Roles of CYP2C19 Gene Polymorphisms in Susceptibility to POAG and Individual Differences in Drug Treatment Response.

BACKGROUND: The aim of this study was to investigate the roles of cytochrome P450 2C19 (CYP2C19) polymorphisms in primary open-angle glaucoma (POAG) susceptibility and individual responses to drug treatment. MATERIAL/METHODS: This case-control study consisted of 93 cases with POAG and 125 controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze CYP2C19 single-nucleotide polymorphisms (SNPs). After timolol treatment, patients were classified into side effect (SE) group and non-side effect (NSE) group. According to drug treatment responses, patients were divided into 3 groups: excellent group (Ex) (IOP ≥8 mm Hg); utility group (Ut) (5 0.05). Frequencies of extensive metabolizer phenotype and poor metabolizer phenotype or poor metabolizer phenotype and intermediate metabolizer phenotype were significantly different between the SE group and NSE group (both P<0.05). The distribution of intermediate metabolizer phenotype and extensive metabolizer phenotype were significantly different among Ex group, Ut group, and In group (all P<0.05). CONCLUSIONS: We found no evidence that CYP2C19 polymorphisms are associated with susceptibility to POAG. However, different CYP2C19 metabolizer phenotypes were identified and observed to have important effects on the individual differences in drug treatment response.

Histopathology and treatment of a huge overhanging filtering bleb.

BACKGROUND: The giant filtering bleb encroaching onto the corneal surface is a rare occurrence in our and other's clinical experience (Kapoor and Syed, Int. Ophthalmol 31(5):403-404, 2011), even in patients having had a trabeculectomy with mitomycin C, and how it developed is debated. In this paper, we report a patient who developed a huge overhanging filtering bleb after trabeculectomy, and present our intraoperative photographs, histopathology and immunohistochemistry results. CASE PRESENTATION: A 62-year-old female visited our hospital due to the giant filtering bleb encroaching onto the corneal surface which was about 6 mm × 8 mm × 3 mm. We dissected the filtering bleb from the cornea and present the histopathology and immunohistochemistry results of it. CONCLUSION: The results from histopathology and immunohistochemistry in this study are consistent with the filtering cicatrix hypothesis. However, our finding that the overhanging blebs had tight connections with the corneal tissue or corneoscleral limbus, rather than simply leaning on it, might be highly related to their development and still needs to be further studied.

Changes of optic nerve head microcirculation in high myopia.

AIM: To analyze the correlation of age, spherical equivalent (SE), and axial length (AL) with the microcirculation of optic nerve head (ONH) in high myopia (HM). METHODS: In this cross-sectional clinical study, 164 right eyes were included. Optical coherence tomography angiography (OCTA) was used to detect ONH vessel density. Eyes were classified based on age, SE, and AL. Groups of Age1, Age2, and Age3 were denoted for age classification (Age1<20y, 20y≤Age2<30y, Age3≥30y); Groups SE1, SE2, and SE3 for the SE classification (-9≤SE1<-6 D, -12≤SE2<-9 D, SE3<-12 D); Groups AL1, AL2, AL3, and AL4 for the AL classification (AL1<26 mm, 26≤AL2<27 mm, 27≤AL3<28 mm, AL4≥28 mm). RESULTS: No significant difference was observed in vessel density among the Age1, Age2, and Age3 groups (all P>0.05) and the SE1, SE2, and SE3 groups (all P>0.05). No significant difference was observed in the intrapapillary vascular density (IVD) among AL1, AL2, AL3, and AL4 groups (P>0.05). However, a significant decrease was found in the peripapillary vascular density (PVD) in the AL1, AL2, AL3, and AL4 groups (F=3.605, P=0.015), especially in the inferotemporal (IT; F=6.25, P<0.001), temporoinferior (TI; F=2.865, P=0.038), and temporosuperior (TS; F=6.812, P<0.001) sectors. The IVD was correlated with age (r=-0.190, P<0.05) but not with SE or AL (P>0.05). The PVD was correlated with AL (r=-0.236, P<0.01) but not with age or SE (P>0.05). CONCLUSION: With the increase of AL, the IVD remains stable while the PVD decreases, especially in the three directions of temporal (IT, TI, and TS). The main cause of microcirculation reduction may be related to AL elongation rather than an increase in age or SE.

[Ocular surface injury resulted from topical anti-glaucoma medications: prevention and cure].

The accumulating evidences from experimental and clinical studies suggested that the ocular surface could be injured by topical anti-glaucoma medications. The ocular surface injury not only caused dry eyes, red eye, eye itching, photophobia and other discomforts, but also increased the risk of failure of glaucoma surgery in patients. The commonly used preservative Benzalkonium Chloride (BAK) plays an important role in ocular surface damage and its side effects are dose- and time-dependent, particularly, in the combined medications. Topical application of preservative BAK could result in the damage of epithelial cells and endothelial cells, and also affect the central corneal thickness. Prevention of ocular injury should be seriously taken into consideration in the anti-glaucoma medical treatment. Development of complex preparations, preservative-free and/or novel preservative preparations for glaucoma therapy may provide a promising approach in the prevention of ocular surface injury.

Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress.

Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.

[Development of glaucoma drainage device].

Glaucoma drainage device (GDD) is moderately successful in patients with refractory glaucoma. However, bleb fibrosis appears to be the major cause of long-term GDD failure. In recent years, many researchers tried to explain the cause of fibrosis and its influence on the clinical effects of GDD from histopathological study. It has reported that antifibrotic agents are effective in controlling capsule fibrosis around GDD, but this view has been challenged recently. Although GDD can effectively reduce the intraocular pressure (IOP) in refractory glaucoma, it is associated with many serious complications, such as endophthalmitis, corneal decompensation and hypotony. Because of the disadvantages of GDD, many new implant and modified surgical technique emerged in recent years. The anterior segment OCT is able to visualize the whole outline and the position of the tube, therefore it is useful for guiding the postoperative treatment. Furthermore, the application of novel materials and nanotechnology could open up new avenues for GDD.

Biomechanics of the sclera and effects on intraocular pressure.

Accumulating evidence indicates that glaucoma is a multifactorial neurodegenerative disease characterized by the loss of retinal ganglion cells (RGC), resulting in gradual and progressive permanent loss of vision. Reducing intraocular pressure (IOP) remains the only proven method for preventing and delaying the progression of glaucomatous visual impairment. However, the specific role of IOP in optic nerve injury remains controversial, and little is known about the biomechanical mechanism by which elevated IOP leads to the loss of RGC. Published studies suggest that the biomechanical properties of the sclera and scleral lamina cribrosa determine the biomechanical changes of optic nerve head, and play an important role in the pathologic process of loss of RGC and optic nerve damage. This review focuses on the current understanding of biomechanics of sclera in glaucoma and provides an overview of the possible interactions between the sclera and IOP. Treatments and interventions aimed at the sclera are also discussed.

ABCB1 variants confer susceptibility to primary open-angle glaucoma and predict individual differences to latanoprost treatment.

OBJECTIVE: We investigated whether ABCB1 variants confer susceptibility to primary open-angle glaucoma and predict individual differences to latanoprost treatment. METHODS: Between May 2013 and May 2015, 129 POAG patients enrolled in the Department of Ophthalmology, the Second People's Hospital of Yunnan Province were identified as the case group and 121 healthy individuals were included as the control group. Direct DNA sequencing was used to detect four ABCB1 gene polymorphisms, namely, -129T>C (rs3213619), 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642). All POAG patients received latanoprost eye drops once daily. The differences in intraocular pressure (IOP) and visual acuity (VA) before and 1 month after latanoprost treatment were compared in different SNPs genotypes. RESULTS: Statistically significant differences in genotype frequency were found in ABCB1 gene polymorphism 2677G>T/A and 3435C>T between the case group and the control group (both P<0.05). No significant difference in genotype frequency was found in -129T> C and 1236C>T between the two groups (both P>0.05). Importantly, ABCB1 gene 3435C>T polymorphism was associated with a remarkably reduced IOP and an improved VA in POAG patients before and after latanoprost eye drops treatment (both P < 0.05). However, no significant differences in IOP and VA were found in other three genotypes between the two groups (all P>0.05). CONCLUSION: Our results suggest that ABCB1 gene polymorphisms 2677G>T/A and 3435C>T may confer to associated with the susceptibility to POAG. The ABCB1 gene polymorphism 3435C>T may be linked to individual differences in response to latanoprost eye drops treatment in POAG patients.

Rosiglitazone inhibits TGF-ß 1 induced activation of human Tenon fibroblasts via p38 signal pathway.

PURPOSE: Transdifferentiation of human Tenon fibroblasts to myofibroblasts and subsequent deposition of extracellular matrix is a key step in the scarring after glaucoma filtration surgery. The p38 signaling pathway plays an important role in cell proliferation and differentiation, and its upstream regulators and downstream molecules are widely distributed in the eye. We aimed to investigate the role of p38 in the activation of Tenon fibroblasts and that of the anti-fibrotic mechanism of rosiglitazone in the modulation of the p38 signaling pathway. METHODS: Cultured Tenon fibroblasts were stimulated with transforming growth factor (TGF)-ß1. Activation of p38 was examined by western blot analysis. Rosiglitazone and blocking of the p38 signaling pathway by SB203580 were used to antagonize stimulation by TGF-ß1. Fibroblast motility was examined by wound closure assay; alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were determined by qPCR and western blot. Expression and localization of alpha-smooth muscle actin were determined by immunofluorescence staining. RESULTS: Phosphorylated p38 was upregulated in fibroblasts stimulated with TGF-ß1, and this effect was substantially inhibited by rosiglitazone. Proliferation and migration of fibroblasts were suppressed by rosiglitazone and SB203580. Expression of alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were decreased at the mRNA and protein levels by rosiglitazone and SB203580. However, the inhibitory effect of SB203580 on transcription and protein expression was weaker than that of rosiglitazone. Similar phenomena were found on immunofluorescence microscopy of alpha-smooth muscle actin. CONCLUSIONS: The p38 signaling pathway mediates the TGF-ß1-induced transdifferentiation of human Tenon fibroblasts to myofibroblasts. Rosiglitazone can exert anti-fibrotic activity by interfering with the TGF-ß/p38 signaling pathway and might be useful for modulating scar formation after glaucoma filtration surgery.

Diagnosis and treatment of myopic traction maculopathy.

In recent years, the broad application of optical coherence tomography and vitrectomy, combined with research efforts in maculopathy in high myopia have provided many achievements, such as the new classification of myopic traction maculopathy (MTM). Here, we review the latest developments in the diagnosis and treatment of MTM, including its conception, clinical characteristics, pathogenesis, clinical stages, and the options for surgical treatment.

Repeatability and agreement of CCT measurement in myopia using entacam and ultrasound pachymetry.

AIM: To evaluate the repeatability of central corneal thickness (CCT) measurement by entacam, and agreement of CCT measured by Pentacam and ultrasound pachymetry (USP) in Chinese myopia. Thereby investigate the possibility of Pentacam as a substitute for USP in CCT measurement before refractive surgery. The effects of corneal curvature measured by Pentacam on CCT were also evaluated. METHODS: One hundred and forty-eight right eyes of 148 individual with myopia were included in this study. Three successive Pentacam CCT measurements followed by 10 successive ultrasound pachymetry were carried out in the 148 eyes. Mean of CCT taken by each device was calculated for comparison. According to the CCT measured by USP, all the 148 eyes were divided into 3 groups: <520µm, 520-560µm, >560µm. For all eyes and each group the CCT obtained by Pentacam and USP were compared. Anterior corneal curvature of the 148 eyes was also adopted for correlation analysis with CCT obtained by ultrasound pachymetry. In addition, CCT measurement using 60 random selected Scheimpflug images was performed by 3 skilled investigators at different time, and this was repeated for 3 times by a forth investigator to assess repeatability of Pentacam CCT measurement using Scheimpflug images. RESULTS: Intraclass correlation coefficient (ICC) analysis revealed high intraobserver repeatability (ICC=0.994, F=158.60, P<0.001) for CCT measurement by Pentacam. The interobserver (ICC=0.998, F=494.73, P<0.001) and intraobserver (ICC=0.997, F=383.98, P<0.001) repeatability for Pentacam CCT measurements using Scheimpflug images were also excellent. There was high positive correlation between the CCT values measured by Pentacam and ultrasound pachymetry (r=0.963, P<0.001). Bland-altman plots showed that the Pentacam underestimate the CCT by 8.02µm compared with ultrasouond pachymetry. The differences between Pentacam and USP increased as the CCT readings by USP increased (Pentacam vs USP: slope=-0.04, P<0.05). The 95% upper and lower limits of agreement between CCT values obtained from the two devices were +9.33µm and -25.37µm. No significant association could be found between CCT and anterior corneal curvature. CONCLUSION: Inter- and intraobserver variability for CCT measurements by Pentacam was considerably below clinically significant levels. CCT of myopia obtained by Scheimpflug camera, Pentacam, were highly correlated to that by ultrasound pachymetry. However, the values obtained are not directly interchangeable between Pentacam and ultrasound pachymetry as the 95% limits of agreement are relatively wide. Pentacam can be a useful instrument for measuring CCT in candidates to refractive surgery in clinic.

Descemet membrane detachment after trabeculectomy.

Descemet's membrane detachment (DMD) can be a potentially serious complication of intraocular surgery or ocular trauma. The cause is not very clear. We are trying to remind an awareness of the spectrum of DMD resulting from trabeculectomy by presenting a case of extensive DMD after trabeculectomy which was successfully repaired.

Assessment of intraocular pressure measured by Reichert Ocular Response Analyzer, Goldmann Applanation Tonometry, and Dynamic Contour Tonometry in healthy individuals.

AIM: To investigate the accuracy of intraocular pressure (IOP) as measured by a Reichert Ocular Response Analyzer (ORA), as well as the relationship between central corneal thickness (CCT) and IOP as measured by ORA, Goldmann applanation tonometry (GAT), and dynamic contour tonometry (DCT). METHODS: A total of 158 healthy individuals (296 eyes) were chosen randomly for measurement of IOP. After CCT was measured using A-ultrasound (A-US), IOP was measured by ORA, GAT, and DCT devices in a randomized order. The IOP values acquired using each of the three tonometries were compared, and the relationship between CCT and IOP values were analyzed separately. Two IOP values, Goldmann-correlated IOP value (IOPg) and corneal-compensated intraocular pressure (IOPcc), were got using ORA. Three groups were defined according to CCT: 1) thin cornea (CCT<520µm); 2) normal-thickness cornea (CCT: 520-580µm); and 3) thick cornea (CCT>580µm) groups. RESULTS: In normal subjects, IOP measurements were 14.95±2.99mmHg with ORA (IOPg), 15.21±2.77mmHg with ORA (IOPcc), 15.22±2.77mmHg with GAT, and 15.49±2.56mmHg with DCT. Mean differences were 0.01±2.29mmHg between IOPcc and GAT (P>0.05) and 0.28±2.20mmHg between IOPcc and DCT (P>0.05). There was a greater correlation between IOPcc and DCT (r=0.946, P=0.000) than that between IOPcc and GAT (r=0.845, P=0.000). DCT had a significant correlation with GAT (r=0.854, P=0.000). GAT was moderately correlated with CCT (r=0.296, P<0.001), while IOPcc showed a weak but significant correlation with CCT (r=-0.155, P=0.007). There was a strong negative correlation between CCT and the difference between IOPcc and GAT(r=-0.803, P=0.000), with every 10µm increase in CCT resulting in an increase in this difference of 0.35mmHg. The thick cornea group (CCT>580µm) showed the least significant correlation between IOPcc and GAT (r=0.859, P=0.000); while the thin cornea group (CCT<520µm) had the most significant correlation between IOPcc and GAT (r=0.926, P=0.000). The correlated differences between IOPcc and DCT were not significant in any of the three groups (P>0.05). CONCLUSION: Measurement of IOP by ORA has high repeatability and is largely consistent with GAT measurements. Moreover, the ORA measurements are affected only to a small extent by CCT, and are likely to be much closer to the real IOP value than GAT.

Efficacy and necessity of prophylactic vitrectomy for acute retinal necrosis syndrome.

AIM: To compare the efficacy of prophylactic vitrectomy for acute retinal necrosis syndrome(ARN) with routine treatment in Chinese patients, thereby investigate the necessity of prophylactic vitrectomy for ARN. METHODS: Thirty patients (37 eyes) were retrospectively included in this study. The eyes were divided into 2 groups by treatment, including routine treatment, which consisted of antiviral medication and vitrectomy after retinal detachment (RD) (n=21), and prophylactic vitrectomy, which consisted of antiviral medication and vitrectomy for the prevention of RD performed during the active inflammatory phase (n=16). The extent of necrosis was determined by fundus photographs at the time of presentation (for eyes with mild vitreous opacity) or the drawings in the operation records. Necrosis of the 37 eyes was divided into 3 grades, including peripheral, middle-peripheral and extensive. The follow-up period ranged from 8 to 57 months. Differences in visual acuity and necrosis between groups were identified using independent samples t-test. RESULTS: Necrosis was more extensive in the routine treatment group than in the prophylactic vitrectomy group (P<0.05). In the routine treatment group, conservative treatment improved necrosis and prevented RD in 6 eyes (29%). Seven eyes (33%) obtained anatomical success, but retinal redetachment occurred in 8 eyes (57%). There were also 5 eyes (24%) developed ocular hypotony or atrophy. Ten eyes (48%) achieved equal or increased visual acuity. In the prophylactic vitrectomy group, RD occurred in 2 eyes (13%). Twelve eyes (75%) were completely anatomically successful, and 10 eyes underwent silicone oil removal. Only one eye (6%) became ocular hypotony. Fourteen eyes (88%) achieved equal or increased visual acuity. The prophylactic vitrectomy group achieved better vision trends than the routine treatment group (P<0.05). Eyes with peripheral necrosis had better visual outcomes than those with mid-peripheral (P<0.05) or extensive (P<0.05) necrosis. However, there was no significant difference between eyes with mid-peripheral and extensive necrosis (P=0.3008) CONCLUSION: Prophylactic vitrectomy can prevent RD and improve the prognosis of ARN, making it an option for cases with rapidly progressing necrosis despite antiviral treatment and cases with moderate to extensive necrosis and severe vitreous opacity.

Alteration of anterior chamber in 81 glaucomatous eyes using Pentacam Scheimpflug system.

AIM: To study the effects of gender, eye side and age on anterior chamber measurements; To compare the anterior chamber parameters between glaucoma and normal subjects. METHODS: A total of 169 patients (299 eyes), of which 122 normal subjects (218 eyes), 24 cases (39 eyes) with primary angle-closure glaucoma (PACG) and 22 cases (42 eyes) with primary open-angle glaucoma (POAG) visiting our hospital from Apr. 2008 to Oct. 2008 were enrolled. The parameters measured by Pentacam between different sexes, eye sides, ages and different groups were compared. RESULTS: The mean central anterior chamber depth (CACD), anterior chamber volume (ACV) and anterior chamber angle (ACA) measurements of normal eyes were 2.82±0.43mm, 159.74±43.64mm(3) and 35.47±7.92°. There were no significant differences between different eye sides. There was a negative correlation between age and anterior chamber parameters (all P<0.001); The mean CACD, ACV and ACA were 1.87±0.29mm, 82.00±24.17mm(3) and 21.94±7.11° in PACG group, and 2.67±0.34mm, 147.24±43.40mm(3) and 31.19±6.34° in POAG group. The differences between PACG and age-matched normal subjects were significant (all P<0.05), but there was no significant difference between POAG and age-matched normal subjects (P>0.05). CONCLUSION: CACD, ACV and ACA decrease mildly with age. Anterior chamber parameters of PACG are smaller than that of normal eyes, but there is no difference between POAG and normal eyes.