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| October 2006 | Inside IOVS | Volume 47/10 |
Variable Expression of TGF-b in Amniotic Membrane Affects Surgical Results
The amniotic membrane is increasingly being used in ocular surface surgery with beneficial effects. This study reports variations between membranes obtained from different donors and in different parts of the membrane from the same donor. This variation also depends on the methods of preparing and preserving the membrane before use. Hopkinson et al. (p. 4316) illustrate such variation using one marker molecule, namely TGF-b, which is known to promote wound healing and scarring. Membranes with excess of this molecule could result in undesirable scarring at the ocular surface. The study emphasizes the need for standardization of amniotic membrane supplied for clinical use.
Rac1 Activation by Fibronectin in Corneal Epithelial Cells
The fibronectin-integrin system plays important roles in cell adhesion and migration in the wound healing of corneal epithelium. Kimura et al. (p. 4323) demonstrate that, using the dominant negative mutant form of Rac1, the promotion of cell adhesion and motility by fibronectin in corneal epithelial cells is mediated by Rac1 and then the accumulation of F-actin and formation of focal adhesions at the cell periphery. These results provide not only a better understanding of the mechanism of corneal epithelial wound healing, but also a basis for the development of new treatments for corneal epithelial wounds.
Osteopontin Increases Severity of Experimental Autoimmune Uveitis
Uveitis encompasses a group of ocular inflammatory diseases that can lead to irreversible destruction of retinal tissues and vision loss. Experimental autoimmune uveitis (EAU) is an animal model of retinal inflammation. Osteopontin (OPN) was previously shown to increase in EAU eyes, but its role in EAU pathogenesis was unknown. Hikita et al. (p. 4435) demonstrate that OPN is involved in activation and recruitment of immune cells in EAU and show that OPN null mice exhibit attenuated disease. These findings suggest a pro-inflammatory role for OPN in EAU. Thus, inhibition of OPN may be a novel therapy for autoimmune uveitis.
Salicylic Acid Modulates Pseudomonas aeruginosa Virulence Factors
Bandara et al. (p. 4453) report the use of salicylic acid to downregulate several important virulence factors of P. aeruginosa. These factors included motility, protease production, and interactions with corneal epithelial cells. These findings are of importance as they highlight the potential for salicylic acid to be used in a novel way to treat bacterial ocular infections. This is of relevance in the age of increasing resistance to currently used antibiotics.
Molecular Diagnosis of Microsporidial Keratitis
To evaluate generic and species-specific 16S rRNA-based PCR in microsporidial keratitis, Joseph et al. (p. 4468) tested 31 smear positive test samples and 103 controls by pan-microsporidial PCR followed by species-specific PCR and sequencing. Twenty-eight (26-test, 2-control) were positive by pan-microsporidian PCR. Species identified were E. cuniculi in 9 (test-7, control-2), E. hellem in 3, E. intestinalis in 1, and Vittaforma corneae in 15 samples. Pan-microsporidian PCR appears to be a useful adjunct to smear examination of corneal scrapings, for the diagnosis of microsporidial keratitis.
A Dose-Escalation Study of Bevacizumab for AMD
Costa et al. (p. 4569) report a phase I dose-escalation study involving a single intravitreal injection of bevacizumab. They found that this was a safe and well tolerated procedure associated with short-term overall VA improvement and no unfavorable macular changes in patients with neovascular age-related macular degeneration. Among the dose-regimens tested, the most favorable morphological and functional outcome was observed in patients receiving 2.0 mg of bevacizumab.
When Sequencing Isn’t Enough
Screening genes for disease-causing mutations usually involves sequencing of amplified DNA. This technique detects base substitutions and small insertions or deletions but will fail to detect larger deletions or rearrangements. Sullivan et al. (p. 4579) used multiplex ligation-dependent probe amplification (MLPA) to screen the PRPF31 gene in patients with autosomal dominant retinitis pigmentosa and found genomic rearrangements, undetected by sequencing, in 2.5% of cases. Observed rearrangements ranged from deletion of internal exons to large deletions encompassing PRPF31 and several neighboring genes. MLPA is a powerful addition to standard mutation screening, especially for genes that cause disease by haploinsufficiency.
Oxidant-Mediated Akt Activation in Human RPE Cells
RPE cell survival and death is crucially important in the normal eye and in diseases such as age-related macular degeneration (AMD). Oxidative stress contributes to AMD. Protein kinase B, also called Akt, is a critical mediator of cell survival. Yang et al. (p. 4598) show that H2O2, used as a model oxidant, activates phosphatidylinositol 3-kinase (PI3K)-Akt pathway and inactivates downstream pro-apoptotic effector molecules in human RPE cells. PI3K-Akt inhibition enhances H2O2-induced apoptotic and non-apoptotic RPE cell death by caspase-dependent and caspase-independent pathways. The PI3K-Akt signaling pathway serves as an important protective mechanism to prevent oxidant-mediated RPE cell death.
Exclusive Expression of Hemochromatosis Gene HFE in RPE
Hemochromatosis, a disorder of iron overload, is caused principally by mutations in HFE, which encodes an iron-regulatory protein. This gene is expressed in the intestine and liver, which are critical determinants of the body's iron status. Little is known about the retinal iron status in hemochromatosis; nor is it known if HFE is expressed in retina. Martin et al. (p. 4238) studied the expression of HFE in mouse retina. They found that HFE is expressed in the retina, exclusively in RPE, where the protein is found at the basolateral membrane. These studies suggest that hemochromatosis may lead to disruption of iron homeostasis in RPE.
Aquaporin-3 in Corneal Epithelial Migration and Proliferation
Water and glycerol channel aquaporin (AQP)-3 has been detected previously in basal corneal epithelial cells, though without any recognized function. Comparing wild-type mice and transgenic mice deficient in AQP3, Levin and Verkman (p. 4365) reported AQP3-dependent corneal epithelial water and glycerol transport. They then demonstrated slowed re-epithelialization in AQP3-null mouse cells using in vivo, organ culture, and primary culture models of wound healing. Distinct defects in migration and proliferation were identified in AQP3-deficient cells, implicating AQP3 in two fundamental cellular processes. Their findings support an evolving paradigm linking AQPs to cell migration and provide the first evidence for involvement of an AQP in cell proliferation.
Choroid-Bruch's Layer Is a Barrier for Transscleral Drug Delivery to the Retina
Although sclera is known to be highly permeable, the barrier properties of the underlying choroid-Bruch's layer in transscleral drug transport are not known. To this end, Cheruvu and Kompella (p. 4513) show that the choroid-Bruch's layer, when compared to the sclera, offers equal or greater resistance to the permeability of solutes of varying lipophilicities (Log D: -2.89 to 4.02) and binds lipophilic drugs preferentially. Further, solute permeabilities across sclera as well as choroid-Bruch's layer decrease with increasing lipophilicity or decreasing aqueous solubility, with the decline being steeper for choroid-Bruch's layer. The findings of this study are relevant to the design and development of drugs with enhanced transscleral delivery.
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