Differences in characteristics, aetiologies, isolated pathogens, and the efficacy of antibiotics in adult patients with preseptal cellulitis and orbital cellulitis between 2000-2009 and 2010-2019.

BACKGROUND/AIMS: To understand whether the epidemiology, aetiologies, common pathogens and the antibiotic efficacy against the identified bacteria of periorbital cellulitis in adults have changed recently (2010-2019) compared with the past decade (2000-2009). METHODS: Adult patients (n=224) diagnosed with preseptal cellulitis and orbital cellulitis admitted to Kaohsiung Veterans General Hospital during 2000-2019 were retrospectively reviewed. Demographic and clinical characteristics, isolated pathogens and antibiotic susceptibility tests against the commonly cultured bacteria were analysed. RESULTS: Preseptal cellulitis showed a tendency of female predominance. Patients in their 60s showed an incidence peak; more cases were observed during winter. The most common predisposing factor was dacryocystitis (15.5%-30.5%), followed by hordeolum (15.5%-24.8%). Aetiology of sinusitis (p=0.001) decreased and that of conjunctivitis (p=0.007) increased significantly with time. Culture results of nasopharyngeal swabs and local abscess showed higher positivity rate than conjunctival swab. The most common isolates were methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative staphylococci and Pseudomonas aeruginosa. Antibiotics including fluoroquinolones and vancomycin were effective; in contrast, ampicillin/sulbactam and oxacillin showed decreasing efficacy against gram-positive bacteria. For antibiotic treatment against P. aeruginosa, fluoroquinolones, ceftazidime, piperacillin and imipenem were ideal choices. CONCLUSION: In isolated pathogens, the increasing trend of methicillin-resistant S. aureus detection was compatible with reducing oxacillin efficacy against periorbital infection. In our study, the report of antibiotic efficacy against the most common identified bacteria offered empirical choices for hospitalised patients with periorbital infection before obtaining culture results.

Antibiotic Choices for Pediatric Periorbital Cellulitis-A 20-Year Retrospective Study from Taiwan.

The delayed treatment of pediatric periorbital cellulitis may have severe consequences. In addition, the antibiotic efficacy against causative bacteria may change over time, and it is important to understand the appropriate antibiotic options for effective treatment in pediatric patients. We compared the changes in cultured bacteria and drug susceptibility tests between two decades, 2010-2019 and 2000-2009, to establish antibiotics for empirical use. The patient characteristics, etiologies, culture sites, and isolated bacteria, and the antibiotic susceptibility tests of the admitted pediatric patients (n = 207) diagnosed with preseptal and orbital cellulitis during 2000 to 2019, were recorded. Insect/animal bites (p = 0.084) showed an increasing trend, and sinusitis (p = 0.016) showed a significant decrease in the past decades. The most common bacteria were Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) infections increased in recent decades (p = 0.01). Moreover, we found that vancomycin was ideal for MRSA infections. The decreasing efficacy of oxacillin correlates with the increasing proportion of MRSA in pediatric periorbital cellulitis. Our study thus offers antibiotic choices against the most common isolates that can be administered before culture results are available.

Therapeutic Effect of α-MSH in Primary Cultured Orbital Fibroblasts Obtained from Patients with Thyroid Eye Disease.

Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it's toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1ß, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1ß-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.

Detection of Autophagy-Related Gene Expression by Conjunctival Impression Cytology in Age-Related Macular Degeneration.

PURPOSE: To investigate the association of autophagy-related gene expression with age-related macular degeneration (AMD). METHODS: Patients with AMD were recruited for analysis by conjunctival impression cytology. mRNA was assessed by real-time polymerase chain reaction (RT-PCR) to evaluate whether the expression of 26 autophagy-related genes (ATGs) was correlated with AMD. Further studies on cell viability and autophagic flux in response to oxidative stress by H2O2 were performed in human retinal pigment epithelial (RPE) cell lines based on the results of impression cytology. RESULTS: Both the neovascular AMD (nAMD) and polypoidal choroidal vasculopathy (PCV) groups had significantly higher mRNA levels of gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) than the control group, but there was no significant difference between these two groups. Age difference existed only in the AMD group. GABARAPL1 and MAP1LC3B mRNA expression increased significantly after acute oxidative stress in adult retinal pigment epithelial (ARPE-19) cells. Cell viability significantly increased and decreased in the cells harboring GABARAPL1 expression vector and silenced with siRNA against GABARAPL1, respectively, during short-term oxidative stress, whereas viability increased in the GABARAPL1-silenced cells after long-term oxidative stress. Silencing GABARAPL1 itself caused a reduction in autophagic flux under both short and long-term oxidative stress. CONCLUSION: Our study showed the possibility of assessing autophagy-related gene expression by conjunctival impression cytology. GABARAPL1 was significantly higher in AMD. Although an in vitro study showed an initial protective effect of autophagy, a cell viability study revealed the possibility of a harmful effect after long-term oxidative injury. The underlying mechanism or critical factors require further investigation.

Metformin and rapamycin protect cells from vital dye-induced damage in retinal pigment epithelial cells and in vivo.

PURPOSE: To evaluate the effect of autophagy inducers on damage caused by vital dye in adult human RPE (ARPE) cells and in a rat model. METHODS: ARPE-19 cells were exposed to ICG or BBG (0.05 mg/ml) with rapamycin (200 nM) or metformin (2 mM) for 30 min and treated with or without 20 µM chloroquine (CQ) to identify the protein levels of LC3 and SQSTM1 by immunoblotting. In vivo study was performed by injecting 10 µl 0.05% ICG and 0.25% BBG into the subretinal space of the rat eyes, and/or co-treated them with metformin and rapamycin. The retinas were used to determine autophagy with the LC3-II level and apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay. RESULTS: In this study, both ICG and BBG inhibited autophagy flux in adult human retinal pigment epithelium cells (ARPE-19), whereas only ICG consistently reduced autophagy in the retina of rats. Moreover, rapamycin and metformin induced autophagic flux in ARPE-19 cells and increased the LC3-II level in retinal tissues exposed to vital dyes. Both ICG and BBG increased apoptosis in the retina of rats. However, both rapamycin and metformin induced autophagy and reduced the apoptosis caused by vital dyes. CONCLUSION: Taken together, these results suggest that rapamycin and metformin may diminish vital dye-induced retinal damage in vivo through activation of autophagy.

Distant metastasis in choroidal melanoma with spontaneous corneal perforation and intratumoral calcification: A case report.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults, but its incidence is low in Asian populations. Spontaneous corneal perforation and intratumoral calcification are rare presentations of choroidal melanoma (CM) , and reports regarding these presentations have been limited. Even after complete surgical treatment, the prognosis of CM patients is usually poor if distant metastasis is present. We here present a case of CM with unique presentations and early distant metastasis to the liver. CASE SUMMARY: A 63-year-old Asian woman presented to our hospital with complaint of pain and brownish discharge from her left eye for 3 d. Imaging studies revealed intratumoral calcification within the left eye with eyeball rupture. Enucleation of the left eye was performed and pathological examination confirmed the diagnosis of CM. Systemic surveillance revealed no metastatic diseases. However, the patient was lost to follow-up 3 mo after surgery. At 1.5 years after the operation, she presented to our emergency department with complaint of dull epigastric pain that radiated to the back for 1 d. Imaging studies revealed a large mass at the upper abdomen abutting the pancreatic neck and body as well as several nodular lesions in the liver. Fine needle biopsy was performed and findings confirmed liver and pancreatic metastases. CONCLUSION: This case highlights the importance of continued follow-up of patients with CM.

ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress.

Age-related macular degeneration (AMD) is an ocular disease with retinal degeneration. Retinal pigment epithelium (RPE) degeneration is mainly caused by long-term oxidative stress. Kinase activity could be either protective or detrimental to cells during oxidative stress; however, few reports have described the role of kinases in oxidative stress. In this study, high-throughput screening of kinome siRNA library revealed that erb-b2 receptor tyrosine-protein kinase 2 (ERBB2) knockdown reduced reactive oxygen species (ROS) production in ARPE-19 cells during oxidative stress. Silencing ERBB2 caused an elevation in microtubule associated protein light chain C3-II (MAP1LC3B-II/I) conversion and sequesterone (SQSTM)1 protein level. ERBB2 deprivation largely caused an increase in autophagy-regulating protease (ATG4B) expression, a protease that negatively recycles MAP1LC3-II at the fusion step between the autophagosome and lysosome, suggesting ERBB2 might modulate ATG4B for autophagy induction in oxidative stress-stimulated ARPE-19 cells. ERBB2 knockdown also caused an accumulation of nuclear factor erythroid 2-related factor 2 (NRF2) and enhanced its transcriptional activity. In addition, ERBB2 ablation or treatment with autophagy inhibitors reduced oxidative-induced cytotoxic effects in ARPE-19 cells. Furthermore, ERBB2 silencing had little or no additive effects in ATG5/7-deficient cells. Taken together, our results suggest that ERBB2 may play an important role in modulating autophagic RPE cell death during oxidative stress, and ERBB2 may be a potential target in AMD prevention.

Epidemiology of benign essential blepharospasm: A nationwide population-based retrospective study in Taiwan.

IMPORTANCE: This study provides a nationwide, population-based data on the incidence of benign essential blepharospasm in Asian adults. BACKGROUND: To describe the incidence, patient demographics, and risk factors associated with benign essential blepharospasm. DESIGN: Population-based retrospective study. PARTICIPANTS AND SAMPLES: A total of 1325 patients with benign essential blepharospasm were identified. METHODS: Patients with diagnosis of blepharopsasm between January 2000 and December 2013 were sampled using the Longitudinal Health Insurance Database 2000. Secondary blepharospasm that may be related to neurological, trauma, and ocular surface disease were excluded. MAIN OUTCOME MEASURED: Multivariate conditional logistic regression was used to estimate the odds ratios for potential risk factors of benign essential blepharospasm. RESULTS: The mean annual incidence was 0.10‰ (0.07‰ for males, and 0.12‰ for females). The peak incidence was in the 50 to 59-year-old age group (0.19‰). People living in urban regions have more risk of developing blepharospasm comparing to people living in less urban regions (p <0.01). White-collar workers also have higher chance of having blepharospasm (p<0.001). Significant difference between control group and case group in hyperlipidemia (p <0.001), sleep disorders (p <0.001), mental disorders (depression, anxiety, obsessive compulsive disorder) (p <0.001), dry eye-related diseases (dry eye, Sjögren's syndrome) (p <0.001), Parkinson's disease (p <0.004), and rosacea (p <0.021) were also identified. CONCLUSIONS AND RELEVANCE: Higher level of urbanization, white-collar work, sleep disorders, mental health diseases, dry eye-related diseases, Parkinsonism, and rosacea are possible risk factors for benign essential blepharospasm.

Factors related to amblyopia in congenital ptosis after frontalis sling surgery.

BACKGROUND: Amblyopia is a main concern in children undergoing frontalis sling surgery for repairing congenital ptosis. This study aimed to evaluate factors related to amblyopia in children undergoing frontalis sling surgery. METHODS: IRB-approved retrospective review of children under the age of 12 who received frontalis sling surgery. Preoperative demographic data, strabismus, margin reflex distance 1 (MRD1), lid fissure height, sling type, refraction errors, surgical outcome and amblyopia were evaluated. RESULTS: This study included 48 eyelid procedures performed in 38 patients. Median age was 4.0 years. Etiology was congenital ptosis in 42 eyes (87.5%) and blepharophimosis in 6 eyes (12.5%). Mersilene mesh was the sling material used in 36 eyes (75%), silicone in 6 eyes (12.5%), and polytetrafluoroethylene (PTFE) in 6 eyes (12.5%). Mean duration of follow-up was 27.8 ± 25.0 months (range, 3 to 128 months). Amblyopia was observed in 17 eyes (35.4%) at the final follow-up. Factors significantly associated with final amblyopia included blepharophimosis (p = 0.017), preoperative MRD1 ≤ - 1.0 mm (p = 0.038), preoperative lid fissure ≤4.5 mm (p = 0.035), preoperative anisometropia (spherical equivalent) (p = 0.011), and postoperative astigmatism (p = 0.026). CONCLUSIONS: Study results suggest that blepharophimosis, preoperative MRD1 ≤ - 1.0 mm, preoperative lid fissure ≤4.5 mm, preoperative anisometropia (spherical equivalent), and postoperative astigmatism are associated with amblyopia after frontalis sling surgery in patients with congenital ptosis.

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain.

Choroidal neovascularization (CNV) is a key pathological feature of several leading causes of vision loss including neovascular age-related macular degeneration. Here, we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation, migration of endothelial cells, and vascular sprouting from rat aortic ring explants. In a rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10 µg and 20 µg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10 µg/mL and 20 µg/mL of CAD27 instilled, respectively). Retinal function was unaffected, as measured using electroretinography in both groups receiving interareal injection or topical applications of CAD27 for at least fourteen days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in diseases such as neovascular age-related macular degeneration.

AAV-mediated gene delivery of the calreticulin anti-angiogenic domain inhibits ocular neovascularization.

Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. The expression of CAD180 and CAD112 was elevated in human umbilical vein endothelial cells transduced with scAAV2-CAD180 or scAAV2-CAD112, respectively, and both inhibited angiogenic activity in vitro. Intravitreal gene delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly inhibited ischemia-induced retinal neovascularization in rat eyes (CAD180: 52.7% reduction; CAD112: 49.2% reduction) compared to scAAV2-mCherry, as measured in retinal flatmounts stained with isolectin B4. Moreover, the retinal structure and function were unaffected by scAAV2-CAD180 or scAAV2-CAD112, as measured by optical coherence tomography and electroretinography. Moreover, subretinal delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly attenuated laser-induced choroidal neovascularization in mouse eyes compared to scAAV2-mCherry, as measured by fundus fluorescein angiography (CAD180: 62.4% reduction; CAD112: 57.5% reduction) and choroidal flatmounts (CAD180: 40.21% reduction; CAD112: 43.03% reduction). Gene delivery using scAAV2-CAD180 or scAAV2-CAD112 has significant potential as a therapeutic option for the management of ocular neovascularization.

Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland.

Importance: Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies. Objective: To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups. Design, Setting, and Participants: In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017. Main Outcomes and Measures: The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis. Results: Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores. Conclusions and Relevance: Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.

Gene Delivery of Calreticulin Anti-Angiogenic Domain Attenuates the Development of Choroidal Neovascularization in Rats.

Choroidal neovascularization (CNV) is a common pathological feature in neovascular age-related macular degeneration, which is the leading cause of vision loss among elderly populations in developed countries. This study evaluated the effect of a novel endogenous inhibitor of angiogenesis, calreticulin anti-angiogenic domain (CAD), subconjunctivally delivered by an adenoviral vector (Ad-CAD) in a rat model of laser-induced CNV. CAD was expressed in Ad-CAD-infected cells and inhibited the angiogenic activity in human umbilical vein endothelial cells in vitro. CAD expression was also found in various ocular tissues after in vivo subconjunctival Ad-CAD injection. Via bioluminescence imaging it is shown that a single subconjunctival injection of Ad-luciferase induced the expression of the transgene in the injected eyes within 24 h, which lasted for at least 112 days. Forty-two days after subconjunctival injection of Ad-CAD, retinal structure and function were unaffected, as measured using optical coherence tomography and electroretinography, respectively. After laser injury, subconjunctival Ad-CAD gene delivery significantly inhibited CNV lesions as measured via choroid flat-mounts (51% reduction at 21 days; p < 0.001), as well as by fundus fluorescein angiography (19.3%, 28.2%, 31%, and 27.5% reductions at days 21, 28, 35, and 42, respectively; p < 0.05) in rats. The data suggest that subconjunctival Ad-CAD gene therapy could effectively inhibit laser-induced CNV and might be an attractive therapeutic approach for the management of choroidal neovascularization.

Differential autophagic effects of vital dyes in retinal pigment epithelial ARPE-19 and photoreceptor 661W cells.

Indocyanine green (ICG) and brilliant blue G (BBG) are commonly used vital dyes to remove internal limiting membrane (ILM) in vitreoretinal surgery. The vital dyes have shown cytotoxic effects in ocular cells. Autophagy is a stress responsive pathway for either protecting cells or promoting cell death. However, the role of autophagy in ocular cells in response to the vital dyes remains unknown. In this study, we found that ICG and BBG reduced cell viability in both human retinal pigment epithelial ARPE-19 and mouse photoreceptor 661W cells. ICG and BBG induced lipidated GFP-LC3-II and LC3-II in ARPE-19 and 661W cells. Combination treatment with the autophagy inhibitor chloroquine indicated that ICG and BBG reduced autophagic flux in ARPE-19 cells, whereas the vital dyes induced autophagic flux in 661W cells. Moreover, genetic and pharmacological ablation of autophagy enhanced vital dyes-induced cytotoxicity in ocular cells. Dietary supplements, including resveratrol, lutein, and CoQ10, induced autophagy and diminished the cytotoxic effects of ICG and BBG in ocular cells. These results suggest that autophagy may protect ARPE-19 and 661W cells from vital dyes-induced damage.

Gene Delivery by Subconjunctival Injection of Adenovirus in Rats: A Study of Local Distribution, Transgene Duration and Safety.

Subconjunctival injection is a minimally invasive route for gene delivery to ocular tissues, but has traditionally been limited to use in the cornea. The accurate ocular distribution of virus has not, however, been previously investigated. Adenovirus is an attractive gene vector as it can deliver large genes and allow for short-term gene expression, but how safe it is when delivered via subconjunctival injection remains to be established. We have characterized the bio-distribution and safety of subconjunctivally administered adenovirus in Brown Norway rats. The bio-distribution and transgene duration of adenovirus carrying luciferase gene (Ad-Luci) at various time intervals were evaluated via bioluminescence imaging after subconjunctival injection. Adenovirus carrying a reporter gene, ß-galactosidase (Ad-LacZ) or hrGFP (Ad-hrGFP) was administered subconjunctivally and the viral distribution in various ocular tissues was assessed by histological analysis and quantitative PCR (qPCR). Hepatic damage was assessed by biochemical and immunohistological analysis with TUNEL stain. Systemic immunogenicity was assessed by measuring serum level of TNF-α via ELISA, 2 hours and 14 days after administration of adenovirus. Retinal function was examined by electroretinography. Subconjunctival injection of Ad-Luci induced luciferase expression in the injected eyes within 24 hours, for at least 64 days. Histological analysis showed adenovirus distributed across anterior and posterior ocular tissues. qPCR demonstrated different amounts of adenovirus in different ocular tissues, with the highest amounts closest to the injection site Unlike the intravenous route, subconjunctivally delivered adenovirus did not elicit any detectable hepatic injury or systemic immunogenicity. Retinal function was unaffected by adenovirus irrespective of administration route. In conclusion, an adenoviral vector administered subconjunctivally can infiltrate into different ocular tissues and lead to short-term ocular transgene expression, without causing hepatic injury and immune activation. Therefore, subconjunctivally administered adenovirus may be a promising gene delivery approach for managing anterior and posterior segment eye diseases requiring short-term therapy.

Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery.

Pathologic neovascularization of the retina is a major cause of substantial and irreversible loss of vision. Drugs are difficult to deliver to the lesions in the back of the eye and this is a major obstacle for the therapeutics. Current pharmacological approach involves an intravitreal injection of anti-VEGF agents to prevent aberrant growth of blood vessels, but it has limitations including therapeutic efficacy and side-effects associated with systemic exposure and invasive surgery. Nanotechnology provides novel opportunities to overcome the limitations of conventional delivery system to reach the back of the eye through fabrication of nanostructures capable of encapsulating and delivering small molecules. This review article introduces various forms of nanocarrier that can be adopted by ocular drug delivery systems to improve current therapy. The application of nanotechnology in medicine brings new hope for ocular drug delivery in the back of the eye to manage the major causes of blindness associated with ocular neovascularization.

Coral-derived compound WA-25 inhibits angiogenesis by attenuating the VEGF/VEGFR2 signaling pathway.

BACKGROUND: WA-25 (dihydroaustrasulfone alcohol, a synthetic derivative of marine compound WE-2) suppresses atherosclerosis in rats by reducing neointima formation. Because angiogenesis plays a critical role in the pathogenesis of atherosclerosis, the present study investigated the angiogenic function and mechanism of WA-25. METHODS: The angiogenic effect of WA-25 was evaluated using a rat aortic ring assay and transgenic zebrafish models were established using transgenic Tg(fli-1:EGFP)y1 and Tg(kdrl:mCherryci5-fli1a:negfpy7) zebrafish embryos. In addition, the effect of WA-25 on distinct angiogenic processes, including matrix metalloproteinase (MMP) expression, endothelial cell proliferation and migration, as well as tube formation, was studied using human umbilical vein endothelial cells (HUVECs). The effect of WA-25 on the endothelial vascular endothelial growth factor (VEGF) signaling pathway was elucidated using qRT-PCR, immunoblot analysis, immunofluorescence and flow cytometric analyses. RESULTS: The application of WA-25 perturbed the development of intersegmental vessels in transgenic zebrafish. Moreover, WA-25 potently suppressed microvessel sprouting in organotypic rat aortic rings. Among cultured endothelial cells, WA-25 significantly and dose-dependently inhibited MMP-2/MMP-9 expression, proliferation, migration and tube formation in HUVECs. Mechanistic studies revealed that WA-25 significantly reduced the VEGF release by reducing VEGF expression at the mRNA and protein levels. In addition, WA-25 reduced surface VEGF receptor 2 (VEGFR2/Flk-1) expression by repressing the VEGFR2 mRNA level. Finally, an exogenous VEGF supply partially rescued the WA-25-induced angiogenesis blockage in vitro and in vivo. CONCLUSIONS: WA-25 is a potent angiogenesis inhibitor that acts through the down-regulation of VEGF and VEGFR2 in endothelial cells. GENERAL SIGNIFICANCE: WA-25 may constitute a novel anti-angiogenic drug that acts by targeting endothelial VEGF/VEGFR2 signaling.

Ocular adnexal lymphoma: Five case reports and a literature review.

This article reports the clinical course and treatment of ocular adnexal lymphoma based on a retrospective review of five cases with a histologically approved ocular adnexal lymphoma at Kaohsiung Veterans General Hospital over 10 years. Extranodal B-cell lymphoma in the orbit, lacrimal gland, eyelid, or conjunctiva was found in these patients. Four of them were female, and they were aged 45-64 years. All patients were also consulted with hematologists for possible systemic involvement and therapeutic plan. The patient with retrobulbar and orbital apex involvement received systemic chemotherapy. The patient with lacrimal gland involvement experienced tumor recurrence after local excision, and therefore received adjuvant radiotherapy. The remaining three patients had localized lymphoma on the eyelid or bulbar conjunctiva, and they all showed no recurrence after surgical excision. The incidence of ocular adnexal lymphoma has risen worldwide over the last few decades. Although most cases are confined to ocular adnexal, some may also be associated with disseminated lymphoma. Accurate diagnosis and staging is mandatory for appropriate treatment. Generally speaking, localized and low-grade ocular adnexal lymphoma involved eyelid or conjunctiva seem to have good outcome after surgical excision only. Systemic chemotherapy should be considered in patients with advanced disease or systemic manifestations, and radiotherapy also offers a good choice for lacrimal gland lymphoma.

Review of AlloDerm Acellular Human Dermis Regenerative Tissue Matrix in Multiple Types of Oculofacial Plastic and Reconstructive Surgery.

PURPOSE: AlloDerm acellular human dermis is used for repair or replacement of damaged or inadequate skin tissue. It has been used successfully in multiple types of surgeries, including abdominal wall reconstruction, breast reconstruction, and head and neck reconstruction. Its application to ophthalmic plastic and reconstructive surgery is less well described. This study seeks to evaluate the efficacy and factors influencing surgical outcomes using Alloderm in multiple types of oculofacial plastic surgery. METHODS: Institutional Review Board-approved retrospective review of 84 patients who underwent surgical procedures using Alloderm. Preoperative demographic data, comorbidities, smoking, clinical etiology, surgical methods, Alloderm type, and outcome (cosmetic and functional) were evaluated. RESULTS: This study included 84 patients, accounting for a total of 98 procedures. Mean age was 52.5 years (3-93 years). Etiologies necessitating surgery included malignancy in 26 patients (31.0%), trauma in 19 patients (22.6%), congenital lesions in 15 patients (17.9%), and senile change in 11 patients (13.1%). Surgical procedures included lower eyelid posterior lamella elongation, socket and fornix reconstruction, scar repair, patch grafts, and filler. Mean duration of follow up was 530 days. Overall, 92.8% of patients had favorable outcomes. Factors associated with significantly worse outcomes included smoking, congenital anomaly etiologies, and previous graft/flaps in the same area (p = 0.03, p = 0.029, and p = 0.007, respectively). CONCLUSIONS: This study suggests that Alloderm acellular human dermis can be used safely and effectively in multiple types of oculofacial procedures. Smoking, congenital anomaly etiologies, and previous graft/flap were associated with poor cosmetic and functional outcomes.