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PubMed1994

Comparison of diode and argon laser trabeculoplasty in cadaver eyes.

PURPOSE: To evaluate differences in the effects of diode and argon trabeculoplasty on cadaver eye trabecular meshwork. METHODS: The argon laser was used at a 50 mu spot size, 500 to 100 mW of power, and a 0.1 second time interval, and the diode laser was used at a 0.1 to 0.2 second time interval, 100 mu spot size, and 400 to 1200 mW of power. Analysis was performed using videography, microscopy, and scanning electron microscopy. RESULTS: This study found grossly that burns with the argon laser caused tissue blanching and pigment dispersion, whereas no reaction was observed with the diode laser. The diode laser made no observable histologic alterations, but the argon caused fragmentation and coagulation of trabecular beams. Scanning electron microscopy showed that the diode laser caused an area of trabecular beam coalescence measuring 50 to 100 mu in diameter with energies > or = 0.12 J. A surrounding zone of more superficial trabecular beam fragmentation measuring 200 to 400 mu in diameter also was observed. Similar energy levels from the argon laser caused hole formation 200 to 400 mu in diameter. Lower argon energy levels (0.05 J) caused inconsistent coalescence 50 to 100 mu in diameter similar to the diode laser. CONCLUSIONS: This study suggests that in the trabecular meshwork the diode laser causes a reaction at, but not at less than, energy levels shown previously to produce a clinical ocular hypotensive effect. Also, at similar energy per area, the tissue effects of the diode and argon laser are comparable.

Argon↗
PubMed2002

[Relevance of the pseudoexfoliation syndrome for the glaucomas].

Secondary chronic open-angle glaucoma associated with pseudoexfoliation (PEX) syndrome accounts for approximately 25% of all glaucomas and represents the most common identifiable cause of glaucoma overall. The underlying disorder, PEX syndrome, is a generalized process of the extracellular matrix characterized by production and progressive accumulation of an abnormal extracellular material in many intra- and extraocular tissues. Recent data support the pathogenetic concept of PEX syndrome as a type of elastosis affecting particularly elastic microfibrils. Active involvement of the trabecular meshwork in this characteristic matrix process may lead to glaucoma development in 40-60% of the patients. In addition, PEX syndrome also represents an important risk factor for a broad spectrum of spontaneous or intra- and postoperative ocular complications as well as for systemic cardiovascular diseases. PEX-associated open-angle glaucoma represents a relatively severe and progressive type of glaucoma with a generally poor prognosis due to high intraocular pressure levels and fluctuations in the diurnal pressure curve. The primary cause of chronic pressure elevation appears to be local production of PEX material by trabecular meshwork cells and Schlemm's canal cells with subsequent degenerative changes of Schlemm's canal and juxtacanalicular tissues. Additional pathogenetic factors contributing to pressure increase include pronounced melanin dispersion, increased protein concentrations of the aqueous humor, vascular factors, and connective tissue alterations of the lamina cribrosa. Other types of glaucoma, such as acute open-angle glaucoma, provoked by melanin showers during diagnostic mydriasis, or secondary angle closure glaucoma due to pupillary or ciliary block, are also common in PEX patients. The pathogenetic factors TGF-beta1 and TIMP-1/2 appear to be causally involved in this fibrotic process and thus may represent potential targets for specific, rational therapeutic approaches.

Exfoliation Syndrome↗
PubMed2000

Localization of MYOC transcripts in human eye and optic nerve by in situ hybridization.

PURPOSE: To evaluate MYOC (myocilin) gene expression at the RNA level in normal intact human eyes and optic nerve using in situ hybridization. METHODS: Normal human eyes and optic nerves from donors 62 to 83 years of age with no history of glaucoma were fixed, embedded in paraffin, and sectioned. Sections were hybridized with (35)S-labeled sense and antisense riboprobes derived from a full-length MYOC cDNA. RESULTS: High levels of MYOC expression were observed throughout the trabecular meshwork as well as in the most anterior nonfiltering meshwork (Schwalbe's line), in the scleral spur, and in the endothelial lining of Schlemm's canal. MYOC transcripts were also detected in the anterior corneal stroma, in the ciliary muscle, beneath the anterior border of the iris, in the iris stroma, and in the sclera. Expression in the retrolaminar region of the optic nerve was present in the pial septa that divide the nerve fiber bundles, in the perivascular connective tissue surrounding the central retinal vessels, and in the dura mater, arachnoid, and pia mater of the meningeal sheath surrounding the optic nerve. CONCLUSIONS: MYOC gene expression in the trabecular meshwork, Schlemm's canal, scleral spur, and ciliary muscle indicates a structural or functional role for myocilin in the regulation of aqueous humor outflow that may influence intraocular pressure. MYOC expression in the optic nerve suggests that changes in the structural, metabolic, or neurotropic support of the optic nerve may influence its susceptibility to glaucomatous damage.

Aged↗
PubMed2001

Factors associated with elevated intraocular pressure in eyes with iris melanoma.

AIM: To identify clinical factors associated with secondary elevated intraocular pressure (IOP) in eyes with iris malignant melanoma METHODS: A retrospective case series of 169 consecutive patients with microscopically confirmed iris malignant melanoma. The main outcome measure was the presence of tumour induced secondary elevated IOP. Cox proportional regression models were used to calculate the relation of clinical features to elevated IOP. RESULTS: Of 169 patients with microscopically proved iris melanoma, 50 (30%) presented with tumour induced secondary elevated IOP. The mean pressure in those eyes with elevated IOP at diagnosis was 33 mm Hg (median 31 mm Hg, range 23-65 mm Hg). The tumour configuration was nodular in 23 (46%) and diffuse in 27 (54%) with a mean base dimension of 7.4 mm and thickness of 2.0 mm. Invasion of the angle structures by melanoma seeds was visible for a mean of 7 clock hours (median 7, range 0-12 clock hours). The mechanism of elevated IOP was judged to be outflow obstruction from tumour invasion into the trabecular meshwork. There were no cases of neovascular glaucoma. The tumour was ultimately managed with enucleation in 30 patients (60%), local resection (iridectomy, iridocyclectomy, or iridocyclogoniectomy) in 11 (22%), and plaque radiotherapy in five (10%). In four cases (8%), observation of cytologically low grade tumour was the patient's preference. Using multivariate analysis, the clinical factors at initial evaluation associated with tumour induced secondary elevated IOP from iris melanoma included increasing extent of tumour seeding in the anterior chamber angle (p=0.01) and poor visual acuity at presentation (p=0.02). CONCLUSIONS: Microscopically confirmed iris melanoma demonstrates tumour related elevated IOP in 30% cases at the time of presentation, usually secondary to tumour involvement of the trabecular meshwork obstructing aqueous outflow. Enucleation is necessary in the majority of these patients (60%) as opposed to those cases without elevated intraocular pressure (18%).

Adolescent↗
PubMed1996

Ethacrynic acid disrupts steady state microtubules in vitro.

PURPOSE: Ethacrynic acid (ECA) has been shown to increase facility of aqueous outflow in whole eyes and perfused anterior segments, to open up spaces between cells in the trabecular meshwork and inner wall of Schlemm's canal, and to cause separation and retraction of trabecular meshwork and endothelial cells in culture. One mechanism by which ECA has been proposed to act in cells is via disruption of microtubules, leading to cell retraction. Although it is known that ECA can inhibit de novo assembly of microtubules from tubulin subunits in vitro, we wanted to determine, as a better correlate to the proposed effect of ECA in cells, whether ECA could disrupt microtubule polymers that had reached steady state. We also wanted to determine whether calcium ion could enhance this process. METHODS: We therefore assembled purified and crude porcine brain tubulin to steady state at 37 degrees C and then added ECA and/or calcium. Reaction kinetics were followed spectrophotometrically. RESULTS: We found that ECA effectively disrupted assembled microtubules in vitro. Although 0.8-1.0 mM ECA was required to produce a half-maximal effect in pure tubulin microtubules and 0.2-0.3 mM ECA was necessary with crude microtubule protein, significant disassembly also occurred in the 0.01-0.2 mM range. Calcium had a greater maximal effect than ECA, and was more potent on a molar basis, showing half maximal effect between 2 and 12 microM free calcium ion. Combination experiments showed that ECA did not act synergistically with calcium to increase microtubule disassembly. CONCLUSIONS: Our results are consistent with the proposed disruptive action of ECA on the assembled microtubules of outflow pathway cells, but do not support a rise in intracellular calcium as being an added factor.

Animals↗
PubMed2004

[Effect of non-penetrating trabecular surgery with amniotic membrane implant on patients with juvenile glaucoma].

OBJECTIVE: To evaluate the effect of non-penetrating trabecular surgery (NPTS) with amniotic membrane implant in patients with juvenile glaucoma. METHODS: NPTS with amniotic membrane implant was performed on 32 eyes of 26 patients with juvenile glaucoma aged between 12 approximately 28 years. Intraocular pressure (IOP) was measured pre- and post-operatively by CT-60 non-contact tonometer, intraocular irritations and the bleb appearances were recorded, and the anterior chamber angle of post-operation was observed by gonioscopy. Follow-up was (8.3 +/- 4.2) months after surgery. RESULTS: IOP of post-operation was significantly decreased (15.7 +/- 3.7) mm Hg (1 mm Hg = 0.133 kPa; t = 4.82, P < 0.01) compared with that of pre-operation (28.6 +/- 7.3) mm Hg. The mean number of drug usage was significantly reduced to 0.8 (t = 128, P < 0.01) after surgery when compared with 3.2 before surgery. On the last visit, the IOP was <or= 21 mm Hg in 30 eyes (93.8%), among them, there were 18 eyes (56.3%) without anti-glaucoma medication and 12 eyes (37.5%) with anti-glaucoma compounds. There was a small amount of hyphema that was absorbed in 3 approximately 5 days in 6 eyes. The gonioscopy showed that the remnant trabecular meshwork and Descemet membrane were thinner at the surgical site, and microperforation occurred in the trabecular meshwork in 5 eyes. The complications such as flat chamber, inflammation and choroidal detachment were not observed. There was no significant difference in visual acuity between pre- and post-operation. CONCLUSIONS: NPTS with amniotic membrane implant effectively controls elevated IOP in patients with juvenile glaucoma and reduced the number of anti-glaucoma drug usage without significant post-operative complications. NPTS with amniotic membrane implant is an effective and new method for the treatment of patients with juvenile glaucoma.

Adolescent↗
PubMed2005

A trabecular bypass flow hypothesis.

PURPOSE: To introduce a hypothesis that theorizes the effect of a trabecular bypass, a channel created through the trabecular meshwork, on the facility of outflow and the intraocular pressure (IOP). METHODS: Equations that govern the pressure and circumferential flow in Schlemm's canal are established, based on the linear relationships between pressure drop and flow, the balance of flows in the canal, and a uniform leaking structure of collector channels. Two types of bypasses permitting either unidirectional or bidirectional flow are incorporated through boundary conditions to solve the equations and to derive the facility of outflow and the reduced IOP. RESULTS: In normal healthy eyes, the facility of outflow increases by 13% and 26% in the presence of a unidirectional and bidirectional bypass, respectively. The circumferential flow is significant only in the immediate quadrant to the bypass. The elevated IOP due to the abnormally high resistance in trabecular meshwork in open angle glaucoma is substantially reduced with a single bypass. Mean physiological level of IOP is attained if the bidirectional bypass is placed; slightly higher IOP is attained if a unidirectional bypass is placed. In either case, the higher the baseline IOP, the greater the reduction. The effectiveness of the bypass on IOP reduction is related to the resistances in the canal and the collector channels. Multiple bypasses can be used to further reduce the IOP. CONCLUSION: It is theoretically demonstrated that a single patent trabecular bypass can enhance the facility of outflow and reduce the IOP to physiological levels.

Aqueous Humor↗
PubMed2001

Unilateral or asymmetric pseudoexfoliation syndrome? An ultrastructural study.

BACKGROUND: Clinically, most patients with pseudoexfoliation (PEX) syndrome reveal only unilateral ocular involvement. However, the generalized nature of the disorder suggests that PEX syndrome is clinically asymmetric rather than strictly unilateral. OBJECTIVE: To perform an ultrastructural study of the contralateral eyes in patients with unilateral PEX syndrome. METHODS: Five pairs of donor eyes with slitlamp microscopic, macroscopic, and light microscopic evidence of unilateral PEX syndrome and 6 normal control eyes were investigated by transmission electron microscopy and light and electron microscopic immunohistochemistry using antibodies against the human natural killer (HNK-1) epitope and against latent transforming growth factor beta1-binding protein, both markers for the identification of PEX deposits. RESULTS: Ultrastructural alterations were observed in anterior segment tissues of all apparently not involved fellow eyes. These included (1) deposits of typical PEX fibrils on the iris and ciliary epithelia and in the dilator muscle of the iris; (2) increased accumulation of extracellular matrix, including microfibrils and reduplicated basement membrane material in the periphery of iris vessels, in the dilator muscle and in the juxtacanalicular tissue of the trabecular meshwork; and (3) degenerative changes of the iris pigment epithelium and dilator muscle cells. Latent transforming growth factor beta1-binding protein- and HNK-1-positive deposits indicating PEX material accumulations were detected in the periphery of iris vessels and in the dilator muscle in all affected and contralateral eyes, but not in the control eyes. CONCLUSIONS: These subclinical alterations of contralateral eyes in clinically so-called unilateral PEX syndrome support the concept that PEX syndrome is a generalized basically bilateral disorder with a clinically marked asymmetric manifestation. The iris changes may account for the clinical signs characteristic of early stages, such as melanin dispersion, peripupillary atrophy, trabecular meshwork pigmentation, and insufficient asymmetric mydriasis. The findings should be considered in the clinical management of the patients. CLINICAL RELEVANCE: In view of the fact that PEX syndrome is the most common identifiable cause of open-angle glaucoma worldwide and as it is an important risk factor for a wide spectrum of ocular complications, particularly during cataract surgery, the potential involvement of both eyes in the PEX process is of clinical significance.

Aged↗
PubMedDate not supplied

Laser trabeculodissection with a photopolishing scanning excimer laser.

A phase I study of nonpenetrating trabeculectomy (Zimmerman procedure) using a scanning excimer laser system was conducted to evaluate the ability of this laser system to achieve the deep dissection required to allow significant filtration without inadvertent penetration into the anterior chamber. A photopolishing, scanning 193 nm excimer laser system (LS 2000, LaserSight, Inc.) was used with a proprietary fluence, spot size, scanning pattern, and ablation shape to perform a trabeculodissection under a scleral flap with a limbal-based conjunctival flap in 8 cases of advanced glaucoma including 5 eyes that had a failed trabeculectomy. The laser trabeculodissection (LTD) was carried through Schlemm's canal and the juxtacanalicular trabecular meshwork, achieving vigorous aqueous outflow. No peripheral iridectomy was done. The scleral flap was closed loosely with a 10-0 suture. Mitomycin-C was used intraoperatively. In no case did inadvertent penetration into the anterior chamber occur. No peripheral iridectomy was performed. No intraoperative hyphema occurred. There was no postoperative iritis except minimal anterior chamber reaction in 1 eye with preoperative rubeosis. Postoperatively, a good filtering bleb was achieved in all 8 eyes with substantial reduction in the intraocular pressure without topical antiglaucoma therapy. No cases of postoperative shallowing (overfiltration) occurred. Gonioscopy, postoperatively, revealed no new peripheral anterior synechiae (PAS) to the filtration site and an intact inner trabecular meshwork. All eyes were followed for a minimum of 6 months. In this phase I study, laser trabeculodissection (LTD) with a 193 nm photopolishing, scanning system appears to be a promising alternative to full-thickness trabeculectomy, achieving significant filtration while perhaps avoiding much of the risk of filtration surgery. The laser system seemed to provide a more reliable, better-controlled dissection than a knife. The aqueous drainage seems to have acted as a self-regulating endpoint by absorbing UV energy, thus avoiding inadvertent penetration into the anterior chamber. More study is needed to establish the appropriate role of LTD in glaucoma therapy.

Chronic Disease↗
PubMed1999

[Transforming growth factor-beta1 induced cultured human trabecular cells to produce elastin].

OBJECTIVE: To understand transforming growth factor-beta(1) (TGF-beta(1)) inducing cultured human trabecular cells (HTCs) to produce elastin and to approach the effect of resistance of aqueous outflow in the pathogenesis and mechanism of primary open angle glaucoma (POAG). METHODS: Trabecular meshwork's specimens were collected from twelve normal eyeballs of six human donors under six years of age within 24 hours after death. HTCs were primarily cultured and subcultured. Cultured cells were observed under light and electron microscopes. Laminin (LN) and IV collagen (IV C) in extracellular matrix (ECM) were immunohistochemically stained by S-P method. The third passage confluent cells after two weeks were divided into three groups: control group, TGF-beta(1) group and neutralizing antibody of TGF-beta(1) group. Concentration of neutralizing antibody of TGF-beta(1) was 30 microg/ml. After culturing for two weeks, elastin in the media of three groups was respectively determined by western blotting from sodium dodecylsulfate-polyacrylamide gel electrophoresis using anti-human aortic alpha-elastin rabbit serum, biotin conjugated goat anti-rabbit IgG and anti-biotin conjugated horse radish peroxidase. RESULTS: Cultured HTCs were identified from cultured cell's growing characteristics, morphological features under light and electron microscopes, and stained peculiarities of LN and IV C in ECM. With western blotting, elastin in the control group was not detected, elastin in TGF-beta(1) group was detected, and elastin in neutralizing antibody of TGF-beta(1) group was not detected. CONCLUSION: TGF-beta(1) induces cultured HTCs to produce elastin, which the neutralizing antibody of elastin can antagonize; the increase of the amount of elastin may aggravate its stacking in ECM and increase the resistance of aqueous outflow in trabecular meshwork, leading to the occurrence of glaucoma.

Cells, Cultured↗
PubMed1999

Acto-myosin drug effects and aqueous outflow function.

PURPOSE: Previous studies have identified the cytoskeletal proteins actin and tubulin as potential cellular targets in the trabecular meshwork for novel glaucoma therapy. The authors and others have hypothesized that acto-myosin interactions may be important for outflow function. The current study was conducted to evaluate 2,3-butanedione 2-monoxime (BDM), a compound that interferes with acto-myosin function through the myosin adenosine triphosphatase (ATPase) reaction; 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7), a proposed myosin light-chain kinase inhibitor; and the direct actin disrupter, latrunculin B, in an outflow pathway cell culture and perfused excised eye model system. METHODS: Freshly enucleated porcine eyes were perfused using the constant-pressure method at 15 mm Hg and 25 degrees C. Human trabecular meshwork (HTM) cells and Schlemm's canal (SC) cells were grown in culture, treated with BDM, H-7, and latrunculin B, and then fixed, stained for beta-tubulin and filamentous actin, and observed by epifluorescence. RESULTS: Twenty millimolar BDM, 100 microM H-7, and 1 microM latrunculin B increased outflow facility 36%, 63%, and 72%, respectively, compared to sham-treated controls, 13%, 15%, and 4% (n=7, 8, and 8; P=0.01, 0.0001, and 0.0002), respectively. In cultured HTM and SC cells, 100 microM H-7 caused a rapid loss of filamentous actin staining but did not produce a change in cell shape or cell- cell attachment. In contrast, 20 mM BDM induced a loss of cell- cell attachment and a change in cell shape that was associated with a 50% to 60% loss of filamentous actin staining, often in a distinct stick-and-ball pattern. Latrunculin B caused a severe loss of actin staining and cell shape changes. No drug altered beta-tubulin staining. CONCLUSIONS: Interference with myosin function can cause a secondary loss of actin organizational structure. Our study indicates that myosin, perhaps through its various phosphorylation reactions, may have a potential regulatory role in outflow function.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

[Influence of transforming growth factor-beta1 on actin in cultured human trabecular cells].

OBJECTIVE: To understand transforming growth factor-beta(1) (TFG-beta(1)) influencing microfilament actins in cultured human trabecular cells (HTCs) and approach to the effect of resistance of aqueous outflow in the pathogenesis and mechanism of primary open angle glaucoma (POAG). METHODS: Trabecular meshwork was collected from 68 eyeballs of 34 human donors under 6 years old within 24 hours after death. HTCs were primarily cultured and subcultured. Cultured cells were observed by light and electron microscopes. Laminin (LN) and IVcollagen (IVC) in extracellular matrix (ECM) were immunohistochemically stained by S-P method. Various doses (0, 1, 5 ng/ml) of TFG-beta(1) and 30 microg/ml neutralizing antibody of TFG-beta(1) were respectively added to the third passage cells before confluence and acted for 6, 12, 24 hours. Stress fibers stained with fluorescein isocyanate (FITC)-phalloidin were observed under light and electron microscopes. Various doses (0, 0.5, 1, 5 ng/ml) of TFG-beta(1) and 30 microg/ml neutralizing antibody of TFG-beta(1) were respectively added to the third passage cells after confluence for one week and acted for 6, 12, 24, 48 hours. The positive numbers of labeled F-actins were quantitatively evaluated by flow cytometry. Various doses (0, 0.5, 1, 5 ng/ml) of TFG-beta(1) and 30 microg/ml neutralizing antibody of TFG-beta(1) were respectively added to the third passage cells after confluence for one week and acted for 6, 12, 24, 36, 48 hours. The amount of beta-actin mRNA expression was semi-quantitatively evaluated by densitometry with reverse transcription-polymerase chain reaction (RT-PCR) using specific oligonucleotide primers for beta-actin and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) as an internal standard. RESULTS: According to the growing characteristics and morphological features of the cultured cells, they were identified as HTCs. In comparison with the control group, TGF-beta(1) could increase the stress fibrous bundle, the contents of F-actins and the expression of beta-actin mRNA; the effects of TFG-beta(1) appeared time dependent and were antagonized by neutralizing antibody of TFG-beta(1). When TFG-beta(1) was at higher concentration and longer acting time, cell proliferation was inhibited, cell membrane ruptured and cells peeled off in cultured HTCs before confluence. CONCLUSIONS: Application of reverse transcription-semiquantitative PCR can promote the pathogenic research of POAG at genetic level, in a certain extent, TFG-beta(1) can obviously upregulate microfilament actins in the confluent HTCs, enhance the contractility of trabecular cells and decrease the resistance of aqueous outflow in trabecular meshwork.

Actin Cytoskeleton↗
PubMed2001

"Masked" pseudoexfoliation syndrome in unoperated eyes with circular posterior synechiae: clinical-electron microscopic correlation.

OBJECTIVE: To investigate the prevalence of "masked" pseudoexfoliation (PEX) syndrome in eyes with circular posterior synechiae receiving antiglaucomatous therapy with miotics. DESIGN: Cross-sectional prospective study. METHODS: Twenty-eight eyes of 27 consecutive patients with circular posterior synechiae and a history of miotic drug use without previous intraocular surgery, inflammation, or trauma, and without conventional signs of PEX material in the anterior chamber were included in the study. All eyes were investigated by slitlamp biomicroscopy and gonioscopy of the anterior chamber before extracapsular cataract surgery for the presence of typical PEX-associated iris pigment epithelial changes, such as peripupillary atrophy and trabecular meshwork melanin granule deposition. The anterior chamber depth, lens thickness, and axial lengths of the eyes were measured by A-scan immersion sonography. The excised anterior lens capsules obtained during extracapsular cataract surgery were investigated for the presence of precapsular fibrillar PEX deposits by electron microscopy. MAIN OUTCOME MEASURE: The prevalence of masked PEX syndrome in eyes with circular posterior synechiae receiving antiglaucomatous therapy with miotics. RESULTS: Transmission electron microscopy of unselected nonserial sections revealed a precapsular layer consisting of typical PEX fibers or microfibrils, which indicated early stages of PEX syndrome in 18 (64%) of 28 eyes with circular posterior synechiae. Melanin granules were frequently found adhering to the fibrillar layer. Eyes with precapsular fibrillar deposits showed significantly greater trabecular meshwork pigmentation than eyes without such deposits. Differences in age, lens thickness, axial length of the eye, anterior chamber depth, and degree of peripupillary atrophy were, however, not statistically significant between the groups with and without electron microscopic evidence of PEX deposits. CONCLUSIONS: Circular posterior synechiae were more frequently associated with manifest or early stages of PEX syndrome. However, the formation of broad posterior synechiae in miosis prevented a definite clinical diagnosis based on the classic changes of the anterior lens capsule. In eyes with spontaneous or miotic-induced circular posterior synechiae without other obvious cause, the masked variant of PEX syndrome should always be considered.

Aged↗
PubMed2003

Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide.

PURPOSE: To investigate long-term changes in the anterior segment of primate eyes treated for one year with different prostaglandin agonists and a prostamide. The results were compared with those obtained after vehicle treatment and in untreated controls. METHODS: Sixteen young cynomolgus monkeys were unilaterally topically treated for 1 year with either bimatoprost 0.03% (prostamide), sulprostone 0.03% (EP(3)/EP(1) agonist), AH13205 0.1% (EP(2) agonist), or latanoprost 0.005% (FP agonist), which all lower IOP in this species at the doses applied. Four animals were treated with the vehicle only. In all cases the left eye was treated, the right eye remained untreated. Six monkeys served as untreated controls. Sections from 4 quadrants each of the circumference of the eyes of 16 drug-treated, 4 vehicle-treated and 6 untreated control animals were investigated qualitatively and quantitatively using light- and electronmicroscopy. The area of widened spaces between ciliary muscle bundles, the number of nerve fiber bundles at the muscle tips, and the width and length of the ciliary muscle were quantitated. RESULTS: The general morphology of the ciliary muscle and trabecular meshwork was normal in appearance and shape in all animals, whereas some localized morphologic changes were observed in the drug-treated animals. The changes were found to be similar in all four treatment groups. In the ciliary muscle, there was a significant increase in optically empty spaces between muscle bundles in the anterior portion of the longitudinal and the reticular ciliary muscle compared with untreated and vehicle-treated control animals. Within these spaces, significantly more myelinated nerve fiber bundles were found in drug-treated compared with normal control animals. Ultrastructurally the spaces were partly covered by endothelial-like cells which, in some areas, were in contact with the basement membrane of the microvasculature. In all treatment groups, there were also changes in the trabecular meshwork region. Significant regional differences among the different quadrants of the eyes and quantitative differences between treatment groups were observed. The ciliary epithelium had a normal appearance in all treatment groups. CONCLUSIONS: After one year of treatment with different prostaglandins and a prostamide, uveoscleral outflow pathways are enlarged and appear organized. Conventional outflow routes were also affected. Long-term treatment with AH13205, latanoprost, sulprostone, or bimatoprost also induces sprouting of nerve fibers.

Administration, Topical↗
PubMed1985

Neodymium: YAG laser trabeculopuncture in open-angle glaucoma.

Ten eyes of eight patients with open-angle glaucoma (OAG) had neodymium (Nd):YAG trabeculopuncture performed in an investigational protocol as an alternative to surgical intervention. In each, at four to six sites in the mid-trabecular meshwork, three to six superimposed applications were made (2 to 6 mJ). In four of six patients with adult OAG, a small decrease in intraocular pressure (IOP) was noted (from a mean of 25.5 to 20.0 mmHg after 3-4 weeks in the treated eyes, compared to no change at 21 mmHg in the fellow eyes). There appeared to be further attenuation of this IOP effect over the subsequent 2 to 11 months, and all patients demonstrated gonioscopic closure of all the puncture sites with time. One patient demonstrated an acute IOP elevation to 58 mmHg after the procedure, necessitating emergency filtration surgery. In contrast, in four eyes of two patients with juvenile open angle glaucoma, a dramatic lowering of IOP and improvement in tonographic outflow facility was demonstrated, although the effects were only temporary in one patient. YAG laser treatment to the trabecular meshwork may have its greatest potential usefulness when abnormalities in the uveal meshwork are involved, such as in certain cases of juvenile or congenital glaucoma, and may help identify the need for a surgical goniotomy. With more usual forms of OAG, however, widespread use of this technique should be avoided until greater efficacy can be achieved.

Adolescent↗
PubMed2003

Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients.

BACKGROUND: Little is known about the molecular mechanisms responsible for the development of glaucoma, the leading cause of irreversible blindness worldwide. Some investigators have hypothesized that oxidative damage may be involved. We evaluated oxidative deoxyribonucleic acid (DNA) damage, in terms of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the eyes of glaucoma patients. METHODS: Levels of 8-OH-dG were measured in the trabecular meshwork region from 42 patients with glaucoma and 45 controls of similar age and sex. Genotypes of glutathione S-transferase isoenzymes (GSTM1 and GSTT1) were assessed by polymerase chain reaction in the same DNA samples. RESULTS: Levels of 8-OH-dG were significantly higher in glaucoma patients than in controls. Oxidative DNA damage in patients with glaucoma correlated significantly with intraocular pressure; in patients with primary open-angle glaucoma, it also correlated with visual field defects. GSTT1 was similar in the two groups, and had no effect on 8-OH-dG levels. Conversely, 8-OH-dG levels were significantly higher in GSTM1-null than in GSTM1-positive subjects. The GSTM1-null genotype was significantly more common in patients with primary open-angle glaucoma than in controls. CONCLUSION: Oxidative DNA damage is significantly increased in the trabecular meshwork of glaucoma patients. GSTM1 gene deletion, which has been associated with an increased risk of cancer at various sites and molecular lesions in atherosclerosis, predisposes to more severe oxidative DNA damage in glaucoma patients. These findings may contribute to understanding the pathogenesis of glaucoma and may be useful in the prevention and treatment of this disease.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

In the mammalian eye type VI collagen tetramers form three morphologically different aggregates.

The organization of the aggregates occurring in the stroma: (1) of the murine and human cornea after incubation in an ATP acidic solution; (2) of surgically excised epiretinal membranes (ERM); and (3) of the trabecular meshwork of monkey eyes was investigated morphologically and immunocytochemically on thin section electron microscopy. Morphology. The aggregates in the cornea appeared as cross-banded fibrils. The bands were uniformly electron dense (single banded form); they were separated from each other by interbands consisting of a bundle of filaments emerging in cross section as small areas of randomly assembled dot-like structures. In the ERM, most of the aggregates stood out as heteromorphic cross-banded bodies showing dense bands with electron denser borders (double banded form) and interbands composed of longitudinally oriented, parallel sheets or laminae of amorphous material enclosing thin, similarly oriented filaments. These extended, thinner and double in number (since interlacing with similar components of the opposite sheet), into the pale central zone of the dense band. The aggregates of the trabecular meshwork were heteromorphic, had uniformly dense bands (single banded form as in the cornea), but their interbands displayed longitudinal sheets (as the ERM aggregates). Immunocytochemistry revealed type VI collagen in the three eye aggregates with gold particles preferentially localized at the interbands. The specificity of the antibodies used was tested by Western blot analysis of type VI collagen samples extracted from human placenta and on homogenates of human cornea. In conclusion, the results indicate that the tetramers of type VI collagen may aggregate differently into structures with distinct supramolecular arrangements. These are illustrated in schematic drawings.

Aged↗
PubMed2004

Heparin II domain of fibronectin uses alpha4beta1 integrin to control focal adhesion and stress fiber formation, independent of syndecan-4.

Co-signaling events between integrins and cell surface proteoglycans play a critical role in the organization of the cytoskeleton and adhesion forces of cells. These processes, which appear to be responsible for maintaining intraocular pressure in the human eye, involve a novel cooperative co-signaling pathway between alpha5beta1 and alpha4beta1 integrins and are independent of heparan sulfate proteoglycans. Human trabecular meshwork cells isolated from the eye were plated on type III 7-10 repeats of fibronectin (alpha5beta1 ligand) in the absence or presence of the heparin (Hep) II domain of fibronectin. In the absence of the Hep II domain, cells had a bipolar morphology with few focal adhesions and stress fibers. The addition of the Hep II domain increased cell spreading and the numbers of focal adhesions and stress fibers. Cell spreading and stress fiber formation were not mediated by heparan sulfate proteoglycans because treatment with chlorate, heparinase, or soluble heparin did not prevent Hep II domain-mediated cell spreading. Cell spreading and stress fiber formation were mediated by alpha4beta1 integrin because soluble anti-alpha4 integrin antibodies inhibited Hep II domain-mediated cell spreading and soluble vascular cell adhesion molecule-1 (alpha4beta1 ligand)-induced cell spreading. This is the first demonstration of the Hep II domain mediating cell spreading and stress fiber formation through alpha4beta1 integrin. This novel pathway demonstrates a cooperative, rather than antagonistic, role between alpha5beta1 and alpha4beta1 integrins and suggests that interactions between the Hep II domain and alpha4beta1 integrin could modulate the strength of cytoskeleton-mediated processes in the trabecular meshwork of the human eye.

Binding Sites↗