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1.  Evaluation of real-world mobility in age-related macular degeneration 
BMC Ophthalmology  2015;15:9.
Previous research has suggested an association between poor vision and decreased mobility, including restricted levels of physical activity and travel away from home. We sought to determine the impact of age-related macular degeneration (AMD) on these measures of mobility.
Fifty-seven AMD patients with bilateral, or severe unilateral, visual impairment were compared to 59 controls with normal vision. All study subjects were between the ages of 60 and 80. Subjects wore accelerometers and cellular network-based tracking devices over 7 days of normal activity. Number of steps taken, time spent in moderate-to-vigorous physical activity (MVPA), number of excursions from home, and time spent away from home were the primary outcome measures.
In multivariate negative binomial regression models adjusted for age, gender, race, comorbidities, and education, AMD participants took fewer steps than controls (18% fewer steps per day, p = 0.01) and spent significantly less time in MVPA (35% fewer minutes, p < 0.001). In multivariate logistic regression models adjusting for age, sex, race, cognition, comorbidities, and grip strength, AMD subjects showed an increased likelihood of not leaving their home on a given day (odds ratio = 1.36, p = 0.04), but did not show a significant difference in the magnitude of time spent away from home (9% fewer minutes, p = 0.11).
AMD patients with poorer vision engage in significantly less physical activity and take fewer excursions away from the home. Further studies identifying the factors mediating the relationship between vision loss and mobility are needed to better understand how to improve mobility among AMD patients.
PMCID: PMC4328075  PMID: 25636376
Age-related macular degeneration; Physical activity; Mobility
2.  Post-cataract endophthalmitis caused by multidrug-resistant Stenotrophomonas maltophilia: clinical features and risk factors 
BMC Ophthalmology  2015;15:14.
To report clinical features and risk factors of post-cataract surgery endophthalmitis (PE) due to Stenotrophomonas maltophilia.
A retrospective case review from December 10, 2010 to April 7, 2011 was performed at the Eye & ENT Hospital, Fudan University. Data were collected for surgical details, disease characteristics, antibiotic sensitivity of the pathogen, and treatment response. Visual outcomes were examined with a minimum follow-up of 12 months.
Fourteen cases of S. maltophilia endophthalmitis were identified. The onset of infection occurred from 1–56 days postoperatively (median, 13.5 days). Obvious cellular reactions were found in all patients in the anterior chamber, along with the absence of pupil synechia. Retinal periphlebitis was an early sign of PE. S. maltophilia was positive in eight patients (57.1%). The fluids from aspiration tubes revealed the same bacteria, which were resistant to multiple drugs (e.g., amino glycosides, most of the β-lactams, aztreonam, imipenem, and ciprofloxacin), except levofloxacin. Compared with the culture-negative group, the infection was more rapid, more severe, and more difficult to control in the culture-positive group. Among 14 patients, 11 patients (78.6%) underwent pars plana vitrectomy (PPV) with intravitreal injection. Three patients had PPV twice, and three patients had intraocular lens and capsular bag removal. A final visual acuity of ≥20/100 was achieved by 13/14 patients (92.9%). Complications included retinal detachment in three cases (21.4%) and recurrence of infection in two cases (14.8%). Statistical analysis showed that age over 90 years and posterior capsule rupture were risk factors of infection (P = 0.034 and P = 0.034, respectively). The phacoemulsifier allowed potential contamination between the aspiration and irrigation tubes.
S. maltophilia should be considered a pathogenic organism of PE. The infection often occurs in older patients with posterior capsule rupture. Intravitreal or systemic administration of effective antibiotics and earlier initial PPV may contribute to better clinical outcomes. Tubes with connections between aspiration and irrigation should be avoided during surgery.
PMCID: PMC4320429  PMID: 25618260
Cataract surgery; Endophthalmitis; Intraocular lens; Drug resistance; Stenotrophomonas maltophilia
3.  Vector analysis of low to moderate astigmatism with small incision lenticule extraction (SMILE): results of a 1-year follow-up 
BMC Ophthalmology  2015;15:8.
To evaluate the refractive outcomes for the correction of low to moderate astigmatism up to 1 year following small incision lenticule extraction (SMILE) surgery.
This retrospective study enrolled 98 eyes from 98 patients who underwent SMILE surgery for the correction of myopia and astigmatism. Only right eyes were included in this study to avoid the bias of orientation errors. The vector method was used to analyze the outcomes of astigmatism at 1 month, 6 months and 12 months after the procedure, including the double-angle plots, correction index (CI), index of success (IOS), angle of error (AofE) and magnitude of error (MofE). The effectiveness, safety, stability and predictability were also investigated during the 12-month follow-up.
The preoperative cylinder ranged from -2.75 D to -0.25 D (average of -0.90 ± 0.68 D), and the mean postoperative cylinder values were -0.24 ± 0.29 D, -0.24 ± 0.29 D, and -0.20 ± 0.27 D at 1 month, 6 months, and 12 months, respectively. The mean astigmatism in vector form was -0.14 D × 27.19° at 1 month, -0.13 D × 27.29° at 6 months, and -0.10 D × 28.63° at 12 months after surgery. The CI was 1.00 ± 0.32 and IOS was 0.29 ± 0.44 at the 12-month follow-up. Significant negative correlations were found between the CI and absolute target induced astigmatism (TIA) value, and positive correlations were found between the IOS and absolute AofE value (P < 0.05). The MofE was limited within ±1.00 D at the 12-month follow-up. Fifty-six eyes (57.1%) gained one line in corrected distance visual acuity (CDVA) and five eyes (5.1%) gained two lines. There were no significant differences observed in the refractive outcomes among time points.
SMILE surgery was effective and safe in correcting low to moderate astigmatism, and stable refractive outcomes were observed at the long-term follow-up. The undercorrection of astigmatism could possibly be influenced by attempted astigmatism correction preoperatively, the axis rotation during the surgery or wound healing postoperatively. This study suggested that nomograms should be adjusted in correcting astigmatism with SMILE surgery.
PMCID: PMC4328987  PMID: 25618419
Vector analysis; Astigmatism; Femtosecond laser; Small incision lenticule extraction; Refractive surgery; Long-term
4.  Comparison of the effects of bimatoprost and a fixed combination of latanoprost and timolol on 24-hour blood and ocular perfusion pressures: the results of a randomized trial 
BMC Ophthalmology  2015;15:7.
To compare the effect of bimatoprost and the fixed combination latanoprost-timolol (LTFC) on 24-hour systolic (SBP) and diastolic (DBP) blood pressure and on 24-hour ocular perfusion pressure (OPP).
200 patients with glaucoma or ocular hypertension, controlled on the unfixed combination of latanoprost and timolol or eligible for dual therapy being not being fully controlled on monotherapy were enrolled in a randomized, double-masked, placebo-controlled, multicentre clinical trial. They were randomized to LTFC (8 a.m.) or bimatoprost (8 p.m.) and received 24-hour IOP curve at baseline, 6 and 12 weeks (supine and sitting position IOPs were recorded at 8 p.m., midnight, 5 a.m., 8a.m., noon and 4 p.m.). Holter 24-hour blood pressure curve was obtained between weeks 2 and 12. SBP, DBP, OPP were calculated and compared with ANOVA. Rates of diastolic OPP (DPP) ≤50, ≤40, ≤30 mmHg in the 2 groups were calculated and compared using Fisher’s test.
Mean baseline SBP and DBP were 136.5 ± 18.3 vs 134.2 ± 20.1 mmHg (p = 0.1) and 79.1 ± 10.2 vs 78.2 ± 10.1 mmHg (p = 0.4) in the bimatoprost and LTFC groups respectively. Holter SBP was significantly higher for bimatoprost (135.1 mmHg vs 128.1 mmHg, p = 0.04), while no statistically significant difference in DBP was found. DPP was similar in the 2 groups, and proportions of patients with at least one value of the 24-hour curve ≤50, ≤40, ≤30 mmHg were 94%, 86%, 41% respectively.
Bimatoprost and LTFC had similar DBPs and OPPs; SBP was significantly lower with LTFC. In this study, the percentage of “dippers” was considerably higher than the one described in previous studies on the role of perfusion pressure in glaucoma.
Trial registration
NCT02154217, May 21, 2014.
PMCID: PMC4320581  PMID: 25613811
5.  Impact of epiphora on vision-related quality of life 
BMC Ophthalmology  2015;15:6.
The study aimed to evaluate vision-related quality of life (QOL) in epiphora (excessive tear production) patients.
A total of 342 epiphora patients who visited ophthalmology clinics at 21 general hospitals during a 1-week period were enrolled; 245 females and 97 males with a mean age of 52 ± 13 years. Participants completed a self-administered questionnaire on the extent to which epiphora limited their daily activities. Questions on frequency of discomfort with daily activities were answered on scale of a 0–4. Daily activities that were assessed included reading, daytime and nighttime driving, working at a computer, watching TV, work-related activities, household activities, outdoor activities, interpersonal relations, and general happiness. A correlation analysis was performed between the scores and patient ages. Scores were compared with the clinical factors of gender, bilaterality, and lacrimal irrigation pattern. Presurgical and postsurgical scores in a subset of epiphora patients who underwent surgery were compared.
Outdoor activities were among those that epiphora most significantly hindered. Age had a negative correlation with interpersonal relations scores. Female patients tended to have more discomfort than males in conducting household activities, outdoor activities, and interpersonal relations. Bilaterality showed no differences in QOL. Patients with complete obstruction of lacrimal irrigation recorded higher scores in all daily activities than those with partial or no obstruction. For vision-related QOL, post-surgical scores were improved significantly compared with pre-surgical scores.
Epiphora can affect a broad array of daily activities. Corrective measures for epiphora can improve vision-related QOL, and this may provide guidance for physicians in managing epiphora patients.
PMCID: PMC4320496  PMID: 25613683
Dacryocystorhinostomy; Epiphora; Self-assessment questionnaire; Vision-related quality of life
6.  Square-edge intraocular lenses and epithelial lens cell proliferation: implications on posterior capsule opacification in an in vitro model 
BMC Ophthalmology  2015;15:5.
To evaluate lens epithelial cell (LEC) proliferation with two different designs (one-piece or three-piece) of hydrophobic acrylic IOLs with 360° square optic edge using an in vitro culture model of posterior capsule opacification (PCO).
This experimental study was conducted at the Department of NEUROFARBA, Section of Pharmacology, University of Florence, Italy. Human LECs were seeded and cultured in transwell cell culture inserts coated with a type-IV collagen membrane on which an IOL (one-piece Tecnis-1 or three-piece AR40E, Abbott Medical Optics Inc.) had been previously placed. As control, cells were plated on the insert membrane without an IOL. At day six (cells confluent in controls) IOLs were removed and cell counting, viability and cell density under and outside the IOLs were evaluated.
No statistically significant difference in the number of cells (p > 0.05) between inserts with the one-piece and three-piece IOLs was found. Cell density in the area under each IOL was significantly lower than in the area outside of it (p < 0.05), or in the control insert. (p < 0.05). Cell density under the single-piece IOL was not significantly different from that under the three-piece IOL (p > 0.05).
A 360° sharp-edge played a crucial role in avoiding LEC migration under the IOL and preventing the formation of PCO after cataract surgery. Long term clinical evaluation is necessary to estimate functional results.
PMCID: PMC4324805  PMID: 25599704
Posterior capsule opacification; Intraocular lens; Square edge; Cataract
7.  Weill-Marchesani syndrome with advanced glaucoma and corneal endothelial dysfunction: a case report and literature review 
BMC Ophthalmology  2015;15:3.
To report the diagnostic features and management strategy of a rare case of Weill-Marchesani syndrome with advanced glaucoma and corneal endothelial dysfunction.
Case presentation
A patient presented with advanced glaucoma with an intraocular pressure of 49 mmHg in the left eye, and subsequently received trabeculectomy to control the intraocular pressure. Surprisingly, slit lamp examination through the dilated pupil revealed a dislocated microspherophakic lens almost touching the corneal endothelium. A microspherophakic lens was confirmed by anterior segment optical coherence tomography. Weill-Marchesani syndrome was then diagnosed by ocular examinations, and was accompanied by systemic abnormalities, including brachymorphia and brachydactyly. Corneal endothelial microscopy showed severe corneal endothelial dysfunction, and lens extraction and intraocular lens implantation were subsequently performed to prevent further endothelial damage. At the 1-year follow-up visit, the patient had well-controlled intraocular pressure, transparent cornea, and normal anterior chamber depth, while the intraocular lens remained correctly in place.
Weill-Marchesani syndrome could be diagnosed by microspherophakia, high myopia, secondary glaucoma, and systemic abnormalities such as brachymorphia and brachydactyly. Removal of the microspherophakia is recommended to control intraocular pressure and improve vision. Advanced glaucoma in Weill-Marchesani syndrome should be treated with combined glaucoma surgery and lens extraction.
PMCID: PMC4298062  PMID: 25571963
Weill-Marchesani syndrome; Microspherophakia; Glaucoma; Corneal endothelium dysfunction
8.  A case report of progressive obstruction of Ex-PRESS miniature glaucoma shunt after transient flat anterior chamber and treatment using Nd:YAG laser 
BMC Ophthalmology  2015;15:2.
We report a case of Ex-PRESS miniature glaucoma shunt obstruction resulting from progressive iris synechial formation after transient anterior chamber shallowing.
Case presentation
A 68-year-old woman with pseudoexfoliation glaucoma in her right eye underwent filtration surgery with implantation of the Ex-PPESS shunt (model P-50, Alcon Japan, Tokyo, Japan) in combination with intra-surgical 0.04% mitomycin C use. After the anterior chamber injection of viscoelastic material and 100% sulfur hexafluoride gas for treatment of early postoperative over filtration, the intraocular pressure (IOP) was controlled between 9 and 12 mmHg. On postoperative day 121, gonioscopy showed that synechial formation around the shunt obstructed the axial port leaving the relief port opened. On postoperative day 274, the intraocular pressure increased to 40 mmHg and synechiae obstructed both the axial and relief ports. Dispersion of iris tissue by neodymium:yttrium-aluminium-garnet (Nd:YAG) laser (2 mJ, one shot to each port) opened both ports and immediately lowered the IOP, leaving peripheral anterior synechiae around the shunt. Up to postoperative day 400, the IOP was controlled between 13 and 15 mmHg, and the cystic bleb was maintained.
The synechiae formed gradually extends around the shunt’s shaft and can result in later external obstruction of the relief port. The current case requires further follow-up since synechiae remaining around the shaft can cause future obstruction. We emphasize the fact that, if the iris synechiae to the shunt once formed, it can progress and obstruct the shunt ports later.
PMCID: PMC4293806  PMID: 25571925
Ex-PRESS miniature glaucoma shunt; Trabeculectomy, Surgical complication; Flat anterior chamber; Hypotony; Neodymium:yttrium-aluminium-garnet (Nd:YAG) laser
9.  Characterization of ex vivo cultured neuronal- and glial- like cells from human idiopathic epiretinal membranes 
BMC Ophthalmology  2014;14:165.
Characterization of the neuro-glial profile of cells growing out of human idiopathic epiretinal membranes (iERMs) and testing their proliferative and pluripotent properties ex vivo is needed to better understand the pathogenesis of their formation.
iERMs obtained during uneventful vitrectomies were cultivated ex vivo under adherent conditions and assessed by standard morphological and immunocytochemical methods. The intracellular calcium dynamics of the outgrowing cells was assessed by fluorescent dye Fura-2 in response to acetylcholine (ACh)- or mechano- stimulation.
The cells from the iERMs formed sphere-like structures when cultured ex vivo. The diameter of the spheres increased by 5% at day 6 and kept an increasing tendency over a month time. The outgrowing cells from the iERM spheres had mainly glial- and some neuronal- like morphology. ACh- or mechano- stimulation of these cells induced intracellular calcium propagation in both cell types; in the neuronal-like cells resembling action potential from the soma to the dendrites. Immunocytochemistry confirmed presence of glial- and neuronal cell phenotype (GFAP and Nestin-1 positivity, respectively) in the iERMs, as well as presence of pluripotency marker (Sox2).
iERMs contain cells of neuronal- and glial- like origin which have proliferative and pluripotent potential, show functionality reflected through calcium dynamics upon ACh and mechano- stimulation, and a corresponding molecular phenotype.
PMCID: PMC4324881  PMID: 25540050
Idiopathic epiretinal membrane; Glial- and neuronal cell growth; Pluripotency; Calcium dynamics; Acetylcholine; Mechanostimulation; GFAP; Nestin-1; Sox2; Pax2
10.  Efficacy and tolerability of fixed-combination bimatoprost/timolol versus fixed-combination dorzolamide/brimonidine/timolol in patients with primary open-angle glaucoma or ocular hypertension: a multicenter, prospective, crossover study 
BMC Ophthalmology  2014;14(1):161.
Fixed-combination ocular hypotensives have multiple advantages, but triple-therapy dorzolamide/brimonidine/timolol (dorz/brim/tim) is only available in Latin and South America, and information on its relative efficacy is limited. This study compares the efficacy and tolerability of fixed-combination bimatoprost/timolol (bim/tim) and dorz/brim/tim in Mexican patients with primary open-angle glaucoma or ocular hypertension.
In this investigator-masked, crossover study, patients with unmet target intraocular pressure (IOP) on once-daily bim/tim or twice-daily dorz/brim/tim received the opposite medication for 3 months before returning to their pre-baseline medication for 3 months. IOP was evaluated before and after morning instillation at months 2, 3, 5 and 6. Primary endpoints were mean IOP change and Ocular Surface Disease Index© (OSDI) score at each visit. The intent-to-treat population was the a priori analysis population, but due to the number of discontinuations, the per-protocol and intent-to-treat populations were used for the primary efficacy and sensitivity analyses, respectively.
Seventy-eight and 56 patients were included in the intent-to-treat and per-protocol populations, respectively. At month 3, statistically significant IOP reductions from baseline were observed in the bim/tim (P < 0.01) and dorz/brim/tim (P < 0.0001) groups, regardless of assessment time. At month 6, patients returned to bim/tim exhibited no significant IOP increase (regardless of assessment time), but patients returned to dorz/brim/tim exhibited a statistically significant IOP increase (P < 0.001) when assessed before instillation of study treatment. Results were similar in both intent-to-treat and per-protocol analysis populations. In the per-protocol analysis, 70% of patients on bim/tim at month 3 had an IOP <14 mm Hg, which declined to 58% (P = 0.0061) at month 6 (ie, after 3 months of dorz/brim/tim treatment). In patients receiving dorz/brim/tim at month 3, 38% had an IOP <14 mm Hg, which remained comparable after return to bim/tim. OSDI scores and incidence of adverse events were similar in both groups.
In this first direct comparison of the efficacy of dorz/brim/tim and bim/tim, patients switched from dorz/brim/tim to bim/tim demonstrated improved/lower IOP; when returned to dorz/brim/tim, IOP increased to levels seen at study initiation, suggesting that once-daily bim/tim may have greater IOP-lowering efficacy. Both bim/tim and dorz/brim/tim were well tolerated with minimal ocular surface damage.
Trial registration NCT01737853 (registered October 9, 2012)
PMCID: PMC4298061  PMID: 25527295
Bimatoprost; Brimonidine; Dorzolamide; Timolol; Fixed combination; Glaucoma; Ocular hypertension
11.  A hyporeflective space between hyperreflective materials in pigment epithelial detachment and Bruch’s membrane in neovascular age-related macular degeneration 
BMC Ophthalmology  2014;14(1):159.
The purpose of this study was to investigate the clinical characteristics of a hyporeflective space between hyperreflective materials in pigment epithelial detachment (PED) and Bruch’s membrane in neovascular age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT) or swept source optical coherence tomography (SS-OCT).
Among 223 patients with neovascular AMD, 227 eyes were studied retrospectively. Using SD-OCT or SS-OCT, we reviewed clinical characteristics of the space.
Twenty-two (10%) of the 227 eyes showed a space between hyperreflective materials in PED and Bruch’s membrane. In all spaces, fibrovascular changes of the choroidal neovascularization (CNV) membrane were seen on funduscopy, with OCT images showing the retinal pigment epithelium (RPE) above the space adhering tightly and continuously to the CNV membranes. Nineteen (86%) of the 22 eyes with this cleft also had serous retinal detachment or cystoid macular edema. Five eyes (23%) had an RPE tear during follow-up.
A hyporeflective space between hyperreflective materials in PED and Bruch’s membrane sometimes appears in neovascular AMD. The appearance of such a space may indicate residual activities of the hyperreflective materials.
PMCID: PMC4274686  PMID: 25515712
Age-related macular degeneration; Optical coherence tomography; Pigment epithelial detachment; Bruch’s membrane
12.  Kimura’s disease of the lacrimal gland mimicking IgG4-related orbital disease 
BMC Ophthalmology  2014;14(1):158.
Kimura’s disease (KD) is a rare and benign chronic inflammatory soft tissue disorder of unknown origin, which predominantly inflicts young male adults in Asia. IgG4-related disease is a new disease concept, established this century and characterized by fibrosis and sclerosis of the involved organs, with infiltration of IgG4-positive plasma cells. These two kinds of diseases share similar characteristics, which may complicate their diagnosis.
Case presentation
A 47-year-old Chinese man presented to our Department of Ophthalmology with a 26-month history of painless swelling and redness left upper eyelid. Surgical excisions of the left lacrimal gland were performed. A histopathology examination showed follicular hyperplasia with reactive germinal centres and eosinophilic infiltration involving the interfollicular areas as well as proliferation of post capillary venules, all signs of Kimura disease. Immunohistochemical analysis of the cells demonstrated positive staining for CK, Vimentin, CD3, CD4, CD20, CD21, CD117, CD5, CD8, CD23, IgG and IgG4 (30 per high-power field) and negative staining for CD10 and CD34. Some ophthalmologists in our department questioned whether the histological and immunohistochemical findings were also compatible with features of IgG4-related diseases. There was no sign of recurrence during the twelve months of regular follow-up.
Kimura’s disease may present with high serum IgG4 levels, which may be an epiphenomenon related to chronic antigen exposure. As clinical doctors, especially ophthalmologists, we should recognize the possibility of the occurrence of increased serum levels of IgG4 in Kimura’s disease to ensure correct diagnosis.
PMCID: PMC4274717  PMID: 25511019
Kimura’s disease; IgG4-related disease; Lacrimal gland
13.  Prevalence and risk factors of superior segmental optic hypoplasia in a Korean population: the Korea National Health and Nutrition Examination Survey 
BMC Ophthalmology  2014;14(1):157.
This study investigated the prevalence and risk factors for superior segmental optic hypoplasia (SSOH) in a Korean population based on the data from the nationwide Korea National Health and Nutrition Examination Survey (KNHANES).
We performed a retrospective review of the KNHANES dataset covering January 2012 to December 2012. The study population comprised 5,612 subjects (≥19 years of age) who had participated in a medical interview covering demographic and systemic information, been issued a questionnaire regarding associated SSOH risk factors including gender, age, systemic disease, and family history, and had undergone an ophthalmologic examination. Two masked readers evaluated fundus photography, paying special attention to the presence of SSOH. Associations of risk factors (identified in the medical interview portion) with SSOH prevalence were investigated using multivariate logistic regression analysis.
SSOH was detected in 16 eyes of 14 subjects, or 0.24% of the 5,612 subjects. All 16 eyes showed a corresponding visual-field defect. In multivariate logistic regression analyses, maternal history of diabetes (Odds ratio (OR), 7.666; 95% Confidence interval (CI), 2.601 ~ 22.593, p < 0.001) and paternal history of ischemic heart disease (IHD) (OR, 11.105; CI, 3.361 ~ 36.686, p < 0.001) were associated with increased risk of SSOH.
This study provides the first representative population-based data on SSOH prevalence in Korea. Additionally, multivariate analyses revealed that a history of maternal diabetes and paternal IHD was the most important factor influencing the prevalence of SSOH.
PMCID: PMC4274754  PMID: 25510911
Superior segmental optic hypoplasia; Prevalence; Risk factor; Korea National Health and Nutrition Examination survey
14.  Prevalence of anti-retinal autoantibodies in different stages of Age-related macular degeneration 
BMC Ophthalmology  2014;14(1):154.
Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults. Anti-retinal autoantibodies (AAbs) have been found in individuals with AMD. The goal of the study was to determine the AAb specificity in different stages of AMD, and determine whether there is a prevalent AAb signature.
Sera of 134 participants in the Age-related Eye Disease Study were analyzed for anti-retinal AAbs by western blotting. The subjects were classified by diagnostic subgroups based upon their clinical classification: No AMD, Intermediate AMD, and Late AMD - geographic atrophy (GA) and Late AMD - neovascular (NV).
The presence of anti-retinal AAb was detected in 58% patients with Intermediate and Late AMD, and 54% of those with no AMD. AAbs bound to fifteen different retinal antigens. Most individuals had 1 specific AAbs (67%), with the remainder having 2 to 4 different AAbs. Over 40% of patients with Intermediate AMD, and 46% of those with GA had anti-enolase AAbs, compared with 29% of individuals with NV and 29% with no AMD. Different AAbs signatures related to NV as compared to GA and/or Intermediate AMD were distinguished. Anti-40-kDa (10%) and 42-kDa (16%) autoantibodies were associated with Intermediate AMD, while anti-30-kDa AAbs (23%) were primarily present in GA. Anti-32-kDa (12%), 35-kDa (21%), and 60-kDa (8%) AAbs were more frequent in NV AMD.
A unique AAb pattern for each of the disease subgroups was present when AMD progressed from the intermediate to the late forms of severity. Differences in the frequency of specific AAbs between AMD subgroups suggested that they may participate in pathogenicity of AMD. Further studies are necessary to confirm these observations in the larger cohort and individual AMD patients over time.
PMCID: PMC4269864  PMID: 25488058
Age-related macular degeneration; AREDS; Autoantibodies; Enolase; Antibody signature; Biomarker; Retina; Macula; Smoking; Arthritis
15.  Lipofuscin accumulation and autophagy in glaucomatous human lamina cribrosa cells 
BMC Ophthalmology  2014;14(1):153.
Disease associated alterations in the phenotype of lamina cribrosa (LC) cells are implicated in changes occurring at the optic nerve head (ONH) in glaucoma. Lipofuscin, the formation of which is driven by reactive oxygen species (ROS), is an intralysosomal, non-degradable, auto-fluorescent macromolecule which accumulates with age and can affect autophagy - the lysosomal degradation of a cell’s constituents. We aimed to compare the content of lipofuscin-like material and markers of autophagy in LC cells from normal and glaucoma donor eyes.
The number and size of peri-nuclear lysosomes were examined by transmission electron microscopy (TEM). Cellular auto-fluorescence was quantified by flow cytometry. Cathepsin K mRNA levels were assessed by PCR. Autophagy protein 5 (Atg5) mRNA and protein levels were analysed by PCR and Western blot. Protein levels of subunits of the microtubule associated proteins (MAP) 1A and 1B, light chain 3 (LC3) I and II were analysed by Western blot. Immunohistochemical staining of LC3-II in ONH sections from normal and glaucomatous donor eyes was performed.
A significant increase in the number of peri-nuclear lysosomes [4.1 × 10,000 per high power field (h.p.f.) ± 1.9 vs. 2.0 × 10,000 per h.p.f. ± 1.3, p = 0.002, n = 3] and whole cell auto-fluorescence (83.62 ± 45.1 v 41.01 ± 3.9, p = 0.02, n = 3) was found in glaucomatous LC cells relative to normal LC cells. Glaucomatous LC cells possessed significantly higher levels of Cathepsin K mRNA and Atg5 mRNA and protein. Enhanced levels of LC3-II were found in both LC cells and optic nerve head sections from glaucoma donors.
Increased lipofuscin formation is characteristic of LC cells from donors with glaucoma. This finding confirms the importance of oxidative stress in glaucoma pathogenesis. Intracellular lipofuscin accumulation may have important effects on autophagy the modification of which could form the basis for future novel glaucoma treatments.
PMCID: PMC4265474  PMID: 25444463
Glaucoma; Lipofuscin; Oxidative stress; Lamina cribrosa; Autophagy
16.  Relationship between diabetes and grayscale fractal dimensions of retinal vasculature in the Indian population 
BMC Ophthalmology  2014;14(1):152.
Diabetes mellitus is rapidly increasing in the Indian population. The purpose of this study was to identify changes in the retinal vasculature of diabetic people, ahead of visual impairments. Grayscale Fractal Dimension (FD) analysis of retinal images was performed on people with type 2 diabetes from an Indian population.
A cross-sectional study comprising 189 Optic Disc (OD) centred retinal images of healthy and diabetic individuals aged 14 to 73 years was conducted. Grayscale Box Counting FD of these retinal photographs was measured without manual supervision. Statistical analysis was conducted to determine the difference in the FD between diabetic and healthy (non-diabetic) people.
The results show that grayscale FD values for diabetic cases are higher compared to controls, irrespective of the gender. It was also observed that FD was higher for male compared with females.
There is difference in the grayscale fractal dimension of retinal vasculature of diabetic patients and healthy subjects, even when there is no reported retinopathy.
PMCID: PMC4265429  PMID: 25434291
17.  Late-day intraocular pressure–lowering efficacy and tolerability of travoprost 0.004% versus bimatoprost 0.01% in patients with open-angle glaucoma or ocular hypertension: a randomized trial 
BMC Ophthalmology  2014;14(1):151.
Medications to control intraocular pressure (IOP) are frequently preserved using benzalkonium chloride (BAK), which can negatively affect the ocular surface. Data are needed to assess efficacy and safety of prostaglandin drugs preserved with and without BAK. The present study compared the efficacy and safety of BAK-free travoprost 0.004% (TRAV) and BAK 0.02%–preserved bimatoprost 0.01% (BIM) during late-day time points in patients with open-angle glaucoma or ocular hypertension.
This was a 12-week, phase 4, randomized, investigator-masked, crossover study. 84 patients with IOP ≥24 and <36 mmHg were randomized 1:1 to receive once-daily TRAV or BIM for 6 weeks followed by an additional 6-week crossover period. IOP was measured at the end of each treatment period at 4, 6, and 8 pm. TRAV was considered noninferior to BIM if the upper limit of the 95% CI of the between-group difference in mean IOP was ≤1.5 mmHg. Adverse events were assessed throughout the study.
One patient discontinued due to allergic conjunctivitis, and 2 patients with missing data were excluded; 81 patients were included in the per-protocol population (mean ± SD age, 58.3 ± 11.4 years; TRAV/BIM, n = 41; BIM/TRAV, n = 40). After 6 weeks, mean IOP with TRAV (17.4 ± 2.7 mmHg; change from baseline, -6.0 mmHg) was similar to BIM (17.2 ± 2.6 mmHg; change from baseline, -6.3 mmHg); the between-group difference was 0.22 mmHg (95% CI, -0.22 to 0.67). Thus, noninferiority of TRAV versus BIM was demonstrated. Mean IOP at each time point and mean and percentage IOP change from baseline were not significantly different between treatments. All treatment-emergent adverse events were mild to moderate. The incidences of mild ocular hyperemia with TRAV and BIM were 31% and 39%, respectively; moderate hyperemia was observed in 2% of patients receiving BIM.
Late-day IOP-lowering efficacy of BAK-free TRAV was noninferior to that of BAK 0.02%–preserved BIM; both reduced baseline IOP by 25%. Both treatments were well tolerated, although a higher incidence of moderate ocular hyperemia was observed with BIM.
Trial registration identifier, NCT01464424; registered November 1, 2011.
PMCID: PMC4298043  PMID: 25432143
Travoprost; Bimatoprost; Prostaglandin analog; Intraocular pressure; Hyperemia
18.  Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: an updated meta-analysis 
BMC Ophthalmology  2014;14(1):147.
To evaluate the role of plasma total homocysteine (tHcy) and homozygosity for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in the risk of retinal vein occlusion (RVO).
Relevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Summary weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CI) were calculated with a random-effects model.
Forty-two studies with 6445 participants were included in this updated systematic review and meta-analysis. The mean plasma tHcy level in the RVO patients was significantly higher than in the controls (WMD =2.13 μmol/L; 95% CI: 1.29 to 2.98, P < 0.001), but there was evidence of between-study heterogeneity (P < 0.001). No significant association between MTHFR C677T genotype and RVO was found under all genetic models.
There was some evidence that plasma tHcy is associated with an increased risk of RVO. There was no evidence to suggest an association between homozygosity for the MTHFR C677T genotype and RVO.
PMCID: PMC4255450  PMID: 25428529
Homocysteine; Methylenetetrahydrofolate reductase; Retinal vein occlusion
19.  Outcomes of cytomegalovirus retinitis-related retinal detachment surgery in acquired immunodeficiency syndrome patients in an Asian population 
BMC Ophthalmology  2014;14(1):150.
This study reports the surgical outcomes of acquired immunodeficiency syndrome (AIDS) patients with Cytomegalovirus retinitis (CMVR) -related retinal detachments(RD) in an Asian population.
Review of CMVR characteristics, surgical outcomes and complications in 19 eyes with CMVR-related RD that underwent surgery from January 2000 to June 2011.
CMVR was inactive in 73.7% of the eyes at time of surgery. Anatomical success was achieved in 14 eyes. Seven eyes (36.8%) had improvement of two or more lines in visual acuity (VA) and 8 eyes (42.1%) maintained VA. Thirteen eyes presented with worse than 6/120 vision, with 30.8% of them achieving ambulatory vision or better. Five eyes had re-detachments. Median durations from CMVR and immune recovery uveitis (IRU) diagnoses to RD were 2.7 and 1.0 months respectively.
Surgery for CMVR-related RD is associated with good anatomical outcomes with most eyes maintaining or having improved vision. CMVR lesion size of <50% retinal area is associated with better outcomes. Eyes with CMVR and IRU require close monitoring for RD.
PMCID: PMC4280744  PMID: 25429876
Retinal detachment; Cytomegalovirus retinitis; HIV; Surgery
20.  Oxidant/antioxidant state in tissue of prymary and recurrent pterygium 
BMC Ophthalmology  2014;14(1):149.
Pterygium is a disorder of the ocular surface induced by chronic exposure to UV-light. Abundant data is available from patients with primary pterygium, but scarce from those with recurrent pterygium. The present study aimed to explore the oxidant/antioxidant status in tissue of primary and recurrent pterigium in men and women.
Pathological tissue samples were taken during surgery on patients with primary and recurrent pterygium. Healthy conjunctive tissue samples were taken during cataract surgery. After homogenization of 77 tissue samples, evaluation was made of thiobarbituric reactive substances (TBARS), nitric oxide (NO), total antioxidant status (TAS) and the activity of the three main antioxidant enzymes: glutathione peroxidase, superoxide dismutase and catalase. Gender differences were evaluated.
Compared to the control group, in the primary pterygium group there was an increase in NO and TAS, and a tendency to a decrease of all antioxidant enzymes, indicating an increase in non-enzymatic antioxidant activity. Compared to the control group, in the recurrent pterygium group there was a significant decrease in the level of TAS and antioxidant enzymes. A high positive correlation was found between most of measured parameters within the control group and the recurrent pterygium group, but not within the primary pterygium group. Compared to men, a significant difference was observed in the elevated NO level and low TAS level of women in the prymary pterygium group.
The diminished antioxidant defense in the recurrent pterygium group, possibly determined mainly by decreased non-enzymatic activity, supports the idea that oxidative stress plays an important role in the recurrence of this disorder.
PMCID: PMC4280750  PMID: 25428713
Pterygium; Oxidative stress; Antioxidant; Nitric oxide; Gender differences
21.  The effect of incorrect scanning distance on boundary detection errors and macular thickness measurements by spectral domain optical coherence tomography: a cross sectional study 
BMC Ophthalmology  2014;14(1):148.
To investigate the influence of scan distance on retinal boundary detection errors (RBDEs) and retinal thickness measurements by spectral domain optical coherence tomography (SD-OCT).
10 eyes of healthy subjects, 10 eyes with diabetic macular edema (DME) and 10 eyes with neovascular age-related macular degeneration (AMD) were examined with RTVue SD-OCT. The MM5 protocol was used in two consecutive sessions to scan the macula. For the first session, the device was set 3.5 cm from the eye in order to obtain detectable signal with low fundus image quality (suboptimal setting) while in the second session a distance of 2.5 cm was set with a good quality fundus image. The signal strength (SSI) value was recorded. The score for retinal boundary detection errors (RBDE) was calculated for ten scans of each examination. RBDE scores were recorded for the whole scan and also for the peripheral 1.0 mm region. RBDE scores, regional retinal thickness values and SSI values between the two sessions were compared. The correlation between SSI and the number of RBDEs was also examined.
The SSI was significantly lower with suboptimal settings compared to optimal settings (63.9±12.0 vs. 68.3±12.2, respectively, p = 0.001) and the number of RBDEs was significantly higher with suboptimal settings in the “all-eyes” group along with the group of healthy subjects and eyes with DME (9.1±6.5 vs. 6.8±6.3, p = 0.007; 4.4±2.6 vs. 2.5±1.6, p = 0.035 and 9.7±3.3 vs. 5.1±3.7, p = 0.008, respectively). For these groups, significant negative correlation was found between the SSI and the number of RBDEs. In the AMD group, the number of RBDEs was markedly higher compared to the other groups and there was no difference in RBDEs between optimal and suboptimal settings with the errors being independent of the SSI. There were significantly less peripheral RBDEs with optimal settings in the “all-eyes” group and the DME subgroup (2.7±2.6 vs. 4.2±2.8, p = 0.001 and 1.4±1.7 vs. 4.1±2.2, p = 0.007, respectively). Retinal thickness in the two settings was significantly different only in the outer-superior region in DME.
Optimal distance settings improve SD-OCT SSI with a decrease in RBDEs while retinal thickness measurements are independent of scanning distance.
PMCID: PMC4280767  PMID: 25428608
Optical coherence tomography; Image segmentation; Imaging pitfalls; Diabetic retinopathy; Macular degeneration
22.  Overexpression p21WAF1/CIP1 in suppressing retinal pigment epithelial cells and progression of proliferative vitreoretinopathy via inhibition CDK2 and cyclin E 
BMC Ophthalmology  2014;14(1):144.
P21 is one kind of cyclin-dependent kinase inhibitor that can prevent cells from going through the G1/S phase checkpoint and inhibit cell proliferation. Proliferative vitreoretinopathy (PVR) is a proliferative response in the eye. The aim of this study was to determine whether p21Waf1/Cip1 (p21) suppresses the proliferation and migration of retinal pigment epithelial (RPE) cells in vitro and controls PVR development in vivo.
Cell cycle analyses and transwell assays were conducted to assess cell proliferation characteristics and the migration ability of RPE cells after transfection with p21. Western blot and reverse-transcription polymerase chain reaction technologies were used to detect the expression of p21, CDK2 and cyclinE in RPE cells and rabbit retinal tissues. The impact of increasing p21 expression on PVR development was conducted by implantation of an adenovirus vector containing rabbit p21 (rAd-p21) in a PVR rabbit model. The prevalence of PVR and retinal detachment was determined by indirect ophthalmoscopy on days 3, 7, 14, and 21 after the injection of rAd-p21 into the vitreous. B scans and hematoxylin-eosin staining were employed to check rabbit retinas on day 21.
Cell cycle analyses and transwell assays showed that p21 inhibited the proliferation and migration of RPE cells. Increased expression of p21 was detected in cultured RPE cells and rabbit retinas after transfection with the p21 gene, whereas levels of CDK2 and cyclinE were decreased. The increase in p21 expression effectively suppressed the development of PVR in a rabbit model.
The increase in p21 expression in RPE cells not only inhibits the proliferation and migration of RPE cells in vitro, but also suppresses the development of PVR in vivo, which indicates its therapeutic potential in treating PVR.
PMCID: PMC4255444  PMID: 25421815
P21Waf1/Cip1; Cell cycle arrest; Retinal pigment epithelial cells; Proliferative vitreoretinopathy
23.  Choroidal thickness measurement by enhanced depth imaging and swept-source optical coherence tomography in central serous chorioretinopathy 
BMC Ophthalmology  2014;14(1):145.
We evaluated subfoveal choroidal thickness measured with two different forms of optical coherence tomography (OCT), enhanced-depth imaging (EDI) and swept-source (SS) OCT, in central serous chorioretinopathy (CSC).
Fifty-six eyes of 48 patients diagnosed with acute or chronic CSC, were studied prospectively. Subfoveal choroidal thickness was measured as the distance between the outer border of the retinal pigment epithelium-Bruch’s membrane complex, and the chorioscleral border under the fovea. Subfoveal choroidal thickness was measured using EDI-OCT and SS-OCT. We also measured serous retinal detachment (SRD) only with SS-OCT. The Pearson correlation coefficient was used to assess the correlation between subfoveal choroidal thickness values determined by the two different OCT modalities.
The mean patient age was 52 ± 13 years (range, 32–82 years). Among the 56 eyes, 21 had acute CSC and 35 had chronic CSC. Subfoveal choroidal thickness measured with EDI-OCT was 336.6 ± 91.6 μm in acute and 388.0 ± 103.4 μm in chronic CSC. With SS-OCT, the thickness in acute CSC was 332.0 ± 96.7 μm and that in chronic CSC was 392.6 ± 101.3 μm. Acute CSC (p <0.001, correlation coefficient; r = 0.99) and chronic CSC (p <0.001, correlation coefficient; r = 0.97) values obtained with the two different OCT modalities correlated significantly. Among the 56 eyes, 43 (19 eyes with acute and 24 with chronic CSC) were evaluable for SRD height by SS-OCT. The mean SRD height was 128.9 ± 83.6 μm in acute cases and 96.3 ± 62.0 μm in chronic cases.
Subfoveal choroidal thickness obtained with two different OCT modalities correlated significantly.
PMCID: PMC4255445  PMID: 25421855
24.  Retinal microvascular abnormalities overlying choroidal nodules in neurofibromatosis type 1 
BMC Ophthalmology  2014;14(1):146.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder involving aberrant proliferation of multiple tissues of neural crest origin. Retinal vascular alterations in NF1 have rarely been reported in the literature and their nature is not clear. This study describes distinctive retinal microvascular alterations and their relationship to choroidal nodules in patients with neurofibromatosis type 1.
This was a retrospective study where records of seventeen consecutive patients with diagnosis of NF1, presenting Lisch nodules and choroidal alterations, and 17 age and gender-matched healthy control patients were evaluated. Fundus photographs, near infrared reflectance and enhanced depth imaging - optical coherence tomography images were reviewed. Retinal microvascular abnormalities and choroidal and retinal alterations in proximity of the retinal microvacular alterations were carefully noted.
6 patients (35%) presented distinctive microvascular abnormalities. These consisted of small, tortuous vessels with a “spiral” or “corckscrew” aspect. They were second or third order, small tributaries of the superior or inferior temporal vein. These vessels were all located overlying choroidal alterations as observed with near infrared reflectance. Enhanced depth imaging - optical coherence tomography showed alteration of choroidal vasculature due to the presence of choroidal nodules but otherwise retinal and choroidal cross-sections were unremarkable for morphology.
Retinal microvascular alterations overlying choroidal nodules in patients with NF1 can be considered another distinctive characteristic of the disease. Although the nature of these alterations is not clear, the authors speculate that functional disorders of vasomotor nerve cells, which originate in the embryonal neural crest can lead to their formation.
PMCID: PMC4258815  PMID: 25424184
Neurofibromatosis type 1; Retinal microvascular alterations; Near infrared reflectance; Optical coherence tomography-enhanced depth imaging; Phakomatoses
25.  Rare ocular features in a case of Kabuki syndrome (Niikawa-Kuroki syndrome) 
BMC Ophthalmology  2014;14(1):143.
Kabuki syndrome is a multi-system disorder with peculiar facial features, and ophthalmic abnormalities are frequently involved. This case report of a child with Kabuki syndrome describes two new previously unreported ophthalmic conditions.
Case presentation
A 3-year-old Taiwanese boy with Kabuki syndrome had a short stature, spinal dysraphism, intellectual disability and typical facial features. Ophthalmic findings which have been previously reported in the literature and in this patient, included ptosis, esotropia, coloboma of the iris, retina, choroid and optic disc, and microcornea. The newly identified ophthalmic features in this patient included colobomatous microphthalmos and a dysplastic and elevated disc without central cupping. The genetic analysis identified an MLL2 gene mutation.
The presentations of a dysplastic disc and colobomatous microphthalmia are rarely reported in patients with Kabuki syndrome, but these ophthalmic abnormalities may affect vision. Detailed ophthalmic evaluations in children with Kabuki syndrome are advised.
PMCID: PMC4251844  PMID: 25421742
Kabuki syndrome; Colobomatous microphthalmia; Optic disc dysplasia; MLL2 gene mutation

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