Publications by authors named "Alastair K O Denniston"

9 Publications

  • Page 1 of 1

Conjunctival Neutrophils Predict Progressive Scarring in Ocular Mucous Membrane Pemphigoid.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5457-5469

Academic Unit of Ophthalmology, Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom 2Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom.

Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a rare autoimmune disorder resulting in progressive conjunctival fibrosis and ocular surface failure leading to sight loss in up to 50%. This study was designed to optimize an ocular surface sampling technique for identification of novel biomarkers associated with disease activity and/or progressive fibrosis.

Methods: Fifty-seven patients with OcMMP underwent detailed examination of conjunctival inflammation and fibrosis using fornix depth measurement. Ocular surface impression cytology (OSIC) to sample superior bulbar conjunctiva combined with flow cytometry (OSIC-flow) profiled infiltrating leukocytes. Profiles were compared with healthy controls (HC) and disease controls (primary Sjögren's syndrome, pSS). Thirty-five OcMMP patients were followed every 3 months for 12 months.

Results: Overall neutrophils were elevated in OcMMP eyes when compared to pSS or HC (109 [18%] neutrophils/impression [NPI]; 2 [0.2%]; 6 [0.8%], respectively [P < 0.0001]) and in OcMMP patients with no visible inflammation when compared with HC (44.3 [7.9%]; 5.8 [0.8%]; P < 0.05). At 12 months follow-up, 53% of OcMMP eyes progressed, and this was associated with baseline conjunctival neutrophilia (P = 0.004). As a potential biomarker, a value of 44 NPI had sensitivity, specificity, and positive predictive values of 75%, 70%, and 73%, respectively. Notably, eyes with no visible inflammation and raised conjunctival neutrophils were more likely to progress and have a greater degree of conjunctival shrinkage compared to those without raised neutrophils.

Conclusions: These data suggest that OSIC-flow cytometric analyses may facilitate repeated patient sampling. Neutrophils may act as a biomarker for monitoring disease activity, progressive fibrosis, and response to therapy in OcMMP even when the eye appears clinically uninflamed.
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October 2016

Safety profile of anterior chamber paracentesis performed at the slit lamp.

Clin Exp Ophthalmol 2011 Nov 27;39(8):725-8. Epub 2011 Apr 27.

Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: Anterior chamber paracentesis is a valuable diagnostic tool in the management of uveitis, but may be underutilized because of concerns over its safety. We evaluated the safety profile of anterior chamber paracentesis performed at the slit lamp as an outpatient procedure.

Design: Retrospective, observational case series in a single tertiary centre.

Participants: Five hundred and sixty patients with uveitis undergoing anterior chamber paracentesis.

Methods: All anterior chamber paracenteses performed at the slit lamp for diagnostic or research purposes between January 1997 and June 2009 were analysed with regard to adverse events and pipet/syringe used. Procedures were included whether carried out on undilated or dilated pupils.

Main Outcome Measures: Adverse events and serious adverse events.

Results: Out of 560 paracenteses, 510 were performed with a 27-gauge fixed-needle tuberculin syringe, and 50 using an O'Rourke aqueous pipet. All patients were prescribed a short course of topical antibiotic and examined post-procedure and 1-2 weeks later. Out of 560 procedures there were four complications (0.7%). Two patients had inadvertent injection of sterile air into the anterior chamber but with spontaneous resolution and no adverse outcome (O'Rourke pipet for both). One patient had anterior lens capsule touch that was self-sealing and left a tiny localized opacity (tuberculin syringe). One patient had an allergic reaction to povidone iodine. No patients reported pain, and there were no cases of iris trauma, entry site leak, hypotony, hyphaema or endophthalmitis.

Conclusion: Anterior chamber paracentesis can be performed safely as an outpatient procedure at the slit lamp following adequate aseptic precaution, and appropriate counselling.
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November 2011

The dominant human conjunctival epithelial CD8αβ+ T cell population is maintained with age but the number of CD4+ T cells increases.

Age (Dordr) 2012 Dec 27;34(6):1517-28. Epub 2011 Sep 27.

Academic Unit of Ophthalmology, College of Medical and Dental Sciences, University of Birmingham, UK.

The conjunctiva is a highly specialized ocular mucosal surface that, like other mucosa, houses a number of leukocyte populations. These leukocytes have been implicated in age-related inflammatory diseases such as dry-eye, but their phenotypic characteristics remain largely undetermined. Existing literature provides rudimentary data from predominantly immunohistochemical analyses of tissue sections, prohibiting detailed and longitudinal examination of these cells in health and disease. Using recovered cells from ocular surface impression cytology and flow cytometry, we examined the frequency of leukocyte subsets in human conjunctival epithelium and how this alters with age. Of the total CD45+ leukocyte population within the conjunctival epithelium, 87% [32-99] (median) [range] comprised lymphocytes, with 69% [47-90] identified as CD3 + CD56- T cells. In contrast to peripheral blood, the dominant conjunctival epithelial population was TCRαβ + CD8αβ + (80% [37-100]) with only 10% [0-56%] CD4+ cells. Whilst a significant increase in the CD4+ population was seen with age (r = 0.5; p < 0.01) the CD8+ population remained unchanged, resulting in an increase in the CD4:CD8 ratio (r = 0.5;p < 0.01). IFNγ expression was detectable in 18% [14-48] of conjunctival CD4+ T cells and this was significantly higher among older individuals (<35 years, 7[4-39] vs. >65 years, 43[20-145]; p < 0.05). The elevation of CD4+ cells highlights a potentially important age-related alteration in the conjunctival intra-epithelial leukocyte population, which may account for the vulnerability of the aging ocular surface to disease.
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December 2012

Survey of expert practice and perceptions of the supporting clinical evidence for the management of uveitis-related cataract and cystoid macular oedema.

Ocul Immunol Inflamm 2011 Oct 8;19(5):353-7. Epub 2011 Aug 8.

Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Purpose: To survey the practice of uveitis experts in the management of uveitic cataract and cystoid macular oedema (CMO).

Methods: A structured questionnaire containing two clinical scenarios was sent to members of the International Uveitis Study Group (IUSG). The questionnaire surveyed both respondents' current practice and their perception of the supporting clinical evidence.

Results: For uveitic cataract, 70% required a 3-month inflammation-free period before surgery, and 76% gave a prophylactic preoperative systemic corticosteroid. For uveitic CMO, 87% gave corticosteroids, usually orally. Preferred second-line agents were methotrexate (39%), cyclosporin (24%), azathioprine (17%), and mycophenolate (7%). Respondents suggested the evidence underlying their decisions was either absent or relatively weak (levels III or IV), and in most cases personal experience was a factor.

Conclusions: This survey highlights areas of consensus and variation among uveitis experts in managing uveitic cataract and CMO, and emphasizes the need for further clinical trials to establish the best practice.
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October 2011

Distinct types of fibrocyte can differentiate from mononuclear cells in the presence and absence of serum.

PLoS One 2010 Mar 18;5(3):e9730. Epub 2010 Mar 18.

Institute of Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Background: Fibrocytes are bone-marrow derived cells, expressing both haematopoietic and stromal cell markers, which contribute to tissue repair as well as pathological fibrosis. The differentiation of fibrocytes remains poorly characterised and this has limited understanding of their biology and function. In particular two methods are used to generate fibrocytes in vitro that differ fundamentally by the presence or absence of serum.

Methodology/principal Findings: We show here that fibrocytes grown in the absence of serum (SF) differentiate more efficiently from peripheral blood mononuclear cells than CD14(+) monocytes, and respond to serum by losing their spindle-shaped fibrocyte morphology. Although fibrocytes generated in the presence of serum (SC) express the same range of markers, they differentiate more efficiently from CD14(+) monocytes and do not change their morphology in response to serum. Transcriptional analysis revealed that both types of fibrocyte are distinct from each other, fibroblasts and additional monocyte-derived progeny. The gene pathways that differ significantly between SF and SC fibrocytes include those involved in cell migration, immune responses and response to wounding.

Conclusions/significance: These data show that SF and SC fibrocytes are distinct but related cell types, and suggest that they will play different roles during tissue repair and fibrosis where changes in serum proteins may occur.
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March 2010

Is ethnicity a risk factor for severe retinopathy of prematurity?

Arch Dis Child Fetal Neonatal Ed 2010 May 29;95(3):F174-6. Epub 2009 Nov 29.

Birmingham and Midland Eye Centre, City Hospital, Dudley Road, Birmingham, West Midlands, UK.

Objective: To assess the risk of severe retinopathy of prematurity (ROP) requiring treatment in different ethnic groups.

Design: Retrospective observational study on ROP screening and treatment. It involved a cross-sectional review of all eligible infants over a seven-year period. Statistical tests used were the Kruskal-Wallis test and Mann-Whitney U test. Logistic regression was used to control for any differences in birth weight and gestational age.

Setting: City Hospital and Birmingham Women's Hospital, Birmingham, UK.

Results: 1690 preterm infants underwent ROP screening. Birth weight was lower in black (1142.5 g) and Asian infants (1180 g) when compared to white infants (1196.5 g). Gestational age was lower in black infants (28.5 weeks) compared to Asian and white infants (both 29 weeks). Compared to white infants, the odds of severe ROP requiring treatment was higher in Asian infants (odds ratio (OR): 2.52; 95% CI 1.41 to 4.50) and black infants (OR: 2.51; 95% CI 1.30 to 4.86). The additional risk from ethnicity was present even after adjusting for birth weight and gestational age (adjusted OR for Asian vs white infants: 2.45; 95% CI 1.334 to 4.497); (adjusted OR for black vs white infants: 2.0; 95% CI 1.004 to 4.014).

Conclusions: Ethnicity is a risk factor for severe ROP. Asian and black infants have a higher risk of developing threshold ROP compared to white infants.
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May 2010

Soluble gp130, an antagonist of IL-6 transsignaling, is elevated in uveitis aqueous humor.

Invest Ophthalmol Vis Sci 2008 Sep 9;49(9):3988-91. Epub 2008 May 9.

Institute of Biomedical Research, MRC Centre for Immune Regulation, Division of Immunity and Infection, Medical School, The University of Birmingham, Birmingham, United Kingdom.

Purpose: To determine the concentrations of soluble gp130, a natural antagonist of IL-6 transsignaling, in the serum and aqueous humor (AqH) of patients with uveitis.

Methods: Serum was obtained from the peripheral blood of patients with active uveitis and healthy control subjects. AqH samples were collected from patients with active uveitis and those without uveitis who were undergoing routine cataract surgery. Samples were centrifuged and the cell-free supernatant frozen at -80 degrees C. Concentrations of sgp130, sIL-6R, and IL-6 were determined by a sandwich ELISA or multiplex bead immunoassay, using standard curves of known concentrations of recombinant cytokines.

Results: Serum concentrations of sgp130 were not significantly different between control individuals and patients with active anterior uveitis, regardless of the degree of intraocular inflammation cells. By contrast, the concentration of sgp130 in AqH was very low in patients with no or little inflammation, but increased significantly with disease severity. The greatest elevations of AqH sgp130 were found in patients with the highest cellular activity. Simultaneous measurement of IL-6, sIL-6R, and sgp130 revealed a high degree of correlation between the levels of these molecules, especially for sIL-6R and sgp130.

Conclusions: Soluble gp130 is increased in the AqH of patients with active uveitis. It is likely that sgp130 partially inhibits the process of IL-6 transsignaling during inflammation. However, the concentration found is still far below that in serum, suggesting that increasing the level of sgp130 further may assist in reducing the inflammatory changes induced by IL-6 transsignaling.
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September 2008

More on porphyrias.

Lancet 2005 Mar 12-18;365(9463):937

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April 2005

The use of oxygen in acute exacerbations of chronic obstructive pulmonary disease: a prospective audit of pre-hospital and hospital emergency management.

Clin Med (Lond) 2002 Sep-Oct;2(5):449-51

Department of Respiratory Medicine, Birmingham Heartlands Hospital.

Treatment with high-flow oxygen in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) can cause or aggravate acute hypercapnic respiratory failure and adversely affect prognosis. National guidelines for the management of COPD recommend an initial fractional inspired oxygen concentration (FiO2) of no more than 0.28. However, a prospective audit of 101 consecutive episodes of AECOPD demonstrated that oxygen therapy with an FiO2 in excess of 0.28 is common, potentially deleterious and predominantly initiated in the ambulance. Patient awareness, aids to disease identification and ambulance protocols are likely to hold the key to improvement in the acute care of these patients.
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March 2003