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Biomedical subjects

S Lightman

Publications and source records attributed to S Lightman.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1997

Conjunctival fibrosis in ocular cicatricial pemphigoid--the role of cytokines.

Ocular cicatricial pemphigoid (OCP) is a systemic, autoimmune disease characterised by conjunctival scarring that is often progressive. The pathophysiology of the fibrosis is unknown. This study aimed to determine which fibrogenic cytokines are present in the conjunctiva in patients with acute and chronic OCP as a first stage in determining the mechanisms of fibrosis. Conjunctival biopsies from patients with acute, subacute and chronic OCP (n=13) were compared to normal conjunctiva (n=10). Production of mRNA for, and expression of, transforming growth-beta1, 2 and 3 (TGF-beta), TGF-beta receptor, platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) were assessed using in situ hybridisation and immunohistochemistry. Acute disease showed increased levels of mRNA for TGF-beta1 and 3, mainly in stromal fibroblasts and macrophages. In the stroma, there were concordant increases in latent and activated TGF-beta1 and 3 and TGF-beta receptor expression by fibroblasts. There were no significant increases in the expression of TGF-beta2, PDGF or FGF in acute disease. No cytokines or receptors were significantly increased in chronic disease. Acutely inflamed conjunctiva in OCP is associated with significant stromal levels of TGF-beta1 and 3 but not PDGF or FGF and none were increased in chronic disease. This suggests that TGF-beta may have a key role in the pathogenesis of the fibrosis. The absence of fibrogenic cytokines in chronic progressive OCP provides support for the proposal that fibroblasts in OCP conjunctiva may remain functionally and morphologically abnormal after the withdrawal of cytokine influences.

Acute Disease↗
PubMed1997

New therapeutic options in uveitis.

Most patients with sight-threatening posterior uveitis eventually end up on systemic medication to control their disease. Although the more aggressive approach to the use of these drugs does offer the patient a better chance of significant visual improvement at least in the short term, this is often associated with severe systemic side-effects in both the young and older patient. Cyclosporin has become a very useful second-line agent as a steroid sparer in those patients who can tolerate it. However, it is not suitable for or effective in everyone and the other currently available drugs are often of limited effectivity or associated with major systemic sequelae. This paper summarises the therapeutic approaches currently being examined to define whether they have a role in the better management of these patients in the future. Particularly exciting is the potential for sustained intraocular drug delivery so that adequate drug levels are achieved inside the eye without the necessity for systemic administration.

Adrenal Cortex Hormones↗
PubMed1997

Adhesion molecule expression in vivo on extraocular muscles (EOM) in thyroid-associated ophthalmopathy (TAO).

TAO is an autoimmune condition characterized by mononuclear cell infiltration of the extraocular muscles (EOM) and/or the orbital fat/connective tissue with associated deposition of glycosaminoglycans (GAG) in the interstitial spaces. In this study, the presence and distribution of the vascular adhesion molecules intercellular adhesion molecule-1 (ICAM-1), endothelial-leucocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1) and the leucocyte integrins CD11a/CD18, CD11b/CD18, CD11c/CD18 were investigated. Nineteen EOM biopsies were collected from 17 patients with early (n = 6) and late (n = 13) TAO as well as from 12 non-TAO control patients. Consecutive cryostat sections of these biopsies were immunostained with MoAbs to the above-mentioned molecules and haematoxylin and eosin. Primary antibody binding was visualized using an avidin-biotin system. In early untreated TAO specimens, the interstitial and perimysial connective tissue surrounding EOM fibres and numerous mononuclear cells stained strongly for ICAM-1. In contrast, the vascular endothelial cells (ulex lectin-positive) stained strongly for ELAM-1 (E-selectin), VCAM-1 as well as ICAM-1. In late disease, the same distribution of immunoreactivity for ICAM-1, ELAM-1 and VCAM-1 was observed, but with significantly lower staining. The leucocyte integrins (CD11a, CD11b, CD11c) were again expressed at significantly higher levels in early TAO specimens compared with late TAO specimens and were minimal or absent in the EOM biopsies harvested from control patients. In conclusion, increased expression of adhesion molecules studied correlated with early active disease and was reduced in later stages.

Adult↗
PubMed1997

Analysis of extraocular muscle-infiltrating T cells in thyroid-associated ophthalmopathy (TAO).

TAO is characterized by an autoimmune process affecting the orbital contents. T cells have been suggested to have a major role in pathogenesis, but so far only limited data are available to clarify the extraocular muscle (EOM)-infiltrating T cell phenotype, antigenic reactivity and cytokine profile in TAO patients. In the present study, biopsies of affected EOM were taken and the infiltrating T cells isolated and expanded in vitro with mitogen. Their phenotype was determined by flow cytometric (FACS) analysis and compared with peripheral blood-derived T cell lines, treated in the same way from the same patient. Cytokines present in the supernatant after mitogen stimulation of the T cell lines were assayed by ELISA. In addition, cytokine mRNA present at the time of biopsy was determined by rapid RNA extraction from EOM and reverse transcription-amplification with specific cytokine oligonucleotide probes (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL- 15, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha)). In the T cell lines from two patients, proliferation assays were carried out with antigens derived from thyroid gland, EOM and a thyrotropin (TSH) receptor preparation. Most T cell lines were CD4+, CD45RO+, and TCR alpha/beta+, both from the EOM and the peripheral blood. A wide variety of cytokines was detected by analysis of supernatants or mRNA, but the profiles were not identical comparing the two approaches. However, IL-4 was detected by both. Dose-dependent proliferation was observed in response to thyroid extract in a biopsy-derived T cell line. In conclusion, EOM-infiltrating T cells from patients with TAO, expanded in vitro, were chiefly CD4+ and produced a mixture of cytokines, including IL-4. The proliferation data suggest that there are thyroid-reactive T cells in EOM.

Adult↗
PubMed1997

Reassessment of the PAS patterns in uveal melanoma.

BACKGROUND: Previous work has highlighted the prognostic importance of patterns of periodic acid Schiff (PAS) staining (the Folberg patterns) in uveal melanoma. These patterns have been ascribed to blood vessels but the patterns are different from those seen with other staining techniques for blood vessels. It has recently been shown that microvessel density is the dominant prognostic factor in uveal melanoma. This study reinvestigates the nature and significance of the PAS patterns. METHODS: The PAS patterns were compared with the patterns seen with conventional connective tissue stains and with the patterns seen in sections stained for the presence of blood vessels (by immunohistochemistry for factor VIII related antigen). The PAS patterns were determined on a panel of 117 cases of uveal melanoma. The prognostic significance of each of these patterns was determined and, as more than one pattern can exist in a tumour, principal components analysis was performed to determine the number of underlying factors. RESULTS: Comparison of the PAS patterns with other stains demonstrates that they are based on connective tissue including fibrovascular tissue. Five of the nine PAS patterns carried prognostic significance on univariate analysis. Principal components analysis suggested that these patterns represented three underlying factors, which were tentatively identified as representing disordered growth (factor 1), emergence of rapidly growing subclones (factor 2), and section orientation (factor 3). CONCLUSIONS: The PAS patterns are based on fibrovascular tissue and can be ascribed to three underlying factors. The first two of these factors carried prognostic significance and the first (disordered growth) retained independent prognostic significance in a multivariate Cox model which included microvessel density and tumour size.

Biomarkers, Tumor↗
PubMed1997

Assessment of a standard treatment protocol on visual outcome following presumed bacterial endophthalmitis.

AIMS: The aim of this prospective study was, firstly, to judge the effect of early aggressive treatment with a standardised regimen of high dose broad spectrum intraocular and systemic antibiotics on visual outcome and, secondly, to assess the sensitivity of isolated organisms to the treatment regimen utilised. METHODS: Thirty two consecutive patients presenting with presumed bacterial endophthalmitis were treated and completed follow up. In every case, intraocular sampling was undertaken and treatment with intraocular vancomycin, amikacin, and systemic ciprofloxacin was commenced immediately, followed by systemic steroids 1 day later. RESULTS: In 69% of patients vision improved with 47% achieving a final visual acuity of 6/36 or better and 31% achieving 6/12 or better. Of the intraocular samples taken from post-surgical and post-traumatic cases, 10/27 (37%) and 3/5 (60%) were culture positive, respectively. All the bacteria isolated were sensitive to at least one of the three antibiotics used. CONCLUSIONS: The study demonstrated that the combination of vancomycin, amikacin, and ciprofloxacin is adequate as a standard regimen for the treatment of most patients with suspected bacterial endophthalmitis. The prognosis for a good visual outcome, however, remains poor with 15/27 (55%) post-surgical and 2/5 (40%) post-traumatic cases achieving a final acuity of 6/60 or less.

Adult↗