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Ocular abnormalities are common in Patau syndrome (trisomy 13), but only a few cases with congenital glaucoma have been reported, some of which were associated with other ocular defects. This report describes a case of primary congenital glaucoma in an 11-year-old patient with full trisomy 13.
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Infrared free-electron lasers ablate tissue with high efficiency and low collateral damage when tuned to the 6-microm range. This wavelength-dependence has been hypothesized to arise from a multi-step process following differential absorption by tissue water and proteins. Here, we test this hypothesis at wavelengths for which cornea has matching overall absorption, but drastically different differential absorption. We measure etch depth, collateral damage and plume images and find that the hypothesis is not confirmed. We do find larger etch depths for larger spot sizes--an effect that can lead to an apparent wavelength dependence. Plume imaging at several wavelengths and spot sizes suggests that this effect is due to increased post-pulse ablation at larger spots.
While Blood vessel epicardial substance (Bves) confers adhesive properties, the molecular mechanism of regulating this activity is unknown. No predicted functional motifs in this highly conserved integral membrane protein, other than the transmembrane domain, have been identified. Here, we report for the first time that Bves interacts with itself through an intracellular interaction domain that is essential for its intercellular adhesion activity. Glutathione-S-transferase (GST) pull-down and SPOTs analyses mapped this domain to amino acids 268-274 in the intracellular C-terminus. Site-directed mutagenesis revealed that lysines 272 and 273 are essential for homodimerization and cell adhesion. Human corneal cells transfected with wild-type Bves trafficked the protein to the cell surface, assembled junction complexes and formed epithelial sheets. In contrast, cells expressing Bves mutated at these positions did not form continuous epithelial sheets or maintain junctional proteins such as ZO-1 and E-cadherin at the membrane. A dramatic reduction in transepithelial electrical resistance was also observed indicating a functional loss of tight junctions. Importantly, expression of mutated Bves in epithelial cells promoted the transformation of cells from an epithelial to a mesenchymal phenotype. This study is the first to demonstrate the essential nature of any domain within Bves for maintenance of epithelial phenotype and function.
PURPOSE - To investigate the possibility that Angiopoietin-like 7 (ANGPTL7) protein is involved in the pathogenesis of glaucoma.
METHODS - Primary human trabecular meshwork (TM) cells and corneoscleral explants were stimulated with either dexamethasone (DEX) or transforming growth factor beta (TGFbeta), and ANGPTL7 protein secreted into culture medium was determined by Western blot analysis. The effect of stable overexpression of ANGPTL7 in transfected immortalized TM cell lines on collagen expression was investigated by immunocytochemistry. Localization of ANGPTL7 protein in human eyes was determined by immunohistochemistry. The concentration of ANGPTL7 protein in aqueous humor (AH) from patients with glaucoma and control patients was compared by Western blot analysis. The beagle model of primary open-angle glaucoma (POAG) was used to correlate ANGPTL7 protein levels in canine AH with disease progression.
RESULTS - TGFbeta and DEX stimulated secretion of ANGPTL7 protein by TM cells and corneoscleral explants. Overexpression of ANGPTL7 by immortalized TM cell lines increased expression of type I collagen. Expression of ANGPTL7 protein was located in the corneal stroma, near the limbus, and throughout the sclera, with lower expression in the TM. In the lamina cribrosa, ANGPTL7 expression was associated with the cribriform plates. The concentration of ANGPTL7 protein was elevated in AH from patients with glaucoma and increased as disease progressed in POAG beagle dogs.
CONCLUSIONS - Induction of ANGPTL7 secretion by glaucoma stimuli and increased concentration of ANGPTL7 in glaucomatous AH suggest that ANGPTL7 is overexpressed in glaucoma. Since overexpression of ANGPTL7 increases collagen expression, a potential disease mechanism, ANGPTL7 could have a pathogenic role in glaucoma, and may serve as a potential therapeutic target.
We ablated porcine corneas with a free electron laser tuned to either 2.77 or 6.45 microm, two matched wavelengths that predominantly target water and protein, respectively. The ejected nonvolatile debris and the crater left behind were examined by circular dichroism, Raman spectroscopy, and scanning electron microscopy to characterize the postablation conformation of collagen proteins. We found near-complete unfolding of collagen secondary and tertiary structure at either ablating wavelength. On the other hand, we found excess fibril swelling and evidence for excess cis-hydroxyproline in the 6.45-microm debris. These results support the hypothesis that the favorable ablative properties of protein-targeting wavelengths rest on selective heating of tissue proteins.
BACKGROUND AND OBJECTIVES - Investigations with a Mark-III free electron laser, tuned to 6.45 microm in wavelength have demonstrated minimal collateral damage and high ablation yield in ocular and neural tissues. While the use of mid-IR light produced by the free electron laser (FEL) has shown much promise for surgical applications, further advances are limited due the high costs of its use. Further investigation and widespread clinical use of six-micron radiation requires the development of an alternative laser source. In this research, we compared a Mark-III FEL and an Er:YAG pumped ZGP-OPO with respect to the effect of pulse duration on ablation efficiency and thermal damage on porcine cornea.
STUDY DESIGN/MATERIALS AND METHODS - A five by seven grid of craters was made about the center of each cornea. Craters were made with a 60-microm spotsize with a 500-microm spacing. Ablation craters were made using 50 pulses per crater at approximately three times the ablation threshold (for water). Histological analysis was used to determine crater depth and thermal damage.
RESULTS - The average zone of thermal damage at 6.1 microm was found to be 4.1 microm for the optical parametric oscillator (OPO) and 5.4 microm for the FEL. At 6.45 microm, the damaged zone was 7.2 microm for the OPO and 7.2 microm for the FEL. At 6.73 microm, the damaged zone was 6.3 microm for the OPO and 7.6 microm+/-0.3 microm for the FEL.
CONCLUSIONS - The OPO caused similar or significantly less thermal damage in porcine cornea when compared with the FEL while generating significantly deeper craters. We determined that the ZGP-OPO has much promise as a bench-top replacement for the FEL for soft tissue ablation.
(c) 2007 Wiley-Liss, Inc
PURPOSE - To determine and compare the central corneal thickness (CCT) and corneal diameter among groups of patients with childhood glaucomas and assess the relationship between CCT and corneal diameter in these patients.
DESIGN - A multicenter observational case series using prospective and retrospective data.
METHODS - Patients from the Scheie Eye Institute, Children's Hospital of Philadelphia, and Emory and Vanderbilt Medical Centers with childhood glaucomas were eligible to participate. Retrospective data on CCT and corneal diameter of these patients were collected when available; otherwise, patients were asked to return to the ophthalmology clinics for measurements. Patients with corneal edema or central corneal scarring were excluded. One hundred eighty four glaucomatous eyes from 109 patients (median age = 9.0 y; age range = 0 to 60 y) were included.
RESULTS - The mean CCT (+/-SE) was 651.1+/-63.5 microm for aphakic, 528.7+/-38.5 microm for Axenfeld-Rieger, and 563.4+/-67.9 microm for 1 degrees infantile eyes. The mean corneal diameter in aphakic, Axenfeld-Rieger, and 1 degrees infantile glaucoma eyes were 11.2+/-1.0, 12.5+/-0.9, and 13.2+/-1.2 mm, respectively. There was a significant difference in CCT and in corneal diameter between aphakic and 1 degrees infantile glaucoma eyes, and between aphakic and Axenfeld-Rieger eyes (P < 0.0001). There was a negative correlation between CCT and corneal diameter in all eyes (r = -0.41, P < 0.0001).
CONCLUSIONS - Patients with aphakic glaucoma are different from those with congenital glaucoma or Axenfeld-Rieger in CCT and corneal diameter. A patient with pediatric glaucoma and a larger corneal diameter was more likely to have a thinner CCT. Attention should be paid to the CCT of patients with childhood glaucomas for interpretation of intraocular pressure.
Mid-infrared free-electron lasers have proven adept in surgical applications. When tuned to wavelengths between 6 and 7 microm, such lasers remove defined volumes of soft tissue with very little collateral damage. Previous attempts to explain the wavelength-dependence of collateral damage have invoked a wavelength-dependent loss of protein structural integrity. However, the molecular nature of this structural failure has been heretofore ill-defined. In this report, we evaluate several candidates for the relevant transition by analyzing the nonvolatile debris ejected during ablation. Porcine corneas were ablated with a free-electron laser tuned to 2.77 or 6.45 microm-wavelengths with matched absorption coefficients for hydrated corneas that respectively target either tissue water or protein. The debris ejected during these ablations was characterized via gel electrophoresis, as well as Fourier transform infrared spectroscopy, micro-Raman and 13C-NMR spectroscopy. We find that high-fluence (240 J/cm2) ablation at 6.45 microm, but not at 2.77 microm, leads to protein fragmentation accompanied by the accumulation of nitrile and alkyne species. The candidate transition most consistent with these observations is scission of the collagen protein backbone at N-alkylamide bonds. Identifying this transition is a key step toward understanding the observed wavelength-dependence of collateral damage in mid-infrared laser ablation.