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Background/aims: To compare the efficacy of adalimumab in eyes with active and inactive non-infectious uveitis in the real-world setting., Methods: Multicentre, retrospective, chart review of patients with refractory non-infectious uveitis treated with adalimumab. Main outcome measures included reduction of prednisolone dose, ability to taper immunosuppressives and a composite endpoint of treatment failure encompassing active inflammatory chorioretinal or retinal vascular lesions, intraocular inflammation grade and visual acuity., Results: Thirty-seven eyes of 22 patients were studied. Mean follow-up was 20.1 months (median: 13). Most had either posterior or panuveitis (n=12, 55%). Mean duration of uveitis at baseline was 83.2 months (median: 61), where the majority (n=15, 68%) had already been treated with two or more conventional immunosuppressive agents in addition to prednisolone. Oral prednisolone was reduced to ≤10 mg/day in 9 of 12 patients (75%) by 6 weeks. At 6 months of therapy, nine (90%) of the active eyes achieved a 2-step improvement in anterior chamber inflammation, with six (60%) demonstrating a similar improvement in vitreous haze grade. Almost all (n=17, 94%) of the initially inactive eyes maintained clinical quiescence at this time point. The incidence rate of treatment failure during follow-up was 88 per 100 eye-years for the active eyes and 24 per 100 eye-years for the initially inactive eyes. There were no serious adverse effects., Conclusion: Adalimumab appears to reduce the corticosteroid burden in active and inactive non-infectious uveitis in the real-world setting. Inflammatory activity at the time of adalimumab commencement may determine long-term treatment success., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We report the case of an 83-year-old man who presented with a history of fluctuating delirium of insidious onset, secondary to an amoebic liver abscess more than 30 years after acute exposure. We describe a 2-year clinical journey that started with a fall and was additionally complicated by severe weight loss and acute kidney injury (AKI). The likely prognosis for such a combination of comorbidities in an older person is for lasting morbidity, institutionalisation and significant mortality. However, the case demonstrates that with timely assessment and care complete recovery is possible though it may take many months. It reminds us of the catalytic implications of falls for older persons and to maintain a differential diagnostic approach to delirium of insidious onset avoiding misdiagnosis as dementia with which it may be associated. Our case report includes extracts from the patient's own account providing added insight into such experiences.

Aims: To investigate the effects of conditioned media from mesenchymal stem cells (MSC) on the wound healing activities of corneal stromal fibroblasts., Methods: Cell cycle analysis and early stage activation of apoptosis, chemotactic chambers and fibroblast-populated type I collagen gels were used to assess corneal stromal fibroblast proliferation, migration and contraction, respectively. Fibroblasts were obtained from human donor corneas and MSC from fresh rat bone marrow. MSC conditioned media and fibroblast culture medium (FCM), with and without calf serum supplementation, were compared., Results: MSC conditioned media and serum-free FCM had an inhibitory effect on the progression of corneal fibroblasts through the cell cycle. There was a significant increase in the number of cells in the G0-G1 phase for MSC conditioned media and serum-free FCM (p=0.001, p=0.97 respectively). Fibroblast migration and relaxed and stressed gel contraction were significantly inhibited by MSC conditioned media and serum-free FCM compared with FCM with serum (all p=0.001). Glucose and lactate analysis confirmed that these factors were not contributing to this effect., Conclusion: MSC conditioned media was found to inhibit the wound healing activities of corneal stromal fibroblasts in vitro. Putative factors secreted by MSC could be developed for therapeutic use in corneal repair.

The pathogenesis of acute and recurrent anterior uveitis is poorly understood. Here, recent evidence is presented for the hypothesis that this disease may be associated with activation of receptors of the innate immune system, such as Toll-like receptors, by pathogen associated molecule patterns, such as lipopolysaccharide, derived from triggering gram negative bacteria. Acute anterior uveitis results in ocular tissue damage and the release of endogenous molecules (damage associated molecular patterns), such as heat shock proteins and S100 proteins that can also activate Toll-like receptors and thus perpetuate or reactivate intraocular inflammation.

Background: The use of verbal orders has been identified as a potential contributor to poor quality and less safe care. As a result, many organisations have encouraged changing the verbal orders process and/or reducing/eliminating verbal orders altogether (Joint Commission (2005), Institute of Medicine (2001), Leapfrog organisation, Institute of Safe Medication Practices). Ironically there is a paucity of research evidence to support the widespread concern over verbal order., Aims: This paper describes the very limited existing research on verbal orders, presents a model of verbal order use identifying potential error trigger points and suggests a verbal order research agenda in order to better understand the nature and extent of the potential patient care safety threat posed by verbal orders.

Background: The use of verbal orders, while essential in some healthcare settings, has been identified as a potential contributor to poor quality and less safe care. Despite the widespread use of verbal orders, little research attention has been paid to understanding and measuring the content of verbal orders or variables related to the context in which verbal orders are made., Aim: This paper first identifies variables related to verbal order content and context, and then provides detailed analyses from two exploratory studies conducted in one community hospital., Methods: The data presented were collected using both a paper-based manual audit, and an analysis of data generated from a computerised order entry system., Discussion: Selected analyses focus of variations in types and timing of verbal orders hospital-wide as well as for specific inpatient units, changes in verbal order utilisation following implementation of a computerised provider order entry system, and an analysis of the presence of sound-alike and high-alert medications in verbal orders.

Aim: To characterise the clinical and pathological features of 24 patients with biopsy proven Idiopathic Orbital Inflammatory Syndrome (IOIS)., Methods: Retrospective case series., Results: The study included 14 men and 10 female patients, ranging in age from 14 to 75 years. The presenting symptoms and signs included pain (14/24), swelling/mass (19/24), diplopia (9/24), proptosis (15/24), extraocular muscle restriction (13/24), decreased vision (5/24) and ptosis (4/24). Histopathology was varied and included classical orbital pseudotumour (9/24), sclerosing orbital pseudotumour (13/24), vasculitic orbital pseudotumour (1/24) and granulomatous orbital pseudotumour (1/24). Treatments included oral steroids (19/24), intravenous steroids (1/24), methotrexate, azathioprine, mycophenalate and ciclosporin. Forty-two per cent of the patients had recurring episodes during the follow-up period, with 29% of patients requiring two or more treatment regimens to maintain remission. Two-thirds of patients (16/24) had complete resolution of their symptoms and signs. There was no correlation between the histopathological subtype, relapse rate or symptoms and resolution of signs., Conclusion: Idiopathic Orbital Inflammatory Syndrome has variable clinical and pathological features. Although, in some patients, symptoms and signs resolve spontaneously, most require treatment with oral steroids and additional immunosuppressant drugs or radiotherapy. The clinical and pathological features do not correlate with treatment outcomes.

Background: This study was initiated after observation of some intriguing epithelial growth properties of contact lenses used as a bandage for patients after pterygium surgery., Aim: To determine the efficacy of culturing human ocular surface epithelial cells on therapeutic contact lenses in autologous serum with a view of using this system to transfer epithelial cells to patients with persistent corneal or limbal defects., Methods: Excess graft tissue resected from patients undergoing pterygium surgery (n = 3) consisting of limbal epithelium was placed on siloxane-hydrogel contact lenses (lotrafilcon A and balafilcon A). Limbal explants were cultured in media with 10% autologous serum. Morphology, proliferative capacity and cytokeratin profile were determined by phase contrast, light and electron microscopy, and immunohistochemical analysis., Results: Lotrafilcon A contact lenses sustained proliferation and migration from limbal tissue. Cells became confluent after 10-14 days and consisted of 2-3 layers with a corneal phenotype (CK3(+)/CK12(+)/CK19(-)) and a propensity to proliferate (p63(+)). Electron microscopy showed microvilli on the apical surface with adhesive projections, indicating that these cells were stable and likely to survive for a long term. Growth was not observed from limbal explants cultured on balafilcon A contact lenses., Conclusion: A method for culturing human ocular surface epithelium on contact lenses that may facilitate expansion and transfer of autologous limbal epithelial cells while avoiding the risks associated with transplanting allogeneic tissue has been developed. This technique may be potentially useful for the treatment of patients with limbal stem cell deficiency.

Microbial agents have an important role in the pathogenesis of various inflammatory eye diseases, such as uveitis and keratitis. Microbial infections of the eye such as microbial keratitis, ocular onchocerciasis, bacterial endophthalmitis, viral retinitis, and other infectious uveitis are unfortunately common. In addition, microbial agents have been implicated in the pathogenesis of "non-infectious" immune mediated diseases such as HLA-B27 associated acute anterior uveitis. Toll-like receptors (TLR) are a family of pattern recognition receptors that initiates rapid host innate immune response to microbial components known as pathogen associated molecular patterns, which are unique to a given class of microbes, such as lipopolysaccharide of Gram negative bacteria. Recent in vitro and in vivo studies have demonstrated the expression and function of TLRs in the eye, with significant implications for better understanding of ocular immunity and the pathogenesis of inflammatory eye diseases affecting the cornea, uvea, and retina.

Aim: To determine the expression and distribution of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the normal human iris and ciliary body., Methods: Seven postmortem human eyes were fixed with formalin. The iris and ciliary body were dissected out and embedded in paraffin. The expression of MMPs -1, 2, 3, and 9, and TIMPs 1-4 in the iris and ciliary body was determined by a novel immunofluorescence technique and the results graded by masked observers., Results: Positive staining for MMPs and TIMPs was observed in all regions of the anterior uvea, and was more intense in the ciliary body than in the iris. Most MMPs and TIMPs showed similar patterns in their distribution. In the ciliary body, staining was strongest in the epithelium, and was localised to the epithelial cell cytoplasm, except for TIMP-3 which was strongly expressed in the basement membranes. In the iris, staining was most noticeable in the anterior border and anterior epithelial layer. Blood vessels in the stroma of the iris and ciliary body also stained moderately for MMPs and TIMPs., Conclusion: Both MMPs and TIMPs are widely expressed in the anterior uvea, with a positive correlation between their expressions. Their differential localisation in the ciliary body suggests they may have a role in maintaining homeostasis in the uveal tract.

Background/aim: Anterior uveitis is a common inflammatory ocular disease characterised by protein accumulation and leucocyte infiltration in the anterior chamber. The aim of this study was to determine the expression of gelatinases in the aqueous humour (AH) and uvea in an animal model of endotoxin induced uveitis (EIU)., Methods: EIU was established in Lewis rats following an intraperitoneal injection of lipopolysaccharide (LPS). AH and ocular tissue were obtained from control animals and those with EIU over a 1 week time course and the samples analysed immunohistochemically and by gelatin zymography., Results: Matrix metalloproteinase (MMP) 2 and 9 levels were elevated in rat AH over a 1 week time course. MMP-2 and MMP-9 levels peaked at the time of maximum uveal inflammation, before returning to baseline levels as the inflammation subsided. MMP-9 was detected in the latent and functionally active form. Total protein extracted from inflamed rat uveal tissue displayed no significant gelatinolytic modulation throughout the time course of EIU. Anterior chamber neutrophils and ciliary body epithelial cells were the most abundant source of the gelatinases., Conclusion: This study has revealed a correlation between infiltrating neutrophils and the presence of elevated gelatinases in EIU. The results suggest that these proteolytically active enzymes may be important mediators of the inflammatory response and contribute to matrix remodelling observed in uveitis. Furthermore, the excess production of MMPs may be a mechanism by which leucocytes, such as neutrophils, gain access to uveal tissue and AH. Therapeutic strategies aimed at reducing MMP activity may be of some benefit in the treatment of uveitis.

Background/aims: Pterygia are a common disorder of the ocular surface. The disease represents a chronic fibrovascular and degenerative process thought to originate at the conjunctival-corneal junction, where altered limbal stem cells are proposed to be the cell of origin. Extensive epidemiological evidence exists to implicate ultraviolet B irradiation in the pathogenesis of pterygia. To date no animal or in vitro culture model has been developed to test such an hypothesis. The aim of this study was to establish and characterise a pure population of epithelial cells derived from pterygium tissue., Methods: Tissue specimens were obtained from patients undergoing pterygium excision. Explants were cultured in either serum free or serum supplemented medium. Primary and passaged cells were processed for light microscopy, analysed by flow cytometry, and characterised immunohistochemically using specific antibodies., Results: In serum free culture, cuboidal cells with typical morphology of epithelial cells migrated from the pterygium explants from 3 days onwards and eventually formed a cohesive monolayer. Passaged cells consisted of 98.4% cytokeratin positive cells and demonstrated immunoreactivity for multiple cytokeratins, including AE1, AE3, AE5, but were negative for AE8. These cells also expressed an epithelial specific antigen, together with vimentin and mucin, as did epithelial cells in sections of pterygia., Conclusions: A relatively simple method of isolating pterygium epithelial cells has been established. Cultured pterygium epithelial cells are phenotypically and functionally similar to their in vivo counterparts with respect to keratin, vimentin, and mucin expression. In vitro assays using these cells may aid in elucidating the pathogenesis of pterygia.

Mooren's ulcer is a rare disease of presumed autoimmune aetiology. Some cases run a chronic severe course and fail to respond to local and systemic therapy. We report here such a case with bilateral Mooren's ulcer that failed to respond to local therapy with topical corticosteroids, silver nitrate, and conjunctival resection, as well as systemic immunosuppression with corticosteroids, cyclophosphamide, and azathioprine. Systemic cyclosporin (10 mg/kg/day) resulted in resolution of the corneal ulceration within two weeks of beginning treatment, and the patient has remained in remission after 15 months of therapy. Cyclosporin side effects included hirsutism, hypertension, increased blood levels of urea and creatinine, and abnormalities in liver function tests. All these resolved on reducing the dosage of cyclosporin. The results in this case suggest that cyclosporin is an effective agent in patients with severe sight threatening Mooren's ulcer.

To ascertain the efficacy of systemic cyclosporin therapy in the management of scleritis we performed an open, uncontrolled study of the use of this drug in severe refractory disease. Five of seven patients whose disease had previously been poorly controlled with a combination of corticosteroids and immunosuppressive drugs responded to cyclosporin therapy (10 mg/kg/day). Systemic side effects occurred in all but one patient, with tremor, hirsutism, hypertension, and raised serum creatinine being common. Recurrence of disease activity on decreasing the dosage of cyclosporin was frequent. The results indicate that cyclosporin is a useful additional drug in the treatment of severe scleritis.

Peripheral blood immunological features were assessed in 21 patients with clinical and angiographic evidence of retinal vasculitis (RV). Abnormalities of humoral and cellular immunity were frequent in this group of patients. Lymphopenia was the most common immunological abnormality, being present in 76% of patients at presentation (p less than 0.05). Peripheral blood T and B cells were decreased with a normal helper (OKT4) to suppressor (OKT8) T cell ratio in 11 patients tested (five with Behçet's syndrome and six with idiopathic RV). Significantly increased concentrations of serum immune complexes were present in 55% of patients (p less than 0.05). Results of the present study indicate the frequent association of peripheral blood immunological abnormalities in patients with active RV and indicate the possible role of immunological mechanisms in its pathogenesis.

alpha 1 antitrypsin is an important immunoregulatory protein, the serum level of which is genetically determined. Deficient phenotypes of this ubiquitous protease inhibitor are associated with a variety of inflammatory diseases including anterior uveitis. In order to investigate the role of this protease inhibitor in the pathogenesis of retinal vasculitis (RV) 25 patients were investigated. Diseases associated with RV included Behcet's syndrome (8), SLE (2), and sarcoidosis (1). Deficient phenotypes of alpha 1 antitrypsin were not associated with RV. However, the serum alpha 1 antitrypsin level was significantly increased in patients with active RV and paralleled disease activity in patients studied prospectively.