Search PubMed⌕ Search

Biomedical subjects

S Lightman

Publications and source records attributed to S Lightman.

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

Characterization of phenotype and cytokine profiles of T cell lines derived from vitreous humour in ocular inflammation in man.

Intermediate uveitis (IU) and Fuchs' heterochromic cyclitis (FHC) are two chronic ocular inflammatory disorders. They differ considerably in ocular morbidity, which is higher in IU. T cell lines were derived from the vitreous humour (VH) and peripheral blood (PB) of 10 patients with IU and four patients with FHC. There was a predominance of CD8+ in all the lines. However, there was a significantly higher percentage of CD4+ T cells in the T cell lines derived from VH of IU (32.0 +/- 8.6%) compared with FHC patients (19. 2 +/- 8.9%) (P = 0.04). The VH-derived T cell lines (VDTC) produced significantly higher levels of IL-2, interferon-gamma (IFN-gamma) and IL-10, but not IL-4, compared with PB-derived T cell lines (PBDTC) in both entities. There was significantly higher IL-2 production by VDTC from IU when compared with FHC patients (1810 +/- 220 pg/ml versus 518 +/- 94 pg/ml; P = 0.009), which could account for the more aggressive clinical features of this condition. In contrast IL-10 production was significantly higher by the VDTC from FHC compared with IU patients. The high IL-10 production by T cells infiltrating VH of FHC patients could down-regulate the inflammatory responses, thereby contributing to the benign clinical course seen in these patients. The accumulation of T cells with differing cytokine profiles in the VH suggests an important role for these cytokines in the pathogenesis of these chronic uveitides.

Adult↗
PubMed1999

Posterior uveitis in Hodgkin's disease.

PURPOSE: To describe the features of posterior uveitis in patients who either developed or were known to have, biopsy-proven Hodgkin's disease (HD). METHODS: Four patients were identified who were attending the uveitis clinic. Their charts were reviewed retrospectively and information on their HD was obtained from other hospitals where necessary. Their case histories are presented. RESULTS: Two patients presented with uveitis prior to the diagnosis of HD and in the other two, the HD was thought to be in remission. The commonest ocular signs were of vitritis and discrete, white, chorioretinal lesions. No difference in the ocular findings were apparent between those who had a known diagnosis of HD and the those that did not. CONCLUSIONS: HD can occur in the eye and can mimic posterior uveitis. In two of the patients, the uveitis preceded the diagnosis of HD and at the time of presentation all investigations were normal. No specific diagnostic features were apparent, though three of the patients had vitritis and chorioretinal lesions.

Adult↗
PubMed1999

Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing.

When the human glucocorticoid receptor (GR) was first sequenced, a predominant form (GRalpha) and a minor variant (GRbeta) were identified. In the present communication, we describe a new variant of the glucocorticoid receptor (GRgamma) in which, as a result of alternative splicing, three bases are retained from the intron separating exons 3 and 4. These three bases code for an additional amino acid (arginine) in the DNA binding domain of the receptor. Insertion of arginine at this site has previously been shown to decrease transcriptional activation by the GR to 48% that of GRalpha. Analysis of cDNA from different tissues shows that the novel form is widely expressed at a relatively high level (between 3.8 and 8.7% of total GR).

Alternative Splicing↗
PubMed1999

Current and novel agents for the treatment of cytomegalovirus retinitis.

The incidence of cytomegalovirus (CMV) retinitis appears to be declining with improved treatment protocols for HIV and prophylaxis protocols for other high risk patients. Despite this, CMV retinitis remains a major cause of visual loss in patients who are severely immunocompromised. Treatment options are evolving in the light of viral resistance, new methods of drug delivery, new drugs, and the increased potential for improvement of immune function that modern antiretroviral therapy provides. In this article, we review the changing options available for the management of CMV retinitis and discuss possible therapeutic agents for the future.

Animals↗
PubMed1999

Increased CD4+ expression and decreased IL-10 in the anterior chamber in idiopathic uveitis.

PURPOSE: To compare cell types and cytokines in aqueous humor from patients with uveitis either occurring in association with a systemic disease or apparently isolated and not associated with a systemic disease. METHODS: Cells were collected by centrifugation of fresh aqueous humor from uveitis and controls, and immunofluorescence techniques were performed with markers for T cells, B cells, and monocytes. Cytokines were measured in the aqueous supernatants, and serum samples were assayed for soluble interleukin-2 receptors. RESULTS: When aqueous samples from idiopathic uveitis were compared with those from uveitis associated with a systemic disease, there were increases in CD3+, CD4+ (p = 0.001), and activated CD4+ T cells (p = 0.02) and a decrease in B cells (p = 0.0013). This was not reflected in the peripheral blood where there were no differences in the cell types or in soluble interleukin-2 receptor levels. No cells were obtainable from control aqueous. Interleukins-10 and -12, interferon-gamma, and transforming growth factor-beta2 were detected in aqueous supernatants. Interleukin-10 was reduced (p = 0.024) in uveitis in comparison with controls. CONCLUSIONS: The results suggest a selective recruitment of CD4+ T cells within aqueous humor but only in idiopathic uveitis. In both disease groups there was a decrease in the immunoregulatory cytokine interleukin-10, which might enable an immune response to occur in an otherwise highly immunosuppressive microenvironment. Increases in activated CD4+ T cells combined with depressed interleukin-10 levels could partially explain why, for example, in acute anterior uveitis, the inflammatory disease is often more severe.

Adult↗
PubMed1999

The immunomodulatory effect of topical cyclosporin A in atopic keratoconjunctivitis.

PURPOSE: To perform a detailed examination of the immunomodulatory effects of topical cyclosporin A (CsA) in conjunctival tissue from patients with atopic keratoconjunctivitis (AKC). METHODS: Patients with active AKC were randomly allocated into two groups of four patients. For 3 months one group received 2% CsA drops, and the other group received placebo drops. Superior tarsal conjunctival biopsy specimens were harvested before and after treatment and examined by one- and two-color immunohistochemistry to compare leukocyte counts, HLA-DR+ and IL-2R+ cell counts, HLA-DR positivity of conjunctival epithelial cells, and counts of T cells expressing the cytokines interleukin (IL)-2, IL-3, IL-4, IL-5, and interferon (IFN)-gamma. RESULTS: Posttreatment values were significantly less than pretreatment values for the total number of leukocytes and in the numbers of CD3+ T cells, CD4+ cells, CD8+ cells, CD20+ B cells, neutrophils, and macrophages, and there was a decrease in the CD4-CD8 ratio (P = 0.03) in the CsA group. There was a reduction from before CsA treatment to after CsA-treatment in the numbers of HLA-DR+ and IL-2R+ cells (P = 0.03), but the reduction in the epithelial cell HLA-DR expression did not reach significance. The number of T cells staining for IL-3 and IL-5 was reduced, although not to statistical significance, but there was a significant reduction in the number of T cells expressing IL-2 and IFN-gamma (P = 0.03) after CsA treatment compared with initial values. There were no statistically significant differences between pretreatment and posttreatment values in the placebo group. There was a clinical improvement in the CsA group and a clinical worsening in the placebo group. CONCLUSIONS: The in vitro effects of CsA translate into a reduction in T cells, a normalization of the CD4-CD8 ratio, a decrease in T-cell activation, and a reduction in T-cell cytokine expression, especially IL-2 and IFN-gamma. The decrease in HLA-DR expression may be mediated by the change in IFN-gamma. There were fewer B cells but not fewer plasma cells after CsA and no change in IL-4 expression, suggesting minimal effects on type I hypersensitivity responses. There was no significant reduction in mast cell or eosinophil numbers, but direct effects of topical CsA on their function may play a role in the therapy of ocular allergic disease. These results show that the beneficial effects of topical CsA in AKC are accompanied by important changes in conjunctival immune cell profiles.

Administration, Topical↗
PubMed1998

Multifocal choroiditis: clinicopathologic correlation.

Many of the white dot syndromes are considered to have a granulomatous pathogenesis. The histopathologic characteristics of this case of multifocal choroiditis seen within 15 months of apparent clinical onset show that the white dot lesions were nongranulomatous perivascular choroidal infiltrates, consisting mainly of B lymphocytes. Early choroidal neovascularization was also seen.

Adult↗
PubMed1998

A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis.

OBJECTIVE: This study aimed to investigate the therapeutic effect of topical cyclosporin A (CsA) 2% in maize oil as a steroid-sparing agent in steroid-dependent atopic keratoconjunctivitis. DESIGN: Prospective, randomized, double-masked, placebo-controlled trial. PARTICIPANTS: Twenty-one patients with steroid-dependent atopic keratoconjunctivitis were studied. INTERVENTION: Patients used either topical CsA or vehicle four times daily for 3 months in addition to their usual therapy, and the clinical response was used to taper or stop topical steroids when possible. MAIN OUTCOME MEASURES: Steroid drop usage per week, ability to cease steroid use, scores for symptoms and clinical signs, drop side effects, and overall subjective rating of trial drop by patients and clinician were measured. RESULTS: Cyclosporin A had a greater steroid-sparing effect than did placebo. Nine of 12 CsA patients ceased steroids compared to 1 of 9 placebo patients (P = 0.01), the final steroid use was lower in the CsA group (2.6 +/- 1.4 vs. 27.7 +/- 17.7, P = 0.005), and the mean reduction in steroid use was greater for CsA (85.5 +/- 14.7 vs. 13.9 +/- 16.0, P = 0.005). Clinical signs and symptom scores were reduced to a greater level for CsA. Serious side effects were lid skin maceration in one patient using CsA and an allergic reaction in one placebo patient. Marked blurring of vision after drop instillation was common in both groups, but intense stinging was more common in CsA patients (9/12 vs. 1/9, P = 0.01), limiting frequency of drop use. The clinician rated the trial drops as good or excellent more frequently for CsA (11/12 vs. 0/9, P < 0.0001). CONCLUSIONS: Topical CsA is an effective and safe steroid-sparing agent in atopic keratoconjunctivitis and, despite difficulties in patient tolerance, also improves symptoms and signs.

Administration, Topical↗
PubMed1998

Presence of GHRH mRNA in human pituitary somatotrophinomas and its relationship to in vitro effect of a GHRH-antagonist on GH secretion and cAMP production.

Several earlier studies have shown that some human pituitary GH-secreting somatotrophinomas are able to synthesise and release hypothalamic GHRH and it has been proposed that a positive autocrine feedback loop involving this tumor-derived GHRH may participate in tumorigenesis. We have used in-vitro cell culture and exploited an antagonist to GHRH, (Ac-Tyr1,D-Arg2)-GHRH (1-29)-amide (GHRH-A), to further investigate whether an autocrine loop involving somatotrophinoma-derived GHRH may exist. In situ hybridization demonstrated presence of GHRH transcripts in 5 of 9 human somatotrophinomas. In culture, GHRH-A failed to inhibit basal release of GH or production of cAMP irrespective of presence or absence of GHRH transcripts. However, GHRH-A was able to completely or partially abolish the stimulatory effects of exogenously added GHRH peptide. Additionally, the average stimulatory effect of exogenous GHRH on in vitro GH secretion by somatotrophinomas possessing GHRH mRNA was identical to that shown by tumors not expressing the GHRH gene. Whilst confirming that many human pituitary somatotrophinomas are able to express the GHRH gene, the failure of GHRH-A to inhibit basal GH secretion argues against the concept of the existence of an autocrine stimulatory loop involving secreted GHRH peptide.

Adenoma↗
PubMed1998

An ultrastructural and systemic analysis of glycosaminoglycans in thyroid-associated ophthalmopathy.

PURPOSE: To determine the ultrastructural localisation of glycosaminoglycans (GAGs) in the extraocular muscles (EOMs) of patients with thyroid-associated ophthalmopathy (TAO) and to see whether the quantity and type of GAGs present in blood and urine are markers of the disease. METHODS: Biopsies of affected EOMs were taken and studied by transmission electron microscopy (TEM). These were either fixed conventional for TEM, or in 0.5% tannic acid and others for immunogold staining. Serum hyaluronan (HA) was measured using a radioimmunoassay in patients with TAO as well as control subjects, and urinary GAG levels assessed by photometric quantitation of hexuronic acid after reaction with carbazole. The excretion pattern of the urinary GAGs was determined by discontinuous electrophoresis. RESULTS: TEM showed that there is a marked expansion of the endomysial space in TAO EOM biopsies as compared with non-TAO strabismus specimens. This is caused by an increased number of collagen fibres, interspersed with a granular amorphous material surrounding striated collagen fibres shown to be hyaluronan by immunogold staining. In contrast, serum hyaluronan concentrations were similar in TAO and control patients, although there was a statistically significant difference in the urinary GAG excretion between the two groups of patients examined. By discontinuous electrophoresis, chondroitin sulphate and heparan sulphate were present in both patients and controls. CONCLUSION: GAGs and in particularly HA are present at the EOM level in patients with recently inactive TAO. However, serum levels of HA and urinary GAGs are not sensitive indicators for their presence within the EOMs.

Adult↗
PubMed1998

Characterization of T cells and cytokines in the aqueous humour (AH) in patients with Fuchs' heterochromic cyclitis (FHC) and idiopathic anterior uveitis (IAU).

FHC and IAU are two forms of anterior uveitis which are localized to the eyes with no evidence of systemic involvement. However, FHC has distinct clinical features and differs from IAU in that the inflammation is low grade, steroid non-responsive, and has a less aggressive clinical course. To try to dissect the mechanism for this difference the phenotypes of the cells in the AH and blood (PB) and the cytokines present in the AH in patients with FHC and IAU were compared. Three-colour flow cytometry was performed on the cells isolated from the AH and PB. Percentage of cells bearing the following markers were determined: CD3, CD4, CD8, CD4/CD25, CD8/CD25, CD19 and CD14. The cytokines IL-4, IL-10, IL-12 and interferon-gamma (IFN-gamma) were assayed by ELISA. In both groups T cell numbers were higher in the AH than PB, although the distribution of T cell subsets in PB was similar. In the AH, CD8+ T cell numbers were higher in FHC than in IAU (P = 0.003), whilst CD4+ numbers were higher in IAU than FHC (P = 0.01). AH cytokine profiles were different in the two groups: IFN-gamma levels were higher and IL-12 levels lower in the FHC group than IAU (P = 0.02), whilst IL-10 levels tended to be higher in the FHC group (P = 0.5). We suggest that different local mechanisms governing the balance of T cell/cytokine-mediated inflammation in the anterior segment may underlie clinical differences such as chronicity and response to steroids in these disorders.

Adolescent↗
PubMed1998

Enterobacter cloacae endophthalmitis: report of four cases.

Members of the genus Enterobacter are commensal organisms of the gastrointestinal tract and are considered pathogenic only for patients with lowered resistance to infection (e.g., chronic infection, cancer, or diabetes mellitus) or those with impaired immunity (congenital, acquired, or impaired immunity secondary to therapy). We report on four cases of endophthalmitis caused by Enterobacter cloacae: two in patients with acute postoperative endophthalmitis, one in a patient with delayed bleb-related endophthalmitis, and one in a patient presenting with presumed posttraumatic endophthalmitis. Each patient presented with severe disease many days after the onset of ocular symptoms, and two patients had systemic risk factors accounting for a reduced resistance to infection. Endophthalmitis caused by gram-negative bacilli is characterized by acute onset, rapid progression, and poor final visual outcome. Each of these patients was treated by a standard protocol with intravitreal, systemic, and topical antibiotics and systemic steroids. Despite treatment, the final visual outcomes for three of these patients was no perception of light, and that for one patient remained perception of hand movements only. In common with endophthalmitis caused by other gram-negative organisms, intraocular infection secondary to Enterobacter cloacae infection is a devastating disease which, despite treatment, results in extensive ocular damage and severe visual loss. Since 1966, only four cases of endophthalmitis secondary to infection with members of this genus have been reported. This report presents four cases which occurred over a period of 14 months and, to the best of our knowledge, the first case of bleb-related endophthalmitis secondary to E. cloacae infection.

Adult↗
PubMed1998

Neuroendocrine, appetitive and behavioural responses to d-fenfluramine in women recovered from anorexia nervosa.

BACKGROUND: Increased central serotonin (5-HT) function has been hypothesised to be a vulnerability trait in anorexia nervosa. METHODS: Eighteen women with a history of DSM-III-R anorexia nervosa and 18 female controls were examined. The subjects had recovered weight and menstrual function. A placebo-controlled d-fenfluramine test was used. Subjects ingested d-fenfluramine or placebo and after three hours were offered a 'free' meal. The amounts eaten were recorded and plasma cortisol and prolactin levels were measured. Questionnaires related to eating attitudes and behaviour, to personality, and to mood were administered. RESULTS: Unlike the control subjects, those recovered from anorexia nervosa did not show the expected appetite-suppressing responses to d-fenfluramine; their eating attitudes and behaviour were more restrained, 'negative' perfectionism was more pronounced, and post-meal plasma cortisol levels did not rise as expected. CONCLUSIONS: Our results do not suggest that increased central 5-HT function is a trait marker in anorexia nervosa, but dysregulation in part of the central 5-HT system may be a vulnerability factor. The flattened post-meal response to cortisol in the subjects who had recovered from anorexia nervosa suggests that their hypothalamic pituitary--adrenal axis may be altered and deserves further investigation.

Adult↗
PubMed1998

Polymerase chain reaction and restriction fragment length polymorphism mediated detection and speciation of Candida spp causing intraocular infection.

PURPOSE: To determine the usefulness of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis in the identification and speciation of Candida spp that causes ocular infection. METHODS: Oligonucleotide primers based on the cytochrome P450 L1 A1 demethylase gene were used to successfully amplify by PCR a single 1.0-kb and a single 500-bp DNA fragment from C. albicans, C. tropicalis, C. krusei, C. glabrata, C. parapsilosis, and C. pelliculosa genomic DNA. RFLPs within the PCR product were identified after restriction enzyme digestion. RESULTS: The sensitivity of the amplification reaction after two rounds of PCR was 10 fg genomic C. albicans DNA or one copy of the gene. No amplification product was obtained when DNA from C. guilliermondii, Aspergillus fumigatus, Fusarium solani, human leukocytes, or 10 species of bacteria was used as a template. Experiments with spiked normal vitreous demonstrated equal sensitivity as long as the volume of vitreous did not exceed 20% of the total PCR volume. RFLP analysis of the PCR product generated from each species obtained from the first- and second-round amplification products enabled species identification after digestion with specific endonucleases. Application of the technique to four clinical samples was successful. CONCLUSIONS: It is expected that the simplicity of the DNA extraction technique allied with the broad specificity of the outer primers for all ophthalmically relevant Candida spp and the sensitivity of the second-round PCR will aid in the detection of fungal DNA in small intraocular samples. PCR-RFLP analysis has great potential in the rapid detection and identification of Candida spp and in the provision of a useful laboratory tool for the future.

Aqueous Humor↗
PubMed1998

Effects of drug therapy on Toxoplasma cysts in an animal model of acute and chronic disease.

PURPOSE: To evaluate the effects of drug therapy on the clinical course of acute acquired Toxoplasma retinochoroiditis and on the number of Toxoplasma cysts present in the brain and ocular tissues in the hamster animal model. METHODS: The Syrian golden hamster animal model of Toxoplasma retinochoroiditis was used. In acute disease, systemically administered atovaquone was compared with conventional therapies (pyrimethamine combined with sulfadiazine; clindamycin; and spiramycin). The clinical course of the ocular disease was determined with retinal examination and photography of the fundus. The number of Toxoplasma cysts remaining after treatment was evaluated in aliquots of brain homogenate and in retinal tissue. The effect of atovaquone on cerebral Toxoplasma cyst count was also studied in chronic disease. RESULTS: None of the drugs administered altered the course of the acute disease, judged by clinical examination. Atovaquone alone significantly reduced the number of cerebral Toxoplasma cysts after acute disease. Atovaquone also significantly reduced the cerebral Toxoplasma cyst count in chronic disease. CONCLUSIONS: Tissue cysts are believed to be responsible for reactivation of Toxoplasma retinochoroiditis. Atovaquone has the potential to reduce the risk of recurrent disease.

Acute Disease↗
PubMed1997

Paecilomyces lilacinus endophthalmitis with secondary keratitis: a case report and literature review.

A case of endogenous fungous endophthalmitis with secondary pupillary block glaucoma and corneal invasion requiring penetrating keratoplasty is reported. Initially Paecilomyces lilacinus was isolated from a vitreous and a lens aspirate, but a second vitreous tap revealed Aspergillus fumigatus and P lilacinus. This case highlights the difficulty of diagnosing endogenous fungous endophthalmitis presenting without risk factors and the difficulties of managing such cases using the antifungous agents available. To our knowledge, this is the first case report documenting a progression to stromal keratitis from endogenous endophthalmitis secondary to P lilacinus.

Adult↗