: The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Administration, Oral↗