PubMed Health⌕ Search

Biomedical subjects

Andrew D Dick

Publications and source records attributed to Andrew D Dick.

At least 19 recordsLinked to original sources
PubMed2007

Recovery from macular phototoxicity after corneal triple procedure.

PURPOSE: Visual recovery from macular phototoxicity in 2 cases after prolonged exposure to operating microscope light from uncomplicated corneal triple-procedure surgery. Recovery is discussed in the context of repair and regeneration. METHODS: Retrospective case reports. RESULTS: Immediately postoperatively, both patients reported positive scotomata and were found to have macular retinal pigment epithelial depigmentation. In 1 case, the fovea was involved. By 6 to 12 months, the scotomata had disappeared despite large areas of retinal pigment epithelial hyperpigmentation remaining. CONCLUSION: Recovery from macular phototoxicity occurs, although the mechanism remains unclear. Positive scotomata in these cases resolved over several months. The time scale of recovery was consistent with the time required for cellular replacement and possible differentiation from neural progenitor cells.

Aged↗
PubMed2006

Ultrastructural evaluation of explanted opacified Hydroview (H60M) intraocular lenses.

AIM: To describe the ultrastructural appearance of explanted opacified Hydroview H60M intraocular lenses. METHODS: 14 explanted lenses were examined by scanning electron microscopy, and their appearance compared with a non-implanted H60M lens from the same time period. Wavelength-dispersive x ray spectroscopy (WDX) was performed on two opacified lenses. RESULTS: Subsurface deposits were seen in all explanted opacified lenses. These deposits broke only onto the surface of more densely opacified lenses. WDX confirmed that the deposits contained both calcium and phosphorous, consistent with their being calcium apatite. CONCLUSION: These findings challenge the widely accepted opinion that H60M intraocular lens opacification begins on the surface of the optic.

Calcium↗
PubMed2006

Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis.

AIM: To evaluate the responsiveness of the Vision core module 1 (VCM1) vision-related quality of life (VR-QOL) questionnaire to changes in visual acuity in patients with posterior and intermediate uveitis and to validate its use as a clinical end point in uveitis. METHODS: Logarithm of the minimum angle of resolution visual acuity and VR-QOL using the VCM1 questionnaire were prospectively recorded in 37 patients with active posterior segment intraocular inflammation before starting systemic immunosuppression with ciclosporin, tacrolimus or the anti-tumour necrosis factor (TNF) agent, p55TNFr-Ig, and again 3 months later. Spearman analysis was used to correlate improvements in visual acuity and VR-QOL between baseline and 3 months. RESULTS: The correlation between changes in visual acuity and VR-QOL was moderate to good for the worse eye (r = 0.47, p = 0.003), but poor for the better eye (r = -0.05, p = 0.91). The responsiveness indices effect size and standardised response mean were 0.57 and 0.59, respectively, showing that the VCM1 questionnaire is moderately responsive to immunsosuppressive therapy for active uveitis. CONCLUSION: Changes in VR-QOL measured with the VCM1 questionnaire correlated moderately well with changes in the worse eye visual acuity, suggesting that the VCM1 is a valid instrument for monitoring response to treatment in uveitis.

Adult↗
PubMed2006

Differences in leukocyte phenotype and interferon-gamma expression in stroma and endothelium during corneal graft rejection.

Critical to the success of human corneal transplants is prevention of corneal endothelial rejection, yet little is known about the endothelial infiltrate. To examine the endothelium, a method for removal and processing this layer as a flat sheet was used and the infiltrate was compared with stroma and epithelium. LEW or PVG strain rat corneas were transplanted to PVG strain recipients. Clinical changes after transplantation were monitored by slit lamp and animals sacrificed at a range of time points during rejection. Clinically defined rejection, accompanied by an epithelial rejection line and endothelial cell infiltration, occurred between days 10 and 15. There was some infiltration of leukocytes in the stroma of isografts at these time points, but significantly more in allografts (p<0.003 for all subsets). There was no infiltration of isograft endothelium at any time and no infiltration of allograft endothelium on day 10. On day 15, there were similar numbers of all major subsets except B cells in the stroma, while on the endothelium macrophages, MHC class II(+) cells and CD8(+) cells predominated (p<0.001 CD4(+) vs CD8(+) cells). T cells and NK cells predominated in the epithelial rejection line. While TNF-alpha and IFN-gamma-producing cells were numerous in stroma and epithelium, no IFN-gamma-producing cells were found on endothelium. Distinct differences in infiltrative profile within layers of the cornea suggest that the mechanisms of rejection may also differ. The restricted endothelial cell profile and lack of IFN-gamma suggests that the anti-endothelial response may be modulated by the anterior chamber environment.

Animals↗
PubMed2006

Mechanisms for inducing nasal mucosal tolerance in experimental autoimmune uveoretinitis.

Delivering soluble (auto) antigenic peptides via the naso-respiratory route induces tolerance to that peptide and suppression of experimental models of autoimmune disease. In the normal lung, respiratory tract dendritic cells (RTDCs) efficiently endocytose soluble antigens, migrate to regional lymph nodes and present peptide to T cells that subsequently become tolerant. This article describes protocols for inducing tolerance via the naso-respiratory tract in experimental autoimmune uveoretinitis (EAU); for the isolation of RTDCs to facilitate definition of, and conditions for, maturation and activation of cells; and to test RTDC ability to induce tolerance in murine EAU when adoptively transferred.

Adoptive Transfer↗
PubMed2006

Mapping immune responses to mRBP-3 1-16 peptide with altered peptide ligands.

PURPOSE: Experimental autoimmune uveoretinitis (EAU) can be induced in C57BL/6 mice (I-A(b)) using human retinoid-binding protein-3 (hRBP-3, previously IRBP) residues 1-20. This study of a truncated murine peptide (mRBP-3 1-16) was conducted to determine its pathogenic potential and to characterize partially its interaction with specific T cells. METHODS: After immunization with mRBP-3 1-16 or hRBP-3 1-20, EAU was assessed by immunohistochemistry. The immune response was assessed by tritiated thymidine incorporation and cytokine production analyzed by enzyme-linked immunosorbent assay (ELISA). T-cell receptor (TCR)- and major histocompatibility complex (MHC)-binding of mRBP-3 1-16 was studied by modeling and by using altered peptide ligands (APLs) and T-cell clones. RESULTS: mRBP-3 1-16 induced EAU in C57BL/6 mice, with severity and kinetics comparable to that after immunization with hRBP-3 1-20. T cells taken from mice immunized with mRBP-3 1-16 had a Th1 phenotype and proliferated in response to reactivation with mRBP-3 1-16, hRBP-3 1-20, or mRBP-3 1-16 APLs. mRBP-3 1-16 APLs elicited at least five distinct patterns of reactivity when tested with the mRBP-3 1-16-reactive T-cell clones. CONCLUSIONS: mRBP-3 1-16 immunizes and causes EAU in C57BL/6 mice. The studies using T-cell clones and APLs demonstrate that the immune response to mRBP-3 1-16 is drawn from a diverse population of antigen-specific T cells with a Th1 phenotype. Modeling and analysis of clones indicate that nonpathogenic T cells of an mRBP-3 1-16-reactive T-cell line recognize the peptide in a single register.

Animals↗
PubMed2005

A selective role for the TNF p55 receptor in autocrine signaling following IFN-gamma stimulation in experimental autoimmune uveoretinitis.

IFN-gamma stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN-gamma stimulation because of a requirement for autocrine TNF-alpha signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55-/- mice stimulated with IFN-gamma. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN-gamma activation are controlled by autocrine secretion of TNF-alpha, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors.

Animals↗
PubMed2005

Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis.

OBJECTIVES: To compare the efficacy and tolerability of tacrolimus and cyclosporine therapy for noninfectious posterior segment intraocular inflammation and to evaluate their effect on peripheral blood CD4(+) T-cell phenotype and activation status. METHODS: Thirty-seven patients who required second-line immunosuppression for posterior segment intraocular inflammation were enrolled in this prospective randomized trial of tacrolimus vs cyclosporine therapy. The main outcome measures were visual acuity, binocular indirect ophthalmoscopy score, adverse effects, and quality of life. In addition, peripheral blood CD4(+) T-cell phenotype and activation status were evaluated by flow cytometry before treatment and at 2, 4, and 12 weeks using CD69, chemokine receptor (CCR4, CCR5, and CXCR3), and intracellular cytokine (tumor necrosis factor alpha, interferon-gamma, and interleukin 10) expression. RESULTS: Thirteen patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to treatment. Cyclosporine therapy was associated with a higher incidence of reported adverse effects. Mean arterial pressure and serum cholesterol level were significantly higher at 3 months in the cyclosporine group than the tacrolimus group. No significant difference was detected with regard to effect on quality of life or CD4(+) T-cell phenotype. CONCLUSIONS: Tacrolimus and cyclosporine were similar with regard to efficacy for posterior segment intraocular inflammation, but the results suggested a more favorable safety profile for tacrolimus therapy.

Adult↗
PubMed2005

Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis.

Autoimmune posterior uveitis is a chronic, potentially blinding inflammatory disease of the eye. It is commonly treated with immunosuppressive drugs that have adverse long-term effects. Advances in gene transfer techniques have enabled long-term, stable transduction of retinal cells following subretinal injection with adeno-associated viral (AAV) vectors. Here we report for the first time that subretinal injection of rAAV-2 encoding murine IL-10 into the retina of C57BL/6 mice significantly decreases the median experimental autoimmune uveitis (EAU) disease severity. This protection is shown to be due to a decrease in the number and activation status of infiltrating monocytes during EAU, as determined by costimulatory molecule expression and nitrotyrosine detection. No differences within splenocyte proliferative responses or serum antibody levels were detected, emphasizing the potential of gene therapy strategies in ameliorating autoimmune responses in local microenvironments without unwanted systemic effects.

Animals↗
PubMed2005

Cytokine gene polymorphism in sympathetic ophthalmia.

PURPOSE: Sympathetic ophthalmia (SO) is a prototypical autoimmune disease in which injury to one eye causes sight-threatening inflammation in the otherwise normal contralateral eye. Previous work found that human leukocyte antigen alleles HLA-DRB1*04 and DQA1*03 are markers of increased susceptibility and severity in British and Irish patients. Evidence is accumulating that single nucleotide polymorphisms (SNPs) in cytokine genes can also influence the development of autoimmune disease through their effect on levels of cytokine production. The purpose of this study was to determine whether polymorphisms in the cytokine genes are important markers for disease severity and outcome in patients with SO. METHODS: Twenty-six British and Irish patients meeting well-defined criteria for the diagnosis of SO were compared with 48 matched controls. Genotyping of SNPs in the TNFalpha, TNFbeta, and IL-10 genes was performed using the polymerase chain reaction and sequence-specific primers (SSP-PCRs) and of the CTLA-4 and TNF receptor 2 genes using restriction length polymorphism-PCR (RFLP-PCR). RESULTS: Significant associations were found between the IL-10 -1082 SNP and disease recurrence from previously stable disease and the level of steroids required for maintenance therapy. In addition, the GCC IL-10 promoter haplotype (IL-10 -1082G, -819C, -592C) was found to be protective against disease recurrence. CONCLUSIONS: These results show that cytokine gene polymorphisms are markers for the severity of disease in SO. They were found to be associated with recurrence of previously stable disease and with the level of maintenance steroid treatment required to control inflammatory activity.

Antigens, CD↗
PubMed2004

Factors affecting rejection of second corneal transplants in rats.

BACKGROUND: Second and subsequent corneal transplants in the same eye are more prone to rejection reactions and failure than first grafts. This may be a result of local changes or systemic sensitization to antigen shared by the first and second donors. Because HLA typing is not routine in corneal transplantation, a clear correlation between accelerated rejection and specific sensitization has not been established. METHODS: PVG (RT1), Lewis (LEW; RT1), or AO (RT1) strain corneas were transplanted to PVG strain rats, followed by a LEW strain cornea in the ipsilateral or contralateral eye 6 weeks later. Graft survival was evaluated by slit lamp biomicroscopy. Proliferation of recipient lymph node cells was tested against allogeneic, syngeneic and third-party stimulator cells after the second transplantation. RESULTS: A second allograft in the ipsilateral or contralateral eye was rejected in an accelerated fashion that was not donor MHC specific. Rejection was not significantly accelerated in the ipsilateral eye compared with the contralateral eye. There was a secondary lymphocyte proliferation response to third party (AO strain) in animals previously exposed only to the LEW strain. CONCLUSIONS: Systemic sensitization to donor antigens, rather than local changes induced by first transplantation, contributed to accelerated rejection of a second graft. Accelerated rejection is not dependent on MHC compatibility between the grafts. It could be caused by shared "public" MHC determinants, by minor antigens shared by the first and second donors, or by cross-reactivity of T cells to epitopes on AO and LEW grafts. HLA mismatching of first and second donors may not prolong second graft survival.

Animals↗
PubMed2004

Neutralizing tumor necrosis factor activity leads to remission in patients with refractory noninfectious posterior uveitis.

OBJECTIVE: To evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibition with the p55 TNF receptor fusion protein (TNFr-Ig) for severe sight-threatening noninfectious posterior segment intraocular inflammation. METHODS: Seventeen patients with refractory noninfectious posterior segment intraocular inflammation received TNFr-Ig by intravenous infusion in this nonrandomized, open-label, pilot study. The primary outcome measure was logMAR visual acuity. Secondary outcome measures were binocular indirect ophthalmoscopy score, cystoid macular edema, adverse effects, and vision-related (visual core module 1) and health-related (36-Item Short-Form Health Survey) quality of life. RESULTS: Within 1 month of TNFr-Ig therapy, 9 patients (53%) achieved at least a 2-line improvement in visual acuity, 8 (57%) of 14 patients with vitreous haze before treatment achieved an improvement in binocular indirect ophthalmoscopy score to 0, and macular edema resolved in 5 (56%) of 9 affected patients. Twelve (71%) of the patients achieved complete cessation of intraocular inflammation following TNFr-Ig therapy. A reduction in concomitant immunosuppression was possible for 11 patients (65%) following TNFr-Ig therapy. However, all but 1 patient required continuing adjuvant therapy during the response to TNFr-Ig, which had a median duration of 3 months. Adverse effects included mild infusion reactions in 3 patients and transient lymphocytopenia in 2 patients. CONCLUSION: Therapy with TNFr-Ig was safe and effective for treating patients with sight-threatening noninfectious posterior segment intraocular inflammation resistant to conventional immunotherapy, but adjuvant immunosuppression and repeat infusions would be required to maintain long-term remission.

Adult↗
PubMed2004

Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism.

PURPOSE: Minocycline, a semi-synthetic tetracycline antibiotic is reported to be neuroprotective in degenerative and ischaemic models of central nervous system disease, via mechanisms involving suppression of both cytotoxic microglial activity and caspase-dependent apoptosis. We have investigated the effect of minocycline treatment on a mouse model of retinitis pigmentosa, an inherited photoreceptor neurodegenerative disorder, and contrasted this with the effect of depleting retinal microglia using liposomal clodronate. METHODS: rds mice were treated intraperitoneally from the second postnatal day (P2) with either daily minocycline until P16, P18, P21, P24 and P27 or alternative day clodronate liposomes until P16. Immunohistochemical and immunofluorescent methods were applied for the detection of microglia (F4/80) and apoptosis (TUNEL and caspase 3 activation). RESULTS: Photoreceptor apoptosis was delayed by minocycline treatment but not, ultimately, prevented. Markedly reduced expression of activated caspase 3 was observed in photoreceptors at the early time point, corresponding with the reduced level of apoptosis. Delayed photoreceptor apoptosis due to minocycline treatment was associated with a 50% reduction in the numbers of microglia at early timepoints. Liposomal clodronate treatment also resulted in a marked reduction in the number of microglia (63% reduction in microglia), but in contrast to minocycline treatment, this had no effect on photoreceptor apoptosis. CONCLUSIONS: Minocycline appears to delay photoreceptor apoptosis through a microglia-independent action. Although microglial cytotoxicity has been implicated during other models of neurodegeneration, microglia are unlikely to play such a role in this model of photoreceptor dystrophy.

Animals↗
PubMed2004

Murine respiratory tract dendritic cells: isolation, phenotyping and functional studies.

Respiratory tract dendritic cells (RTDC) form a contiguous subepithelial network within the nasorespiratory tract bridging innate and acquired immunity and have been implicated in nasal mucosal tolerance induction. Discrepancies exist between isolation techniques with respect to phenotype and function of RTDC. Therefore, the aim of this study was to modify previous methods to provide a consistent isolation method whilst maintaining good cell viability and enriched cell numbers so as to facilitate further phenotype and functional studies of murine RTDC. RTDCs isolated by enzyme digestion, Percoll density gradient centrifugation and overnight GM-CSF culture followed by MACS separation retain an archetypical immature dendritic cell phenotype, characterised by MHCII(low) CD40(neg) CD86(neg) CD80(neg) CD11c(low) cell surface expression. Splenic-derived DC (SDC) isolated conformed to a day 1 in vitro phenotype; MHCII(low) CD40(neg) CD86(low) CD80(neg) CD11c(low) but can further mature phenotypically in vitro. Both RTDC and SDC processed and presented antigen efficiently to T cells in vitro. Using such modified isolation procedures for RTDCs, we have developed a consistent method of RTDC enrichment, which maintains the immature phenotype and functional antigen presenting capability.

Animals↗
PubMed2004

The role of tumour necrosis factor (TNF-alpha) in experimental autoimmune uveoretinitis (EAU).

The pleiotropic cytokine tumour necrosis factor-alpha (TNF-alpha) is released from cells that include macrophages and T-cells during inflammatory responses, orchestrating the initiation of further leucocytic infiltration via adhesion molecule upregulation, dendritic cell maturation and survival, macrophage activation and driving Th1 T-cells responses within tissues. Exposure to TNF also plays a role in maintaining tissue homeostasis, particularly relating to resident cell responses of both microglia and retinal pigment epithelium. Depending on the balance between duration and dose of TNF exposure, an environment where full expression of inflammatory and autoimmune responses within tissues may occur. In experimental autoimmune uveoretinitis (EAU), increased tissue concentrations of TNF facilitate the on-going T-cell effector responses and macrophage activation. These are responsible for targeted and bystander tissue damage and can be suppressed by anti-TNF therapies, in particular, those directed at the p55 TNF receptor. The ability to suppress disease experimentally has led to the successful translation of anti-TNF therapy for treatment of uveitis in cohort studies and phase I/II trials where, additionally, altered peripheral blood CD4(+) T-cell profiles can be demonstrated following each treatment.

Animals↗