Correction: AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.

[This corrects the article DOI: 10.1371/journal.pone.0147279.].

Results of a Treat-and-Eextend Regimen of Intravitreal Ranibizumab Injection for Macular Edema due to Branch Retinal Vein Occlusion.

To investigate the effectiveness of a treat-and-extend regimen (TAE) of intravitreal ranibizumab injections (IVR) for macular edema (ME) due to branch retinal vein occlusion (BRVO). We retrospectively examined 35 eyes of 35 patients with ME due to BRVO who underwent TAE for 1 year. Patients whose treatment interval extended to 12 weeks were switched to a pro re nata regimen (PRN; TAE to PRN group), while TAE was continued for patients whose treatment interval was less than 12 weeks (continued TAE group). Changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and predictive factors for inclusion in the TAE to PRN group were analyzed. BCVA and CRT both improved significantly at 1 year compared with baseline (p<0.001). Sixteen eyes (45.7%) were included in the TAE to PRN group, while 19 eyes (54.3%) were included in the continued TAE group. BCVA in the TAE to PRN group was significantly better than that in the continued TAE group at 1 year (p=0.047). BCVA at baseline and macular BRVO were significant predictive factors for inclusion in the TAE to PRN group. TAE was effective for improving BCVA and CRT. The TAE to PRN group showed significantly better prognosis.

Autologous Internal Limiting Membrane Transplants Successfully Close a Large Parafoveal Retinal Hole.

　Parafoveal retinal holes (PRHs) are one of the complications that can occur after internal limiting membrane (ILM) peeling during macular surgery. Here we describe a patient in whom an exceptionally large PRH (1,069-µm dia.) was successfully closed by repeated autologous ILM transplantation.

One-year outcomes of a treat-and-extend regimen of intravitreal aflibercept for polypoidal choroidal vasculopathy.

PURPOSE: To evaluate the 1-year treatment outcomes of intravitreal aflibercept injections (IVA) using a treat-and-extend regimen for polypoidal choroidal vasculopathy (PCV). METHODS: Thirty-seven eyes with treatment-naive PCV treated with IVA using a treat-and-extend regimen for 1 year were reviewed retrospectively. The main outcome measures were changes in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and the treatment interval at 1 year. The predictive factors for patients who could not continue to extend the treatment interval because of poor response to IVA or recurrence were analyzed. RESULTS: The mean logarithm of the minimum angle of resolution BCVA improved from 0.37 at baseline to 0.21 at 1 year (P < 0.001). The mean CRT decreased from 342.3 µm at baseline to 196.6 µm at 1 year (P < 0.001). The mean treatment interval was 9.7 weeks at 1 year (4 weeks in 11 eyes [29.7%], 6 weeks in 1 eye [2.7%], 8 weeks in 2 eyes [5.4%], 10 weeks in 1 eye [2.7%], and 12 weeks in 22 eyes [59.5%]). A larger number of polypoidal lesions at baseline was predictive for patients who could not continue to extend the treatment interval. CONCLUSIONS: IVA using a treat-and-extend regimen is effective for improving BCVA and CRT in eyes with PCV.

Surgical Outcome of Idiopathic Epiretinal Membranes with Intraretinal Cystic Spaces.

OBJECTIVE: To investigate the occurrence ratio, localization, and surgical outcomes of intraretinal cystic spaces in idiopathic epiretinal membranes (ERMs). METHODS: We retrospectively reviewed the charts of 432 eyes of 398 consecutive patients with idiopathic ERM who underwent vitrectomy and ERM peeling from January 2012 to September 2015. We selected cases with intraretinal cystic space prior to surgery, detected by spectral-domain optical coherence tomography. We then evaluated the effects of ERM peeling on intraretinal cystic spaces, best corrected visual acuity, and central retinal thickness at 6 months after surgery. RESULTS: Twenty-four eyes (5.5%) showed intraretinal cystic spaces before surgery, present in the inner retinal layer (the inner group) in 9 eyes, in the outer retinal layer (the outer group) in 6 eyes, and in both the inner and the outer retinal layers (the combined group) in 9 eyes. Additionally, 30 eyes with ERM but without any presence of intraretinal cystic space were selected randomly and classified as the no cyst group. At 6 months after surgery, the disappearance rate of cystic spaces was significantly greater for the outer group than for the inner group (83.3% and 11.1%, respectively, P = 0.011). The mean best corrected visual acuity improved significantly after surgery in the inner group, the outer group, and the no cyst group (P < 0.05 for all three groups) but did not improve in the combined group (P = 0.58). The mean central retinal thickness decreased significantly after surgery in the inner group, the combined group, and the no cyst group (P < 0.05). CONCLUSIONS: Intraretinal cystic spaces were observed in 5.5% of preoperative idiopathic ERM cases. Following surgery, the cystic spaces in the outer retinal layer disappeared at higher rates than those in the inner retinal layer, suggesting that the pathophysiologies of these cystic spaces are different.

Factors Affecting Choroidal Vascular Density in Normal Eyes: Quantification Using En Face Swept-Source Optical Coherence Tomography.

PURPOSE: To quantify the vascular density of the choroid of normal eyes and to identify the influencing factors using en face images obtained with swept-source optical coherence tomography (SS OCT). DESIGN: Prospective cross-sectional study. METHODS: One hundred and sixty-three eyes of 163 healthy volunteers (83 female; mean age 42.2 ± 22.6 years) with a corrected visual acuity of ≥1.0 were investigated. En face SS OCT images of the choroid were used for quantitative assessment of the vascular density in the large choroid vessel layer. Relationships between vascular density of the choroid and age, sex, refractive error (RE), axial length (AL), and subfoveal choroidal thickness (SCT) were also investigated. RESULTS: There was a significant negative relationship between vascular density of the choroid and subject age (P < .001). Analysis according to age showed a significant correlation in the group aged >30 years (P < .001), but not in the group aged ≤30 years (P = .225). SCT had a significant positive relationship with vascular density of the choroid (P < .001). However, a significant correlation was not observed between sex, RE, or AL and vascular density of the choroid (P = .981, P = .292, and P = .216, respectively). Multivariable regression analysis with vascular density of the choroid as the dependent variable and age, sex, RE, AL, and SCT as independent variables showed that age and SCT are important determinants of vascular density of the choroid (P < .001). CONCLUSION: Age and SCT affect vascular density of the choroid.

Efficacy of vitrectomy and inner limiting membrane peeling in age-related macular degeneration resistant to anti-vascular endothelial growth factor therapy, with vitreomacular traction or epiretinal membrane.

PURPOSE: We assessed the efficacy of vitrectomy and inner limiting membrane (ILM) peeling, followed by anti-vascular endothelial growth factor (VEGF) therapy, anti-VEGF-resistant age-related macular degeneration (AMD) due to vitreomacular traction (VMT) or epiretinal membrane (ERM). METHODS: We identified six patients with anti-VEGF-resistant AMD due to VMT or ERM amongst a total of 588 patients with AMD (821 eyes) referred to Okayama University Hospital between February 2012 and May 2014. These patients underwent vitrectomy to release the VMT (4 cases) or remove the ERM (2 cases), along with ILM peeling. The regimen used for intravitreal injections of anti-VEGF reagents after surgery was based on the severity of exudative changes in each patient. Preoperative and postoperative best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were compared. RESULTS: After vitrectomy and ILM peeling, all six patients responded to anti-VEGF therapy, which was then able to maintain dry retinas. Mean BCVA did not improve significantly (0.49 ± 0.28 before vs. 0.43 ± 0.38 after surgery, P = 0.538). However, mean CR was significantly decreased after surgery, from 423 ± 83.5 µm to 257 ± 75.8 µm (P = 0.0078). CONCLUSIONS: Vitrectomy and ILM peeling followed by anti-VEGF therapy may be a useful therapeutic option for anti-VEGF-resistant AMD with VMT or ERM.

AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.

C-C chemokine receptor 2 (Ccr2) is a key pro-inflammatory marker of classic (M1) macrophage activation. Although Ccr2 is known to be expressed both constitutively and inductively, the full regulatory mechanism of its expression remains unclear. AMP-activated protein kinase (AMPK) is not only a master regulator of energy homeostasis but also a central regulator of inflammation. In this study, we sought to assess AMPK's role in regulating RAW264.7 macrophage Ccr2 protein levels in resting (M0) or LPS-induced M1 states. In both M0 and M1 RAW264.7 macrophages, knockdown of the AMPKα1 subunit by siRNA led to increased Ccr2 levels whereas pharmacologic (A769662) activation of AMPK, attenuated LPS-induced increases in Ccr2 expression in an AMPK dependent fashion. The increases in Ccr2 levels by AMPK downregulation were partially reversed by NF-κB inhibition whereas TNF-a inhibition had minimal effects. Our results indicate that AMPK is a negative regulator of Ccr2 expression in RAW264.7 macrophages, and that the mechanism of action of AMPK inhibition of Ccr2 is mediated, in part, through the NF-κB pathway.

EGF-like-domain-7 is required for VEGF-induced Akt/ERK activation and vascular tube formation in an ex vivo angiogenesis assay.

EGFL7 is a secreted angiogenic factor, which in contrast to the well-known secreted angiogenic molecules VEGF and FGF-2, is almost exclusively expressed by endothelial cells and may act in an autocrine fashion. Prior studies have shown EGFL7 to mediate its angiogenic effects by interfering with the Notch pathway and/or via the intronic miR126. Less is known about its effects on VEGF signaling. We wanted to investigate the role of epidermal growth factor-like domain 7 (EGFL7) in VEGF-driven angiogenesis using an ex vivo Matrigel-embedded mouse eye cup assay and siRNA mediated knockdown of EGFL7 by siRNA. Our results suggested that VEGF-induced vascular tube formation was significantly impaired after siRNA downregulation of EGFL7. In addition, knockdown of EGFL7 suppressed VEGF upregulation of phospho-Akt and phospho-Erk(1/2) in endothelial cells, but did not alter VEGFR phosphorylation and neuropilin-1 protein expression or miR126 expression. Thus, in conclusion, EGFL7 is required for VEGF upregulation of the Akt/Erk (1/2) pathway during angiogenesis, and may represent a new therapeutic target in diseases of pathological neovascularization.

Orbital emphysema causing syncope.

Orbital emphysema is an abnormal condition in which air is present within the orbit. We report a rare case of a 19-year-old man who suffered syncopic attacks caused by sniffles following orbital emphysema as a result of trauma. Treating rhinitis is important in patients with orbital emphysema, and patients with cardiac disorders in addition to those with this condition must be warned about the risks of sniffles, sneezing, or nose blowing.

Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension.

Endothelial glycocalyx (GCX) has been reported as a protective factor for vascular endothelial cells (VEC) in diabetes and hypertension. However, the involvement of GCX impairment in ocular vasculopathy remains unclear. We evaluated the changes in the GCX thicknesses of the retinal and choroidal capillaries in rats with diabetes and hypertension by cationic colloidal iron staining using a transmission electron microscope. In the control group, the mean (standard error of the mean) thicknesses of retinal and choroidal GCX were 60.2 (1.5) nm and 84.3 (3.1) nm, respectively. The diabetic rats showed a significant decrease of GCX thickness in the retina, but not in the choroid, compared to controls (28.3 (0.3) nm, p<0.01 and 77.8 (1.4) nm, respectively). In the hypertensive rats, both retinal and choroidal GCX were significantly decreased compared to the control values (10.9 (0.4) nm and 13.2 (1.0) nm, respectively, both p<0.01). Moreover, we could visualize the adhesion of leukocytes and platelets on the luminal surface of VEC, at the site where the GCX was markedly degraded. These findings suggest that the GCX prevents adhesion of leukocytes and platelets to the VEC surface, and this impairment may lead to ocular vasculopathy in diabetes and hypertension.