Machine learning models based on the dimensionality reduction of standard automated perimetry data for glaucoma diagnosis.

INTRODUCTION: Visual field testing via standard automated perimetry (SAP) is a commonly used glaucoma diagnosis method. Applying machine learning techniques to the visual field test results, a valid clinical diagnosis of glaucoma solely based on the SAP data is provided. In order to reflect structural-functional patterns of glaucoma on the automated diagnostic models, we propose composite variables derived from anatomically grouped visual field clusters to improve the prediction performance. A set of machine learning-based diagnostic models are designed that implement different input data manipulation, dimensionality reduction, and classification methods. METHODS: Visual field testing data of 375 healthy and 257 glaucomatous eyes were used to build the diagnostic models. Three kinds of composite variables derived from the Garway-Heath map and the glaucoma hemifield test (GHT) sector map were included in the input variables in addition to the 52 SAP visual filed locations. Dimensionality reduction was conducted to select important variables so as to alleviate high-dimensionality problems. To validate the proposed methods, we applied four classifiers-linear discriminant analysis, naïve Bayes classifier, support vector machines, and artificial neural networks-and four dimensionality reduction methods-Pearson correlation coefficient-based variable selection, Markov blanket variable selection, the minimum redundancy maximum relevance algorithm, and principal component analysis- and compared their classification performances. RESULTS: For all tested combinations, the classification performance improved when the proposed composite variables and dimensionality reduction techniques were implemented. The combination of total deviation values, the GHT sector map, support vector machines, and Markov blanket variable selection obtains the best performance: an area under the receiver operating characteristic curve (AUC) of 0.912. CONCLUSION: A glaucoma diagnosis model giving an AUC of 0.912 was constructed by applying machine learning techniques to SAP data. The results show that dimensionality reduction not only reduces dimensions of the input space but also enhances the classification performance. The variable selection results show that the proposed composite variables from visual field clustering play a key role in the diagnosis model.

Short-term changes of intraocular pressure and ocular perfusion pressure after intravitreal injection of bevacizumab or ranibizumab.

BACKGROUND: The aim of this study was to investigate the effect of intravitreal anti-vascular endothothelial growth factor (VEGF) injection on intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP). METHODS: MOPP results were obtained by measuring mean arterial pressure (MAP) and IOP just before the injection, immediately after the injection, at 30 min, 1 day, and 1 week after injection from 65 eyes of 42 patients. RESULTS: Pre-injection mean IOP was 16.66 ± 3.50 mmHg, and mean IOP was 43.81 ± 9.69 mmHg immediately after the injection, 17.57 ± 4.44 mmHg at 30 min, 15.00 ± 4.21 mmHg at 1 day, and 15.90 ± 3.63 mmHg at 1 week after the injection. Pre-injection mean MOPP was 46.39 ± 5.78 mmHg, and mean MOPP was 25.14 ± 8.79 mmHg immediately after the injection, 45.87 ± 6.31 mmHg at 30 min, 46.93 ± 6.25 mmHg at 1 day, and 46.50 ± 4.94 mmHg at 1 week after the injection. CONCLUSION: The instant increase in IOP by intravitreal anti-VEGF injection led to a transient decrease in MOPP. Based on this finding, the instant increase in IOP after intravitreal anti-VEGF injection does not significantly impair retinal blood flow.

Secondary angle closure glaucoma by lupus choroidopathy as an initial presentation of systemic lupus erythematosus: a case report.

BACKGROUND: We present a rare case of secondary angle closure glaucoma due to systemic lupus erythematosus choroidopathy as initial presentation of systemic lupus erythematosus, accompanied by central nervous system vasculitis and uncontrolled nephropathy. CASE PRESENTATION: A 31-year-old woman presented with decreased visual acuity, nausea, vomiting, fever, and bilateral angioedema-like eyelid swelling. She had persistent dry cough while taking medication for 3 months, and had usual posterior neck pain, which was treated with analgesic medication and Asian medicines. Intraocular pressure was 32 and 34 mmHg in her right and left eyes, respectively. Peripheral anterior chambers were shallow (grade I) using the van Herick method. Gonioscopy revealed 360° closed angle in both eyes. In both eyes, serous retinal detachment was found using optical coherence tomography and B scan ultrasonography, as well as choroidal thickening with effusion. Secondary acute angle closure glaucoma was drug induced, or caused by uveitis of unknown etiology when she was first treated with intraocular pressure-lowering medication. During evaluation of the drug-induced angioedema in the internal medicine department, systemic lupus erythematosus was diagnosed, based on malar rash, photosensitivity, proteinuria, and positive anti-Smith and anti-DNA antibodies, followed by initiation of steroid pulse therapy. Using fluorescein angiography, multifocal subretinal pinpoint foci were detected at the middle phase. We then diagnosed bilateral angle closure glaucoma by choroidal effusions, with lupus choroidopathy. At 2 months after steroid pulse therapy, subretinal fluid was not found, and visual acuity improved to normal. During the subsequent 2 years, lupus choroidopathy was not aggravated but lupus nephritis was not controlled. CONCLUSION: Patients with systemic lupus erythematosus choroidopathy can develop ciliochoroidal effusion, which can lead to acute angle closure glaucoma. Systemic lupus erythematosus choroidopathy is an early sign of severe complications. Angle closure glaucoma by systemic lupus erythematosus choroidopathy can be effectively treated using antiglaucoma drugs and immunosuppressive therapy.

Risk factors for the progression of intima-media thickness of carotid arteries: a 2-year follow-up study in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Intima-media thickness (IMT) of the carotid arteries is known to have a positive correlation with the risk of cardiovascular disease. This study was designed to identify risk factors affecting the progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with newly diagnosed T2DM with carotid IMT measurements were enrolled, and their clinical data and carotid IMT results at baseline and 2 years later were compared. RESULTS: Of the 171 patients, 67.2% of males and 50.8% of females had abnormal baseline IMT of the left common carotid artery. At baseline, systolic blood pressure, body mass index and smoking in male participants, and fasting plasma glucose and glycated hemoglobin levels in females were significantly higher in patients with abnormal IMT than in those with normal IMT. Low density lipoprotein cholesterol (LDL-C) levels in males and high density lipoprotein cholesterol (HDL-C) levels in females at the 2-year follow-up were significantly different between the nonprogression and the progression groups. Reduction of the United Kingdom Prospective Diabetes Study (UKPDS) 10-year coronary heart disease (CHD) risk score after 2 years was generally higher in the nonprogression group than the progression group. CONCLUSION: LDL-C levels in males and HDL-C levels in females at the 2-year follow-up were significantly different between participants with and without progression of carotid IMT. Furthermore, a reduction in the UKPDS 10-year CHD risk score appeared to delay the advancement of atherosclerosis. Therefore, the importance of establishing the therapeutic goal of lipid profiles should be emphasized to prevent the progression of carotid IMT in newly diagnosed T2DM patients.

Regulation of SPARC by transforming growth factor ß2 in human trabecular meshwork.

PURPOSE: An increased aqueous level of TGF-ß2 has been found in many primary open-angle glaucoma patients. Secreted Protein, Acidic, and Rich in Cysteine (SPARC)-null mice have a lower intraocular pressure. The mechanistic relationship between SPARC and TGF-ß2 in trabecular meshwork (TM) is unknown. We hypothesized that TGF-ß2 upregulates SPARC expression in TM. METHODS: Cultured TM cells were incubated with selective inhibitors for p38 MAP kinase (p38), Smad3, p42, JNK, RhoA, PI3K, or TGF-ß2 receptor for 2 hours, and then TGF-ß2 was added for 24 hours in serum-free media. Quantitative polymerase chain reaction (qPCR) and immunoblot analysis were performed. Immunofluorescent microscopy was used to determine nuclear translocation of signaling proteins. Ad5.hSPARC and Lentiviral shRNA for p38 and Smad3 were constructed, and infected human TM cells. RESULTS: SPARC was upregulated by TGF-ß2 in the human TM cells (3.8 ± 1.7-fold, n = 6, P = 0.01 for protein and 7.1 ± 3.7-fold, n = 6, P = 0.01 for mRNA), while upregulation of SPARC had no effect on TGF-ß2. TGF-ß2-induced SPARC expression was suppressed by inhibitors against p38 (-40.3 ± 20.9%, n = 10, P = 0.0001), Smad3 (-56.2 ± 18.9%, n = 10, P = 0.0001), JNK (-49.1 ± 24.6%, n = 10, P = 0.0001), and TGF-ß2 receptor (-83.6 ± 14.4%, n = 6, P = 0.003). Phosphorylation and translocation of Smad3, p38, and MAPKAPK2 were detected at 30 minutes and 1 hour, respectively, following TGF-ß2 treatment. Phosphorylation of JNK and c-jun was detected before TGF-ß2 treatment. SPARC was suppressed 31 ± 13% (n = 5, P < 0.0001) by shRNA-p38 and 41 ± 3% (n = 5, P < 0.0001) by shRNA-Smad3. CONCLUSIONS: TGF-ß2 upregulates SPARC expression in human TM through Smad-dependent (Smad2/3) or -independent (p38) signaling pathways. SPARC may be a downstream regulatory node of TGF-ß2-mediated IOP elevation.

Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes.

This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long- Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve ß-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.

Hong's grading for evaluating anterior chamber angle width.

PURPOSE: To compare Hong's grading method with anterior segment optical coherence tomography (AS-OCT), gonioscopy, and the dark-room prone-position test (DRPT) for evaluating anterior chamber width. METHODS: The anterior chamber angle was graded using Hong's grading method, and Hong's angle width was calculated from the arctangent of Hong's grades. The correlation between Hong's angle width and AS-OCT parameters was analyzed. The area under the receiver operating characteristic curve (AUC) for Hong's grading method when discriminating between narrow and open angles as determined by gonioscopy was calculated. Correlation analysis was performed between Hong's angle width and intraocular pressure (IOP) changes determined by DRPT. RESULTS: A total of 60 subjects were enrolled. Of these subjects, 53.5 % had a narrow angle. Hong's angle width correlated significantly with the AS-OCT parameters (r = 0.562-0.719, P < 0.01). A Bland-Altman plot showed relatively good agreement between Hong's angle width and the angle width obtained by AS-OCT. The ability of Hong's grading method to discriminate between open and narrow angles was good (AUC = 0.868, 95 % CI 0.756-0.942). A significant linear correlation was found between Hong's angle width and IOP change determined by DRPT (r = -0.761, P < 0.01). CONCLUSIONS: Hong's grading method is useful for detecting narrow angles. Hong's grading correlated well with AS-OCT parameters and DRPT.

Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures.

PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding.

Inhibition of NF-κB prevents high glucose-induced proliferation and plasminogen activator inhibitor-1 expression in vascular smooth muscle cells.

Recent epidemiologic studies clearly showed that early intensive glucose control has a legacy effect for preventing diabetic macrovascular complications. However, the cellular and molecular processes by which high glucose leads to macrovascular complications are poorly understood. Vascular smooth muscle cell (VSMC) dysfunction due to high glucose is a characteristic of diabetic vascular complications. Activation of nuclear factor-κB (NF-κB) may play a key role in the regulation of inflammation and proliferation of VSMCs. We examined whether VSMC proliferation and plasminogen activator inhibitor-1 (PAI-1) expression induced by high glucose were mediated by NF-κB activation. Also, we determined whether selective inhibition of NF-κB would inhibit proliferation and PAI-1 expression in VSMCs. VSMCs of the aorta of male SD rats were treated with various concentrations of glucose (5.6, 11.1, 16.7, and 22.2 mM) with or without an inhibitor of NF-κB or expression of a recombinant adenovirus vector encoding an IκB-α mutant (Ad-IκBαM). VSMC proliferation was examined using an MTT assay. PAI-1 expression was assayed by real-time PCR and PAI-1 protein in the media was measured by ELISA. NF-κB activation was determined by immunohistochemical staining, NF-κB reporter assay, and immunoblotting. We found that glucose stimulated VSMC proliferation and PAI-1 expression in a dose-dependent manner up to 22.2 mM. High glucose (22.2 mM) alone induced an increase in NF-κB activity. Treatment with inhibitors of NF-κB such as MG132, PDTC or expression of Ad-IκB-αM in VSMCs prevented VSMC proliferation and PAI-1 expression induced by high glucose. In conclusion, inhibition of NF-κB activity prevented high glucose-induced VSMC proliferation and PAI-1 expression.

Optic disc hemorrhage may be associated with retinal nerve fiber loss in otherwise normal eyes.

PURPOSE: To evaluate quantitatively the structural damage of the peripapillary retinal nerve fiber layer (RNFL) in eyes with disc hemorrhage (DH). DESIGN: Prospective cross-sectional study. PARTICIPANTS: Seventy patients with DH (70 eyes; mean age +/- standard deviation, 60.0+/-11.8 years) and 100 healthy control subjects (100 eyes; mean age +/- standard deviation, 57.7+/-8.0 years) were enrolled from the Glaucoma Clinic of Seoul National University Hospital. METHODS: Normal eyes without DH (group 1: normal control group) served as controls. Eyes with DH were divided into the following groups: (1) eyes with a DH, accompanied by no visible RNFL defect according to red-free fundus photography and normal visual fields (group 2: DH only group); (2) eyes with a DH and a localized RNFL defect in the same quadrant, accompanied by normal visual fields (group 3: DH-preperimetric group); and (3) eyes with a DH and a localized RNFL defect in the same quadrant, accompanied by glaucomatous visual field defect in the corresponding hemifield location (group 4: DH-perimetric group). Optical coherence tomography (OCT)-measured RNFL thicknesses were compared. MAIN OUTCOME MEASURES: Average and segmental (4 quadrants and 12 clock-hours) OCT-measured RNFL thicknesses. RESULTS: The number of eyes in groups 1, 2, 3, and 4 was 100, 25, 22, and 23 eyes, respectively. The OCT-measured RNFL thickness was significantly different among the 4 groups in average RNFL thickness and in inferior, superior, and nasal quadrants (P<0.01, 1-way analysis of variance). On post hoc analysis, the eyes of groups 2 and 3 showed thinner average RNFL thickness than those of group 1, and the average RNFL thickness of group 4 was significantly lower than that of groups 2 and 3 (P<0.001, 1-way analysis of variance and Tukey's test). The OCT-measured RNFL thickness revealed a topographic relationship with the DH location. CONCLUSIONS: Significant RNFL loss was already present in the DH only eyes with apparently normal RNFL configuration by red-free fundus photography, indicating that preperimetric changes of the RNFL are already present. These results suggest that OCT has the potential to detect subclinical or preperimetric RNFL loss in the eyes with DH. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

TGFbeta mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation.

Transglutaminase 2 (TGase2) is a ubiquitously expressed enzyme that catalyzes irreversible post-translational modification of protein, forming cross-linked protein aggregates. We previously reported that intracellular TGase2 is activated by oxidative stress. To elucidate the functional role of TGase2 activation in cells under the oxidatively stressed condition, we identified the mediator that activates TGase2. In this study, we showed that low levels of oxidative stress trigger the release of TGFbeta, which subsequently activates TGase2 through the nuclear translocation of Smad3. Analysis of substrate proteins reveals that TGase2-mediated protein modification results in a decrease of protein solubility and a collapse of intermediate filament network, which leads to aggregation of proteins. We confirm these results using lens tissues from TGase2-deficient mice. Among several antioxidants tried, only N-acetylcysteine effectively inhibits TGFbeta-mediated activation of TGase2. These results indicate that TGFbeta mediates oxidative stress-induced protein aggregation through activation of TGase2 and suggest that the formation of protein aggregation may not be a passive process of self-assembly of oxidatively damaged proteins but may be an active cellular response to oxidative stress. Therefore, TGFbeta-TGase2 pathway may have implications for both the pathogenesis of age-related degenerative diseases and the development of pharmaceutics.

Correlation between a disc hemorrhage and peripapillary atrophy in glaucoma patients with a unilateral disc hemorrhage.

PURPOSE: To investigate the correlation between a disc hemorrhage and peripapillary atrophy in glaucoma patients with a unilateral disc hemorrhage. METHODS: The 44 glaucoma patients (7 with primary open-angle glaucoma and 37 with normal-tension glaucoma) with a unilateral disc hemorrhage from June 1997 to November 2002 were selected randomly and included sequentially. The topographic measurements were performed using Heidelberg Retina Tomograph (HRT) within 3 months of detecting the disc hemorrhage. The zone beta parameters of the peripapillary atrophy were analyzed by the Atrophy Zone Analysis software. The intraocular pressure, refractive error, visual field parameters, and optic disc parameters were compared between both eyes. Univariate and multivariate regression analysis were performed. RESULTS: The area, angular and radial extent of the zone beta, and the ratio of the zone beta area to the disc area were significantly greater in the hemorrhagic eyes than in the contralateral eyes (P < 0.001). The prevalence of peripapillary atrophy was significantly higher in the hemorrhagic eyes (84%) than in the contralateral eyes (66%) (P = 0.034, chi2 test). The rim area and the rim volume of the hemorrhagic eyes were significantly smaller than those of the contralateral eyes (P = 0.02, < 0.001, respectively). In multivariate regression analysis, the peripapillary atrophy area was the independent significant factor associated with disc hemorrhage (P = 0.03, Odds Ratio = 1.51). The refractive error, intraocular pressure, Mean Deviation (MD), and Corrected Pattern Standard Deviation (CPSD) of the visual fields in both eyes were similar. CONCLUSION: The area and extent of the peripapillary atrophy was significantly greater and more prevalent in the eyes with a disc hemorrhage than in the contralateral control eyes. Peripapillary atrophy is closely associated with a disc hemorrhage in glaucoma patients irrespective of small neuroretinal rim area and volume.