Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease.

We investigated the efficacy and safety of autologous serum eye drops for the treatment of severe dry eye after allogeneic haematopoietic stem cell transplantation (SCT). A total of 14 patients (four males and 10 females; median age, 31.0 years) with severe dry eye associated with chronic graft-versus-host disease (cGVHD) were enrolled in this study. All patients were refractory to treatment with conventional artificial tears. Autologous serum eye drops, a solution made of 20% autologous serum in sterile saline, were applied 10 times per eye per day. The patients were evaluated every 4 weeks according to visual acuity, corneal sensitivity, vital staining of the ocular surface, tear dynamics, and subjective assessments of symptoms (complaints scores). The median follow-up period was 19.4 months (range: 4-41 months). After 4 weeks of treatment, significant improvement was observed in both complaint scores (from 33.7+/-12.3 to 23.6+/-10.6 points; P<0.01) and fluorescein scores (from 5.8+/-2.0 to 2.4+/-0.9 points; P<0.005). Significant improvements were observed also in rose-bengal staining and tear break-up time. In seven of the 14 patients, the responses were maintained for 6-41 months (median:19.4+/-8.3 months), while six of the other seven patients required treatment with punctal plugs in addition to autologous serum eye drops. One of these other seven patients developed eczema around the eyelids, after which the treatment was discontinued. No serious adverse events were observed. We conclude that autologous serum eye drops are safe and effective for treating severe dry eye associated with cGVHD and that more efficient control of dry eye may be achieved by the combined use of autologous serum eye drops with punctal plugs.

Interleukin-8 concentrations in conjunctival epithelium brush cytology samples correlate with neutrophil, eosinophil infiltration, and corneal damage.

PURPOSE: To evaluate whether interleukin-8 (IL-8) and RANTES (regulated on activation, normal T-cell expressed and secreted) concentrations in the supernatants of conjunctival epithelial samples from patients with vernal keratoconjunctivitis (VKC) correlate with the number of infiltrating eosinophils or neutrophils and with the severity of corneal lesions. METHODS: Thirty-four patients with VKC, 5 patients with seasonal allergic conjunctivitis, and 10 volunteers without allergic diseases were enrolled in this study. Conjunctival epithelial cells were collected by brush cytology and the number of inflammatory cells was counted. The chemokine expression in the cells was investigated by immunocytochemistry and the chemokine concentrations of the cell suspensions were measured by enzyme-linked immunosorbent assay. RESULTS: The percentages of eosinophils and neutrophils in cell suspensions from VKC patients with corneal erosion or ulcer were higher than those from subjects with clear corneas or superficial punctate keratopathy. IL-8 concentrations in the supernatant of samples correlated significantly with the percentages of neutrophils and eosinophils in paired cell suspensions. No correlation was observed between RANTES and the percentages of eosinophils. Positive staining for IL-8 was observed in the cytosol of conjunctival epithelial cells. CONCLUSION: IL-8 in the extracellular space of the conjunctival epithelium may play a role in the recruitment of neutrophils and possibly eosinophils and in the pathogenesis of corneal damage in severe allergic diseases.

Light induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apoptotic bcl-2 related gene.

BACKGROUND/AIM: EAT/mcl-1 (EAT), an immediate early gene, functions in a similar way to bcl-2 in neutralising Bax mediated cytotoxicity, suggesting that EAT is a blocker of cell death. The aim of this study was to determine the effect of overexpression of the human EAT gene on light induced retinal cell apoptosis. METHODS: EAT transgenic mice incorporating the EF-1alpha promoter were utilised, and expression of human EAT was detected by RT-PCR. Light damage was induced by raising mice under constant illumination. Two groups of animals, EAT transgenic mice (n=14) and littermates (n=13), were examined by ERG testing and histopathology at regular time points up to 20 weeks of constant light stimulation. Electrophysiological and histopathological findings were evaluated by established systems of arbitrary scoring as scores 0-2 and scores 0-3, respectively. RESULTS: The mean score (SD) of ERG response was significantly lower in EAT transgenic mice (0.79 (0.89)) than in littermates (1.69 (0.48)) (p<0.01). Although the differences between the two survival curves did not reach statistical significance (p=0.1156), the estimated incidence of electrophysiological retinal damage was higher in EAT mice (0.0495/mouse/week; 95% confidence interval (CI) 0.0347-0.0500) than in littermates (0. 0199/mouse/week; 95% CI 0.0035-0.0364). The mean scores (SD) for histopathological retinal degeneration were 2.31 (0.63) in littermates and 1.43 (1.22) in EAT transgenic mice (p=0.065). However, Kaplan-Meier curves for histopathological failure in two groups of mice showed that retinal photoreceptor cells were preserved significantly against constant light in the littermate compared with transgenic mice (p=0.0241). The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates (95% CI 0-0.0120) and 0.0419/mouse/week in the EAT mice (95% CI 0.0286-0.0500). CONCLUSION: Retinal photoreceptor cell apoptosis under constant light stimulation is likely to be accelerated in transgenic retina overexpressing EAT.

Successful treatment of dry eye in two patients with chronic graft-versus-host disease with systemic administration of FK506 and corticosteroids.

PURPOSE: We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids. METHODS AND RESULTS: A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time. CONCLUSION: Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

A significant role of stromal fibroblasts in rapidly progressive dry eye in patients with chronic GVHD.

PURPOSE: To elucidate histopathologic features of the lacrimal gland in chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. METHODS: Lacrimal gland specimens from five patients who had dry eye as part of the symptoms of chronic GVHD were examined by immunohistochemistry and transmission electron microscopy. Lacrimal gland specimens from five patients with Sjögren's syndrome (SS) were used as control samples. RESULTS: Lymphocytes, predominantly T cells, were found primarily in the periductal areas of the lacrimal gland from patients with chronic GVHD, whereas B cells were the dominant infiltrating cells in the acinar areas of the lacrimal gland from patients with SS. Notable findings in the lacrimal gland from patients with chronic GVHD were marked fibrosis of the glandular interstitium and an increase in the number of CD34(+) stromal fibroblasts. These findings were more prominent in patients with severe dry eye than in those with mild dry eye. Electron microscopic observations of the lacrimal gland from patients with chronic GVHD revealed that stromal fibroblasts were attached to various inflammatory cells, especially T cells, through primitive or rudimentary contacts. In addition, the presence of a well-developed rough endoplasmic reticulum in the fibroblasts and newly synthesized collagen fibrils in the extracellular matrix indicated an active production of extracellular matrix components. Electron micrographs revealed multilayered and thickened basal laminae of blood vessels, ducts, and lobules in the lacrimal gland of patients with chronic GVHD; however, these observations were infrequently observed in the lacrimal glands of patients with SS. CONCLUSIONS: The results suggest substantial differences in the lacrimal gland histopathology of patients with chronic GVHD and SS. In addition, it is likely that stromal fibroblasts are actively involved in the pathogenic process of chronic GVHD in the lacrimal gland by producing excessive extracellular matrix components.

Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy.

PURPOSE: To elucidate vascular endothelial growth factor (VEGF)-mediated pathogenesis of fibrovascular proliferation in diabetic retinopathy. METHODS: Fibrovascular tissues were obtained at vitrectomy from 22 cases with proliferative diabetic retinopathy. The half-divided tissues were processed for reverse transcription-polymerase chain reaction (RT-PCR) analysis to examine the expression of VEGF isoforms and their receptors. Paraffin sections of the other half were used for immunohistochemistry for CD34, glial fibrillary acidic protein and VEGF, and in situ hybridization for VEGF. RESULTS: RT-PCR analysis demonstrated the expression of VEGF receptors VEGF-R1, VEGF-R2, and neuropilin-1 in 12, 14, and 14 of 22 cases, respectively. Notably, VEGF-R2 and neuropilin-1 were simultaneously expressed in the identical 14 tissues. The isoform VEGF121 was constitutively expressed in all the tissues examined, whereas the expression of VEGF165 was confined to the 7 tissues that also expressed VEGF-R2 and neuropilin-1. The vascular density of fibrovascular tissues evaluated by immunohistochemistry for CD34 was significantly higher in the cases with the expression of VEGF-R2 and neuropilin-1 than in those without their expression (P < 0.01), whereas VEGF-R1 expression had no such relationship with the vascular density. The fibrovascular tissues that expressed VEGF165 together with VEGF-R2 and neuropilin-1 were found in significantly younger patients (P < 0.01). In situ hybridization and immunohistochemical studies demonstrated that glial cells in the fibrovascular tissues express and produce VEGF. CONCLUSIONS: Coexpression of VEGF-R2 and neuropilin-1 is suggested to facilitate fibrovascular proliferation in diabetic retinopathy.

Macular hole retinal detachment in highly myopic eyes: ultrastructure of surgically removed epiretinal membrane and clinicopathologic correlation.

PURPOSE: To elucidate the pathogenesis of macular hole retinal detachment (RD) in highly myopic eyes by investigating the ultrastructure of surgically removed epiretinal membranes (ERM). METHODS: Five consecutive Japanese patients with macular hole RD in highly myopic eyes underwent vitrectomy with attempted removal of the ERM around the hole. The surgical specimens were examined by light microscopy and by scanning and transmission electron microscopy. RESULTS: Extremely thin, translucent sheets of epiretinal tissue were harvested from all patients during surgery, resulting in successful retinal reattachment. Ultrastructural examination revealed that the ERM consisted of cortical vitreous and various cellular components. Fibrous astrocytes were the major cell population and extended cytoplasmic processes with membrane-associated vesicles onto the cortical vitreous. Gap junctions were observed between the interdigitating processes of fibrous astrocytes. The cortical vitreous contained abundant newly formed collagen, including fibrous long-spacing collagen, surrounded by sparsely distributed native vitreous collagen. CONCLUSIONS: Active synthesis of new collagen may be regulated by fibrous astrocytes by means of transmission of metabolic substances through gap junctions and cytoplasmic vesicles. The frequent occurrence of newly formed collagen aggregates may subsequently lead to a diffusely condensed posterior cortical vitreous that exerts tangential traction on the posterior retina, causing macular hole RD.

The myocilin (MYOC) gene expression in the human trabecular meshwork.

PURPOSE: We previously reported a novel cytoskeletal protein with a myosin-like domain which is localized in the ciliary rootlet and basal body of connecting cilium of photoreceptor and hence we named it 'myocilin'. It was soon realized that myocilin is identical to a protein called TIGR (trabecular meshwork inducible glucocorticoid response protein) which was found to be responsible for the pathogenesis of juvenile open angle glaucoma. In this study, we employed in situ RNA hybridization to examine the myocilin (MYOC)/ TIGR gene expression in the trabecular meshworks of glaucomatous and nonglaucomatous eyes. METHODS: The glaucomatous specimens were obtained by trabeculectomy from the patients with primary open angle glaucoma (POAG), chronic angle closure glaucoma (CACG) and steroid glaucoma, respectively, and the nonglaucomatous specimens were obtained from a victim of traffic accident at autopsy and from a patient with maxillary sinus carcinoma at enucleation for the operation. The in situ RNA hybridization was carried out with digoxigenin-labeled sense and antisense RNA probes. RESULTS: In all cases, hybridization signals were detected primarily in the trabecular meshwork cells and secondarily in the fibroblast-like cells of corneoscleral wall. CONCLUSIONS: Myocilin gene is expressed clearly in the trabecular meshwork cells of both glaucomatous and nonglaucomatous eyes.

Dry eye after haematopoietic stem cell transplantation.

AIMS: To determine the incidence, natural course, and severity of dry eye occurring or worsening after haematopoietic stem cell transplantation (SCT). METHODS: At a tertiary care hospital, 53 patients undergoing allogeneic or autologous SCT followed by at least 180 days of follow up were studied prospectively. Examination included grading of symptoms of dry eye, evaluation of ocular surface, tear break up time, and Schirmer tests with and without nasal stimulation. Meibomian gland secretion was also examined using a slit lamp while applying steady digital pressure. RESULTS: Of the 53 patients, 44 received allografts. Half of these patients (22) developed dry eye or their pre-existing dry eye worsened after SCT, while none of nine autograft recipients did. Onset of dry eye was 171 (SD 59) days after SCT. Two types of dry eye occurred. One (n=10) was severe with ocular surface findings resembling Sjögren's syndrome and reduction of reflex tearing soon after onset. A mild type (n=12) had unimpaired reflex tearing. Meibomian gland dysfunction (MGD) was more frequent and severe in patients with dry eye and chronic graft versus host disease (GVHD), and overall severity of dry eye was greater in patients with MGD and chronic GVHD. CONCLUSIONS: Dry eye after SCT occurred only in allograft recipients, and was not evident in autograft recipients. The severe form of dry eye had a tendency to develop rapidly. Further study on the prediction and treatment of severe dry eye after SCT is necessary.

Time-dependent effects of stressor application on metastasis of tumor cells in the lung and its regulation by an immunomodulator in mice.

The effects of the timing of stressor application on transplanted tumor cells and its possible regulation by an immunomodulator was investigated. Male C57 BL/6N mice were subjected to rotational stressor for 7 days relative to tumor cell inoculation: stressor after inoculation of Lewis lung cancer cells, stressor during inoculation and stressor before inoculation. Stressor application and tumor cell inoculation induced transient decreases in body weight, particularly in mice stressed after inoculation. The mice exposed to the stressor during inoculation or before inoculation showed significant increases in the number of metastatic foci relative to control mice. Early administration of an immunomodulator, PSK, significantly attenuated the increase of metastatic foci in stressed mice. The weights of thymus gland and spleen at 14 days after inoculation were similar in the three stressor groups and the control group. Application of the stressor reduced NK cell activity of the normal mice as well as tumor bearing mice. The lowest pre-inoculation NK cell activity was observed in mice stressed for 7 days beginning on the day of inoculation. The NK cell activity decreased in the tumor bearing mice which were stressed at the time of tumor inoculation. Decreased NK cell activity was reversed at day 14 after tumor inoculation. The mice exposed to the stressor after inoculation showed lowest level of NK cell activity relative to mice exposed to the stressor before or during inoculation. The treatment of mice with PSK reduced these changes significantly. The present results suggest that the rotational stress reduces splenic NK cell activity, which may influence the magnitude of tumor metastasis, depending on the time of tumor cell injection. Further, administration of an immunomodulator may counteract the reduction of the NK cell activity.

IL-4 regulates chemokine production induced by TNF-alpha in keratocytes and corneal epithelial cells.

BACKGROUND: Eosinophils are thought to play a major role in the pathogenesis of corneal lesions in ocular allergies. The regulation of chemokine production in corneal cells by the Th2 cytokine, interleukin 4 (IL-4), was examined in order to investigate its role in ocular allergies. METHODS: Pure cultures of human corneal epithelial cells and keratocytes were exposed to tumour necrosis factor alpha (TNF-alpha) and/or IL-4. 24 hours after exposure, culture supernatants were removed and concentrations of IL-8 and RANTES were quantified by ELISA assay. RESULTS: Simultaneous addition of IL-4 inhibited TNF-alpha induced IL-8 production in both corneal epithelial cells and keratocytes. TNF-alpha and IL-4 synergistically stimulated the production of RANTES in keratocytes. CONCLUSION: Differential regulation of chemokine production from corneal cells by IL-4 may play a role in the selective recruitment of predominantly eosinophils to the ocular surface in ocular allergies.

Ex vivo delivery of suicide genes into melanoma cells using epidermal growth factor receptor-specific Fab immunogene.

The Fab fragment of monoclonal antibody B4G7 against human epidermal growth factor (EGF) receptor was conjugated with cationic poly-L-lysine and the resulting conjugate was further complexed with reporter genes or therapeutic genes. This Fab/DNA complex was designated as "Fab immunogene." The Fab immunogene transfer in vitro was mediated through the EGF receptors in two melanoma cell lines. The frequency of cells expressing beta-galactosidase (beta-Gal) reporter gene was approximately 1%. The induction of suicide effects after Fab immunogene transfer of herpes simplex virus thymidine kinase (TK) or Escherichia coli cytosine deaminase (CD) gene was quite remarkable, and the growth of melanoma cells was inhibited for over 7 days in the presence of ganciclovir (GCV) or 5-fluorocytosine (5-FC). Similarly, when melanoma cells treated in vitro with the Fab immunogene carrying TK or CD were transplanted into the back of nude mouse, subsequent systemic administration of GCV or 5-FC effectively suppressed the growth of tumors, indicating the occurrence of in vivo suicide effects.

Efficacy and safety of infrared warming of the eyelids.

PURPOSE: To evaluate our newly developed infrared heater (IRH) and compare it to a broad-spectrum heater (BSH) for warming the eyelids. MATERIALS AND METHODS: Ten normal subjects were enrolled in this study. All measurements were recorded in a room with temperature 23 degrees C, 40% humidity, and no wind. The IRH is composed of two hard eye patches that have light-emitting diodes (LEDs) emitting near-infrared radiation. We first compared the temperature rises in the cornea, lacrimal gland, and eyelids after warming through closed eyelids with the IRH for 5 and 10 min. Next, we compared warming with the IRH or BSH for 30 min. We then used the IRH for 5 min with the eyes open to confirm its safety. Finally, we determined subjective feeling after warming the eyes. RESULTS: Direct comparison of 5 versus 10 min of warming with the IRH showed no significant differences in temperature rises in the upper eyelid (p = 0.09). The IRH caused significantly more heating (p < 0.05) than did the BSH everywhere except the cornea. The temperatures never rose above 37.7 degrees C for either heater during 30 min or with the IRH with the eyes open for 5 min. The subjects' comfort level rose significantly (p < 0.05) after treatment with the IRH. CONCLUSIONS: Our study showed the efficacy and safety of warming the eyelids with a newly developed IRH. Only 5 min is necessary to increase ocular temperature and enhance comfort.

[The clinical features of 9 cases of intraocular malignant lymphoma of oculocerebral origin].

We reviewed a series of 13 eyes in 9 cases of intraocular lymphoma with or without intracranial involvement during the past 15 years. The cases were characterized by moderate or no inflammation in the anterior ocular segment and by the presence of vitreous opacity and fundus lesions. Contrary to the accepted view that this disease simulates uveitis with various manifestations, the fundus lesions in the present series showed disseminated or tumorous subretinal lesions suggestive of proliferation of tumor cells. Only a few cases showed retinal vasculitis or retinal exudates. Electrooculograms showed findings suggestive of widespread impairment of the retinal pigment epithelium. Because of poor prognosis and sensitivity to radiation, we advocate early diagnosis and treatment for this disease.

Generation of plasma cells from peripheral blood memory B cells: synergistic effect of interleukin-10 and CD27/CD70 interaction.

B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27- B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10-mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10-mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

Suppression of nuclear factor kappa B and CD18-mediated leukocyte adhesion to the corneal endothelium by dexamethasone.

PURPOSE: To demonstrate that leukocyte adhesion to cultured corneal endothelial cells is mediated by the CD18 antigen, and to determine whether dexamethasone directly suppresses adhesion by inhibiting activation of nuclear factor kappa B (NFkappaB). METHODS: Cultured bovine corneal endothelium was stimulated for 6 hours by 40 micron/ml tumor necrosis factor alpha (TNFalpha). Dexamethasone was added 1 hour before TNFalpha stimulation in the dexamethasone group. After stimulation, neutrophils separated from a healthy human volunteer were added with or without anti-CD18 antibody. The culture plate was settled for 15 minutes at 37 degrees C, and then neutrophils were activated by N-formyl-methionyl-leucyl-phenylalanine for 5 minutes. Nonadherent neutrophils were removed by sealing and inverting the culture well. The intracellular localization of NFkappaB after TNFalpha simulation was determined by confocal immunocytochemistry using an anti-p65 antibody. RESULTS: Neutrophil adhesion to cultured corneal endothelial cells increased significantly on exposure to TNFalpha (451.4+/-45.4 cells/mm2, n = 16) compared to control (156.7+/-27.3 cells/mm2, n = 16, P < 0.01). This increased adhesion was suppressed by the addition of anti-CD18 antibody (157.6+/-25.1 cells/mm2, n = 8, P < 0.01) and by pretreatment with 10(-7) M dexamethasone (207.9+/-31.5 cells/mm2, n = 10, P < 0.01). Immunocytochemistry 60 minutes after stimulation revealed that NFkappaB was located in the cytoplasm in unstimulated cells; however, the addition of TNFalpha caused NFkappaB to translocate into the nucleus. Pretreatment with dexamethasone tapered NFkappaB translocation into the nucleus. CONCLUSIONS: Leukocyte adhesion to the corneal endothelium was shown to be mediated by CD18 expressed on activated leukocytes. Pretreatment of the endothelium with dexamethasone inhibited leukocyte adhesion; this may be due in part to the suppression of NFkappaB entry into the nucleus.

RANTES production in a conjunctival epithelial cell line.

PURPOSE: Although corneal tissue damage in allergic ocular diseases is thought to be induced by inflammatory cells that infiltrate from conjunctival tissue, the mechanisms of recruiting these cells remain unclear. The objective of this study was to demonstrate whether conjunctival epithelial cells have the ability to produce "regulated on activation, normal T-cell expressed and secreted" (RANTES). To test this hypothesis, we investigated RANTES expression in the conjunctival tissue and also RANTES production by cytokine stimulation in a human conjunctival epithelial cell line. METHODS: We investigated the expression of the chemokine RANTES in conjunctival epithelium from two patients with atopic keratoconjunctivitis (AKC) and one patient with vernal keratoconjunctivitis (VKC) by using immunohistochemistry. We also investigated the production and suppression of RANTES from a human conjunctival epithelial cell line, Wong-Kilbourne-derived human conjunctiva (WK-hC) by using enzyme-linked immunosorbent assay (ELISA). RESULTS: Conjunctival epithelium from a patient with AKC stained positively for RANTES. We found that tumor necrosis factor-alpha (TNF-alpha) induced de novo production of RANTES, and interferon-gamma (IFN-gamma) synergistically increased the TNF-alpha-dependent production of RANTES from WK-hC cells. Dexamethasone suppressed the RANTES production from the cell line. CONCLUSION: Taken together, human conjunctival epithelial cells were capable of producing RANTES in response to inflammatory stimuli such as TNF-alpha and may play a role in recruiting inflammatory cells such as eosinophils and T lymphocytes toward the ocular surface.

High incidence of visual recovery among four Japanese patients with Leber's hereditary optic neuropathy with the 14484 mutation.

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Leber's hereditary optic neuropathy (LHON) in Caucasian patients who show a high incidence of visual recovery. We evaluated four Japanese patients with LHON associated with the 14484 mutation who were negative for eight proposed secondary mutations. There was no family history of optic atrophy in three of the four patients. All four patients were initially diagnosed as having optic neuritis, either anterior (Cases 1 and 3) or retrobulbar (Cases 2 and 4), based upon their fundus findings and clinical history. Molecular genetic testing of mtDNA confirmed the diagnosis of LHON in all four patients. The three patients who experienced recovery had their vision return to 20/50 or better in both eyes. The patient who did not was a heavy consumer of alcohol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.