【In Press】Negative effects of transthyretin in high myopic vitreous on diabetic retinopathy

AIM: To analyze the relationship between vitreous transthyretin (TTR) levels, high myopia and diabetic retinopathy (DR). METHODS: We selected 6722 individuals from the southern Jiangsu Province for diabetes and ophthalmic examinations. The TTR concentration in the vitreous of 50 patients with high myopia and diabetes, 50 patients with only DR, and 20 healthy controls were determined by ELISA. Key factors in Tie2 pathway in DR development including VEGF, Tie2, Angpt1, Angpt2, VEGFR1 and VEGFR2 were also detected by ELISA. RESULTS: The prevalence of DR in patients with diabetes and myopia [<6.00 diopter (D)], diabetes and high myopia (>6.00 D), and diabetes without myopia were 11.1%, 2.5%, and 60.0%, respectively. The vitreous TTR concentration of patients with diabetes and high myopia was approximately 6.5- and 4.2-times higher than those of patients with DR and healthy controls, respectively. Following the vitreous TTR concentration, the levels of VEGF, Tie2, Angpt1, Angpt2, VEGFR1 and VEGFR2 in vitreous of diabetes and high myopia patients, DR patients and healthy controls were detected as dramatically fluctuated. CONCLUSION: The results suggest that TTR can affect the vitreous contents of key factors in Tie2 pathway for neovascularization, and there should be a protective association between abundant TTR levels in the vitreous of highly myopic patients and a decreased risk of DR.     

【In Press】 The progress of prophylactic treatment in retinopathy of prematurity

Retinopathy of prematurity (ROP) is a retinal vascular disorder frequently found in premature infants. Different therapeutic strategies have been developed to treat ROP. However, there are still many children with ROP suffering by severe limitations in vision or even blindness. Recently, ROP has been suggested to be caused by abnormal development of the retinal vasculature, but not simply resulted by retinal neovascularization which takes about 4-6wk after birth in premature infants. Thus, instead of focusing on how to reduce retinal neovascularization, understanding the pathological changes and mechanisms that occur prior to retinal neovascularization is meaningful, which may lead to identify novel target(s) for the development of novel strategy to promote the healthy growth of retinal blood vessels rather than passively waiting for the appearance of retinal neovascularization and removing it by force. In this review, we discussed recent studies about: 1) the pathogenesis prior to retinal neovascularization in oxygen-induced retinopathy (OIR, a ROP in animal model) and in premature infants with ROP; 2) the preclinical and clinical research on preventive treatment of early OIR and ROP. We will not only highlight the importance of the mechanisms and signalling pathways in regulating early stage of ROP but also will provide guidance for actively exploring novel mechanisms and discovering novel treatments for early phase OIR and ROP prior to retinal neovascularization in the future.     

【In Press】 The prognostic value of lymphocyte-to-monocyte ratio in retinopathy of prematurity

AIM: To evaluate the associations between development of retinopathy of prematurity (ROP) and serum lymphocyte-to-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). METHODS: A retrospective cohort study was performed, involving infants who were screened for ROP from January 2015 to December 2015. Preterm newborns of ≤32 gestational weeks with ROP were enrolled as the observation group, and non-ROP infants were enrolled as the control group, whose complete blood cell were measured within the first 24h of life. The levels of NLR, LMR and PLR were determined in all groups. The data obtained were analyzed using univariate and multivariate logistic regression analysis. RESULTS: In this study, 40 cases of ROP were enrolled and 40 cases of non-ROP as controls. The LMR levels were significantly higher (p<0.001) in ROP group (3.96±1.16) compared to non-ROP group (2.85±0.79). The NLR levels were significantly lower (p=0.035) in ROP group {median [interquartile range (IQR)], 0.88 (0.67-1.46)} compared to non-ROP group [median (IQR), 1.20 (0.85-1.89)]. The median PLR values were 61.99 (IQR, 50.23-75.98) in ROP group and 69.24 (IQR, 55.52-88.12) in non-ROP group (p=0.104). Logistic regression analysis suggested that LMR was an independent risk factor for ROP (OR: 0.275; 95% CI: 0.134-0.564; p=0.001). CONCLUSION: The findings demonstrate that higher LMR is independently and significantly associated with the development of ROP, and the LMR may be invoked as a predictive tool for identifying risk for ROP.     

【In Press】 Current approaches and future directions in the management of pterygium

Pteryium, a common ocular surface disorder, has a complex pathophysiology that may mimic tumorigenesis. There is altered expression of cell cycle/proliferation-related factors in pterygium tissues. Therefore, similar to cancer treatments, the management of pterygium ought to be multifactorial based on the patient''s condition. Current therapeutic methods for pterygium are focused on surgical resection in conjunction with antimetabolite use, in addition tissue graft is usually performed in the context of the avoidance of bare sclera. However, future directions in the management of pterygia will likely focus on genetic approaches. This perspective views the pathogenesis of pterygium, its existing therapies as well as current and future challenges in its treatment.     

【In Press】 Intravitreal dexamethasone implants for diabetic macular edema

AIM: To evaluate the safety and efficacy of a dexamethasone (DEX) intravitreal implant for diabetic macular edema (DME). METHODS: Totally 113 eyes of 84 patients were divided in three subgroups: naïve patients (n=11), pseudophakic patients (n=72) and phakic patients (n=30). RESULTS: Seventy-three eyes (64.5%) received a single implant, 30 (26.5%) received two implants and 10 (9%) received three implants. At baseline, average in best corrected visual acuity (BCVA), central macular thickness (CMT) and macular volume (MV) were 43.5±20.8, 462.8±145 and 12.6±2.5 respectively. These values improved significantly at 1mo (BCVA: 47.2±19.5, CMT: 339.6±120, MV: 11.11±1.4) and 3mo (BCVA: 53.2±18.1, CMT: 353.8±141, MV: 11.3±1.3) (p <0.05). At 5mo (BCVA: 50.9±19.8, CMT: 425±150, MV: 12.27±2.3), 9mo (BCVA: 48.4±17.6, CMT: 445.5±170, MV: 12.5±2.3) and 12mo (BCVA: 47.7±18.8, CMT: 413.2±149, MV: 12.03±2.5), improvements in the three parameters were no longer statistically significant and decreased progressively but did not reach baseline values. There were no clinical differences between subgroups. Ocular complications were minimal. CONCLUSION: Patients with DEX implants showed maximum efficacy at month 3 which then declined progressively, but was still better than baseline values at the end of follow-up.     

【In Press】 Bioinformatics analysis of differentially expressed miRNAs in premature infants with retinopathy

AIM: To reveal the involvement of miRNAs in retinopathy of prematurity (ROP) by bioinformatics analysis. METHODS: The raw data in this study came from the paper of Wang et al and Zhao et al who analyzed the miRNA expression profile between ROP and controls. Based on the identified differentially expressed miRNAs, we predicted the related target genes, lncRNA and circRNA. Then we performed functional enrichment analysis to analyze the functions of target genes. RESULTS: 1) Hsa-miRNA-128-3p and hsa-miRNA-9-5p showed significantly different expression in both studies; 2) LncRNA of POLDIP2, GAS5, NEFL and UHRF1, circRNA of ZNF280C_hsa_circ_001211 and SIAE_hsa_circ_002083, tar¬get gene of QKI showed meaningful differential expression in ROP; 3) Enrichment analysis showed that TGF-β signaling pathway, PI3K-Akt signaling pathway and MAPK signaling pathway may play important roles in the prog¬ress of ROP. CONCLUSION: This research may provide a comprehensive bioinformatics analysis of differentially expressed miRNAs which might be involved in ROP.     

【In Press】Clinical and experimental study on ANGPTL8 associated with proliferative diabetic retinopathy

AIM: To confirm the role of ANGPTL8 in proliferative diabetic retinopathy (PDR). METHODS: The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy (NDR) patients were collected and the expression of ANGPTL8 was detected by enzyme linked immune-sorbent assay (ELISA). Experimental diabetes mice model was induced with streptozotocin. The expression of glycosylated hemoglobin and ANGPTL8 in sera was detected. Recombinant ANGPTL8 was re-infused into wild type (WT) diabetic mice and spatial frequency threshold and contrast sensitivity were measured. In vitro retinal pigment epithelium (RPE) were stimulated by recombinant ANGPTL8 for 24h. MMT assay were used to detect RPE cell proliferation. At the same time, qRT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells. RESULTS: The expression of ANGPTL8 was markedly increased in the sera and aqueous humor of PDR patients. After successfully establishing the diabetic mice model, we found that glycosylated hemoglobin and ANGPTL8 expression levels were increased. Re-infusion of recombinant ANGPTL8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity. In vitro, RPE cells stimulated by recombinant ANGPTL8 could increase the relative absorbance of MMT assay and PCNA expression. The proliferative effect of ANGPTL8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A, cyclin F and E2F2, and reducing the expression of proliferation-inhibiting factors cdkn1 and cdkn2. CONCLUSION: The expression of ANGPTL8 is increased in PDR, and the increased ANGPTL8 can promote proliferation and increase proliferation-related factors.     

【In Press】 Prevalence of glaucoma in the Israeli Arab population

We describe the prevalence and treatment of glaucoma in a Muslim Arab population in Israel. Based on the medical records of 15 122 persons, the overall prevalence of glaucoma was 3.9%. Prevalence rates for primary open angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) were 3.0% and 0.42%, respectively. Prevalence rates for women were 135% that of men considering all types of glaucoma, 143% for POAG, and 96% for PACG. Prostaglandin analogs and beta blockers, alone or combined with carbonic anhydrase inhibitors, were the preferred medications. Of 68 patients who underwent trabeculectomy, 27 (39.7%) required medications, postoperatively, for treatment of glaucoma; following Ex-Press shunt surgery, 3/11 (27.3%) required medications. During the last three years, 16 (1.3%) individuals with POAG were recorded as legally blind as a result of glaucoma.     

【In Press】 Endoscopy-assisted vitrectomy in the anterior vitreous

Endoscopy-assisted ocular surgery is a relatively old technique that is increasingly being recognized for its application in cases of vitreoretinal disease. This technique is especially useful when both the vitreous and retina are difficult to access because of media opacity, a small pupil, or a microcornea. In this context, the anterior vitreous is often difficult to dissect because of its complex pathological changes. This article reviews the common anatomical features and pathologies that are observed in the anterior vitreous, as well as the applications and indications of endoscopy-assisted vitrectomy in the anterior vitreous.     

【In Press】Comparison of the effects of intravitreal bevacizumab and dexamethasone in experimental posterior penetrating eye injury

AIM: To compare the effects of intravitreal anti-vascular endothelial growth factor (VEGF) and dexamethasone in an experimental rabbit model of posterior penetrating ocular injury. METHODS: Thirty white New Zealand rabbits were included in the study. A posterior penetrating ocular injury was performed at the superotemporal quadrant. They were randomly divided into three groups. The rabbits in group 1 received intravitreal dexamethasone, in group 2 they received intravitreal bevacizumab and those in group 3 received intravitreal physiological saline solution in both eyes. All eyes were examined ophthalmologically on the 1st, 3rd, 7th, 14th and 28th days following the injury and the clinical findings were scored. On the day 28, the eyes were enucleated, evaluated and scored macroscopically, histopathologically and scanning electron microscopically. RESULTS: The median clinical score on the 14th and 28th days and the median macroscopic score of the dexamethasone group was significantly better than that of control (P=0.004, 0.018). Dexamethasone group was also better than that of bevacizumab group but the differences did not reach statistical significance. Retinal detachment rate was 8.3%, 16.6% and 12.5% in the dexamethasone group, bevacizumab group and control group, respectively (P=0.476). More extensive fibrocelluler proliferations were observed in controls compared with dexamethasone and bevacizumab groups. But these differences did not reach the statistical significance (P=0.538). In scanning electron microscopy all groups showed fibreous stalk and dense collagen fibrils in vitreous. CONCLUSION: This study shows that intravitreal injection of both dexamethasone and bevacizumab may reduce the intraocular fibrous proliferation after an experimental posterior penetrating ocular injury in rabbits.     

【In Press】Effect of anti-VEGF treatment on retinopathy of prematurity in Zone II Stage 3+

AIM: To assess the effect of intravitreal ranibizumab injection for retinopathy of prematurity (ROP) in Zone II Stage 3+. METHODS: Data was collected from ROP patients with Zone II Stage 3+ who had intravitreal ranibizumab injections between October 2014 and January 2017 at the department of Ophthalmology in our hospital. No prior laser or other intravitreal therapy was done. Fundus examination was performed prior to the intervention and at each follow-up visit. Gestational age at birth, birth weight, sex, ROP zone, ROP stage, post menstrual age (PMA) at treatment, and follow-up period were recorded. The final clinical status of the retina was noted for each patient. The primary outcome measures included ROP recurrences requiring re-treatment, complete or incomplete peripheral vascularization RESULTS: Eighty-six eyes of 46 premature infants with Zone II Stage 3+ROP were enrolled in the study. The mean gestational age at birth was 28.18±1.67wk (range: 25 to 33wk) and the mean birth weight was 1070.57±226.85 g (range: 720.00 to 1650.00 g). The mean PMA at treatment was 38.32±2.99wk (range: 32.29 to 46.00wk). Seventy-one eyes (82.56%) were treated successfully with intravitreal ranibizumab as monotherapy. Fifteen eyes (17.44%) developed recurrent disease. The mean interval between the treatment and retreatment was 5.96±3.22wk (range: 1.86 to 11.71wk). All eyes vascularized into zone III at the end of the study and among them 62 eyes (72.1%) achieved complete vascularization. CONCLUSION: Intravitreal ranibizumab injection is an effective treatment in patients with zone II stage 3+ ROP. More patients with longer follow-up duration are mandatory to confirm the safety and efficacy of this treatment.     

【In Press】 Transfection with chemokine receptor type 4 potentiates homing of mesenchymal stem cells in vitro and therapy of diabetic retinopathy in vivo

AIM: To investigate the effect of the overexpression of chemokine receptor type 4 (CXCR4) on homing of mesenchymal stem cells (MSCs) in vitro and therapeutic effects of diabetic retinopathy (DR) in vivo. METHODS: MSCs were infected by lentivirus constructed with CXCR4. The expression of CXCR4 was examined by immunofluorescence, Western blot, and quantitative polymerase chain reaction. CXCR4-overexpressing MSCs were cultured in vitro to evaluate their chemotaxis, migration, and apoptotic activities. The cells were then intravitreally injected in a mouse model of DR. The histology DR in rats was inspected by hematoxylin and eosin staining. The expression of rhodopsin, neuron-specific enolase (NSE), and inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α was examined by Western blot and immunohistochemical analyses. RESULTS: The transduction of MSCs by lentivirus was effective, and the transduced MSCs had high expression levels of CXCR4 gene and protein. Improved migration activities were observed in CXCR4-overexpressing MSCs. Further, reduced retinal damage, upregulation of rhodopsin and NSE protein, and downregulation of inflammatory cytokines IL-6 and TNF-α were observed in CXCR4-overexpressing MSCs in vivo. CONCLUSION: The homing of MSCs can be enhanced by upregulating CXCR4 levels, possibly improving histological structures of DR. CXCR4-overexpressing MSCs can be a novel strategy for treating DR.     

【In Press】 The use of Choline in association with the Bangerter filters for the treatment of amblyopia

The study investigated the effects of Choline combined with Bangerter filter in the treatment of amblyopia. All amblyopic subjects used a Bangerter filter on the corrective spectacle lens (1d over the left eye, 1d over the right eye). Choline was then administered orally to 39 patients once daily, five days per week for the entire study period. Subjects treated with the Bangerter filter showed a mean visual acuity of 0.27 logMAR; at 12mo of treatment, the mean visual acuity reached 0.09 logMAR. Patients treated with the Bangerter filter and Citicoline showed a mean visual acuity of 0.35 logMAR; at 12mo of treatment, the mean visual acuity reached 0.01 logMAR. No significant changes in the angle of deviation were observed in both groups. Subjects in both forms of amblyopia therapies demonstrated an increase in visual acuity. However, these effects were markedly enhanced when coupled with the administration of Choline. Findings suggest that the effects are particularly relevant in the more severe amblyopic cases.     

【In Press】 Expression of multidrug resistance proteins in retinoblastoma

AIM: To elucidate the mechanism of multidrug resistance in retinoblastoma (RB), and to acquire more insights into in vivo drug resistance. METHODS: Three anticancer drug resistant Y79 human RBcells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in RB cells. RESULTS: Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION: Our results suggest that multidrug resistant proteins are intrinsically present in RB which causes treatment failure in managingRB with chemotherapy.     

【In Press】 Optical coherence tomography changes following vitrectomy for long standing premacular hemorrhage in Valsalva retinopathy

Letter to the editor     

【In Press】Trans-epithelial accelerated corneal cross-linking for keratoconus in children

The aim of the study is to evaluate the safety and efficacy of trans-epithelial accelerated corneal cross-linking (TE-ACXL) in children with progressive keratoconus. Retrospective, case-series of 23 eyes of 14 children who underwent TE-ACXL. Evaluations were performed at baseline and 1, 3, 6, 12 and 18mo postoperatively. Mean follow-up time of 23.82mo ±3.15 and mean age was 13.7y ±1.4 (range 11 to 16). Mean preoperative uncorrected distance visual acuity changed from 0.92 ± 0.45 logMAR (20/160) to 0.71 ± 0.40 logMAR (20/100) (P=0.001). Mean keratometry (Km) changed from 53.87± 6.03 to 53.00 ± 5.81 (P=0.001). Pachymetry did not have significant changes at last follow-up (P=0.30). The mean preoperative sphere was -5.58±2.48 D and -4.89±4.66 (P=0.11) at last follow-up; refractive cylinder from -5.58±2.48 to -5.02±2.23 (P=0.046). In conclusion, tomographic and refractive stability were shown in over 91% of eyes with pediatric progressive keratoconus who underwent TE-ACXL.     

【In Press】 Protective effect of pomegranate juice on retinal oxidative stress in streptozotocin-induced diabetic rats

AIM: To investigate the effect of pomegranate juice (PJ) intake on overall oxidation status in retinas of diabetic rats. METHODS: Twenty-seven rats were divided into four groups as control (CO), diabetic (DM), control treated with PC (CO-PJ), and diabetic treated with PJ (DM-PJ).The retina tissues were used to determine 8-Hydroxy-2’-deoxyguanosine (8OHdG), malondialdehyde (MDA), reduced glutathione (GSH) levels, and the enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). RESULTS: The levels of 8OHdG and MDA were significantly increased in the retina of DM group compared to CO group (p=0.001, p<0.001 respectively). Both 8OHdG and MDA levels were decreased in PJ-DM group compared to DM group (p=0.004, p<0.001 respectively). The activities of antioxidant enzymes GSH, SOD, and GDH-Px were significantly decreased in the retina of DM group compared to CO group (p≤0.01). GSH and GSH-Px activities were higher in PJ-DM group compared with DM group (p=0.010, p=0.042, respectively) but SOD activity was not statistically different (p=0.938). CONCLUSION: PJ intake was found to be effective in decreasing oxidative end products, and in increasing the activities of antioxidant enzymes in diabetic retinas of rats, which suggests it may be effective against oxidative stress in diabetic retinas.     

【In Press】Efficacy of iontophoresis-assisted epithelium-on corneal cross-linking for keratoconus

Corneal cross-linking (CXL) is a noninvasive therapeutic procedure for keratoconus that is aimed at improving corneal biomechanical properties by induction of covalent cross-links between stromal proteins. It is accomplished by ultraviolet A (UVA) irradiation of the cornea, which is first saturated with photosensitizing riboflavin. It has been shown that standard epithelium-off CXL (S-CXL) is efficacious, and it has been recommended as the standard of care procedure for keratoconus. However, epithelial removal leads to pain, transient vision loss, and a higher risk of corneal infection. To avoid these disadvantages, transepithelial CXL was developed. Recently, iontophoresis has been adopted to increase riboflavin penetration through the epithelium. Several clinical observations have demonstrated the safety and efficacy of iontophoresis-assisted epithelium-on CXL (I-CXL) for keratoconus. This review aimed to provide a comprehensive summary of the published studies regarding I-CXL and a comparison between I-CXL and S-CXL. All articles used in this review were mainly retrieved from the PubMed database. Original articles and reviews were selected if they were related to the I-CXL technique or related to the comparison between I-CXL and S-CXL. Letters and case reports were excluded.     

【In Press】Autophagy: a potential target for the treatment of intraocular neovascularization

The formation of neovascularization is a common pathological feature of many ocular vascular diseases, and is an important cause of vision loss in patients. Neovascularization can cause retinal hemorrhage, vitreous hemorrhage, and other serious complications, leading to loss of vision. The treatment of intraocular neovascularization is the focus of Ophthalmology research. In recent years, some studies have found that autophagy is closely related to vascular endothelial growth factor (VEGF) and the formation of neovascularization. Autophagy is expected to become a new target for the treatment of intraocular neovascularization. Therefore, this article reviews the research on autophagy and the formation of intraocular neovascularization.     

【In Press】 Modified ulcer debridement in the treatment of the superficial fungal infection of the cornea

AIM: To evaluate the efficacy of modified corneal ulcer debridement in superficial fungal keratitis unresponsive to medications. METHODS: A total of 209 patients (209 eyes) with fungal keratitis, involving no more than 50% of the stromal depth and not responding to antifungal agents for 2wk, were recruited in this retrospective, noncomparative study. The patients were treated with modified corneal ulcer debridement. All visible corneal infiltrates were removed under an operating microscope to obtain a clean stromal bed and smooth incised edges. Antifungal drugs were used immediately after surgery. Healing time of the ulcers was recorded. Fungal recurrence, visual acuity, corneal thickness and risk factors for treatment failure were monitored. RESULTS: The follow-up was 13.6±5.8mo. The corneal ulcers healed in 195 of 209 eyes (93.3%), with a mean healing time of 8.4±6.8d. The other 14 eyes were further treated by penetrating keratoplasty (1 eye), anterior lamellar keratoplasty (7 eyes), conjunctival flap covering (4 eyes) or amniotic membrane transplantation (2 eyes). The best corrected visual acuity was ≥20/70 in 80.3% of the eyes, ≥20/40 in 56.9% of the eyes, and ≥20/25 in 27.3% of the eyes. The corneas at the lesions became thinner, but all in the safe range. No fungal recurrence or corneal ectasis developed during the follow-up. The risk of treatment failure was higher in patients with preoperative hypopyon (P=0.036) and ever using steroid (P=0.025). CONCLUSION: Modified surgical debridement is a simple and effective method for the treatment of superficial fungal infection of the cornea, with improved visual acuity and no recurrence. Such an intervention in time can rapidly control fungal infection and largely shorten corneal ulcer healing time.