The Anti-Inflammatory Effects of Glucagon-Like Peptide Receptor Agonist Lixisenatide on the Retinal Nuclear and Nerve Fiber Layers in an Animal Model of Early Type 2 Diabetes.

This study explored the anti-inflammatory effects of a glucagon-like peptide-1 receptor agonist (GLP-1RA), known as lixisenatide, on the eyes of early type 2 diabetic mice. Diabetic (db/db) mice were divided into three groups: GLP-1RA [lixisenatide (LIX)], insulin (INS) with controlled hyperglycemia based on the glucose concentration of lixisenatide, and diabetic control (D-CON). Nondiabetic control mice (db/dm) were also characterized for comparison. After 8 weeks of treatment, mRNA levels of inflammatory markers, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemical staining; Western blot of glial fibrillary acidic protein (GFAP) and thioredoxin-interacting protein; and retinal thickness were assessed in the central and peripheral neurosensory retina. LIX showed decreased immunohistochemical staining for both thioredoxin-interacting protein and GFAP in the central and peripheral neurosensory retina compared with D-CON and INS, and decreased expression of these proteins in the neurosensory retina and immunohistochemical staining in the optic nerve head for GFAP compared with D-CON. The inner nuclear layer in the peripheral retina in LIX was only thinner than those of D-CON and INS. In an early type 2 diabetic mouse model, lixisenatide treatment showed superior anti-inflammatory effects on the retina and optic nerve head independent of hyperglycemia. Thus, the neuroprotective effects of lixisenatide treatment in the peripheral inner nuclear layer should be evaluated in early type 2 diabetic retinopathy.

Retinal nerve fiber layer loss is associated with urinary albumin excretion in patients with type 2 diabetes.

OBJECTIVES: To identify the factors associated with retinal nerve fiber layer (RNFL) loss in patients with type 2 diabetes. DESIGN: Cross-sectional study. PARTICIPANTS: Ninety-six nonglaucomatous patients with type 2 diabetes without renal impairment (estimated glomerular filtration rate, ≥60 ml/minute per 1.73 m(2)). METHODS: Eyes were divided into 2 groups based on the presence or absence of RNFL defects detected by red-free retinal fundus photography. All participants underwent an eye fundus examination, and the urinary albumin-to-creatinine ratio (ACR) was determined. A cardiovascular autonomic function test was performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to the Valsalva maneuver, and standing. Multiple logistic regression analyses were performed to determine potential risk factors related to the presence of RNFL defects in these patients. MAIN OUTCOMES AND MEASURES: The association between RNFL defects and diabetic complications. RESULTS: Among the patients, 43 (44.8%) had localized RNFL defects (group 1), whereas the others (55.2%) did not (group 2). The RNFL defects occurred more frequently on the superior side (75.6% and 71.0% in right and left eyes, respectively) compared with the inferior side (13.8% and 0.0% in right and left eyes, respectively). Patients with RNFL defects (group 1) had significantly higher rates of diabetic retinopathy (60.5%) compared with those without RNFL defects (group 2; 32.1%; P = 0.007). The urinary ACR was significantly higher in patients with RNFL defects than in those without defects (45.3±72.1 µg/mg vs. 15.4±17.3 µg/mg creatinine, respectively; P = 0.015), whereas autonomic function test grading was similar between the groups. The urinary ACR was the only factor related to visual field defect location in both univariate (P = 0.021) and multivariate (P = 0.036) logistic regression analyses after adjusting for age; gender; presence of diabetic retinopathy; diabetes duration; smoking; statin use; and antiplatelet, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment. CONCLUSIONS: Urinary albumin excretion was associated with nerve fiber layer loss in patients with type 2 diabetes. Careful examination of the optic nerve head may be necessary, particularly in patients with type 2 diabetes exhibiting albuminuria.

A case of odontogenic orbital cellulitis causing blindness by severe tension orbit.

We report a very rare case of odontogenic orbital cellulitis causing blindness by severe tension orbit. A 41-yr old male patient had visited the hospital due to severe periorbital swelling and nasal stuffiness while he was treated for a periodontal abscess. He was diagnosed with odontogenic sinusitis and orbital cellulitis, and treated with antibiotics. The symptoms were aggravated and emergency sinus drainage was performed. On the next day, a sudden decrease in vision occurred with findings of ischemic optic neuropathy and central retinal artery occlusion. Deformation of the eyeball posterior pole into a cone shape was found from the orbital CT. A high-dose steroid was administered immediately resulting in improvements of periorbital swelling, but the patient's vision had not recovered. Odontogenic orbital cellulitis is relatively rare, but can cause blindness via rapidly progressing tension orbit. Therefore even the simplest of dental problems requires careful attention.

Direct Visualization of Continuous Meibum Secretion From the Orifices of Meibomian Glands to the Tear Film.

PURPOSE: To present a new method to directly visualize meibum secretion on the tear film from meibomian gland orifices and show that meibum is continuously secreted between blinking. METHODS: Eighteen patients with dry eye syndrome and 17 healthy subjects were included in the study. We used the Lipiscanner to evaluate the tear film lipid layer. The lipid layer was classified into thick, normal, and thin lipid layer. The lipid layer on the lower tear meniscus of the right eye was observed after a drop of saline solution was applied to the eye. We recorded continuous meibum secretion onto the tear meniscus surface. We calculated the rate of continuous meibum secretion by analyzing videos. Noncontact meibography was performed for meibomian glands in the lower eyelid. The quality of meibum from the 5 orifices at the same area was then scored. RESULTS: The mean continuous meibum secretion rate was 2.7 pL/s in the healthy group and 8.0 pL/s in the dry eye group. The rates were 1.3, 6.7, and 9.4 pL/s in the thin, normal, and thick tear film lipid layer group, respectively. They were 3.4, 3.4, 10.7, and 18.1 pL/s in grade 0, 1, 2, and 3 meibomian gland dropout groups, respectively. The rates were 0.00, 4.7, 10.1, 2.0, and 0.7 pL/s in the normal meibum, yellow without increased viscosity, yellow with increased viscosity, toothpaste, and no meibum groups, respectively. CONCLUSIONS: We showed how to visualize meibum being secreted into the tear film from the meibomian gland orifices, and we were able to observe the continuous secretion of meibum between blinks.

Early inner retinal thinning and cardiovascular autonomic dysfunction in type 2 diabetes.

BACKGROUND: To investigate changes in the neural retina according to the presence of retinal nerve fiber layer (RNFL) defects in type 2 diabetes, and to determine the association between inner retina thickness and the severity of diabetic complications. METHODS: We studied non-glaucomatous patients with type 2 diabetes and control subjects Circumpapillary RNFL and macula ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured by spectral-domain optical coherence tomography. In patients with type 2 diabetes, a cardiovascular autonomic function test (AFT) was performed, which included the heart rate parameter of beat-beat variation-with deep breathing, in response to the Valsalva maneuver, and on postural change from lying to standing. The results of each test were scored as 0 for normal and 1 for abnormal. A total AFT score of 1 was defined as early cardiovascular autonomic neuropathy (CAN), and an AFT score≥ 2 as definite CAN. RESULTS: We compared control eyes (n = 70), diabetic eyes with RNFL defects (n = 47), and eyes without RNFL defects (n = 30). The average RNFL and GCIPL thicknesses were significantly different among groups (all, P<0.05). On post-hoc testing, diabetic eyes with RNFL defects had a significantly thinner average GCIPL thickness than those without RNFL defects. On multivariate analyses, significantly thinner average GCIPL was seen in early CAN staging (B = -4.32, P = 0.016) and in definite CAN staging (B = -10.33, P<0.001), compared with no CAN involvement, after adjusting for confounding parameters. CONCLUSIONS: Cardiovascular autonomic dysfunction was associated with early neurodegenerative changes in type 2 diabetes.

Evaluation of Interocular Retinal Nerve Fiber Layer Thickness Symmetry as a Diagnostic Modality for Glaucoma.

PURPOSE OF THE STUDY: The purpose of study was to measure the diagnostic utility of interocular retinal nerve fiber layer (RNFL) symmetry and interocular RNFL thickness comparison. METHODS: Both eyes of 103 normal subjects and 106 glaucoma patients (31 patients with early glaucoma and 75 patients with moderate to severe glaucoma) received comprehensive ophthalmologic evaluation including visual field testing and optic disc scanning using optical coherence tomography. RNFL thickness values for 256 measurement points were rearranged according to a new reference line connecting the optic disc center and the foveola. The interocular RNFL thickness symmetry value and absolute and fractional interocular difference in RNFL thickness were calculated and compared between groups. Area under the receiver operating characteristic curves (AUROCs) were calculated and compared. RESULT: Among the parameters reflecting whole RNFL status, the corrected interocular RNFL thickness symmetry exhibited the largest AUROCs at all glaucoma stages. RNFL thickness and absolute and fractional interocular difference in RNFL thickness exhibited largest AUROC in the inferotemporal area, regardless of glaucoma stage. In the early glaucoma group, absolute and fractional interocular RNFL thickness differences in the temporal and superotemporal areas exhibited equal to or larger AUROCs than RNFL thickness. The AUROCs for RNFL thickness were greater than those for absolute and fractional interocular RNFL thickness differences in the moderate to severe glaucoma group except in the nasal and temporal area. CONCLUSIONS: The corrected interocular RNFL thickness symmetry value is an effective diagnostic tool for glaucoma. Interocular comparison of RNFL thickness has good diagnostic performance and gives information about the RNFL beyond just the RNFL thickness itself.

Effect of trapping vascular endothelial growth factor-A in a murine model of dry eye with inflammatory neovascularization.

AIM: To evaluate whether trapping vascular endothelial growth factor A (VEGF-A) would suppress angiogenesis and inflammation in dry eye corneas in a murine corneal suture model. METHODS: We established two groups of animals, one with non-dry eyes and the other with induced dry eyes. In both groups, a corneal suture model was used to induce inflammation and neovascularization. Each of two groups was again divided into three subgroups according to the treatment; subgroup I (aflibercept), subgroup II (dexamethasone) and subgroup III (phosphate buffered saline, PBS). Corneas were harvested and immunohistochemical staining was performed to compare the extents of neovascularization and CD11b+ cell infiltration. Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and VEGF-A in the corneas. RESULTS: Trapping VEGF-A with aflibercept resulted in significantly decreased angiogenesis and inflammation compared with the dexamethasone and PBS treatments in the dry eye corneas (all P<0.05), but with no such effects in non-dry eyes. The anti-inflammatory and anti-angiogenic effects of VEGF-A trapping were stronger than those of dexamethasone in both dry eye and non-dry eye corneas (all P<0.05). The levels of RNA expression of VEGF-A, TNF-alpha, and IL-6 in the aflibercept subgroup were significantly decreased compared with those in the PBS subgroup in the dry eye group. CONCLUSION: Compared with non-dry eye corneas, dry eye corneas have greater amounts of inflammation and neovascularization and also have a more robust response to anti-inflammatory and anti-angiogenic agents after ocular surface surgery. Trapping VEGF-A is effective in decreasing both angiogenesis and inflammation in dry eye corneas after ocular surface surgery.

Comparison of postoperative corneal changes between dry eye and non-dry eye in a murine cataract surgery model.

AIM: To compare the effects of the surgical insult of cataract surgery on corneal inflammatory infiltration, neovascularization (NV) and lymphangiogenesis (LY) between the dry eye and non-dry eye in murine cataract surgery models. METHODS: We established two groups of animals, one with normal eyes (non-dry eye) and the second with induced dry eyes. In both groups, we used surgical insults to mimic human cataract surgery, which consisted of lens extraction, corneal incision and suture. After harvesting of corneas on the 9(th) postoperative day and immunohistochemical staining, we compared NV, LY and CD11b+ cell infiltration in the corneas. RESULTS: Dry eye group had significantly more inflammatory infiltration (21.75%±7.17% vs 3.65%±1.49%; P=0.049). The dry eye group showed significantly more NV (48.21%±4.02% vs 26.24%±6.01%; P=0.016) and greater levels of LY (9.27%±0.48% vs 4.84%±1.15%; P=0.007). In corneas on which no surgery was performed, there was no induction of NV in both the dry and non-dry group, but dry eye group demonstrated more CD11b+ cells infiltration than the non-dry eye group (0.360%±0.160% vs 0.023%±0.006%; P=0.068). Dry eye group showed more NV than non-dry eye group in both topical PBS application and subconjunctival PBS injection (P=0.020 and 0.000, respectively). CONCLUSION: In a murine cataract surgery model, preexisting dry eye can induce more postoperative NV, LY, and inflammation in corneal tissue.

Interocular retinal nerve fiber layer thickness difference in normal adults.

PURPOSE: To determine the interocular retinal nerve fiber layer (RNFL) thickness difference of normal subjects. METHODS: Both eyes of 230 normal adults received peripapillary RNFL thickness measurements using OCT. The effect of ocular cyclotorsion on the RNFL thickness profile was mathematically corrected. The fractional and absolute interocular RNFL thickness differences at 256 points of peripapillary area were calculated. We divided the subjects into 3 groups according to the locations of superior and inferior peak thickness, respectively, and compared the interocular RNFL thickness differences between the subgroups. RESULTS: The fractional interocular RNFL thickness difference exhibited smaller regional variations than the absolute interocular difference. The means of fractional interocular differences were 0.100 ± 0.077 in the temporal half area and 0.146 ± 0.105 in the nasal half area, and the tolerance limits for the 95th and 99 th distributions were about 0.246 and 0.344 in the temporal half area and 0.293 and 0.408 in the nasal half area, respectively. The fractional interocular differences of subgroups classified by the locations of superior and inferior peak RNFL thickness showed difference at smaller areas than the absolute interocular differences (19 and 8 points versus 49 and 23 points, respectively). CONCLUSION: Glaucoma can be strongly suspected, if interocular fractional RNFL thickness difference is over 25% at 5 consecutive points or over 35% at 3 consecutive points in the temporal half area. The fractional interocular comparison is a better diagnostic approach because the fractional interocular RNFL thickness difference is less influenced by the locations of peak RNFL thickness.

The ocular benefits of estrogen replacement therapy: a population-based study in postmenopausal Korean women.

PURPOSE: To elucidate the prevalence of cataract, glaucoma, pterygia, and diabetic retinopathy among Korean postmenopausal women with or without estrogen replacement therapy (ERT). METHODS: A cross-sectional, nationally representative sample from the 4th Korea National Health and Nutrition Examination Survey (KNHANES IV) (2007-2009) was used. Participants were interviewed for the determination of socioeconomic and gynecologic factors. Each woman also underwent an ophthalmologic examination and provided a blood sample for risk factor assessment. RESULTS: Of 3968 postmenopausal women enrolled, 3390 had never received estrogen, and 578 were undergoing estrogen treatment. After adjusting for age, diabetes, hypertension, high cholesterol levels, and high low-density lipoprotein levels, the prevalence of anterior polar cataract, retinal nerve fiber layer (RNFL) defect, and flesh pterygium was higher in the non-ERT group (OR, 3.24; 95% CI, 1.12-9.35, OR 1.70; 95% CI, 1.04-2.78, OR 3.725; 95% CI, 1.21-11.45, respectively). Further, the prevalence of atrophic pterygium was lower in the non-ERT group compared to that in the ERT group (OR, 0.21, 95% CI, 0.07-0.63). CONCLUSIONS: These data suggest that ERT has a protective effect against the development of anterior polar cataract, flesh pterygium, and RNFL defect.

The effect of C3F8 gas on corneal endothelial cells in rabbits.

PURPOSE: To evaluate the ocular effects of perfluoropropane gas (C(3)F(8)) in the anterior chamber of rabbit eyes in relation to the gas concentration. METHODS: Twenty rabbit eyes were randomly divided into four groups (20%, 15%, and 10% C(3)F(8) gas groups, and an air control group). After injection of 0.3 ml of each gas concentration into the anterior chamber, endothelial damage was evaluated by specular microscopic analysis. The main outcome measurements were endothelial cell density, hexagonality, coefficient of variation, corneal thickness, and intraocular pressure (IOP) 1 day, 1 week, and 2 weeks after injection. Two weeks after injection, transmission electronic microscopy was performed to evaluate the structural integrity. RESULTS: The 20% group had a significant decrease in endothelial cell density (P = 0.023), hexagonality (P = 0.031), and increase in corneal thickness (P = 0.045) from baseline to 2 weeks after injection, whereas the other groups exhibited no significant differences. The 20% group had a significant increase in IOP 1 week after injection (P = 0.041). Transmission electron microscopy revealed that the 20% group had a severe flat cell configuration with a damaged intracellular organization. CONCLUSIONS: The risk of endothelial cell damage and elevation in IOP was greater in the 20% C(3)F(8) group than in the 15% or 10% C(3)F(8) groups. Therefore, an appropriate concentration of C(3)F(8) gas is needed for different surgical purposes.