Clinical Efficacy of Topical Nipradilol and Timolol on Visual Field Performance in Normal- Tension Glaucoma: a Multicenter

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Clinical efficacy of topical nipradilol and timolol on visual field performance in normal- tension glaucoma: A multicenter...

Article in Japanese Journal of Ophthalmology · August 2008 DOI: 10.1007/s10384-008-0540-z · Source: PubMed

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Shiroaki Shirato Yasuo Ohashi SHIRATO EYE CLINIC Chuo University

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The user has requested enhancement of the downloaded file. 60) Clinical efficacy of topical nipradilol and timolol on visual field performance in normal-tension glaucoma: a multicenter, randomized, double-masked comparative study.

Araie M , Shirato S , Yamazaki Y , Kitazawa Y , Ohashi Y ; Nipradilol-Timolol Study Group . Collaborators (55)

Shirato S , Yamazaki Y , Araie M , Matsumoto C , Shirato S , Yamazaki Y , Araie M , Ohashi Y , Hamada C , Kitazawa Y , Ohashi Y , Hara T , Hashimoto T , Tsuru T , Kojima T , Tomidokoro A , Nakajima F , Obata R , Yamazaki Y , Nakagami T , Hayamizu F , Yamagami J , Suzuki J , Kishimoto S , Oshima Y , Nakayama K , Otake Y , Kimura I , Tanino T , Shirato S , Haneda M , Kimura T , Kawabata K , Yasuda N , Nakamoto K , Matsumoto S , Yoshimoto M , Suzumura H , Tomita G , Suzuki Y , Tomidokoro A , Kunimatsu S , Nakano T , Shirato S , Maruyama K , Inoue T , Kouzaki A , Inoue Y , Suzumura H , Yoshikawa K , Miyata H , Shirakashi M, Kashiwagi K , Iwase A , Shono Y .

Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan. [email protected]

PURPOSE: To compare the effects of topical nipradilol and timolol on the visual field in Japanese normal-tension glaucoma (NTG) patients. METHODS: We enrolled 146 NTG patients. At baseline, age, intraocular pressure (IOP), and mean deviation (MD) by the Humphrey field analyzer were 47.6 (SD 8.5), 14.2 (1.7) mmHg, and -4.5 (3.0) dB. Seventy-two patients were randomly assigned to the 0.25% nipradilol group and 74 patients to the 0.5% timolol ophthalmic solution group twice daily for the 3-year study period. The Humphrey full-threshold 30-2 visual field test was performed every 6 months. The primary end point was the nonparametric O'Brien summary score (sum of the ranks of six slopes calculated from the average of the total deviation in each cluster) in each patient. The secondary analyses were differences in the MD slope, average of the total deviation in each cluster, the corrected pattern standard deviation (CPSD), and the time course of IOP. RESULTS: No significant intergroup differences were found in baseline characteristics, or in the parameters of the primary and secondary analyses. In both groups, central superior clusters showed negative slopes and IOP decreased by about 1 mmHg from baseline. CONCLUSION: No significant difference in visual field performance or IOP reduction was seen between the nipradilol and timolol groups.

PMID: 18773262 [PubMed - indexed for MEDLINE]

61) Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure.

Sappington RM , Calkins DJ . Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0654, USA.

PURPOSE: The authors investigated the contributions of the transient receptor potential vanilloid-1 receptor (TRPV1) and Ca(2+) to microglial IL-6 and nuclear factor kappa B (NFkappaB) translocation with elevated hydrostatic pressure. METHODS: The authors first examined IL-6 colocalization with the microglia marker Iba-1 in the DBA/2 mouse model of glaucoma to establish relevance. They isolated microglia from rat retina and maintained them at ambient or elevated (+70 mm Hg) hydrostatic pressure in vitro and used ELISA and immunocytochemistry to measure changes in the IL-6 concentration and NFkappaB translocation induced by the Ca(2+) chelator EGTA, the broad-spectrum Ca(2+) channel inhibitor ruthenium red, and the TRPV1 antagonist iodo-resiniferatoxin (I-RTX). They applied the Ca(2+) dye Fluo-4 AM to measure changes in intracellular Ca(2+) at elevated pressure induced by I-RTX and confirmed TRPV1 expression in microglia using PCR and immunocytochemistry. RESULTS: In DBA/2 retina, elevated intraocular pressure increased microglial IL-6 in the ganglion cell layer. Elevated hydrostatic pressure (24 hours) increased microglial IL-6 release, cytosolic NFkappaB, and NFkappaB translocation in vitro. These effects were reduced substantially by EGTA and ruthenium red. Antagonism of TRPV1 in microglia partially inhibited pressure-induced increases in IL-6 release and NFkappaB translocation. Brief elevated pressure (1 hour) induced a significant increase in microglial intracellular Ca(2+) that was partially attenuated by TRPV1 antagonism. CONCLUSIONS: Elevated pressure induces an influx of extracellular Ca(2+) in retinal microglia that precedes the activation of NFkappaB and the subsequent production and release of IL-6 and is at least partially dependent on the activation of TRPV1 and other ruthenium red-sensitive channels.

PMID: 18362111 [PubMed - indexed for MEDLINE]

62) A comparison of visual field progression criteria of 3 major glaucoma trials in early manifest glaucoma trial patients.

Heijl A , Bengtsson B , Chauhan BC , Lieberman MF , Cunliffe I , Hyman L , Leske MC .

Department of Ophthalmology, Lund University, Malmö University Hospital, Malmö, Sweden. [email protected]

PURPOSE: Three major glaucoma trials, all using the same Humphrey visual field tests, specified different criteria to define visual field progression. This article compares the performance of these criteria with a reference standard of unanimous classifications by 3 independent glaucoma experts. DESIGN: Longitudinal, comparative study of diagnostic criteria. PARTICIPANTS AND CONTROLS: Two hundred forty-five patients with manifest glaucoma in the Early Manifest Glaucoma Trial (EMGT). METHODS: Visual field series of 1 eye of each of 245 EMGT patients were classified by 3 independent glaucoma specialists as definitely progressing, definitely nonprogressing, or neither. Field series that were classified in the first 2 categories by all 3 experts met the reference standards for the progressing and nonprogressing groups and were analyzed according to the progression criteria of the Advanced Glaucoma Intervention Study (AGIS), the Collaborative Initial Glaucoma Treatment Study (CIGTS), and the EMGT. Sensitivity, specificity, time to progression, and sustainability were calculated. MAIN OUTCOME MEASURES: Progression, nonprogression, sensitivity, specificity, time to progression, and sustainability. RESULTS: Seventy-seven field series were definitely progressing, and 95 series were definitely nonprogressing. Among progressing eyes, 45 (58%) of 77 were identified using AGIS criteria, 58 (75%) of 77 were identified with CIGTS criteria, and 74 (96%) of 77 were identified with EMGT criteria; all comparisons of sensitivities were significant, simultaneous (P<0.001), and pairwise (P<0.01). The specificity for EMGT criteria was 89%, lower (P<0.05) than that of AGIS (98%) and CIGTS (99%) criteria. Median time to progression was considerably shorter with EMGT criteria (33 months; 95% confidence interval [CI], 30-36 months) than with AGIS (66 months; 95% CI, 57-78 months) and CIGTS (55 months; 95% CI, 48-66 months) criteria. Sustainability increased with time after progression; it averaged 79%, 84%, and 81%, respectively, for AGIS, CIGTS, and EMGT criteria during the first year after the first progression and 95%, 100%, and 93% during the fourth year after progression. CONCLUSIONS: The EMGT criteria identified progression earlier and more often than AGIS and CIGTS criteria. Specificity was good for all criteria but was better with AGIS and CIGTS than with EMGT criteria. Sustainability was high for all 3 sets of criteria and best for CIGTS criteria and increased with time after progression.

PMID: 18378317 [PubMed - indexed for MEDLINE]

63) Ahmed valve implantation with adjunctive mitomycin C and 5-fluorouracil: long-term outcomes.

Alvarado JA , Hollander DA , Juster RP , Lee LC .

Department of Ophthalmology, Glaucoma Research Laboratory, University of California, San Francisco, San Francisco, California 94143, USA. [email protected]

PURPOSE: To evaluate long-term outcomes after Ahmed valve implantation in patients with glaucoma when using adjunctive intraoperative mitomycin C (MMC) and postoperative 5-fluorouracil (5-FU). DESIGN: Retrospective, interventional, consecutive case series. METHODS: A consecutive series of eyes undergoing Ahmed valve implantation, either alone (AHMED eyes) or in combination with cataract surgery (AHMED+PHACO), using both intraoperative MMC and postoperative 5-FU were evaluated. Failure was defined as the first occurrence of any of the following: 1) the first of three consecutive visits where intraocular pressure (IOP) was >18 mm Hg or <20% IOP reduction from baseline and the final number of topical medications was not reduced by at least two from baseline, 2) the need for additional surgery, or 3) the development of serious complications. RESULTS: A total of 130 eyes underwent Ahmed valve implantation with intraoperative exposure to 0.5 mg/ml MMC (median time: eight minutes; range, four to 10) and postoperative subconjunctival injections of 5 mg of 5- FU (median: five injections; range, zero to nine). Kaplan-Meier estimates of the cumulative probability of valve success and confidence interval (CI) at the sixth follow- up year were 0.72 (95% CI, 0.59 to 0.82) for AHMED eyes (n = 88), 0.84 (95% CI, 0.65 to 0.93) for AHMED+PHACO eyes (n = 42). A median of two fewer medications were required relative to baseline for both AHMED and AHMED+PHACO eyes. CONCLUSIONS: The adjunctive use of both intraoperative MMC and postoperative 5-FU with Ahmed valve implantation results in high success rates. IOP was well controlled in the majority of patients within the six-year postoperative period.

PMID: 18538300 [PubMed - indexed for MEDLINE]

64) Aqueous humor dynamics in exfoliation syndrome.

Johnson TV , Fan S , Camras CB , Toris CB .

Department of Ophthalmology, Universityof Nebraska Medical Center, Omaha, NE 68198-5840, USA.

OBJECTIVE: To examine how aqueous humor dynamics are affected by exfoliation syndrome (XFS) with or without elevated intraocular pressure (IOP). METHODS: Eighty participants were divided into 4 groups: (1) those with XFS and ocular normotension (n = 25), (2) controls with ocular normotension without XFS, age-matched to group 1 (n = 25), (3) those with XFS and ocular hypertension (n = 15), and (4) controls with ocular hypertension without XFS, age-matched to group 3 (n = 15). Following washout of glaucoma medications, assessments were made of IOP, episcleral venous pressure, aqueous flow, outflow facility, and uveoscleral outflow. Differences were analyzed by group mean comparisons and linear regression analyses. RESULTS: Uveoscleral outflow was significantly decreased in individuals with XFS compared with age-matched controls and was independent of IOP. Patients with ocular hypertension (with or without XFS) exhibited decreased outflow facility compared with those with ocular normotension (with or without XFS). Aqueous flow was not affected by the level of IOP or the presence of XFS. CONCLUSIONS: Exfoliation syndrome in normotensive and hypertensive eyes is associated with a decrease in uveoscleral outflow, whereas in hypertensive but not normotensive eyes, it is associated with reduced outflow facility.

PMID: 18625936 [PubMed - indexed for MEDLINE

65) Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients.

Wells AP , Garway-Heath DF , Poostchi A , Wong T , Chan KC , Sachdev N .

Capital Eye Specialists, Wellington, New Zealand. [email protected] PURPOSE: To investigate relationships between acute intraocular pressure (IOP)- induced optic nerve head surface deformation and corneal hysteresis and thickness in glaucomatous and nonglaucomatous human eyes. METHODS: This was a prospective experimental study of 100 subjects (38 with glaucoma, 62 without glaucoma). Data collected included spherical equivalent, optic disc diameter, central corneal thickness (CCT), axial length, cylinder, Goldmann IOP, Pascal IOP, and ocular pulse amplitude and ocular response analyzer (ORA) measurements of corneal hysteresis (CH). Elevation of IOP was induced in the right eye of each subject with a modified LASIK suction ring to an average of 64 mm Hg for less than 30 seconds. Heidelberg Retina Tomography II (HRT) was used to map the optic nerve surface before and during IOP elevation. Mean cup depth was calculated using built-in HRT data analysis software. Change in optic disc depth during IOP elevation was calculated for all right eyes, and tests for correlation with the parameters listed were performed. RESULTS: Both CH and CCT were lower in the glaucoma group (8.8 mm Hg and 532 microm) than in the control group (9.6 mm Hg, P = 0.012; 551 microm, P = 0.011, respectively). There were no statistically significant differences in spherical equivalent, cylinder, axial length, optic disc size, or ocular pulse amplitude between the glaucoma and the control groups. There was no difference between the amount of IOP elevation between the two groups (P = 0.41), and the average difference in mean cup depth between baseline (mean cup depth, 247 microm) and during IOP elevation was 33 microm (29.8 microm in glaucoma and 36.1 microm in control; P = 0.5). Multiple variable analysis, controlling for age and sex, showed that CH was correlated with mean cup depth increase (P = 0.032). This relationship persisted (P = 0.032) after controlling for glaucoma status in addition to age and sex. Other factors, including CCT (P = 0.3), axial length (P = 0.9), ocular pulse amplitude (P = 0.22), and spherical equivalent (P = 0.38), were not significant in this model. CONCLUSIONS: In the glaucoma patients but not the control patients, CH but not CCT or other anterior segment parameters was associated with increased deformation of the optic nerve surface during transient elevations of IOP. (ClinicalTrials.gov number, NCT00328835.).

PMID: 18316697 [PubMed - indexed for MEDLINE]

66) Dietary omega-3 fatty acids and ganglion cell function.

Nguyen CT , Vingrys AJ , Bui BV .

Department of Optometry and Vision Sciences, University of Melbourne, Parkville, Victoria, Australia.

PURPOSE: Diet-induced deficiencies in Omega-3 (omega-3) fatty acids are well known to alter photoreceptor function. In this study, the broader functional changes in a diversity of retinal neurons were considered. METHODS: Sprague-Dawley dams were fed either omega-3-sufficient (omega-3(+), n = 21) or -deficient (omega-3(-), n = 19) diets 5 weeks before conception, with the pups continued on the mothers' diet. After 20 weeks of age, electroretinograms (ERGs) were recorded by using protocols that isolate separate cellular generators, including; photoreceptors (PIII), ON-bipolar cells (PII), and ganglion/amacrine cells (STR). At the brightest energies, rod and cone responses were isolated with a paired-flash paradigm. Retinal tissue (omega-3(+), n = 5; omega- 3(-), n = 5) was harvested at 23 weeks of age for fatty acid assays with thin layer and gas liquid chromatography. RESULTS: Omega-3 deficiency caused a 48.6% decrease in total retinal docosahexaenoic acid (DHA). This change induced significant amplitude decreases only in the rod PII (-8.2%) and positive (p)STR components (-27.4%), with widespread delays in all signals (PIII 5.7%, PII 13.6%, pSTR 7.6%, and negative [n]STR 8.3%). Omega-3 deficiency exerted its greatest effects on signals originating in the inner retina (pSTR). CONCLUSIONS: Increasing dietary omega-3 has beneficial effects across the retina, with the greatest improvement occurring in ganglion cell function.

PMID: 18469188 [PubMed - indexed for MEDLINE]

67) Glaucoma and on-road driving performance.

Haymes SA , LeBlanc RP , Nicolela MT , Chiasson LA , Chauhan BC .

Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. [email protected]

PURPOSE: To investigate the on-road driving performance of patients with glaucoma. METHODS: The sample comprised 20 patients with glaucoma and 20 subjects with normal vision, all licensed drivers, matched for age and sex. Driving performance was tested over a 10-km route incorporating 55 standardized maneuvers and skills through residential and business districts of Halifax, Nova Scotia, Canada. Testing was conducted by a professional driving instructor and assessed by an occupational therapist certified in driver rehabilitation, masked to participant group membership and level of vision. Main outcome measures were total number of satisfactory maneuvers and skills, overall rating, and incidence of at-fault critical interventions (application of the dual brake and/or steering override by the driving instructor to prevent a potentially unsafe maneuver). Measures of visual function included visual acuity, contrast sensitivity, and visual fields (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc., Dublin, CA; mean deviation [MD] and binocular Esterman points). RESULTS: There was no significant difference between patients with glaucoma (mean MD = -1.7 dB [SD 2.2] and -6.5 dB [SD 4.9], better and worse eyes, respectively) and control subjects in total satisfactory maneuvers and skills (P = 0.65), or overall rating (P = 0.60). However, 12 (60%) patients with glaucoma had one or more at-fault critical interventions, compared with 4 (20%) control subjects (odds ratio = 6.00, 95% CI, 1.46-24.69; higher still after adjustment for age, sex, medications and driving exposure), the predominant reason being failure to see and yield to a pedestrian. In the glaucoma group, worse-eye MD was associated with the overall rating of driving (r = 0.66, P = 0.002). CONCLUSIONS: This sample of patients with glaucoma with slight to moderate visual field impairment performed many real-world driving maneuvers safely. However, they were six times as likely as subjects with normal vision to have a driving instructor intervene for reasons suggesting difficulty with detection of peripheral obstacles and hazards and reaction to unexpected events.

PMID: 18326696 [PubMed - indexed for MEDLINE]

68) Glaucoma is associated with peripheral vascular endothelial dysfunction.

Su WW, Cheng ST , Ho WJ , Tsay PK , Wu SC , Chang SH .

Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

PURPOSE: To evaluate peripheral vascular endothelial function in patients with normal- tension glaucoma (NTG) and primary open-angle glaucoma (POAG) using noninvasive endothelium-dependent flow-mediated vasodilation (FMD). DESIGN: Case-control study. PARTICIPANTS: Thirty patients with NTG, 30 with POAG, and 30 healthy age- and gender-matched controls. METHODS: Participants underwent measurement of FMD and endothelium-independent nitroglycerin-mediated vasodilation (NMD) via high- resolution 2-dimensional ultrasonographic imaging of the brachial artery. All patients also underwent blood sampling for biochemistry, lipid profile, and high sensitivity C- reactive protein analysis. MAIN OUTCOME MEASURES: The association of FMD with NTG and POAG. RESULTS: The FMD values differed significantly between the patients with NTG, those with POAG, and controls: NTG, 2.70+/-2.25%; POAG, 5.33+/-2.81%; controls, 7.21+/-2.36%; P<0.001. In comparison with the POAG group and normal controls, the NTG group demonstrated markedly impaired FMD. The POAG group exhibited higher intermediate FMD than the NTG group (P<0.001) but significantly lower FMD than normal controls (P = 0.012). Multivariate analysis indicated that independent predictors for impaired FMD were presence of NTG, presence of POAG, and advanced age. Additionally, FMD values were significantly lower in glaucoma patients than in controls (4.02+/-2.85% vs. 7.21+/-2.36%; P<0.001). CONCLUSIONS: Patients with glaucoma have impaired FMD. Additionally, patients with NTG have lower FMD than those with POAG.

PMID: 18076992 [PubMed - indexed for MEDLINE

69) Intraocular pressure response to topical beta-blockers associated with an ADRB2 single-nucleotide polymorphism.

McCarty CA , Burmester JK , Mukesh BN , Patchett RB , Wilke RA .

Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449, USA. [email protected]

OBJECTIVES: To determine whether candidate pharmacodynamic (beta-adrenergic receptor) and pharmacokinetic (cytochrome P450 2D6) gene polymorphisms are associated with the intraocular pressure (IOP) response to topical beta-blockers. METHODS: Medical records of 18,773 adults in the Personalized Medicine Research Project were searched to extract all IOP measurements for subjects who had been prescribed a topical beta-blocker. Five single-nucleotide polymorphisms in the beta(1)-, beta(2)-, and beta(3)-adrenergic receptor genes and 6 polymorphisms in the CYP2D6 gene were genotyped. RESULTS: A total of 58.1% of the subjects were female; the mean age was 63.8 years. Topical beta-blockers were prescribed for 343 eyes of 215 subjects. An IOP reduction of 20% or more in 1 or both eyes was observed in 61.0% of subjects. Men were significantly more likely than women to have an IOP decrease of 20% or more (69.3% vs 54.9%, respectively; chi(2) = 4.48; P = .04). After adjusting for sex, family history of glaucoma, and use of systemic beta-blockers, subjects with the CC genotype at coding single-nucleotide polymorphism rs1042714 in the ADRB2 gene were significantly more likely to experience an IOP decrease of 20% or more (odds ratio, 2.00; 95% confidence interval, 1.00-4.02). CONCLUSION: We found that a coding single-nucleotide polymorphism in ADRB2 is associated with an increased likelihood of a clinically meaningful IOP response to topical beta-blockers. Clinical Relevance Because topical beta-blockers are the least expensive class of agents used to lower IOP, genotype-based drug prescribing could save health care dollars.

PMID: 18625943 [PubMed - indexed for MEDLINE]

70) Late-stage, primary open-angle glaucoma in Europe: social and health care maintenance costs and quality of life of patients from 4 countries.

Thygesen J , Aagren M , Arnavielle S , Bron A , Fröhlich SJ , Baggesen K , Azuara- Blanco A , Buchholz P , Walt JG .

Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

OBJECTIVE: The purpose of this study was to estimate costs and quality of life (QoL) of late-stage glaucoma patients in 4 European countries. METHODS: Retrospective review of medical charts of patients with POAG who were followed in a low-vision or vision rehabilitation center in one of 4 countries for at least 1 year was used to determine patient characteristics, health status, and health care resource use. Visual impairment was measured by best-corrected visual acuity (Snellen score). Patients were also interviewed over the telephone in order to assess their health-related QoL (using EuroQol EQ-5D) and use of resources including: the number of visits to rehabilitation centers, visits to hospital and non-hospital specialists, the use of low-vision devices, medication, tests, and the use of hired home help. The costs associated with resource use were calculated from the perspective of a third-party payer of health and social care based on resource usage and unit costs in each country. RESULTS: Patients undergoing visual rehabilitation in France (n=21), Denmark (n=59), Germany (n=60), and the United Kingdom (n=22) were identified, interviewed and had their medical charts reviewed. Annual maintenance costs of late-stage glaucoma amounted to euro830 (+/-445) on average. Average home help costs were more than 3 times higher. QoL, on average, was 0.65 (+/-0.28). QoL was positively correlated with the level of visual acuity in the patients' best eye. On the other hand, visual acuity was also positively correlated to health care costs, but negatively correlated to costs of home help. CONCLUSIONS: The study was limited by its observational, uncontrolled design. The finding that late-stage glaucoma is associated with higher home help costs than health care maintenance costs suggests that potential savings from a better preventive treatment are to be found for social care payers rather than health care payers.

PMID: 18559164 [PubMed - indexed for MEDLINE]

71) Light affects mitochondria to cause apoptosis to cultured cells: possible relevance to ganglion cell death in certain optic neuropathies.

Osborne NN , Li GY , Ji D , Mortiboys HJ , Jackson S .

Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK. [email protected]

Retinal ganglion cell axons within the globe are laden with mitochondria that are unprotected from light (400-760 nm) impinging onto the retina. Light can be absorbed by mitochondrial enzymes such as cytochrome and flavin oxidases causing the generation of reactive oxygen species, and we have suggested this may pose a risk to ganglion cell survival if their energy state is compromised, as may be so in glaucoma or in Leber's Hereditary Optic Neuropathy. Here, we demonstrate that light (400-760 nm) provokes apoptosis in cultured retinal ganglion-5 cells, and that this effect is enhanced in low serum, and attenuated by various antioxidants. Apoptosis is shown to be caspase independent, involving reactive oxygen species generation and the activation of poly(ADP-ribose) polymerase-1 and apoptosis-inducing factor. We further show that light-induced apoptosis requires the participation of the mitochondrial respiratory chain. This was demonstrated by culturing fibroblasts (BJhTERT cells) in ethidium bromide for 40 days to deplete their mitochondrial DNA and perturb their mitochondrial respiratory chain function (BJhTERT rh0 cells). Only BJhTERT cells, with intact mitochondrial respiratory chain function were affected by light insult. Finally, we show that exposure of anaesthetized pigmented rat eye to white, but not red light, causes changes in the expression of certain retinal mRNAs (neurofilament light, Thy-1 and melanopsin) and optic nerve proteins (neurofilament light and tubulin), suggesting that ganglion cell survival is affected. Our findings support the proposal that the interaction of light, particularly the blue component, with intra-axonal ganglion cell mitochondria may be deleterious under certain circumstances, and suggest that reducing the light energy impinging upon the retina might benefit patients with certain optic neuropathies.

PMID: 18315568 [PubMed - indexed for MEDLINE]

72) Long-term survival of central visual field in end-stage glaucoma. Much JW, Liu C , Piltz-Seymour JR .

Department of Ophthalmology, University of Virginia, Charlottesville, Virginia 22908, USA. [email protected]

PURPOSE: To evaluate the long-term survival of visual field and visual acuity in treated glaucoma patients with end-stage glaucomatous visual field loss defined by a field constricted to a 10-degree radius or less. DESIGN: Retrospective chart review. PARTICIPANTS: Sixty-four patients with end-stage glaucoma. METHODS: Serial 10-2 Humphrey visual fields with size III stimulus were analyzed. The following data were recorded for each visual field: mean deviation (MD), pattern standard deviation, the largest horizontal and vertical diameters measured in degrees including only locations with thresholds of 10 decibels or more, and the number of points on the pattern deviation plot with a probability value of more than 5%. MAIN OUTCOME MEASURE: Change in visual acuity and visual field. RESULTS: Eighty-four eyes of 64 patients satisfied inclusion criteria with an average follow-up of 8.34+/-3.1 years. Seventy-eight percent of patients were black. During the study period, 14 eyes lost more than 3 lines of visual acuity. Of these 14, 8 eyes progressed to a visual acuity of 20/200 or worse. Seven eyes lost 3 decibels or more from the MD that could be reproduced over 2 visual fields. CONCLUSIONS: In this predominantly black population, most treated patients with end-stage glaucoma did not demonstrate a decline in visual acuity or progressive loss of the central visual field during long-term follow-up.

PMID: 18067965 [PubMed - indexed for MEDLINE]

73) Mapping standard automated perimetry to the peripapillary retinal nerve fiber layer in glaucoma.

Ferreras A , Pablo LE , Garway-Heath DF , Fogagnolo P , García-Feijoo J .

Department of Ophthalmology, Miguel Servet University Hospital, Zaragoza, Spain. [email protected]

PURPOSE: To establish a map relating visual field (VF) test points to corresponding areas of the retinal nerve fiber layer (RNFL) measured with optical coherence tomography (OCT) in patients with glaucomatous optic neuropathy. METHODS: One hundred four consecutive subjects with open-angle glaucoma were prospectively selected. All subjects underwent standard automated perimetry (SAP) and imaging with OCT. Factor analyses of the mean thresholds for the SAP test points were performed, independently for each hemifield, to define regions of related points. Pearson correlations were then calculated between the VF regions and peripapillary RNFL thickness measured with OCT at each of the 12 clock-hour positions. A map relating the VF regions to the OCT sectors was plotted based on the strongest correlations between both techniques. RESULTS: Factor analysis distributed the VF points into five VF regions for each hemifield. A slightly asymmetric distribution of VF regions was obtained for the upper and lower points, with respect to the horizontal meridian. Mild to moderate correlations were observed between the VF regions and RNFL thickness. The superior VF regions and RNFL segments correlated most strongly at the 6- and 7-o'clock positions (r = 0.4-0.5). CONCLUSIONS: There was a moderate association between the VF regions and the RNFL thickness in patients with glaucomatous optic neuropathy, as measured by OCT. Within sectors of the RNFL, there was some overlap in the representation of the VF regions. The map obtained validates previously reported clinical findings and contributes to a better understanding of the relationship between structure and function in patients with glaucoma.

PMID: 18378581 [PubMed - indexed for MEDLINE]

74) Prevalence of ocular surface disease in glaucoma patients.

Leung EW, Medeiros FA , Weinreb RN .

Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA 92093-0946, USA.

PURPOSE: To examine the prevalence of ocular surface disease (OSD) in glaucoma patients. METHODS: This was a cross-sectional study. One hundred and one patients, 18 years of age or older, with open-angle glaucoma or ocular hypertension were consecutively recruited for the study. Patients with a history of use of cyclosporine, steroids, topical ocular nonsteroidal anti-inflammatory drugs, or punctal plugs within the last 3 months were excluded. Each patient completed an Ocular Surface Disease Index questionnaire and underwent evaluation by Schirmer test, corneal and conjunctival lissamine green staining, and tear break-up time. RESULTS: Using Ocular Surface Disease Index for measuring symptoms of dry eye, 60 (59%) patients reported symptoms in at least 1 eye. Severe symptoms were reported by 27 (27%) patients. Schirmer testing showed 62 (61%) patients with decrease in tear production in at least 1 eye. Severe tear deficiency was presented in 35 (35%) patients. Corneal and conjunctival lissamine green staining showed positive results in 22 (22%) patients. None had severe staining. Tear break-up time showed abnormal tear quality in 79 (78%) patients and severe decrease in tear quality was found in at least 1 eye in 66 (65%) patients. Multivariate logistic regression models were used to investigate the association between the number of benzalkonium chloride (BAK)-containing eyedrops and results on the clinical tests of OSD. After adjustment for age and sex, each additional BAK-containing eyedrop was associated with an approximately 2 times higher odds of showing abnormal results on the lissamine green staining test (odds ratio=2.03; 95% confidence interval: 1.06 to 3.89; P=0.034). CONCLUSION: A large proportion of patients with open-angle glaucoma or ocular hypertension had signs and/or symptoms of OSD in at least 1 eye. The coexistence of OSD and the use of BAK- containing medications may impact vision-related quality of life in this patient population.

PMID: 18703943 [PubMed - indexed for MEDLINE] 75) Gamma-synuclein as a marker of retinal ganglion cells.

Surgucheva I , Weisman AD , Goldberg JL , Shnyra A , Surguchov A .

Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, MO 64128, USA.

PURPOSE: Previous studies have described gamma-synuclein as a protein highly expressed in retinal ganglion cells (RGCs), and a loss of RGCs correlates with a downregulation of gamma-synuclein gene expression in glaucoma. Here we asked whether gamma-synuclein expression in the retina can be considered a specific marker of RGCs. METHODS: gamma-Synuclein expression was examined with immunohistochemistry in retinal sections from normal and glaucomatous human eyes. Primary cultures of RGCs from Sprague-Dawley rats purified by sequential immunopanning using a monoclonal antibody to Thy1-1, cultures of A7 immortalized optic nerve astrocytes from newborn rats, and the immortalized RGC-5 cell line were studied using immunofluorescence and quantitative RT-PCR. RESULTS: gamma- Synuclein was highly expressed in RGCs in the human retina and was localized in cytoplasm adjacent to the RGC nuclear marker, Brn-3a. Axons of RGCs were immunopositive for gamma-synuclein in the nerve fiber layer (NFL), the lamina cribrosa and the retrobulbar optic nerve. In the optic nerve of glaucoma patients, axon swellings were likewise immunopositive, whereas in the retina of patients with retinoblastoma, NFL staining appeared reduced. In primary rat RGCs and in immortalized RGC-5 cultures, gamma-synuclein was localized predominantly in the perinuclear area and in cell processes. Among rat retinal cells in culture, all Brn-3a positive cells were stained with a gamma-synuclein antibody; rare gamma-synuclein-positive cells were not stained by the Brn-3a antibody. CONCLUSIONS: gamma-Synuclein is selectively and abundantly expressed in human RGCs in vivo, primary rat RGCs in vitro, and immortalized RGC-5 cells. In pathology, gamma-synuclein abundance may vary between RGC somas and axons. Coincident Brn-3a and gamma-synuclein expression suggests that strong gamma-synuclein expression can be considered a marker of RGCs. Future translational approaches might include using a gamma-synuclein promoter for the specific delivery of siRNA or therapeutic proteins to RGCs.

PMID: 18728752 [PubMed - indexed for MEDLINE]

76) 17Beta-estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat.

Russo R , Cavaliere F , Watanabe C , Nucci C , Bagetta G , Corasaniti MT , Sakurada S, Morrone LA .

Department of Pharmacobiology, University of Calabria, 87036 Arcavacata di Rende, Italy. Glaucoma, is a progressive optic neuropathy often associated with increased intraocular pressure (IOP) and characterized by progressive death of retinal ganglion cells (RGCs). High acute rise of IOP is a model for retinal ischemia and may represent a model of acute angle closure glaucoma. Here we have used this experimental model in combination with a neurochemical and neuropathological approach to gain more insight in the neuroprotective profile of 17beta-estradiol (E2), a steroid hormone, which has been shown to increase the viability, survival, and differentiation of primary neuronal cultures from different brain areas including amygdala, hypothalamus, and neocortex. Our data demonstrate that systemic administration of E2 significantly reduces RGC loss induced by high IOP in rat. In addition, pretreatment with E2, 30 min before ischemia, minimizes the elevation of glutamate observed during the reperfusion period. These effects seem to be in part mediated by the activation of the estrogen receptor, since a pretreatment with ICI 182-780, a specific estrogen receptor antagonist, partially counteracts the neuroprotection afforded by the estrogen.

PMID: 18929136 [PubMed - in process]

77) A placebo-controlled 3-year study of a calcium blocker on visual field and ocular circulation in glaucoma with low-normal pressure.

Koseki N , Araie M , Tomidokoro A , Nagahara M , Hasegawa T , Tamaki Y , Yamamoto S .

Department of Ophthalmology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.

PURPOSE: To study the 3-year effect of oral nilvadipine, a calcium antagonist, on visual field performance and ocular circulation in open-angle glaucoma (OAG) with low-normal intraocular pressure (IOP). DESIGN: A randomized, placebo-controlled, double-masked, single-center trial. PARTICIPANTS: Patients with OAG who were younger than 65 years and had untreated IOP consistently of 16 mmHg or less. INTERVENTION: Oral nilvadipine (2 mg twice daily) or placebo was assigned randomly to patients fulfilling the criteria by the minimization method of balancing the groups according to age, refraction, and the mean deviation (MD) value (Humphrey Perimeter 30-2 SITA Standard Program; Humphrey Instruments, Inc., San Leandro, CA) of the eye with less negative MD. No topical ocular hypotensive drugs were prescribed. Visual field testing was performed every 3 months; fundus examination and IOP, blood pressure, and pulse rate measurements were carried out every month; and quantitative indexes of circulation in the optic disc rim (NB(ONH)) and choroid in the foveal area (NB(fovea)) were determined using the laser speckle method at 0, 3, 6, 12, 18, 24, 30, and 36 months. MAIN OUTCOME MEASURES: The time courses of MD, NB(ONH), and NB(fovea) in the eye with less negative MD. RESULTS: Thirty-three patients were enrolled; 17 were assigned to nilvadipine and 16 were assigned to placebo; 13 in each group completed the study. No significant intergroup difference was seen in age, refraction, or baseline values of any of the parameters. During the 3-year period, the IOP averaged 12.6 mmHg in the nilvadipine group and 12.8 mmHg in the placebo group (P>0.1), and no significant change from baseline or intergroup difference was seen in blood pressure or pulse rate. The estimated slope of change in the MD was less negative in the nilvadipine than in the placebo group (-0.01 vs. -0.27 decibels/year; P = 0.040). The NB(ONH) and NB(fovea) values remained increased compared with baseline for the study period by approximately 30% to 40% only in the nilvadipine group, and the intergroup difference was significant (P = 0.003 for NB(ONH) and P = 0.007 for NB(fovea)). CONCLUSIONS: Nilvadipine (2 mg twice daily) slightly slowed the visual field progression and maintained the optic disc rim, and the posterior choroidal circulation increased over 3 years in patients with OAG with low-normal IOP.

PMID: 18672290 [PubMed - indexed for MEDLINE]

78) Advances in neuroimaging of the visual pathways and their use in glaucoma.

Garaci FG , Cozzolino V , Nucci C , Gaudiello F , Ludovici A , Lupattelli T , Floris R , Simonetti G .

Department of Diagnostic Imaging and Interventional Radiology, University of Rome Tor Vergata, V.le Oxford 81, Rome, Italy. [email protected]

Recently developed neuroimaging techniques such as diffusion tensor (DT) magnetic resonance (MR) imaging, functional MR imaging (fMRI), and MR spectroscopy can be used to evaluate the microstructural integrity of white-matter fibers and the functional activity of gray matter. They have been widely employed to investigate various diseases of the central nervous system, and they can be useful tools for assessing the integrity and functional connections of the visual pathways and areas that play key roles in glaucoma. In vivo degeneration of the optic nerves can be noninvasively demonstrated by DT MR imaging. DT fiber tractography provides valuable information on the axonal density of postgeniculate fibers (optic radiation), and fMRI studies of patients with primary open-angle glaucoma (POAG) have demonstrated alterations involving the human visual cortex that are consistent with clinically documented losses of visual function. This article reviews some of the more recent data supporting the use of MR imaging techniques as reliable, noninvasive tools for monitoring the progression of human glaucoma.

PMID: 18929108 [PubMed - in process]

79) Age-related losses of retinal ganglion cells and axons.

Harwerth RS , Wheat JL , Rangaswamy NV .

College of Optometry, University of Houston, Houston, Texas 77204-2020, USA. [email protected]

PURPOSE: Age-related losses in retinal nerve fiber layer (RNFL) thickness have been assumed to be the result of an age-dependent reduction of retinal ganglion cells (RGCs), but the published rates differ: age-related losses of RGCs of approximately 0.6%/year compared to 0.2%/year for thinning of the RNFL. An analysis of normative data for standard automated perimetry (SAP) sensitivities and optical coherence tomography (OCT) measures of RNFL thickness showed that the apparent disagreement in age-dependent losses of RGCs and axons in the RNFL can be reconciled by an age-dependent decrease in the proportion of the RNFL thickness that is composed of axons. The purpose of the present study was to determine whether the mechanisms of age-related losses that were suggested by the normative data can be confirmed with data from healthy, normal eyes. METHODS: Data were obtained from visual fields (normal results in a Glaucoma Hemifield Test [GHT] on standard automated perimetry [SAP] 24-2 fields) and RNFL thickness measurements (standard OCT scan) of 55 patients (age range, 18-80 years; mean, 44.5 +/- 17.3). The SAP measures of visual sensitivity and OCT measures of RNFL thickness for one eye of each patient were used to estimate neuron counts by each procedure. RESULTS: The age- related thinning of RNFL was 0.27%/year when a constant axon density was used to derive axon counts from RNFL thickness, compared with 0.50%/year for the age- related loss of RGCs from SAP. In agreement with the model developed with normative clinical data, concordance between losses of axons and soma was achieved by an age- dependent reduction of 0.46%/year in the density of axons in the RNFL. CONCLUSIONS: The results suggest that the proportion of RNFL that is composed of RGC axons is not constant with age; rather, the proportion of the total thickness from non-neuronal tissue increases with age. If a similar compensation occurs in the RNFL thickness with axon loss from glaucoma, then a stage-dependent correction to translate OCT measurements to neuronal components is needed, in addition to the age- dependent correction.

PMID: 18539947 [PubMed - indexed for MEDLINE]

80) Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease.

Ning A , Cui J , To E , Ashe KH , Matsubara J .

Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada.

PURPOSE: To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-beta deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD). METHODS: Retinas of transgenic mice harboring a mutant presenilin (PS1) and a mutant APP gene were processed for TUNEL and immunohistochemistry with antibodies against APP, amyloid- beta, monocyte chemotactic protein (MCP)-1, and F4/80. Comparisons were made between age groups and between transgenic and wild-type congeners. RESULTS: The neuroretina demonstrated age-dependent increases in APP in the ganglion cells (RGCs) and in neurons of the inner nuclear layer (INL). Amyloid-beta demonstrated significant age-dependent deposition in the nerve fiber layer (NFL). TUNEL-positive RGC increased in an age-dependent fashion and in transgenic compared with wild-type congeners. Concomitant overexpression of MCP-1 and intense immunoreactivity for F4/80 suggested that RGCs upregulate MCP-1 in response to amyloid-beta. Activated microglia proliferated in response to MCP-1. In the outer retina, retinal pigment epithelium (RPE) demonstrated moderate age-dependent APP immunoreactivity, but nearby drusenlike deposits were not present. Amyloid-beta was observed in the choriocapillaris of the older animals. CONCLUSIONS: Amyloid-beta deposits accumulate with age in the retina of a transgenic mouse model of AD. The amyloid-beta loads are accompanied by increased immunoreactivity for MCP-1, F4/80, and TUNEL-positive profiles in the RGC layer. The results suggest that amyloid-beta causes neurodegeneration in the retina of the doubly mutant transgenic mouse model of AD.

PMID: 18566467 [PubMed - indexed for MEDLINE]

81) Analysis of the origin of atypical scanning laser polarimetry patterns by polarization- sensitive optical coherence tomography.

Götzinger E , Pircher M , Baumann B , Hirn C , Vass C , Hitzenberger CK .

Center for Biomedical Engineering and Physics, General Hospital and Medical University of Vienna, Vienna, Austria.

PURPOSE: To analyze the physical origin of atypical scanning laser polarimetry (SLP) patterns. To compare polarization-sensitive optical coherence tomography (PS-OCT) scans to SLP images. To present a method to obtain pseudo-SLP images by PS-OCT that are free of atypical artifacts. METHODS: Forty-one eyes of healthy subjects, subjects with suspected glaucoma, and patients with glaucoma were imaged by SLP (GDx VCC) and a prototype spectral domain PS-OCT system. The PS-OCT system acquires three-dimensional (3D) datasets of intensity, retardation, and optic axis orientation simultaneously within 3 seconds. B-scans of intensity and retardation and en face maps of retinal nerve fiber layer (RNFL) retardation were derived from the 3D PS-OCT datasets. Results were compared with those obtained by SLP. RESULTS: Twenty-two eyes showed atypical retardation patterns, and 19 eyes showed normal patterns. From the 22 atypical eyes, 15 showed atypical patterns in both imaging modalities, five were atypical only in SLP images, and two were atypical only in PS-OCT images. In most (15 of 22) atypical cases, an increased penetration of the probing beam into the birefringent sclera was identified as the source of atypical patterns. In such cases, the artifacts could be eliminated in PS-OCT images by depth segmentation and exclusion of scleral signals. CONCLUSIONS: PS-OCT provides deeper insight into the contribution of different fundus layers to SLP images. Increased light penetration into the sclera can distort SLP retardation patterns of the RNFL.

PMID: 19036999 [PubMed - indexed for MEDLINE] 82) Apoptosis in the trabecular meshwork of glaucomatous patients.

Baleriola J , García-Feijoo J , Martínez-de-la-Casa JM , Fernández-Cruz A , de la Rosa EJ , Fernández-Durango R .

3D Lab (Development, Differentiation, & Degeneration), Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.

We established and validated an in toto method to perform TdT-mediated dUTP nick end labeling to study apoptosis in human trabecular meshwork tissue obtained during trabeculectomy in glaucoma patients. In specimens from patients with primary open- angle glaucoma and primary angle-closure glaucoma, we detected a tendency for more apoptotic cells to accumulate in patients with primary open-angle glaucoma. The utility of this method to study apoptosis in the trabecular meshwork is discussed, as well as its application as a tool in biologic samples.

PMID: 18728789 [PubMed - indexed for MEDLINE]

83) Association of Toll-like receptor 4 gene polymorphisms with normal tension glaucoma.

Shibuya E , Meguro A , Ota M , Kashiwagi K , Mabuchi F , Iijima H , Kawase K , Yamamoto T , Nakamura M , Negi A , Sagara T , Nishida T , Inatani M , Tanihara H , Aihara M , Araie M , Fukuchi T , Abe H , Higashide T , Sugiyama K , Kanamoto T , Kiuchi Y , Iwase A , Ohno S , Inoko H , Mizuki N .

Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.

PURPOSE: Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG. METHODS: Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects. RESULTS: Strong linkage disequilibrium was observed among all SNPs (D' >or= 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3'-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P(c) = 0.0095). CONCLUSIONS: Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.

PMID: 18586872 [PubMed - indexed for MEDLINE]

84) Astrocytes in glaucomatous optic neuropathy.

Hernandez MR , Miao H , Lukas T .

Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [email protected]

Glaucoma, the second most prevalent cause of blindness worldwide, is a degenerative disease characterized by loss of vision due to loss of retinal ganglion cells. There is no cure for glaucoma, but early intervention with drugs and/or surgery may slow or halt loss of vision. Increased intraocular pressure (IOP), age, and genetic background are the leading risk factors for glaucoma. Our laboratory and other investigators have provided evidence that astrocytes are the cells responsible for many pathological changes in the glaucomatous optic nerve head (ONH). Over several years, in vivo and in vitro techniques characterized the changes in quiescent astrocytes that lead to the reactive phenotype in glaucoma. Reactive astrocytes alter the homeostasis and integrity of the neural and connective tissues in the ONH of human and experimental glaucoma in monkeys. During the transition of quiescent astrocytes to the reactive phenotype altered astrocyte homeostatic functions such as cell-cell communication, migration, growth factor pathway activation, and responses to oxidative stress may impact pathological changes in POAG. Our data also suggests that the creation of a non-supportive environment for the survival of RGC axons through remodeling of the ONH by reactive astrocytes leads to progression of glaucomatous optic neuropathy.

PMID: 18929121 [PubMed - in process]

85) Comet assay analysis of single-stranded DNA breaks in circulating leukocytes of glaucoma patients.

Mozaffarieh M , Schoetzau A , Sauter M , Grieshaber M , Orgül S , Golubnitschaja O , Flammer J .

University Eye Clinic, Basel, Switzerland.

PURPOSE: To investigate the amount of single-stranded DNA breaks in circulating leukocytes of primary open-angle glaucoma (POAG) patients. METHODS: A comparative quantification of DNA breaks was performed in circulating leukocytes of POAG patients and healthy controls. The following groups of subjects were compared: (1) POAG patients having primary vascular dysregulation (PVD), (2) POAG patients without PVD, (3) healthy controls with PVD, and (4) healthy controls without PVD. The damage to DNA resulting in single-stranded breaks was assessed by means of the alkaline comet assay in which the damaged DNA migrates out of the nucleus forming a tail, which can be quantified using image analysis. Damage was quantified as the comet tail moment, which represents the extent of DNA damage in individual cells. RESULTS: Leukocytes of POAG patients exerted a significantly higher amount of comet tails, which are indicative of DNA damage, in comparison to control leukocytes (p<0.001). DNA breaks occurred particularly in the subgroup of POAG patients with PVD in comparison to glaucoma patients without PVD (p=0.002). In the control group, there was no significant difference between controls with PVD and controls without PVD (p=0.86). CONCLUSIONS: POAG patients with PVD have a significantly higher rate of DNA breaks than both POAG patients without PVD and healthy controls with and without PVD.

PMID: 18769648 [PubMed - indexed for MEDLINE]

86) Dendritic and synaptic protection: is it enough to save the retinal ganglion cell body and axon?

Morquette JB , Di Polo A .

Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, University of Montreal, Montreal, Quebec, Canada.

Glaucoma and other optic neuropathies have been traditionally viewed as diseases of the optic nerve that lead to retinal ganglion cell (RGC) degeneration. Accordingly, the primary aim of neuroprotective strategies has been to preserve RGC axons and soma. RGCs are complex and highly polarized central neurons, and their pathologic response in disease is likely to be an integration of signals from all cellular compartments-axons, soma, dendrites, and synaptic contacts. We focus on the role of dendrites and dendritic spines in normal neuronal function, neurologic disorders, and glaucoma. The need to understand the mechanisms underlying RGC dendrite and synapse degeneration in glaucoma and other optic neuropathies is compelling, as it may provide insight into novel therapeutic strategies to prevent vision loss.

PMID: 18562848 [PubMed - indexed for MEDLINE]

87) Disc hemorrhages and treatment in the early manifest glaucoma trial.

Bengtsson B , Leske MC , Yang Z , Heijl A ; EMGT Group .

Department of Clinical Sciences, Ophthalmology, Lund University, Malmö University Hospital, Sweden.

PURPOSE: To evaluate the effect of intraocular pressure (IOP)-reducing treatment on the development of disc hemorrhages in patients with glaucoma. DESIGN: Prospective cohort study of patients in the Early Manifest Glaucoma Trial, followed up to 11 years (median = 8 years). PARTICIPANTS: Patients with newly detected glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no initial treatment (n = 126), followed with tonometry, perimetry, and ophthalmoscopy every 3 months, and fundus photography every 6 months. METHODS: Logistic regression expressed as odds ratios (OR) and 95% confidence intervals (CIs), analysis of variance, and Cox time-dependent models, expressed as hazard ratios (HRs) and CIs. MAIN OUTCOME MEASURES: Presence (yes/no) and frequency of disc hemorrhages. RESULTS: Disc hemorrhages were identified in approximately 55% of all patients, whether by ophthalmoscopy or review of photographs. In analyses including data up to the time of progression, disc hemorrhages were equally common among treated and control patients: 51.2% versus 45.2%, respectively (P = 0.34), based on ophthalmoscopy, and 50.4% versus 44.4%, respectively (P = 0.34), based on photographs. Gender was the only factor related to the presence of disc hemorrhages detected by both ophthalmoscopy (OR = 0.48; CI, 0.26-0.88; P = 0.022) and photographs (OR = 0.64; CI, 0.38-1.09; P = 0.099) for male patients. The frequency of disc hemorrhages over time did not differ between treated and control patients: 8.4% versus 8.5%, respectively (P = 0.93), based on ophthalmoscopy, and 12.4% versus 11.2%, respectively (P = 0.36), based on photographs. Disc hemorrhages were significantly associated with time to progression (HR = 1.02; CI, 1.01-1.04), and there was no evidence of interaction between treatment group and disc hemorrhages. CONCLUSIONS: IOP-reducing treatment was unrelated to the presence or frequency of disc hemorrhages. The results may suggest that disc hemorrhages cannot be considered an indication of insufficient IOP-lowering treatment, and that glaucoma progression in eyes with disc hemorrhages cannot be totally halted by IOP reduction. The results also suggest that disc hemorrhages do not occur in all patients with glaucoma.

PMID: 18692244 [PubMed - indexed for MEDLINE]

88) Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population.

Amerasinghe N , Aung T , Cheung N , Fong CW, Wang JJ , Mitchell P , Saw SM , Wong TY .

Singapore National Eye Centre, Singapore.

PURPOSE: To examine the relationship between retinal vascular caliber and glaucoma in an Asian population. METHODS: A population-based, cross-sectional study of 3019 persons of Asian Malay ethnicity aged 40 to 80 years residing in Singapore. All participants had dilated digital retinal photographs taken of both eyes. From these, retinal vascular caliber was measured with a computer-based technique according to a standardized protocol. Glaucoma was diagnosed based on the International Society of Geographic and Epidemiologic Ophthalmology classification and included people with glaucomatous optic neuropathy and compatible visual field loss. RESULTS: There were 127 (4.2%) participants with glaucoma. Mean retinal arteriolar and venular calibers were significantly narrower in persons with than in those without glaucoma (136.4 microm vs. 139.7 microm, P = 0.02 and 209.2 microm vs. 219.7 microm, P < 0.001, respectively). After adjusting for age, sex, smoking, IOP, and other vascular risk factors, persons with narrower retinal arteriolar and venular caliber were more likely to have glaucoma (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.07-1.56 and OR, 1.49; 95% CI, 1.24-1.79, for each SD reduction in arteriolar and venular caliber, respectively) and a vertical cup-to-disc ratio >or= 0.7 (OR, 1.35; 95% CI, 1.12-1.63 and OR, 1.65; 95% CI, 1.38-1.98, respectively). Retinal vascular caliber was not associated with intraocular pressure. CONCLUSIONS: These findings support an association of narrower retinal arteriolar and venular caliber changes with glaucomatous optic neuropathy, independent of intraocular pressure.

PMID: 18719076 [PubMed - indexed for MEDLINE

89) Is gaze-dependent tonometry a useful tool in the differential diagnosis of Graves' ophthalmopathy?

Herzog D , Hoffmann R , Schmidtmann I , Pfeiffer N , Preussner PR , Pitz S .

Department of Ophthalmology, Johannes Gutenberg-University, Langenbeckstr. 1, 55101, Mainz, Germany.

BACKGROUND: A rise in intraocular pressure (IOP) in upgaze is regarded as a diagnostic sign in Graves' ophthalmopathy (GO). However, the question of erroneous IOP measurement due to applanation carried out on the peripheral cornea has never been addressed. METHODS: In 22 healthy volunteers, as well as in 51 GO patients, applanation tonometry was performed in the primary position of gaze and at 20 degrees of upgaze. In addition, applanation tonometry was repeated using a flexible chin rest to incline the head and produce 20 degrees upgaze. This enabled applanation on the central cornea. RESULTS: In healthy controls, mean IOP in conventional upgaze showed a significant rise compared to primary position (p < 0.0001). IOP measurements in 20 degrees upgaze/head inclination were significantly lower compared to conventional upgaze tonometry (p < 0.0001) and comparable to mean IOP in primary position (p = 0.7930). Mean IOP in GO patients was also significantly higher in conventional upgaze compared to primary position (p < 0.0001). The upgaze measurements obtained by head inclination were significantly lower than those from conventional upgaze tonometry (p < 0.0001), but showed a statistically significant rise compared to mean IOP in primary position (p < 0.0001). The overlap of IOP readings in upgaze between normal individuals and GO patients was considerable, even in patients with severely impaired ocular motility. CONCLUSION: In both normal volunteers and patients suffering from GO, a rise in IOP was observed in conventional upgaze tonometry. However, this increase in IOP was partially due to applanation on the peripheral cornea. Measurements in upgaze by head inclination on the central cornea led to a significant lowering of the gaze-dependent IOP change. The discriminating power of the IOP difference between upgaze and primary position to diagnose GO was found to be limited. The broad overlap of IOP between normal individuals and GO patients as detected by conventionally performed upgaze tonometry leads us to conclude that this sign may not be of relevant differential diagnostic value in patients with a clinically undetermined diagnosis.

PMID: 18751718 [PubMed - in process]

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