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Am Jour Ophthalmol
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Ophthalmic Res[JOUR] Established 1995
1. Ophthalmic Res. 2015 Dec;55(1):45-52. doi: 10.1159/000440767. Epub 2015 Nov 17.

Autologous Internal Limiting Membrane Fragment Transplantation for Large,
Chronic, and Refractory Macular Holes.

De Novelli FJ(1), Preti RC, Ribeiro Monteiro ML, Pelayes DE, Junqueira Nóbrega M,
Takahashi WY.

Author information: 
(1)Division of Ophthalmology, University of Sx00E3;o Paulo Medical School,
Sx00E3;o Paulo, Brazil.

OBJECTIVE: To evaluate a technique of autologous internal limiting membrane (ILM)
fragment transplantation for the treatment of large, chronic, and/or refractory
macular holes (MH).
DESIGN: This was a 6-month prospective interventional case series.
METHOD: Ten eyes of 10 patients with MH underwent pars plana vitretomy (PPV) and 
ILM peeling followed by transplantation of an autologous ILM fragment to the MH. 
Six patients had primary MH with an internal diameter greater than 500 µm and a
duration of more than 18 months, including 1 patient with nonproliferative
diabetic retinopathy previously treated with panretinal photocoagulation. Four
eyes with MH had previously been submitted to PPV (i.e. 1 for retinal detachment 
and 3 to attempt to close large MH). One of the latter also displayed
juxtapapillary choroidal neovascularization due to age-related macular
degeneration. The primary and secondary outcomes were MH closure and improvement 
of the best corrected visual acuity (BCVA), respectively.
RESULTS: Complete MH closure was achieved in all cases. A statistically
significant improvement in the average BCVA was observed after 6 months of
follow-up (p = 0.018; paired t test). The BCVA improved in 8 eyes (80%), and in 6
of those eyes it improved by ≥15 letters. In 1 patient, the BCVA remained
unchanged after the surgery, but the visual field reportedly improved. One
patient experienced a slight worsening (0.16 logMAR). Two cases developed atrophy
of the retinal pigment epithelium despite MH closure and BCVA improvement.
CONCLUSION: Treatment with autologous ILM fragment transplantation seems to be an
efficient alternative for large, chronic, and refractory MH.

© 2015 S. Karger AG, Basel.

PMID: 26569390   [PubMed - in process]

2. Ophthalmic Res. 2015 Nov 17;55(2):53-61. [Epub ahead of print]

Autologous Plasma Rich in Growth Factors Eyedrops in Refractory Cases of Ocular
Surface Disorders.

Merayo-Lloves J(1), Sanchez RM, Riestra AC, Anitua E, Begoña L, Orive G,
Fernandez-Vega L.

Author information: 
(1)Instituto Universitario Fernx00E1;ndez-Vega, Fundacix00F3;n de
Investigacix00F3;n Oftalmolx00F3;gica, Universidad de Oviedo, Oviedo, Spain.

PURPOSE: Preliminary information about the safety and efficacy of plasma rich in 
growth factors (PRGF) eyedrops in the treatment of refractory cases of diverse
ocular surface disorders (OSDs) is presented here.
MATERIAL AND METHODS: This retrospective cohort study included cases with OSDs
refractory to previous treatment with conventional treatments or autologous serum
or cyclosporine, and treated with PRGF eyedrops. The signs and symptoms of ocular
surface disorders [using the ocular surface disease index (OSDI), best-corrected 
visual acuity (BCVA), visual analog scale (VAS) frequency and VAS severity] were 
evaluated before and after treatment with PRGF. A safety assessment was also
performed reporting all adverse events or complications.
RESULTS: Forty-one patients with a total of 80 treated eyes were evaluated.
Statistically significant reductions in the OSDI scale (39.27%), VAS frequency
(38.9%) and VAS severity (40.3%), and a significant improvement in BCVA (54.86%) 
were all observed (p < 0.05). The results were stratified according to the
identified potential effect modifiers. There were only two adverse events (eye
redness and eyelid inflammation), which were reported as mild and resolved in a
few days.
CONCLUSIONS: PRGF eyedrops could be a safe and effective treatment option for
refractory cases of OSDs. When treating patients the possible influence on the
results of some clinical variables must be taken into account.

© 2015 S. Karger AG, Basel.

PMID: 26569104   [PubMed - as supplied by publisher]

3. Ophthalmic Res. 2015 Dec;55(1):37-44. doi: 10.1159/000440885. Epub 2015 Nov 12.

Expression of Vascular Endothelial Growth Factor by Retinal Pigment Epithelial
Cells Induced by Amyloid-β Is Depressed by an Endoplasmic Reticulum Stress

Matsui A(1), Kaneko H, Kachi S, Ye F, Hwang SJ, Takayama K, Nagasaka Y, Sugita T,
Terasaki H.

Author information: 
(1)Department of Ophthalmology, Nagoya University Graduate School of Medicine,
Nagoya, Japan.

PURPOSE: Amyloid-β (Aβ) is a 36- to 43-amino-acid peptide that is a constituent
of drusen, and it has been demonstrated to upregulate vascular endothelial growth
factor (VEGF) expression by retinal pigment epithelial (RPE) cells. This study
aimed to determine whether 4-phenylbutyl phosphonylacetate (PBA), a known
endoplasmic reticulum (ER) stress inhibitor, can reduce Aβ-induced expression of 
VEGF in RPE cells.
METHODS: Aβ was added to the medium of regularly cultured or polarized ARPE-19
cells, a human RPE cell line, with or without PBA. The levels of VEGF and ER
stress markers, namely GRP78/Bip, cleaved caspases 4 and 12 and GADD153/C-EBP
homologous protein, were determined by enzyme-linked immunoassay,
immunocytochemistry and Western blotting.
RESULTS: Exposure of ARPE-19 cells to Aβ induced GRP78/Bip expression and
activated caspases 4 and 12; however, their expression was decreased by
simultaneous exposure to PBA. Aβ increased the expression of VEGF both in
regularly cultured and polarized ARPE-19 cells, but it was suppressed by PBA. PBA
did not cause RPE cell apoptosis.
CONCLUSION: Aβ has been suggested to be involved in the development of
age-related macular degeneration; therefore, our findings suggest that drugs that
target ER stress should be considered for the treatment of age-related macular

© 2015 S. Karger AG, Basel.

PMID: 26560903   [PubMed - in process]

4. Ophthalmic Res. 2015 Dec;55(1):19-25. Epub 2015 Nov 6.

Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to
Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of
Macular Edema.

Vujosevic S(1), Varano M, Egan C, Sivaprasad S, Menon G, Erginay A, Verbraak FD, 
Lund-Andersen H, Martinez JP, Jürgens I, Smets E, Coriat C, Wiedemann P, Ágoas V,
Querques G, Holz FG, Nunes S, Alves D, Neves C, Santos T, Ribeiro L, Bandello F, 
Tejerina AN, Cunha-Vaz J;

Author information: 
(1)Centre for Clinical Trials, Department of Ophthalmology, University of Padova,
Padova, Italy.

PURPOSE: To characterize the relevance of macular thickness changes in the inner 
and outer rings in the progression of macular edema in eyes/patients with
diabetes type 2.
METHODS: A total of 374 type 2 diabetic patients with mild nonproliferative
diabetic retinopathy (ETDRS levels 20-35) were included in a 12-month prospective
observational study to identify retinopathy progression. Retinal thickness
analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166
eyes/patients using Spectralis SD-OCT. The classification of subclinical
and clinical macular edema was used. A composite grading of macular edema is
proposed in this study.
RESULTS: A total of 317 eyes/patients completed the study. SD-OCT identified
clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema
in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central
subfield is the best predictor for the development of clinical macular edema,
with 85.7% sensitivity and 71.9% specificity (OR: 2.57, 95% CI: 0.82-7.99).
However, the involvement of the inner and outer rings is a cumulative predictor
of progression to clinical macular edema (OR: 8.69, 95% CI: 2.85-26.52).
CONCLUSIONS: A composite OCT grading of macular edema taking into account the
retinal thickness changes in the inner and outer macular rings offers a simple
way to characterize macular edema, with added clinical value.

© 2015 S. Karger AG, Basel.

PMID: 26555067   [PubMed - as supplied by publisher]

5. Ophthalmic Res. 2015 Dec;55(1):26-36. doi: 10.1159/000441033. Epub 2015 Nov 11.

Metamorphopsia: An Overlooked Visual Symptom.

Midena E(1), Vujosevic S.

Author information: 
(1)Department of Ophthalmology, University of Padova, Padova, Italy.

Metamorphopsia is a common symptom in different macular disorders. Micropsia and 
macropsia are special types of metamorphopsia. Recent theories suggest that both 
retinal and cortical mechanisms are involved in the development and changes of
metamorphopsia. Different functional tests have been proposed for the evaluation 
of metamorphopsia: from the Amsler grid to the hand-held mobile devices for home 
monitoring. This review addresses some new insights into the pathophysiology of
metamorphopsia and different available tests for the evaluation of this symptom
in most common macular disorders. The importance of quantification of
metamorphopsia in macular diseases is confirmed by the most recent therapeutic

© 2015 S. Karger AG, Basel.

PMID: 26554918   [PubMed - in process]

6. Ophthalmic Res. 2015 Dec;55(1):10-8. doi: 10.1159/000440848. Epub 2015 Nov 6.

Treatment of Retinal Vein Occlusion with Ranibizumab in Clinical Practice:
Longer-Term Results and Predictive Factors of Functional Outcome.

Farinha C(1), Marques JP, Almeida E, Baltar A, Santos AR, Melo P, Costa M,
Figueira J, Cachulo ML, Pires I, Silva R.

Author information: 
(1)Medical Retina Unit, Department of Ophthalmology, Centro Hospitalar e
Universitx00E1;rio de Coimbra (CHUC), Coimbra, Portugal.

PURPOSE: To evaluate long-term results and predictors of efficacy in patients
with macular edema due to retinal vein occlusion (RVO) treated with intravitreal 
ranibizumab in a clinical practice setting.
METHODS: The clinical records of patients with a minimum follow-up of 3 years
were retrospectively analyzed. Sixteen eyes with branch RVO (BRVO) and 16 with
central RVO (CRVO) were included. All patients performed cross-sectional
evaluation with best-corrected visual acuity (BCVA), spectral domain optical
coherence tomography and fluorescein angiography. The foveal avascular zone (FAZ)
was assessed and microstructural morphology of the retina was characterized.
RESULTS: Follow- up was 42.9 ± 9.0 and 44.8 ± 8.0 months in the CRVO and BRVO
groups, respectively. Patients with CRVO received on average 6.9 injections, with
a final VA gain of 8.3 ± 15.0 letters (p = 0.05). BRVO eyes had on average 5.9
injections, with a final VA gain of 1.6 ± 21.0 letters (p > 0.05). The FAZ area
remained stable in both groups (p > 0.05). Baseline BCVA and disruption of the
retinal pigment epithelium (RPE) were predictors of final BCVA (p = 0.001 and
0.011, respectively).
CONCLUSION: Although functional outcomes were inferior to those reported in
clinical trials, ranibizumab was satisfactory in the long-term treatment of
macular edema secondary to RVO and was not associated with increased macular
ischemia. Final BCVA depends on baseline BCVA and RPE integrity.

© 2015 S. Karger AG, Basel.

PMID: 26540281   [PubMed - in process]

7. Ophthalmic Res. 2015 Dec;55(1):1-9. doi: 10.1159/000440847. Epub 2015 Nov 5.

Nornicotine and Nicotine Induced Neovascularization via Increased VEGF/PEDF

Zhang Y(1), Ma A, Wang L, Zhao B.

Author information: 
(1)Department of Ophthalmology, Shandong Provincial Hospital, Shandong
University, Jinan, PR China.

PURPOSE: The purpose of the current study was to evaluate the influences of
nornicotine and nicotine (NT) in cigarette smoke on the expression of vascular
endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in 
retinal pigment epithelium cells and human umbilical vein endothelial cells
(HUVECs). Furthermore, the angiogenic behaviors of endothelial cells under
nornicotine and NT treatment were assessed by using in vitro methods.
METHODS: ARPE-19 cells and HUVECs were treated with different concentrations of
either nornicotine or NT for different periods of time. The cell proliferative
effect was investigated by using the method of MTT analysis. HUVEC migration and 
tube formation were assessed by using the scratch assay and Matrigel models. The 
expressions of VEGF and PEDF gene and protein in both types of cells were
examined by real-time RT-PCR and Western blot.
RESULTS: There was no proliferation of ARPE-19 cells following treatment with
various concentrations of nornicotine or NT. In contrast, nornicotine or NT
significantly stimulated HUVEC proliferation, migration and tube formation.
Nornicotine and NT upregulated the expression of VEGF but suppressed the
expression of PEDF at both mRNA and protein levels in a dose- and time-dependent 
manner in ARPE-19 cells and HUVECs.
CONCLUSIONS: Our results demonstrate that nornicotine and NT promoted endothelial
cellular proliferation, migration and tube formation of HUVECs in vitro. These
effects might be partly due to simultaneous modulation of VEGF/PEDF signaling in 
ARPE-19 cells and HUVECs.

© 2015 S. Karger AG, Basel.

PMID: 26536586   [PubMed - in process]

8. Ophthalmic Res. 2015;54(4):204-11. doi: 10.1159/000440887. Epub 2015 Oct 31.

Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease.

Madeira MH(1), Ambrósio AF, Santiago AR.

Author information: 
(1)Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of
Medicine, University of Coimbra, Coimbra, Portugal.

Alzheimer's disease (AD) is the most common type of dementia worldwide; it is
characterized by a progressive decline in cognitive functions and memory,
resulting from synaptic and cell loss, and accompanied by a strong
neuroinflammatory response. Besides the vast progress in the understanding of the
pathophysiology of AD in the past decades, there is still no effective treatment.
Moreover, the diagnosis occurs usually at an advanced stage of the disease, where
the neurological damage has already occurred. The identification of biomarkers
that would allow an early diagnosis of this disease is a major goal that would
also help managing AD progression. Due to its cellular and physiological
resemblances with the brain, the retina has long been regarded as a window to the
brain. Several brain manifestations have been associated with retinal
alterations. In AD patients, some structural and functional alterations in the
retina can be associated with disease onset. However, only a few studies have
focused on the alterations in retinal glial cells associated with AD. This review
aims at giving an overview of the AD-associated retinal alterations, particularly
in glial cells. The documented alterations in retinal glia will be discussed
concerning their potential to predict the brain alterations occurring in AD.

© 2015 S. Karger AG, Basel.

PMID: 26517861   [PubMed - in process]

9. Ophthalmic Res. 2015;54(4):212-21. doi: 10.1159/000440846. Epub 2015 Oct 31.

Nitric Oxide Increases the Expression of Aquaporin-4 Protein in Rat Optic Nerve
Astrocytes through the Cyclic Guanosine Monophosphate/Protein Kinase G Pathway.

Oku H(1), Morishita S, Horie T, Kida T, Mimura M, Fukumoto M, Kojima S, Ikeda T.

Author information: 
(1)Department of Ophthalmology, Osaka Medical College, Takatsuki, Japan.

AIMS: Nitric oxide (NO) is associated with neuroinflammation in the central
nervous system. We determined whether NO increases the expression of aquaporin-4 
(AQP4) in optic nerve astrocytes of rats.
METHODS: Isolated astrocytes were incubated under normoxic or hypoxic conditions 
with or without glucose (5.5 mM). The astrocytes were also exposed to different
concentrations of S-nitroso-N-acetyl-DL-penicillamine (SNAP, 1.0-100 μM), an NO
donor. The expression of AQP4 was determined by Western blot analyses, and NO
formation was measured by the Griess reaction. The changes in astrocytic cellular
volumes were determined by flow cytometry.
RESULTS: Hypoxia and glucose deprivation increased AQP4 expression and NO
formation. Inhibition of NO synthetase (NOS) significantly suppressed these
changes. SNAP caused a significant increase in AQP4 expression, and the increase 
was significantly suppressed by carboxy-PTIO, a scavenger of NO. Incubation with 
8-Br-cyclic guanosine monophosphate (cGMP) mimicked the effects of SNAP, while
the addition of either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ;
inhibitor of soluble guanylate cyclase) or KT5823 (protein kinase G inhibitor)
suppressed the SNAP-induced increase in AQP4 significantly. SNAP also caused a
significant increase in astrocytic cellular volume through the AQP4 channels.
CONCLUSIONS: NO increased the AQP4 expression of optic nerve astrocytes through
the cGMP/protein kinase G pathway and enlarged their volume.

© 2015 S. Karger AG, Basel.

PMID: 26517822   [PubMed - in process]

10. Ophthalmic Res. 2015;54(4):195-203. doi: 10.1159/000439596. Epub 2015 Oct 27.

Complement Stimulates Retinal Pigment Epithelial Cells to Undergo
Pro-Inflammatory Changes.

Lueck K(1), Busch M, Moss SE, Greenwood J, Kasper M, Lommatzsch A, Pauleikhoff D,
Wasmuth S.

Author information: 
(1)Ophtha-Lab, Department of Ophthalmology at St. Franziskus Hospital, Muenster, 

BACKGROUND/AIMS: We examined the effect of human complement sera (HCS) on retinal
pigment epithelial (RPE) cells with respect to pro-inflammatory mediators
relevant in early age-related macular degeneration (AMD).
METHODS: RPE cells were treated with complement-containing HCS or with
heat-inactivated (HI) HCS or C7-deficient HCS as controls. Cells were analysed
for C5b-9 using immunocytochemistry and flow cytometry. Interleukin (IL)-6, IL-8,
and monocyte chemoattractant protein-1 (MCP-1) were quantified by ELISA and
RT-PCR. Tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1
(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), were analysed by Western
blotting. The intracellular distribution of nuclear factor (NF)-x03BA;B was
investigated by immunofluorescence.
RESULTS: A concentration-dependent increased staining for C5b-9 but no influence 
on cell viability was observed after HCS treatment. ELISA and RT-PCR analysis
revealed elevated secretion and expression of IL-6, IL-8, and MCP-1. Western blot
analysis showed a concentration-dependent increase in ICAM-1, VCAM-1, and TNF-α
in response to HCS, and immunofluorescence staining revealed nuclear
translocation of NF-x03BA;B.
CONCLUSION: This study suggests that complement stimulates NF-x03BA;B activation 
in RPE cells that might further create a pro-inflammatory environment. All these 
factors together may support early AMD development.

© 2015 S. Karger AG, Basel.

PMID: 26502094   [PubMed - in process]

11. Ophthalmic Res. 2015;54(4):175-80. doi: 10.1159/000440768. Epub 2015 Oct 23.

DNA Aptamer Raised against Advanced Glycation End Products Prevents Abnormalities
in Electroretinograms of Experimental Diabetic Retinopathy.

Maeda S(1), Matsui T, Ojima A, Suematsu M, Kaseda K, Higashimoto Y, Yamakawa R,
Yamagishi S.

Author information: 
(1)Department of Ophthalmology, Kurume University School of Medicine, Kurume,

PURPOSE: Abnormalities in electroretinograms (ERG), such as reduced amplitudes
and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are
one of the earliest features of diabetic retinopathy prior to obvious vascular
changes in diabetic retinas. We have previously shown that serum levels of
advanced glycation end products (AGEs) are correlated with a delayed latency of
OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG
abnormalities remains unclear. We examined here whether high-affinity DNA aptamer
directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental
type 1 diabetic retinopathy.
METHODS: Streptozotocin-induced diabetic rats or control rats received continuous
intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic 
mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were
measured, and an ERG was performed.
RESULTS: Although AGE-aptamer did not affect body weight, fasting and random
blood glucose, HbA1c, blood pressure, or lipid parameters, it completely
prevented the increase in serum AGE levels as well as the reduction of a- and
b-wave and OP amplitudes in diabetic rats.
CONCLUSION: The present study demonstrated for the first time that AGE-aptamer
prevents abnormalities in ERG in experimental diabetic retinopathy probably by
blocking the harmful effects of AGEs.

© 2015 S. Karger AG, Basel.

PMID: 26492350   [PubMed - in process]

12. Ophthalmic Res. 2015;54(4):181-94. doi: 10.1159/000438906. Epub 2015 Oct 23.

Colour Vision in Stargardt Disease.

Vandenbroucke T(1), Buyl R, De Zaeytijd J, Bauwens M, Uvijls A, De Baere E, Leroy

Author information: 
(1)Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.

PURPOSE: To investigate the type and severity of acquired colour vision
deficiencies (CVDs) in molecularly proven Stargardt disease (STD) and to
establish whether a relationship exists between best-corrected visual acuity
(BCVA) and full-field electroretinography (ffERG), and the degree of CVD.
METHODS: A retrospective, cross-sectional study of 73 patients with a molecularly
proven diagnosis of STD, who underwent extensive colour vision evaluation, using 
pseudo-isochromatic and arrangement tests. Thirteen patients underwent Nagel
RESULTS: Normal colour vision was found in almost 20% of patients. Red/green
(R/G) CVDs increased as BCVA declined. About 45% of all R/G CVDs were of the
deutan type, although protan type CVDs became progressively apparent when moving 
from the high to the low BCVA group. An additional blue/yellow CVD was noted in
about 25% of patients. In 10/13 patients, a pseudoprotanomaly was noted on
anomaloscopy. Severe CVDs leading to scotopization were noted in patients with
low BCVA and/or long-standing disease. No statistically significant differences
in ERG results were found between groups with or without a CVD.
CONCLUSIONS: The degree and type of colour vision deficiency in STD patients
correlate better with BCVA than with ffERG results. The presence of specific CVDs
may help to establish a diagnosis of STD. A battery of colour vision tests is
required to properly evaluate CVDs in STD.

© 2015 S. Karger AG, Basel.

PMID: 26492201   [PubMed - in process]

13. Ophthalmic Res. 2015;54 Suppl 1:1-74. doi: 10.1159/000440896. Epub 2015 Oct 22.

15th ESASO Retina Academy. October 22-24, 2015, Barcelona, Spain: Abstracts.

[No authors listed]

PMID: 26489087   [PubMed - in process]