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Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disease that occurs in sporadic, genetic, variant, and iatrogenic forms. The transformation of normal prion protein (PrP(C)) to the abnormal form (PrP(Sc)) is a key step in the pathogenesis of CJD and leads to the accumulation of amyloid and spongiform changes in the brain. The presence of PrP(Sc) in tissue is a surrogate marker for CJD infectivity. Sporadic CJD, whose cause is unknown, is by far the most frequent form with 1-2 cases per million population occurring every year-the genetic forms of CJD are rather rarer. The majority of variant CJD cases have occurred in the United Kingdom, where there have been four reports of transmission of vCJD by blood transfusion. The great majority of iatrogenic transmissions of CJD have resulted from the use of pituitary-derived hormones or dura mater with only a very few cases attributable to neurosurgical instruments or corneal transplants. In the absence of a validated test for CJD infectivity in eye donors, the application of appropriate donor selection criteria and the use of single-use instruments in eye banks are currently the most effective means of reducing the risk of CJD transmission. Onward transmission by reusable ophthalmic surgical instruments has not been reported, but the risk cannot be excluded. Use of appropriate cleaning and disinfection protocols and the ability to identify and quarantine instruments that may have been used on an infected patient are important safeguards.

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PURPOSE: To describe the incidence and current management of fungal keratitis in the United Kingdom. METHODS: Cases were identified prospectively through the British Ophthalmologic Surveillance Unit (BOSU) from December 2003 to November 2005. Questionnaire data were requested at diagnosis and at 6 months follow-up. Inclusion criteria were a positive culture or microsopic proof from a scraping or biopsy, and a normal residence in the United Kingdom. RESULTS: Data were available on 39 confirmed cases at diagnosis and 34 cases at follow-up. The minimum average annualised incidence was 0.32 (95% CI, 0.24-0.44) cases per million individuals. In 22 cases (56%), only Candida was isolated and 14 of these (63%) had prior ocular surface disease treated with topical steroid. A filamentary fungus infection was more common in male patients (P=0.02), often following trauma, and the differences in risk factors between types of fungal infection was statistically significant (P<0.001). One case had a mixed yeast and filamentary fungus infection. The most frequent initial topical therapies were amphotericin B (38%) or econazole (28%). In addition, oral fluconazole was used in 11 (31%) patients and oral itraconazole in six (15%). At follow-up, the vision in 15 eyes (44%) was <6/60 including three eyes eviscerated. CONCLUSIONS: This study provides data on the minimum incidence of fungal keratitis in the United Kingdom. It provides evidence of frequent delay in diagnosis after presentation to eye departments, inconsistent management, and poor outcome. Issues that can now be addressed.

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PURPOSE: Allograft rejection is the main cause of graft failure in human corneal transplantation, for which underlying pathomechanism is not yet clear. We compared gene expression in the peripheral blood of patients who after undergoing corneal transplantation experienced graft rejection with those patients who accepted grafts. METHODS: Sixty-six patients who underwent corneal transplantation were studied including 18 patients who suffered subsequent graft rejection. cDNA array technology was used to survey and quantify transcript expression. A semiquantitative reverse transcriptase-PCR (RT-PCR) was used to confirm the gene expression pattern measured by a cDNA array of selected genes. RESULTS: Among 265 genes present on the array, eight genes were found to be differentially expressed. Four genes (Rac 2, RhoA, paxillin, and CD18) were further analysed by semiquantitative RT-PCR, and significant differences in mRNA expression levels in the rejection group were confirmed. CONCLUSIONS: Our study demonstrated that the expression of Rac2 mRNA was upregulated in the peripheral blood of patients experiencing corneal transplantation rejection compared to those patients who had no rejection episodes. In addition, three genes, RhoA, paxillin, and CD18, showed decreased expression in rejecting patients. cDNA array technology provides a potentially useful approach to identify novel genes that might participate in pathogenic pathways during corneal graft rejection.

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PURPOSE: Corneal transplantation is the most common form of transplantation with approximately 2500 grafts undertaken annually in the United Kingdom. The modern day success of transplantation is attributed to eye bank storage techniques, ocular pharmacology, and improved surgical techniques. METHODS: This retrospective case note review identified 203 penetrating keratoplasties (PKs) performed during a period from 1 January 2000 to 31 December 2003 at Manchester Royal Eye Hospital. Preoperative risk factors, surgical technique, postoperative complications, and Snellen acuity were analysed. RESULTS: The mean age of the recipient group was 56.7 years, with 107 right eyes and 96 left eyes. The mean follow-up was 61 months. The overall 5-year survival was 82%, with keratoconus and corneal dystrophies at 93 and 89%, respectively. Visual acuity had improved to 6/12 or better in 48% of patients postoperatively, compared with 8% preoperatively. Forty-three donor grafts (21%) underwent at least a single episode of endothelial rejection. Glaucoma was a finding in 37 (18%) of patients following PK. In all, 16 grafts of 15 patients were noted to have suffered microbial keratitis (MK), an incidence of 8%. CONCLUSIONS: PK is currently an effective long-term treatment option for improving visual function. An overall survival rate of 82% over 5 years is comparable with other published studies and is largely dependent on recipient factors. This report emphasises the significant complications of immunological rejection, glaucoma, and microbial keratitis, which continue to limit success.

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AIMS: To determine the epithelial proliferative capacity of organ cultured limbal tissue and correlate this with various donor and eye banking factors. METHODS: 24 corneoscleral limbal (CSL) rims left over from penetrating keratoplasty were split in half and set up as in vitro explant cultures. Corneal epithelial proliferative potential (CEPP) was assessed by the number of "cycles" of growth achieved before explants underwent exhaustion and failure to generate an epithelium to subconfluence. The dependence of CEPP on the age of the donor, time of death to enucleation, time of enucleation to organ culture, and time in organ culture in the eye bank was determined. RESULTS: CSL rims were capable of up to four cycles of culture with a wide variation between tissue samples. Of the various factors examined, death to enucleation time was the only statistically significant factor affecting the CEPP (regression coefficient: -0.062 (cycles/hour), CI -0.119 to -0.004, p = 0.037). Time in organ culture had little effect on CEPP. CONCLUSIONS: Preselected organ cultured CSL rims from eye banks may offer a viable alternative tissue source for use in allo-limbal transplantation.

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PURPOSE: Applanation tonometry as performed in routine clinical practice is a significant potential vehicle for cross-infection particularly in an emergency eye care setting. The aim of this study is to evaluate the accuracy and reliability of three single-use devices (Tonoshield, Tonosafe, Tonojet) as an alternative to standard Goldmann prisms in an emergency eye department. METHODS: All patients attending the eye casualty at the Manchester Royal Eye Hospital for a period of 4 months who required intraocular pressure measurement were eligible for this prospective study. Exclusion criteria were: age below 18 years, corneal anomalies that might affect measurement, and refusal to participate. After taking informed consent, the patient was examined by one experienced nurse practitioner, who measured the intraocular pressure three times. In the first part of the study, we compared the standard Goldmann prism vsTonoshield and Tonosafe prisms, while for the second part of the study we used standard Goldmann, Tonosafe, and Tonojet prisms. Agreement and repeatability tests were carried out on separate samples. RESULTS: Tonosafe and Tonojet correlated well with standard Goldmann tonometry (P<0.001), while the measurements obtained with Tonoshield were higher, especially for raised intraocular pressure measurements. Tonojet and Tonosafe measurements were more reproducible than Tonoshield measurements. CONCLUSIONS: This study shows that Tonosafe and Tonojet are accurate and reliable alternatives to standard Goldmann tonometry.

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BACKGROUND: Involvement of the eye has been reported in patients with variant Creutzfeldt-Jakob disease (vCJD), but there is disagreement on whether retinal involvement occurs in sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: Western blotting, paraffin embedded tissue blotting, and immunohistochemistry were used to test whether the abnormal form of the prion protein (PrPSc) accumulates to detectable levels in the eye in a case of the most common subtype of sCJD (MM1). RESULTS: Low levels of PrPSc were detectable in the retina, localised to the plexiform layers of the central retina. PrPSc was not detectable in other ocular tissues. CONCLUSIONS: The abnormal form of the prion protein is present in the retina in the most common sCJD subtype (MM1), albeit at levels lower than those found previously in vCJD and in sCJD of the VV2 subtype.

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AIM: To determine the incidence of non-severe keratitis (NSK) and severe keratitis (SK) among wearers of current generation contact lenses. METHODS: A 12 month, prospective, hospital based epidemiological study was conducted by examining all contact lens wearers presenting with a corneal infiltrate/ulcer to a hospital centre in Manchester. A clinical severity matrix was used to differentiate between NSK and SK, based on the severity of signs and symptoms. The size of the hospital catchment population and the wearing modalities (daily wear (DW) or extended wear (EW)) and lens types being used were estimated from relevant demographic and market data. RESULTS: During the survey period, 80 and 38 patients presented with NSK and SK, respectively. The annual incidences (cases per 10,000 wearers) for each wearing modality and lens type were: DW rigid--NSK 5.7, SK 2.9; DW hydrogel daily disposable--NSK 9.1, SK 4.9; DW hydrogel (excluding daily disposable)--NSK 14.1, SK 6.4; DW silicone hydrogel--NSK 55.9, SK 0.0; EW rigid--NSK 0.0, SK 0.0; EW hydrogel--NSK 48.2, SK 96.4; EW silicone hydrogel--NSK 98.8, SK 19.8. The difference in SK between EW hydrogel and EW silicone hydrogel was significant (p = 0.04). CONCLUSIONS: A clinical severity matrix has considerable utility in assessing contact lens related keratitis. There is a significantly higher incidence of SK in wearers who sleep in contact lenses compared with those who only use lenses during the waking hours. Those who choose to sleep in lenses should be advised to wear silicone hydrogel lenses, which carry a five times decreased risk of SK for extended wear compared with hydrogel lenses.

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PURPOSE: To describe the strategy used for large-scale ophthalmological monitoring in the clinical development of the novel anticancer agent gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, which had demonstrated ocular effects in preclinical animal models. METHODS: In this extensive clinical trial programme, patients in Phase I and II trials underwent frequent and intensive ophthalmological monitoring at baseline and during the trials. Data were reviewed by an external independent Ophthalmology Advisory Board. RESULTS: Ophthalmological data for 221 patients in Phase I trials of gefitinib and 425 patients in Phase II trials revealed no evidence of any consistent or drug-related ophthalmological toxicity. Interestingly, the baseline data revealed that, in an asymptomatic population, transient ophthalmological events are identified during monitoring. CONCLUSIONS: This study reports the methodology and normative data in an ophthalmological screening programme that should prove useful for future studies.

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PURPOSE: To determine the prevalence and clinical characteristics of external ocular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in an ophthalmic hospital in the UK. METHODS: A retrospective analysis of the case notes of patients who had culture proven external ocular Staphylococcal infections during a 44-month period was undertaken. RESULTS: There were a total of 548 external eye infections caused by Staphylococcus aureus. Of these, 17 (3%) were MRSA positive. The most common presentation was conjunctivitis seen in six patients. All MRSA isolates were sensitive to chloramphenicol. Ofloxacin resistance was observed in all isolates from patients over the age of 50 years. All patients had an underlying history of either an ocular surface disease, malignancy, or a debilitating medical illness. CONCLUSIONS: MRSA is as yet an infrequent cause of external ocular infections. Patients typically have underlying ocular risk factors and/or are medically debilitated. Different strains infect young and old age groups with characteristic antimicrobial sensitivity. This study highlights the need for more work to establish the role of MRSA commensals and ocular infections.

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AIMS: To describe the clinical features of two patients with paraproteinaemia and necrobiotic xanthogranulomatosis together with detailed immunohistochemistry of the lesions in one. METHODS: The clinical history and results of biochemical investigations of the patients were retrieved from the files. Immunohistochemistry was used to investigate the expression of macrophage and mast cell markers, amyloid A and P, S-100 protein, and apolipoprotein AI and B in xanthogranulomatous skin lesions from patient 2. In addition, protein A-sepharose chromatography was used to separate serum from patient 2 and apolipoprotein B and the IgG paraprotein were measured in the fractions eluted. RESULTS: Monocytes/macrophages comprised the major cellular component of the lesion, and unusually for xanthomata, areas of collagen necrosis were also seen. Activated mast cells were present at the margins of macrophage clusters and adjacent to areas of collagen necrosis. Serum paraprotein was bound to low density lipoproteins as judged by protein A-sepharose chromatography, and was also located within macrophagic foam cells of the lesion on immunohistochemistry. CONCLUSIONS: These observations demonstrate many features similar to atherosclerosis including collagen necrosis and mast cell activation.

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PURPOSE: The aim of this study was to detect and identify bacterial contaminants in human corneoscleral tissue after organ culture storage. METHODS: Seventy-two corneoscleral rims and corneal buttons trephined from organ cultured corneoscleral discs using aseptic technique and 45 organ-cultured donor corneoscleral rims postpenetrating keratoplasty) were subjected to a mechanical extraction technique using a Stomacher laboratory blender. As a control, 28 of the corneoscleral rims and buttons were halved; one half of each corneoscleral rim and button was decontaminated in formalin for 48 hours before thorough washing in balanced salt solution. Corneal specimens, culture medium, and transport (5% dextran) medium were cultured in brain-heart infusion broth at 37 degrees C for 5 days. Bacterial isolates were identified after culture of turbid enrichment broth. RESULTS: Bacterial contamination was demonstrated in 29% (21 of 72) of the corneoscleral rims and 15% (11 of 72) of the corneal buttons that were trephined aseptically from corneoscleral discs and in 29% (13 of 45) of postkeratoplasty corneoscleral rims. Bacterial contaminants were not isolated from controls. Isolated microorganisms included coagulase-negative Staphylococcus, Staphylococcus aureus, Streptococcus viridans, Pseudomonas sp, and Bacillus sp. A correlation was not demonstrated between contamination and cause of death, death to enucleation, death to culture time, or time in culture. Postkeratoplasty endophthalmitis was not evident in the patients who had received corneal buttons from those corneoscleral discs that had contaminated corneoscleral rims. CONCLUSIONS: Bacterial contamination exists in corneoscleral tissue after organ culture storage. The difference in distribution of bacteria and percentage of contamination between the peripheral and central corneas causes us to question the value of routine postpenetrating keratoplasty corneoscleral rim cultures.

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BACKGROUND: Our purpose is to examine levels of Fas mRNA expression in blood during human corneal transplant rejection. METHODS: Fas mRNA expression was detected by reverse transcription-PCR in blood from normal controls, corneal recipients at the time of transplantation and during episodes of rejection. RESULTS: Samples taken at the time of a corneal rejection episode showed Fas mRNA levels were significantly lower in these patients than either normal controls (P = 0.017) or corneal transplant recipients not undergoing graft rejection (P = 0.00052). Serial samples from five patients who suffered an episode of rejection showed that the level of Fas mRNA is reduced during the rejection episode and subsequently recovers. CONCLUSIONS: These results indicate low levels of Fas mRNA in blood may have a role in corneal transplant rejection.

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