Baseline 10-2 Visual Field Loss as a Predictor for Future Glaucoma Progression.

PRCIS: Presence of baseline 10-2 visual field (VF) loss was the strongest predictor of future rate of 24-2 VF loss and development of new 24-2 progression events, suggesting a role for 10-2 VF testing in baseline glaucoma risk analysis. PURPOSE: The purpose of this study is to examine the relationship between baseline 10-2 VF loss and future 24-2 VF loss. MATERIALS AND METHODS: Subjects were participating in a prospective longitudinal study within a VA Medical Center outpatient eye clinic. Eligibility required 2 good quality baseline 10-2 VF tests followed by a minimum of 5 good quality 24-2 VF tests over at least 3 years. Longitudinal 24-2 VF testing was completed every 4-6 months after baseline 10-2 testing. Mixed model regression analyses and Cox Proportional Hazard regression analyses were completed to identify predictors of 24-2 mean deviation change rate and new VF loss events. RESULTS: We studied 394 eyes of 202 subjects (119 primary open angle glaucoma and 83 glaucoma suspect). Over 6.7 (±1.5) years, 9.9 (±2.3) good quality 24-2 VF tests were completed. In mixed model regression analyses, baseline variables that predicted faster rate of 24-2 VF loss in order of strength of association were presence of baseline 10-2 VF defect, lower 24-2 mean deviation, and higher age. When analyses were completed without 10-2 variables, predictive capability of the model was reduced compared with when 10-2 variables were included. In Cox Proportional Regression analyses evaluating progression events, baseline 10-2 VF defect demonstrated the largest hazard ratio (22 times greater risk for developing future VF loss event in eyes with vs. without baseline 10-2 VF loss). CONCLUSIONS: Baseline 10-2 VF defect was the most effective predictor of subsequent 24-2 VF progression in this study. These findings imply that presence of baseline 10-2 VF loss may provide unique value for predicting future glaucoma progression.

Corneal Biomechanical Changes Caused by Acute Elevation of IOP in Eyes with and without Glaucoma.

SIGNIFICANCE: Although corneal biomechanical parameters are well linked with glaucoma, their clinical utility has not yet been fully elucidated. This study was designed to provide unique evidence about the dynamic nature of corneal biomechanical parameters and their potential prognostic ability for glaucoma. PURPOSE: This study aimed to evaluate the effect of acute intraocular pressure (IOP) elevation on corneal hysteresis (CH) and corneal resistance factor (CRF) and the associations of these biomechanical parameters with glaucomatous disease. METHODS: Subjects participating in a prospective, longitudinal glaucoma research study had CH and CRF measured before and during ophthalmodynamometry during visits in the years 2011 to 2012. All participants were diagnosed with primary open-angle glaucoma, ocular hypertension, glaucoma suspect, or normal eyes and had a minimum of 3 years of study participation with at least five reliable visual field (VF) tests. Changes in CH, CRF, and IOP induced by ophthalmodynamometry were compared between diagnostic groups and evaluated for relationships with existing and future glaucomatous VF loss. RESULTS: In 248 eyes of 248 subjects followed up for 7.7 ± 2.3 years, ophthalmodynamometry induced a mean IOP increase from 15.1 to 29.9 mmHg, causing a mean 34 ± 28% increase in CRF and 21 ± 25% decrease in CH. Magnitude of CH change did not differ between diagnostic groups or between eyes that did (n = 20) and did not (n = 95) develop new VF loss during the study period, nor was it related to rate of future VF progression. CONCLUSIONS: Ophthalmodynamometry-induced IOP elevation resulted in significant acute changes in CH and CRF in this study; this suggests accounting for IOP may be important in clinical interpretation of these parameters. However, because the degree of CH change was not related to glaucoma or its progression, acute changes in CH and CRF do not seem to have a prognostic value for glaucoma.

Prediction of 10-2 Visual Field Loss Using Optical Coherence Tomography and 24-2 Visual Field Data.

PRECIS: Using standard glaucoma structural and functional tests, clinicians accurately predicted the presence/absence of 10-2 glaucomatous visual field (VF) loss in 90% of the eyes in this study. PURPOSE: To investigate how well clinicians with variable experience can predict the presence and location of 10-2 VF loss using structural and functional data that are routinely obtained for glaucoma assessment. METHODS: Within a test set of 416 eyes (210 subjects) who were diagnosed glaucoma suspect or primary open-angle glaucoma (with most eyes having mild disease), 6 clinicians were asked to predict the presence and hemispheric location of 10-2 VF loss using 24-2 VF and spectral-domain optical coherence tomography structural data. Prediction accuracies were calculated for each clinician and compared using the weighted κ-statistic. Receiver operating characteristic analyses were used to evaluate models for predicting 10-2 VF loss. RESULTS: Among the 6 clinicians, mean (range) accuracy, false negatives, and false positives for predicting presence/absence of 10-2 VF loss were 90% (87% to 92%), 4.7% (2.4% to 7.0%), and 5.4% (1.7% to 7.5%) respectively. The mean (range) weighted κ-statistic was 0.75 (0.64 to 0.83), suggesting good or very good inter-rater agreement between examiners. Mean accuracy for correctly predicting hemispheric location was 73% (range, 65% to 82%) with the most common error occurring in eyes with both superior and inferior 10-2 VF defects in which one hemisphere was correctly identified but the other missed. CONCLUSIONS: In this study, the presence/absence of 10-2 glaucomatous VF loss was highly predictable using standard functional and structural clinical metrics. These findings suggest that 10-2 VF testing is not needed to reliably recognize and confirm central VF involvement in most eyes with glaucoma. Whether error related to identifying second hemisphere involvement in 10-2 VF loss is important requires further study.

Differentiating Occult Branch Retinal Artery Occlusion from Primary Open-angle Glaucoma.

SIGNIFICANCE: Clinical findings in occult branch retinal artery occlusion (BRAO) can mimic those of primary open-angle glaucoma (POAG). Because management of these conditions substantially differs, accurate diagnosis is crucial. Our comparative analysis indicates that specific macular thickness variables reliably differentiate these conditions and that macular scanning may enhance routine glaucoma evaluation. PURPOSE: The aim of this study was to identify clinical factors that reliably and efficiently identify occult BRAO masquerading as POAG. METHODS: All subjects had comprehensive eye examinations including measurements of retinal nerve fiber layer and macular thickness (MT) using spectral-domain optical coherence tomography (SD-OCT). All subjects were asymptomatic for previous acute vision loss episodes, had optic nerve appearances suggestive of glaucoma, and exhibited SD-OCT retinal nerve fiber layer thinning with corresponding visual field loss. Macular thickness scans were divided into 64 individual thickness blocks with thin MT blocks defined by the lower 99% confidence interval from a group of normal eyes. We defined BRAO by the presence of regional inner retinal thinning with lack of inner-layer stratification on macular SD-OCT b-scan images that spatially corresponded with arteriolar distribution and visual field loss location. Primary open-angle glaucoma eyes were selected to match the BRAO eyes by age and disease severity. Pairwise and receiver operating characteristic curve analyses were used to compare occult BRAO and POAG eyes. RESULTS: Compared with POAG (n = 52), occult BRAO eyes (n = 11) demonstrated lower cup-disc ratio, greater intereye and intraeye (superior vs. inferior) MT asymmetry, and higher frequency of thin MT blocks (<200 µm). Area under the receiver operating characteristic curve (AUC) for differentiating these conditions was highest for intraeye MT asymmetry (AUC = 0.990 [95% confidence interval, 0.925 to 1.000]) and number of thin MT blocks (AUC = 0.993 [95% confidence interval, 0.929 to 1.000]). CONCLUSIONS: Macular thickness parameters provided accurate and efficient diagnostic capability in this study. Considering the clinical implications of inaccurate diagnosis, macular scanning may be important in baseline glaucoma evaluation.

Prevalence, Features, and Severity of Glaucomatous Visual Field Loss Measured With the 10-2 Achromatic Threshold Visual Field Test.

PURPOSE: To investigate the clinical characteristics of 10-2 visual field defects in subjects with a diagnosis of glaucoma or glaucoma suspicion. DESIGN: Prospective, observational cohort study. METHODS: From participants enrolled in an ongoing glaucoma research study at our institution, we identified 354 eyes in 180 subjects (97 with primary open-angle glaucoma, 83 with glaucoma suspicion) who had 2 or more reliable 24-2 and 10-2 visual field tests and good-quality spectral-domain optical coherence tomography (SDOCT) scans. Eyes with macular pathology, significant cataract, or nonglaucomatous vision loss were excluded. We applied previously published cluster criteria to define 10-2 visual field loss, and then calculated prevalence, location, severity, and pattern of 10-2 visual field loss as well as its relationships with various functional and structural parameters. RESULTS: Repeatable 10-2 visual field defects were present in 89 of 180 subjects (49%) and usually exhibited an arcuate or nasal pattern. In eyes with no, mild, moderate, and advanced 24-2 visual field loss, 15 of 236 (6%), 49 of 67 (73%), 25 of 26 (96%), and 25 of 25 (100%) had 10-2 visual field defects, respectively. Of the 114 eyes with 10-2 visual field loss, 93 (82%) demonstrated abnormal points within the central 10 degrees of the 24-2 visual field test. Mean defect on the 10-2 and 24-2 tests was highly correlated (r(2) = 0.72). CONCLUSIONS: Although central VF loss appears to be common in glaucoma and may have an important role in glaucoma management, additional study is warranted to more definitively determine the optimal methods to detect presence, severity, and functional impact of central glaucomatous visual field loss.

New systematic review methodology for visual impairment and blindness for the 2010 Global Burden of Disease study.

PURPOSE: To describe a systematic review of population-based prevalence studies of visual impairment (VI) and blindness worldwide over the past 32 years that informs the Global Burden of Diseases, Injuries and Risk Factors Study. METHODS: A systematic review (Stage 1) of medical literature from 1 January 1980 to 31 January 2012 identified indexed articles containing data on incidence, prevalence and causes of blindness and VI. Only cross-sectional population-based representative studies were selected from which to extract data for a database of age- and sex-specific data of prevalence of four distance and one near vision loss categories (presenting and best-corrected). Unpublished data and data from studies using rapid assessment methodology were later added (Stage 2). RESULTS: Stage 1 identified 14,908 references, of which 204 articles met the inclusion criteria. Stage 2 added unpublished data from 44 rapid assessment studies and four other surveys. This resulted in a final dataset of 252 articles of 243 studies, of which 238 (98%) reported distance vision loss categories. A total of 37 studies of the final dataset reported prevalence of mild VI and four reported near VI. CONCLUSION: We report a comprehensive systematic review of over 30 years of VI/blindness studies. While there has been an increase in population-based studies conducted in the 2000s compared to previous decades, there is limited information from certain regions (eg, Central Africa and Central and Eastern Europe, and the Caribbean and Latin America), and younger age groups, and minimal data regarding prevalence of near vision and mild distance VI.

Relative importance of factors affecting corneal hysteresis measurement.

PURPOSE: To evaluate the relative influences of several demographic, ocular, and systemic parameters on corneal hysteresis (CH). METHODS: This is a prospective, observational, cross-sectional study using subjects recruited from consecutive Albuquerque VAMC eye clinic patients. We classified eligible subjects as primary open-angle glaucoma (POAG), ocular hypertension, glaucoma suspect, or normal. We used the Ocular Response Analyzer, Pascal Dynamic Contour Tonometer, and Goldmann applanation tonometer to obtain intraocular pressure (IOP), CH, corneal resistance factor, and ocular pulse amplitude values. We also obtained corneal curvature, central corneal thickness (CCT), axial length, retinal nerve fiber layer thickness, clinical cup/disc ratio (CDR) estimates, and standard automated perimetry metrics (mean defect, pattern standard deviation). We gathered glycosylated hemoglobin (A1C) data through chart review. Multivariate regression analyses were used to determine independent relationships between CH and the other parameters. RESULTS: Three hundred seventeen eyes in 317 subjects were studied (116 POAG, 87 ocular hypertension, 47 glaucoma suspect, and 67 normal). In univariate regression analysis, CH varied directly with CCT (ß = 0.39, p < 0.001), corneal curvature (ß = 0.16, p = 0.01), corneal resistance factor (ß = 0.57, p < 0.001), A1C (ß = 0.15, p = 0.01), mean defect (ß = 0.29, p < 0.001), and retinal nerve fiber layer (ß = 0.31, p < 0.001). Factors inversely related to CH were age (ß = -0.22, p < 0.001), IOP (ß = -0.29, p < 0.001), ocular pulse amplitude (ß = -0.11, p = 0.04), CDR (ß = -0.34, p < 0.001), and pattern standard deviation (ß = -0.29, p < 0.001). CH was lower in POAG compared with the other diagnostic groups. In multivariate analysis, CH was independently associated with age, IOP, CCT, A1C, glaucoma diagnosis, and CDR. Of these factors, CCT and IOP demonstrated twice as much influence on CH compared with the other four factors. CONCLUSIONS: Although this study identified six separate variables that independently influence CH values, the overall r value indicates that these variables together only explain 40% of CH variability. These results suggest that other significant sources of variability exist and deserve investigation.

Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft.

Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. The use of nontoxic phytochemicals in the prevention and intervention of colorectal cancer has been suggested as an alternative to chemotherapy. Here we assessed the anticancer efficacy of silibinin against advanced colorectal cancer LoVo cells both in vitro and in vivo. Our results showed that silibinin treatment strongly inhibits the growth of LoVo cells (P < 0.05-0.001) and induces apoptotic death (P < 0.01-0.001), which was associated with increased levels of cleaved caspases (3 and 9) and cleaved poly(ADP-ribose) polymerase. Additionally, silibinin caused a strong cell cycle arrest at G(1) phase and a slight but significant G(2)-M-phase arrest at highest concentration (P < 0.01-0.001). Molecular analyses for cell cycle regulators showed that silibinin decreases the level of cyclins (D1, D3, A and B1) and cyclin-dependent kinases (1, 2, 4, and 6) and increases the level of cyclin-dependent kinase inhibitors (p21 and p27). Consistent with these results, silibinin treatment also decreased the phosphorylation of retinoblastoma protein at Ser(780), Ser(795), and Ser(807)/Ser(811) sites without significantly affecting its total level. In animal studies, oral administration of silibinin for 6 weeks (at 100 and 200 mg/kg/d for 5 days/wk) significantly inhibited the growth of LoVo xenograft (P < 0.001) in athymic nude mice without any apparent toxicity. Analyses of xenograft tissue showed that silibinin treatment inhibits proliferation and increases apoptosis along with a strong increase in p27 levels but a decrease in retinoblastoma phosphorylation. Together, these results suggest the potential use of silibinin against advanced human colorectal cancer.

Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation.

Phytochemicals show promise as potential chemopreventive or chemotherapeutic agents against various cancers. Here we report the chemotherapeutic effects of berberine, a phytochemical, on human prostate cancer cells. The treatment of human prostate cancer cells (PC-3) with berberine induced dose-dependent apoptosis but this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. This effect of berberine on prostate cancer cells was initiated by the generation of reactive oxygen species (ROS) irrespective of their androgen responsiveness, and the generation of ROS was through the increased induction of xanthine oxidase. Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells. Berberine-induced apoptosis was blocked in the presence of antioxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. In conclusion, the present study reveals that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer.

Interleukin-12 deficiency is permissive for angiogenesis in UV radiation-induced skin tumors.

We have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumor-uninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVB-exposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers.

Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair.

Human skin is constantly exposed to numerous noxious physical, chemical and environmental agents. Some of these agents directly or indirectly adversely affect the skin. Cutaneous overexposure to environmental solar ultraviolet (UV) radiation (290-400 nm) has a variety of adverse effects on human health, including the development of melanoma and nonmelanoma skin cancers. Therefore, there is a need to develop measures or strategies, and nutritional components are increasingly being explored for this purpose. The polyphenols present in green tea (Camellia sinensis) have been shown to have numerous health benefits, including protection from UV carcinogenesis. (-)-Epigallocatechin-3-gallate (EGCG) is the major and most photoprotective polyphenolic component of green tea. In this review article, we have discussed the most recent investigations and mechanistic studies that define and support the photoprotective efficacy of green tea polyphenols (GTPs) against UV carcinogenesis. The oral administration of GTPs in drinking water or the topical application of EGCG prevents UVB-induced skin tumor development in mice, and this prevention is mediated through: (a) the induction of immunoregulatory cytokine interleukin (IL) 12; (b) IL-12-dependent DNA repair following nucleotide excision repair mechanism; (c) the inhibition of UV-induced immunosuppression through IL-12-dependent DNA repair; (d) the inhibition of angiogenic factors; and (e) the stimulation of cytotoxic T cells in a tumor microenvironment. New mechanistic information strongly supports and explains the chemopreventive activity of GTPs against photocarcinogenesis.

Silymarin inhibits UV radiation-induced immunosuppression through augmentation of interleukin-12 in mice.

We have shown previously that silymarin, a plant flavonoid, inhibits UVB-induced photocarcinogenesis in mice. As UVB-induced immunosuppression has been implicated in the development of skin cancer, we investigated whether silymarin can modulate the effects of UVB radiation on the immune system. Treatment of C3H/HeN mice with topically applied silymarin (0.5 or 1.0 mg/cm(2)) or silibinin, a major component of silymarin, markedly inhibited UVB (180 mJ/cm(2))-induced suppression of contact hypersensitivity response in a local model of immunosuppression and had a moderate inhibitory effect in a systemic model of contact hypersensitivity. Silymarin reduced the UVB-induced enhancement of the levels of the immunosuppressive cytokine, interleukin (IL)-10, in the skin and draining lymph nodes and enhanced the levels of the immunostimulatory cytokine, IL-12. Intraperitoneal injection of mice treated with silymarin with an endotoxin-free neutralizing anti-IL-12 antibody abrogated the protective effects of the silymarin against UVB-induced suppression of the contact hypersensitivity response. Furthermore, the treatment of silymarin did not prevent UVB-induced suppression of the contact hypersensitivity response in IL-12 knockout mice but prevented it in their wild-type mice. Moreover, i.p. injection of IL-12 to silymarin-treated or non-silymarin-treated IL-12 knockout mice resulted in an enhanced response to contact hypersensitivity compared with the response in mice that were exposed to either UVB alone or silymarin plus UVB. These data indicate for the first time that silymarin has the ability to protect mice from UVB-induced immunosuppression and that this protective effect is mediated, at least in part, through IL-12.