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In this genomewide association study of age-related corneal dystrophy, there was a significant association with variants of TCF4, which encodes the E2-2 transcription factor. The risk variant of the most strongly associated genetic marker had an odds ratio of approximately 5. Fuchs's corneal dystrophy (FCD) is a progressive, bilateral condition characterized by dysfunction of the corneal endothelium, leading to reduced vision. The prevalence of FCD has been estimated at about 5% among persons over the age of 40 years in the United States. 1 Corneal edema that is associated with FCD may progress after cataract surgery and is the most common indication for the 42,000 corneal transplantations that take place each year in the United States. Enthusiasm for refractive surgery is decreased among patients who are at high risk for FCD. 2 Thus, the ability to diagnose FCD before symptoms develop and knowledge . . .

AimsA blind, randomised, prospective, bilateral study to investigate the efficacy of riboflavin/ultraviolet A corneal collagen cross-linkage to halt the progression of keratoconus.Methods24 patients with early/moderate bilateral keratoconus with recent progression were recruited. One eye was randomly assigned to undergo collagen cross-linkage following epithelial removal with riboflavin 0.1% and ultraviolet A (370 nm at 3 mW/cm2). The other remained untreated as a control. The follow-up was 18 months in 22 patients.ResultsAt 18 months, Orbscan II 3 mm, 5 mm keratometry and simulated astigmatism and cone apex power and wave-front measurements (Keraton Scout), including root mean square, coma and pentafoil showed significant reductions from baseline in treated compared with untreated eyes (p=0.04). In treated eyes at 18 months, the best spectacle-corrected acuity improved (p=0.01), and Orbscan II-simulated keratometry (p<0.001), 3 mm keratometry (p=0.008), simulated astigmatism (p=0.007), cone apex power (p=0.002), root mean square, coma, spherical aberration, secondary astigmatism and pentafoil (p=0.05) decreased from baseline. One treated eye experienced transient recurrent corneal erosions; otherwise there were no complications attributable to the treatment.ConclusionsCorneal collagen cross-linkage appears to be an effective and safe modality to halt the progression of keratoconus. Improvements in visual and topographic parameters are seen in some eyes.

Background/aims:Tissue degradation in corneal thinning disorders, such as keratoconus (KC), involves the expression of inflammatory mediators. The purpose of this study was to determine the levels of proinflammatory cytokines and matrix metalloproteinase 9 (MMP-9) in tears from both eyes of unilateral keratoconus (KC) patients.Methods:Thirty patients diagnosed as having asymmetrical KC (30 KC eyes, and 30 subclinical KC eyes) and 20 normal control subjects (one eye) were studied in a prospective, cross-sectional study. Keratoconus screening programmes were performed on these participants. Ten microlitres of tears was collected from each eye. The concentrations of cytokines (interleukin-6 (IL-6) and tumour necrosis factor α (TNF-α)) and MMP-9 were measured by ELISA.Results:Mean values for IL-6 levels were similar in KC and subclinical KC samples (5.5 (4.9 to 6.9) vs 5.7 (4.5 to 6.2) pg/ml, p = 0.131), but significantly higher in relation to the control group (2.2 (1.0 to 4.1) pg/ml, p<0.0001). Significant differences were found in TNF-α levels between KC and subclinical KC eyes (5.4 (4.1 to 6.8) vs 4.8 (4.2 to 6.0) pg/ml, p = 0.032) and control group (1.8 (1.5 to 2.3) pg/ml, p<0.0001). Increased values of MMP-9 were found in KC (59.4 (50.6 to 66.1) ng/ml) vs subclinical KC eye (7.0 (4.8 to 8.6) ng/ml) (p<0.0001). MMP-9 levels in the control group (6.1 (3.9 to 8.3) ng/ml) and subclinical KC were similar (p = 0.203).Conclusions:IL-6 and TNF-α are overexpressed in the tears of subclinical and KC eyes. Increased MMP-9 levels were found only in the KC eye. These results indicate that the pathogenesis of KC may involve chronic inflammatory events.

Contact lens wear is a common predisposing factor in microbial keratitis and is one of the two preventable risk factors for corneal infection in a working age population. Our understanding of the prevention and prophylaxis of contact lens-related corneal infection is informed by recent epidemiological studies describing the incidence of and risk factors for the disease, the effect of causative organism on disease severity, and an appreciation of individual immune profiles in susceptibility to and severity of the disease. Although contemporary contact lenses have not reduced the overall incidence of keratitis, a reduction in morbidity may be achievable through recognition of appropriate risk factors in severe disease, including avoiding delays in presenting for appropriate treatment, and attention to storage case hygiene practise. Severe keratitis is most commonly associated with an environmental causative organism, and daily disposable lenses are associated with less severe disease. Pseudomonas aeruginosa remains the commonest cause of contact lens-related corneal infection probably because of its unique virulence characteristics and ability to survive in the contact lens/storage case/ocular environment. In two recent outbreaks of contact lens-related infections, there has been a strong association demonstrated with particular contact lens solutions. Since the recall of these specific contact lens solutions, the rate of Acanthamoeba keratitis has remained above the expected baseline, indicating unidentified risk factors that may include environmental exposures. Individual differences in susceptibility to microbial keratitis may be partly explained by differences in single-nucleotide polymorphisms in certain cytokine genes, particularly those with a proven protective role in corneal infection.

PurposeTo investigate the long-term outcome of autologous cultivated oral mucosal epithelial transplantation (COMET) for the treatment of the scar phase of severe ocular surface disorders.ParticipantsThis study involved 19 eyes of 17 patients who received autologous COMET for total limbal stem-cell deficiency.MethodsAutologous cultivated oral mucosal epithelial sheets were created using amniotic membrane as a substrate. Clinical efficacy was evaluated by best-corrected visual acuity and visual acuity at the postoperative 36th month. The clinical results (clinical conjunctivalisation, corneal opacification, corneal neovascularisation and symblepharon formation) were evaluated and graded on a scale from 0 to 3 according to their severity. Clinical safety was evaluated by the presence of persistent epithelial defects, ocular hypertension and infections.ResultsAutologous cultivated oral mucosal epithelial sheets were successfully generated for all 17 patients. All patients were followed up for more than 36 months; the mean follow-up period was 55 months and the longest follow-up period was 90 months. During the long-term follow-up period, postoperative conjunctivalisation and symblepharon were significantly inhibited. All eyes manifested various degrees of postoperative corneal neovascularisation, but it gradually abated and its activity was stable at 6 months after surgery. Best-corrected visual acuity was improved in 18 eyes (95%) during the follow-up periods, and visual acuity at the postoperative 36th month was improved in 10 eyes (53%).ConclusionsThese long-term clinical results strongly support the conclusion that tissue-engineered cultivated oral mucosal epithelial sheets are useful in reconstructing the ocular surface of the scar phase of severe ocular surface disorders.

AimsTo determine the accuracy of diagnosing microbial keratitis by masked medical and non-medical observers using the Heidelberg Retina Tomograph II/Rostock Cornea Module in vivo confocal microscope.MethodsConfocal images were selected for 62 eyes with culture- or biopsy-proven infections. The cases comprised 26 Acanthamoeba, 12 fungus, three Microsporidia, two Nocardia and 19 bacterial infections (controls). The reference standard for comparison was a positive tissue diagnosis. These images were assessed on two separate occasions by four observers who were masked to the tissue diagnosis. Diagnostic accuracy indices, κ statistic and percentage agreement values were calculated. The Spearman correlation coefficient (rs) was calculated for the number of correct diagnoses versus duration of disease.ResultsThe highest sensitivity and specificity values were 55.8% and 84.2%, respectively, and the lowest sensitivity and specificity values were 27.9% and 42.1%, respectively. The highest positive and lowest negative likelihood ratios were 2.94 and 0.59, respectively. Agreement values were: fair to moderate (κ 0.22–0.44) for reference standard versus observer diagnosis, moderate to good in intraobserver variability (repeatability, κ 0.56–0.88) and poor to moderate in interobserver variability (reproducibility, κ 0.15–0.47). The correct diagnosis was associated with duration of disease for Acanthamoeba keratitis (rs=0.60, p=0.001).ConclusionsThe diagnostic accuracy of microbial keratitis by confocal microscopy is dependent on observer experience. Intraobserver repeatability was better than interobserver reproducibility. Difficulty in distinguishing host cells from pathogenic organisms limits the value of confocal microscopy as a stand-alone tool in diagnosing microbial keratitis.

A herpes simplex virus-1 entry protein The entry of herpes simplex virus-1 (HSV-1) into cells requires the presence of cellular receptors for both envelope glycoproteins B and D. Now a proteomics-based search for further molecules interacting with HSV-1 has identified non-muscle myosin heavy chain IIA (NMHC-IIA) as a functional entry receptor, acting together with glycoprotein D. NMHC-IIA knockdown reduces HSV-1 infection in cell culture and a mouse model, suggesting that drugs or vaccines that target NMHC-IIA and non-muscle myosin IIA regulators may be effective against herpes infections. Entry of herpes simplex virus-1 into cells requires cellular receptors for both envelope glycoprotein B and envelope glycoprotein D. These authors show that the interaction of non-muscle myosin heavy chain IIA with envelope glycoprotein B is important for entry of herpes simplex virus-1. Herpes simplex virus-1 (HSV-1), the prototype of the α-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis 1 . HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD) 2 , 3 , 4 . However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo 1 remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection 5 became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell–cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation 6 , reduced the redistribution of NMHC-IIA as well as HSV-1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types 7 and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo . The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development.

ABSTRACTPURPOSE: To use the anterior corneal surface higher order aberrations as a tool to detect and grade keratoconus using corneal map analysis videokeratoscopy.METHODS: A prospective observational comparative study of 80 eyes was performed. The eyes were divided into two groups. Group A comprised 40 eyes of 20 asymptomatic individuals with no ocular pathology. Mean sphere was -0.03 diopters (D) (range: +0.75 to -0.75 D), mean cylinder was -0.27 D, mean average K was 43.28 D, and mean uncorrected visual acuity (UCVA) was 1.01. Group B comprised 40 eyes of 25 patients with keratoconus. Mean sphere was -3.70 D (range: +2.00 to -10.00 D), mean cylinder was -3.82 D, mean average K was 49.29, and mean best spectacle-corrected visual acuity (BSCVA) was 0.61.RESULTS: In group A, mean root-mean-square (RMS) of spherical (Z4 and Z6), coma-like (Z3, Z5, and Z7), and higher order aberrations (Z^sub 3-7^) were 0.38 µm, 0.35 µm, and 0.52 µm, respectively. In group B, mean RMS of spherical, coma-like, and higher order aberrations were 1.06 µm, 2.90 µm, and 3.14 µm, respectively, for a 6.0-mm simulated pupil diameter. Mean RMS differences between the two groups were 0.68 µm (P≤.0002), 2.55 µm (P≤.0001), and 2.61 µm (P≤.0001) for spherical, coma-like, and total higher order aberrations, respectively. In group B, according to Amsler-Krumeich classification, the mean RMS of coma-like aberration was 1.87 µm in grade I (14 eyes), 2.97 µm in grade II (11 eyes), 3.46 µm in grade III (12 eyes), and 5.20 µm in grade IV (3 eyes).CONCLUSIONS: Corneal higher order aberrations, especially coma-like aberrations, are significantly higher in eyes with keratoconus than normal eyes. Coma-like aberrations, with the aid of a corneal aberrometry map, are good indicators for early detection and grading of keratoconus. [J Refract Surg. 2006;22:539-545.]

AimTo evaluate the efficacy of intrastromal voriconazole, as a modality of treatment for management of recalcitrant fungal keratitis.MethodsTwelve patients of smear and/or culture positive fungal keratitis not responding to topical and systemic antifungal therapy were treated with additional intrastromal voriconazole therapy. Patients were given one or more intrastromal injection of voriconazole (50 μg in 0.1 ml) at the junction of clear cornea and infiltrates, using a 30-gauge needle in five quadrants to form a barrage around the ulcer. All patients continued to receive topical and systemic antifungal therapy.ResultsThe mean age of the patients was 47.58±15.13 years, and the mean time to presentation at the centre was 37.58±10.54 days. Organisms isolated were Aspergillus species (n=8), Fusarium species (n=3) and Curvularia (n=1). Of 12 eyes, 10 eyes healed with scar formation, and the mean resolution time was 39.75±7.62 days. Two corneas perforated and required therapeutic penetrating keratoplasty. The best-corrected visual acuity was less than 20/1200 in all patients at the time of presentation, which improved to better than 20/400 in 10 eyes and 20/40 in eyes that underwent penetrating keratoplasty at the end of 24.75±2.14 weeks' follow-up.ConclusionIntrastromal injection of voriconazole may be used as a modality of treatment for managing cases of recalcitrant fungal keratitis.

Aim To investigate and correlate the corneal, refractive, topographic and familial characteristics of a large cohort with keratoconus. Methods Prospective observational study of 200 consecutive patients presenting with keratoconus during the 4 year-period 1997–2000. Subjects were examined at enrolment and at a final review. Data were collected on demographic characteristics, referral route, symptoms, refractive correction, eye rubbing, family history, medical history, slit-lamp biomicroscopic corneal signs, and computerized corneal topography. Results Mean age at enrolment was 30.9±10.4 (range, 12.2–72) years ( N =200, 62.5% male, 93% white Caucasian) with a 5% family history of keratoconus. Atopic diseases included asthma (23%), eczema (14%), and hay fever (30%). Only 9% wore contact lenses before referral. Mean follow-up was 1004 days ±282 (range, 390–1335) and 9.7±8.9 (range, 1.1–60) years from diagnosis. The mean simulated K1 corneal power at enrolment was 51.74±5.36 (range, 42.59–67.32) D and 88.5% exhibited bilateral keratoconus. Fifty-three (15%) topographically confirmed cones exhibited no clinical corneal signs at presentation. At enrollment, 56% had a pachymetry <0.480 mm increasing to 77% at final review. Forty-eight percent of subjects reported significant eye rubbing and there was a highly statistically significant difference (two sample t -test P =0.018) between keratoconus and control groups. TMS-2 axial corneal power was strongly associated with corneal scarring and age at diagnosis. The size of the scarring effect was 2.2 D (95% confidence interval (CI) 1.34, 3.06). Conclusions This study provides an overview of a large population with keratoconus highlighting presenting features and clinical and topographic progression over a 4 year-period.