Tono-Pen determination of intraocular pressure in patients with band keratopathy or glued cornea

Aims. To evaluate the intraocular pressure (IOP) measurements in patients with band keratopathy or glued corneas obtained from affected and non-affected areas. Methods. 15 patients with band keratopathy or glued corneas were prospectively recruited. When both eyes were affected, only the right eye was analysed. Tono-Pen readings of IOP were obtained sequentially from the affected and non-affected corneal surface. Additionally, Goldmann applanation tonometry was attempted. Results. Determination of IOP with the Tono-Pen was possible in all cases, while Goldmann tonometry was not performed in three patients because of severe corneal irregularities. The average of the Tono-Pen readings obtained from the affected cornea (34.8 (SD 14.0) mmHg) was consistently and significantly higher (p <0.001) than mean IOP obtained by the Tono-Pen from the non-affected area (14.8 (4.3) mmHg). The average of Goldmann tonometry readings (14.4 (6.1) mmHg) did not differ significantly from the Tono-Pen values obtained from the non-affected corneal area (p = 0.47) but was significantly lower than the Tono-Pen measurements obtained from the affected area (p <0.001) Conclusion. In patients with band keratopathy or glued corneas determination of IOP by Tono-Pen tonometry varies from affected to non-affected area. The Tono-Pen overestimates the level of IOP when it is applied to areas with band keratopathy or with glue.

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

Key biological issues in contact lens development

A contact lens is a medical device widely used as an alternative to spectacles in order to correct refractive vision problems. The evolution of polymeric biomaterials has heralded a continuous development in the materials used to produce contact lenses and maximize patient comfort and limit adverse events. Microbial keratitis (MK) is a relatively rare but potentially devastating condition associated with contact lens use, particularly with the extended wear of hydrogel lenses. It is the principal complication related to contact lens wear and the large population at risk make it a public health concern. Bacterial binding to the contact lens material is a precursor to the development of MK and is influenced by properties of the material and the bacteria. In order for bacteria to infiltrate the cornea there must be some degree of corneal damage, usually caused by trauma or hypoxia. The most recent materials available aim to allow the continuous wear of lenses while limiting corneal hypoxia, thus helping to prevent the development of MK. Limitations to the treatment of MK require that novel approaches may be necessary in order to limit bacterial adhesion to contact lens materials.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

Mutation altering the miR-184 seed region causes keratoconus with cataract

MicroRNAs (miRNAs) bind to complementary sequences within the 3? untranslated region (UTR) of mRNAs from hundreds of target genes, leading either to mRNA degradation or suppression of translation. We found that a mutation in the seed region of miR-184 (MIR184) is responsible for familial severe keratoconus combined with early-onset anterior polar cataract, by deep sequencing of a linkage region known to contain the mutation. The mutant form fails to compete with miR-205 (MIR205) for overlapping target sites on the 3? UTRs of INPPL1 and ITGB4. Although these target genes and miR-205 are expressed widely, the phenotype is restricted to the cornea and lens because of the very high expression of miR-184 in these tissues. Our finding highlights the tissue-specificity of a gene network regulated by a miRNA. Awareness of the important function of miRNAs may aid identification of susceptibility genes and new therapeutic targets for treatment of both rare and common diseases.

Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus

Purpose. Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. Methods. Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. Results. The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10 ). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10 ) and rs17501108 (P = 9.9 × 10 ). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). Conclusions. Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Wild-type measles virus infection of primary epithelial cells occurs via the basolateral surface without syncytium formation or release of infectious virus

The lymphotropic and myelotropic nature of wild-type measles virus (wt-MV) is well recognized, with dendritic cells and lymphocytes expressing the MV receptor CD150 mediating systemic spread of the virus. Infection of respiratory epithelial cells has long been considered crucial for entry of MV into the body. However, the lack of detectable CD150 on these cells raises the issue of their importance in the pathogenesis of measles. This study utilized a combination of in vitro, ex vivo and in vivo model systems to characterize the susceptibility of epithelial cells to wt-MV of proven pathogenicity. Low numbers of MV-infected epithelial cells in close proximity to underlying infected lymphocytes or myeloid cells suggested infection via the basolateral side of the epithelium in the macaque model. In primary cultures of human bronchial epithelial cells, foci of MV-infected cells were only observed following infection via the basolateral cell surface. The extent of infection in primary cells was enhanced both in vitro and in ex vivo cornea rim tissue by disrupting the integrity of the cells prior to the application of virus. This demonstrated that, whilst epithelial cells may not be the primary target cells for wt-MV, areas of epithelium in which tight junctions are disrupted can become infected using high m.o.i. The low numbers of MV-infected epithelial cells observed in vivo in conjunction with the absence of infectious virus release from infected primary cell cultures suggest that epithelial cells have a peripheral role in MV transmission.

Anatomy and physiology of the human eye: effects of mucopolysaccharidoses disease on structure and function - a review

P>The current paper provides an overview of current knowledge on the structure and function of the eye. It describes in depth the different parts of the eye that are involved in the ocular manifestations seen in the mucopolysaccharidoses (MPS). The MPS are a group of rare inheritable lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in cells and tissues all over the body, leading to widespread tissue and organ dysfunction. GAGs also tend to accumulate in several tissues of the eye, leading to various ocular manifestations affecting both the anterior (cornea, conjunctiva) and the posterior parts (retina, sclera, optic nerve) of the eye.

Environmental tobacco smoke exposure and eye disease

Aim: To undertake a systematic review of the literature on the effect of environmental tobacco smoke (ETS) and eye disease. Methods: Medline (1950-January Week 2 2007), EMBASE (1980 to 2007 Week 07), SCOPUS and Science Direct were searched on ETS exposure and eye disease using various combinations of the following terms: passive smoking, environmental tobacco smoke, sidestream smoke, involuntary smoking, secondhand smoke; with eye, conjunctiva, sclera, episclera, cornea, lens, iris, retina, choroid, uvea, optic nerve, uveitis, iritis, blindness, visual loss, cataract, thyroid eye disease, conjunctivitis, age-related macular degeneration, dry eye, tears. The above terms were also used to search abstracts published on The Association for Research in Vision and Ophthalmology Annual Meeting abstracts, from 1995 to 2006, and the grey literature, including PhD and MSc theses/dissertations. A search was further conducted specifically on eye diseases where active smoking has been proposed to be a risk factor, including age-related macular degeneration, Graves ophthalmology, glaucoma, uveitis, refractive errors, strabismus, tobacco-alcohol amblyopia, non-arteritic ischaemic optic neuropathy, Leber optic neuropathy and diabetic retinopathy. Given the scarce number of studies found through the above search, all articles found on ETS and eye disease were included in this review. Results: Seven studies evaluated the possible relationship between ETS and an eye disease. These studies referred to refractive errors in children (n = 2), cataract (n = 1), age-related macular degeneration (n = 3) and Grave ophthalmopathy (n = 1). The data available were insufficient to establish conclusive relationships between ETS and these eye diseases. Conclusion: Very scarce data exist in the literature on the effect of ETS on diseases of the eye. It seems appropriate that ETS should be included in future studies addressing the effect of smoking on eye disease.

Mycobacterium chelonae keratitis:Resolution after debridement and presoaked collagen shields

We report a case of Mycobacterium chelonae keratitis following corneal injury by a foreign body. Diagnosis was made by Ziehl-Neelsen staining and Lowenstein-Jensen culture of corneal scrapings. On the basis of the in vitro susceptibility testing, the patient was treated with topical fortified amikacin. Given the lack of response to this therapy, we decided to carry out a debridement of the infiltrative areas to eliminate infected tissue, and to use an amikacin-soaked collagen shield supplemented every 4 h with topical fortified amikacin to promote healing of the debrided area and to potentiate the effects of the antibiotic therapy. After this treatment, clinical resolution was observed and a further acid-fast stain and culture for mycobacterium were negative. Debridement of the infiltrative areas could be used in cases of mycobacterium keratitis when early diagnosis is made and before the corneal infection has become widespread.

A new model of posterior capsule opacification in rodents

PURPOSE. To describe a new model of posterior capsule opacification (PCO) in rodents METHODS. An extracapsular lens extraction (ECLE), by continuous curvilinear capsulorrhexis and hydrodissection, was performed in 42 consecutive Brown Norway rats. Animals were killed at 0, 6, and 24 hours and 3, 7, and 14 days after surgery. Eyes were enucleated and processed for light microscopy and immunohistochemistry. RESULTS. In 34 (81%) of the animals the operated eye appeared well healed before death, with a clear cornea and a well-formed anterior chamber. In eight (19%) there was no view of anterior segment structures because of hyphema, fibrin, or corneal opacification. PCO was clinically evident 3 days after ECLE and was present in all animals at 2 weeks. Immediately after ECLE, lens epithelial cells (LECs) were present in the inner surface of the anterior capsule and lens bow. Twenty-four hours after surgery, LECs started to migrate toward the center of the posterior capsule. At 3 days, multilayered LECs, some spindle shaped, were present throughout the lens capsule. Capsular wrinkling was apparent. Lens fibers and Soemmering's ring were observed in all animals 14 days after surgery, indicating some degree of cellular differentiation. Activated macrophages were present in greater numbers at 3 and 14 days after surgery (P <0.05), when proliferation and migration of LECs appeared to be greatest, and lens fiber differentiation was evident, respectively. CONCLUSIONS. In rodents PCO occurs after ECLE and is associated with low-grade inflammation, mostly of mononuclear macrophages. Although no intraocular lens implantation was performed, this model appears to be valuable for studying the sequence of events that leads to PCO after cataract surgery and the extracellular matrix cues that promote lens fiber differentiation.

Long-term graft survival in patients with flexible open-loop anterior- chamber intraocular lenses

Purpose. To evaluate the long-term graft survival and complications of flexible, open-loop anterior-chamber intraocular lenses in patients with penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy. Methods. We reviewed charts of all consecutive patients who underwent penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy combined with implantation of a flexible, open-loop, anterior-chamber intraocular lens at our institution between 1983 and 1988. One-hundred one eyes of 99 patients were evaluated. Graft-survival rates were calculated by using the Kaplan-Meier actuarial method. Results. Mean follow-up was 49.8 months (range. 1-144). The probability of graft survival at 1, 2, 4, 6, and 8 years was 93, 87, 78, 65, and 65%, respectively. A total of 25 (24.8%) grafts failed. Progressive corneal edema without signs of rejection was the most common finding in patients with failed grafts (10 eyes, 40%). The most frequent complication observed was newly diagnosed or worsening of preexisting glaucoma (46 eyes, 45.5%). Conclusions. Our long-term results support flexible, open-loop anterior-chamber intraocular lenses as a reasonable option, at the time of penetrating keratoplasty, in patients with pseudophakic and aphakic bullous keratopathy.