| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| July 2003 | Inside IOVS | Volume 44/7 |
Extravascular Matrix Patterns and Risk of Metastasis in Uveal Melanomas
Chen et al. (p. 2834) reconstructed laser scanning confocal microscopy image stacks from serial tissue sections of retinoblastoma and uveal melanoma in an interactive, immersive, three-dimensional virtual reality environment. With this novel strategy, looping extravascular matrix patterns associated with increased risk of metastasis from uveal melanoma were visualized to wrap around cylindrical, branching clusters of tumor cells. With double labeling, fibrinogen, a surrogate marker for plasma, was co-localized to these extravascular matrix patterns. The technique developed in this study can be used to discriminate between the distribution of plasma in blood vessels and the extravascular matrix patterns in human tissue and in animal models.
ABCA4: Lack of Relationship to Age-Related Maculopathy
Sequence variants in the ABCA4 gene have been proposed to increase the risk of age-related maculopathy (ARM). Schmidt et al. (p. 2868) screened a clinically well-characterized population of patients from multiplex families and disease-free controls for variants in any of the 50 exons of this gene. They did not obtain any evidence for a single- or multi-locus association of ABCA4 and ARM. Sequence variants that have previously been implicated in ARM were not present in this patient population. Thus, this study adds to the body of evidence suggesting that ABCA4 is not a major susceptibility gene for this disorder.
Closer Fibril Packing in the Prepupilliary Cornea
Fibril diameters and interfibrillar spacings across human cornea have been mapped in detail by Boote et al. (p. 2941) using X-ray scattering methods. Hitherto it was thought that fibrils were equally spaced across the cornea. However, these new data point to anisotropy in fibril packing across the tissue ¨C disclosing, on average, ~ 5% lower fibril spacings in the optical, prepupilliary corneal zone. This could help strengthen the central cornea by compensating for reduced thickness, and has further implications for corneal optics. The study provides new and fundamental information on corneal ultrastructure, essential to the formulation of accurate corneal models for refractive surgery.
MAPK Activation in Glaucoma
Retinal immunostaining using phosphorylation site-specific antibodies against mitogen-activated protein kinases (MAPKs) demonstrated a prominent and persistent activation of ERK in activated glial cells in glaucomatous eyes. In contrast, immunostaining for phospho-JNK or phospho-p38 was mainly associated with non-glial cells. These findings, as reported in Tezel et al. (p. 3025), provide evidence that ERK signaling is likely associated with the induction and/or maintenance of the activated glial phenotype in glaucoma. Differential activity of MAPKs in neuronal and glial cells in the glaucomatous retina may be associated, in part, with the differential susceptibility of these cell types to glaucomatous injury.
Anti-Tumor Necrosis Factor Therapy: Its Possible Use in Treatment of Uveitis
Anti-tumor necrosis factor (TNF) therapies have been of major value in the treatment of severe rheumatoid arthritis. Their use in uveitis, to date, is restricted to small, uncontrolled case series. Experimentally, Robertson et al. (p. 3034) have demonstrated that inhibition of TNF, by use of TNF receptor fusion protein results in down-regulation of macrophage activity within the retina, which markedly reduces the tissue damage and apoptosis of photoreceptors during retinal inflammation. Clinically, these data increase the evidence for the possible value anti-TNF therapies in uveitis.
Matrix Metalloproteinases (MMPs) and Corneal Ulcers in Vernal Keratoconjunctivitis
While understanding the pathogenesis of severe allergic keratoconjunctivitis is still incomplete, the activation of metalloprotease enzymes can now be added to the host of known pro-inflammatory and amplificatory mechanisms involved. In this study by Leonardi et al. (p. 3052), MMP-1 and MMP-9 were shown to be active in tears of vernal keratoconjunctivitis patients and to be correlated with the clinical severity of the disease. The immunolocalization of MMP-9 and eosinophil cationic protein in the corneal ulcer bed suggests that pharmacological inhibition of proteases and eosinophil activation may be a specific focus in future treatment strategies of vernal keratoconjunctivitis.
Delaying Virus Spread in Herpes Simplex Virus-Induced Retinitis
Acute retinal necrosis syndrome (ARN) affects predominantly healthy individuals. Untreated, the disease is rapidly progressive and may lead to loss of vision in one or both eyes. Archin et al. (p. 3066) produced a mouse model of ARN, in which anterior chamber inoculation of animals with a neurovirulent and neuroinvasive strain of HSV-1 results in bilateral retinitis. Co-inoculation of wild type HSV-1 and a recombinant virus expressing IL-16, a cytokine with chemoattractant properties for lymphocytes and monocytes, resulted in an increase in Mac-1+ cells in the injected eye. Early Mac-1 infiltration of the injected eye corresponded with a delay of virus spread to the brain, a delay of virus infection of the uninoculated eye, and a decrease in virus titer in the uninoculated eye. These observations suggest that cytokine gene delivery vectors might be efficacious in combating infections caused by HSV-1 and that such vectors might be used to treat and/or prevent ARN in human patients.
VEGF Doesn't Work Alone
Its cardinal importance during vessel formation has made VEGF and its main receptor (VEGFR-2) a promising target for inhibiting choroidal neovascularization. Rakic et al. (p. 3186) provide evidence for the involvement of another member of the VEGF family, placental growth factor (PlGF) and its receptor, VEGFR-1, during the development of experimental choroidal neovascularization. Since both PlGF and VEGFR-1 have recognized effects on mononuclear cells, these findings also suggest the possibility of an inflammatory component of choroidal neovascularization in age-related macular degeneration and other forms of neovascularizing choroidal diseases.
Retinal ELOVL4 Gene Expression
Mutations in the ELOVL4 gene underlie various forms of macular dystrophy, however little else is known about the biological role of this gene or its importance to retinal function. Lagali et al. (p. 2841) examined the gene and its products in a variety of species and demonstrate that the pattern of retinal ELOVL4 expression is highly conserved. They show that the ELOVL4 protein is immunolocalized to mammalian photoreceptor cell inner segments, and they define it as a member of a large family of evolutionarily related proteins. These findings suggest that ELOVL4 plays an important role in retinal cell biology across diverse species.
Melanoma: Uveal vs. Cutaneous
Mutations in one of the RAF genes, BRAF, have been recently discovered in the majority of cutaneous melanomas and cutaneous nevi. The predominant BRAF mutation reported in these tumors was thymine-to-adenine (T→A) transversion at nucleotide position 1796. Although common in cutaneous nevi and cutaneous melanoma, Cohen et al. (p. 2876) find that T1796A BRAF mutation is absent in uveal melanomas. These findings support further genetic diversity between cutaneous and uveal melanomas.
Unnerving Genes
Loss of vision due to open-angle glaucoma appears to occur when the age-related loss of optic nerve fibers exceeds the number of nerve fibers available for the remainder of a person's life. Hougaard et al. (p. 3011) suggest that the number of retinal nerve fibers available in adults is determined predominantly by hereditary factors. The thickness of the retinal nerve fiber layer in healthy adults demonstrated a heritability of 82% in a cross-sectional study of twins. Consequently, susceptibility to glaucoma appears to be innate rather than acquired.
Hypoxia and Retinal Neovascularization
For 50 years, it has been commonly assumed that retinal hypoxia causes neovascularization (NV) in proliferative retinopathies, such as retinopathy of prematurity (ROP). However, direct test of this assumption have not been conclusive. Using a magnetic resonance based oximetry measure, Zhang et al. (p. 3119) found retinal hypoxia during normal vessel development both in normal control newborn rats, as well as before the appearance of NV in an ROP model. These data raise the possibility that hypoxia is not a causative factor in the development of retinal NV and suggest that other physiologic factors contribute to NV pathogenesis.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |