Radhakrishnan S, Chen PP, Junk AK, Nouri-Mahdavi K, Chen TC. Laser Peripheral Iridotomy in Primary Angle Closure: A Report by the American Academy of Ophthalmology. Ophthalmology 2018;125(7):1110-1120.Abstract
PURPOSE: To examine the efficacy and complications of laser peripheral iridotomy (LPI) in subjects with primary angle closure (PAC). METHODS: Literature searches in the PubMed and Cochrane databases were last conducted in August 2017 and yielded 300 unique citations. Of these, 36 met the inclusion criteria and were rated according to the strength of evidence; 6 articles were rated level I, 11 articles were rated level II, and 19 articles were rated level III. RESULTS: Reported outcomes were change in angle width, effect on intraocular pressure (IOP) control, disease progression, and complications. Most of the studies (29/36, 81%) included only Asian subjects. Angle width (measured by gonioscopy, ultrasound biomicroscopy, and anterior segment OCT) increased after LPI in all stages of angle closure. Gonioscopically defined persistent angle closure after LPI was reported in 2% to 57% of eyes across the disease spectrum. Baseline factors associated with persistent angle closure included narrower angle and parameters representing nonpupillary block mechanisms of angle closure, such as a thick iris, an anteriorly positioned ciliary body, or a greater lens vault. After LPI, further treatment to control IOP was reported in 0%-8% of PAC suspect (PACS), 42% to 67% of PAC, 21% to 47% of acute PAC (APAC), and 83%-100% of PAC glaucoma (PACG) eyes. Progression to PACG ranged from 0% to 0.3% per year in PACS and 0% to 4% per year in PAC. Complications after LPI included IOP spike (8-17 mmHg increase from baseline in 6%-10%), dysphotopsia (2%-11%), anterior chamber bleeding (30%-41%), and cataract progression (23%-39%). CONCLUSIONS: Laser peripheral iridotomy increases angle width in all stages of primary angle closure and has a good safety profile. Most PACS eyes do not receive further intervention, whereas many PAC and APAC eyes, and most PACG eyes, receive further treatment. Progression to PACG is uncommon in PACS and PAC. There are limited data on the comparative efficacy of LPI versus other treatments for the various stages of angle closure; 1 randomized controlled trial each demonstrated superiority of cataract surgery over LPI in APAC and of clear lens extraction over LPI in PACG or PAC with IOP above 30 mmHg.
Oellers P, Mowery YM, Perez BA, Stinnett S, Mettu P, Vajzovic L, Light K, Steffey BA, Cai J, Dutton JJ, Buckley EG, Halperin EC, Marks LB, Kirsch DG, Mruthyunjaya P. Efficacy and Safety of Low-Dose Iodine Plaque Brachytherapy for Juxtapapillary Choroidal Melanoma. Am J Ophthalmol 2018;186:32-40.Abstract
PURPOSE: To evaluate low- vs high-dose plaque brachytherapy for juxtapapillary choroidal melanoma. DESIGN: Retrospective interventional case series. METHODS: Setting: Single institution. STUDY POPULATION: Forty-seven patients with juxtapapillary choroidal melanoma. INTERVENTION: Iodine-125 plaque brachytherapy. Eyes were divided into apex low-dose (LD) and high-dose (HD) groups (≤ or > median apex dose 84.35 Gy). Main outcome measures were time to distant failure, local failure, death, enucleation, radiation retinopathy, optic neuropathy, and best-corrected visual acuity (BCVA). RESULTS: Freedom from distant failure rates were 96% and 95% in apex LD and HD groups at 5 years and 77% and 95% at 10 years, respectively (P = .84). Freedom from local failure rates were 90% in the apex LD group vs 89% in the HD group at 5 and 10 years (P = .96). Apex LD and HD groups did not differ for time to death or enucleation. Five- and 10-year freedom from radiation retinopathy and optic neuropathy rates were higher in the apex LD than HD group. Loss of ≥3 BCVA lines, final BCVA 20/40 or better, and final BCVA 20/200 or worse were more favorable in the 5 mm LD compared to HD group. Visual acuity outcomes did not differ between apex LD and HD groups. CONCLUSIONS: Low-dose iodine-125 plaque brachytherapy (67.5-81 Gy at tumor apex) provides safe and effective tumor control for juxtapapillary choroidal melanoma and may be associated with reduced radiation toxicity. Larger trials are needed to determine the optimal therapeutic dose for juxtapapillary choroidal melanoma.
Katikireddy KR, White TL, Miyajima T, Vasanth S, Raoof D, Chen Y, Price MO, Price FW, Jurkunas UV. NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy. Free Radic Biol Med 2018;116:19-30.Abstract
Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.
Ismail AM, Cui T, Dommaraju K, Singh G, Dehghan S, Seto J, Shrivastava S, Fedorova NB, Gupta N, Stockwell TB, Madupu R, Heim A, Kajon AE, Romanowski EG, Kowalski RP, Malathi J, Therese KL, Madhavan HN, Zhang Q, Ferreyra LJ, Jones MS, Rajaiya J, Dyer DW, Chodosh J, Seto D. Genomic analysis of a large set of currently-and historically-important human adenovirus pathogens. Emerg Microbes Infect 2018;7(1):10.Abstract
Human adenoviruses (HAdVs) are uniquely important "model organisms" as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to "one-time" appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population.
Nilsson AK, Löfqvist C, Najm S, Hellgren G, Sävman K, Andersson MX, Smith LEH, Hellström A. Long-chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation. Acta Paediatr 2018;107(6):1020-1027.Abstract
AIM: Our aim was to perform an in-depth analysis of the composition of fatty acids in milk from mothers delivering extremely preterm babies. We investigated longitudinal changes in milk fatty acid profiles and the relationship between several types of fatty acids, including omega-3 and omega-6. METHODS: Milk samples were collected at three stages of lactation from 78 mothers who delivered at less than 28 weeks of pregnancy at the Sahlgrenska University Hospital, Gothenburg, Sweden, from April 2013 to September 2015. Fatty acid composition was analysed by gas chromatography-mass spectrometry. RESULTS: A reduction in long-chain polyunsaturated fatty acids (LCPUFAs) was observed during the lactation period. The concentrations of arachidonic acid and docosahexaenoic acid declined from medians of 0.34 to 0.22 mol% and 0.29 to 0.15 mol%, respectively, between postnatal day 7 and a postmenstrual age of 40 weeks. Strong correlations were found between the intermediates of several classes of fatty acids, including omega-3, omega-6 and omega-9. CONCLUSION: A rapid reduction in LCPUFA content in the mother's milk during the lactation period emphasises the importance of fatty acid supplementation to infants born extremely preterm, at least during the period corresponding to the third trimester, when rapid development of the brain and adipose tissue requires high levels of LCPUFAs.
Wang JC, Elliott AT. Acute transient large-angle exotropia caused by traumatic orbital contusion. Orbit 2018;:1-3.Abstract
We report an unusual case of acute large-angle left exotropia associated with blunt orbital trauma in a healthy 8-year-old boy. Examination revealed a large-angle left exotropia with limitation in adduction of the left eye. Microhyphema and commotio retinae of the left eye were also present. High-resolution orbital magnetic resonance imaging (MRI) demonstrated perimuscular and intramuscular edema mostly involving the left medial rectus muscle but also involving the left lateral rectus muscle. The extraocular muscle insertions were intact. Complete resolution of the strabismus and adduction limitation occurred within 24 hours of starting systemic steroid therapy. This case highlights the utility of high-resolution imaging to assess for injury to the extraocular muscles. If disinsertion, transection, or rupture of the muscle is not present on imaging, resolution may occur with systemic steroid therapy and surgical intervention is not needed.
Shiga Y, Akiyama M, Nishiguchi KM, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yamashiro K, Kashiwagi K, Iwata T, Mabuchi F, Takamoto M, Ozaki M, Kawase K, Aihara M, Araie M, Yamamoto T, Kiuchi Y, Nakamura M, Ikeda Y, Sonoda K-H, Ishibashi T, Nitta K, Iwase A, Shirato S, Oka Y, Satoh M, Sasaki M, Fuse N, Suzuki Y, Cheng C-Y, Khor CC, Baskaran M, Perera S, Aung T, Vithana EN, Cooke Bailey JN, Kang JH, Pasquale LR, Haines JL, Wiggs JL, Burdon KP, Gharahkhani P, Hewitt AW, Mackey DA, Macgregor S, Craig JE, Allingham RR, Hauser M, Ashaye A, Budenz DL, Akafo S, Williams SEI, Kamatani Y, Nakazawa T, Kubo M. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. Hum Mol Genet 2018;27(8):1486-1496.Abstract
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
Fu Z, Wang Z, Liu C-H, Gong Y, Cakir B, Liegl R, Sun Y, Meng SS, Burnim SB, Arellano I, Moran E, Duran R, Poblete A, Cho SS, Talukdar S, Akula JD, Hellström A, Smith LEH. Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice. Diabetes 2018;67(5):974-985.Abstract
Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.
Kloek CE, Jeng-Miller KW, Jacobs DS, Dunn IF. Prosthetic Replacement of the Ocular Surface Ecosystem Treatment of Ocular Surface Disease After Skull Base Tumor Resection. World Neurosurg 2018;110:e124-e128.Abstract
BACKGROUND: Prosthetic replacement of the ocular surface ecosystem (PROSE) treatment is an effective, nonsurgical therapeutic option for patients with ocular surface disease related to cranial nerve deficits secondary to skull base tumor resection. METHODS: This case series describes the impact of PROSE treatment in patients with symptomatic exposure keratopathy or neurotrophic keratitis after skull base tumor surgery. RESULTS: All patients improved symptomatically and functionally with PROSE treatment, and have had sustained improvement for as long as 3 years. CONCLUSIONS: In postneurosurgical cases in which neurologic function may recover, PROSE treatment offers a safe, nonsurgical treatment option to support the ocular surface during the period of observation awaiting neurologic recovery.
Zhang S, Lebreton F, Mansfield MJ, Miyashita S-I, Zhang J, Schwartzman JA, Tao L, Masuyer G, Martínez-Carranza M, Stenmark Pål, Gilmore MS, Doxey AC, Dong M. Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium. Cell Host Microbe 2018;23(2):169-176.e6.Abstract
Botulinum neurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT-like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster.
Löfqvist CA, Najm S, Hellgren G, Engström E, Sävman K, Nilsson AK, Andersson MX, Hård A-L, Smith LEH, Hellström A. Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol 2018;136(3):271-277.Abstract
Importance: Mice with oxygen-induced retinopathy fed matched diets except for ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs ω-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of ω-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. Objective: To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating ω-3 and ω-6 LC-PUFAs. Design, Setting, and Participants: This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Göteborg, Sweden. Main Outcomes and Measures: Serum phospholipid fatty acids were transmethylated and measured by gas chromatography-mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. Results: Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20:4 ω-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks' PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. Conclusions and Relevance: Low postnatal levels of the ω-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction. Trial Registration: Identifier: NCT02760472.
Cao J, Brouwer NJ, Jordanova ES, Marinkovic M, van Duinen SG, de Waard NE, Ksander BR, Mulder A, Claas FHJ, Heemskerk MHM, Jager MJ. HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status. Invest Ophthalmol Vis Sci 2018;59(2):1005-1015.Abstract
Purpose: Antitumor T cells need expression of HLA class I molecules but can be inhibited by ligands such as programmed death ligand 1 (PD-L1). We determined expression and regulation of these molecules in human conjunctival melanoma (CM) samples, cell lines, and murine xenografts. Methods: Immunofluorescence staining was performed to examine the expression of HLA-A, HLA-B/C, and β-2-microglobulin (B2M) in 23 primary CM samples. HLA class I expression was compared with clinicopathologic characteristics, the presence of tumor-infiltrating leukocytes, and PD-L1/PD-1 status. The effect of interferon γ (IFN-γ) on HLA class I expression was tested on three CM cell lines using quantitative PCR and flow cytometry. Furthermore, HLA class I expression was determined in CM cell line-derived murine xenografts. Results: One third of tumors had positive HLA-A, HLA-B/C, and B2M expression. A positive expression was especially seen in thin and epibulbar tumors but was not associated with recurrences. HLA class I expression was correlated with M2 macrophage density and tended to associate with CD8+ T-cell density but was independent of PD-L1 or PD-1 expression. IFN-γ upregulated HLA class I expression and genes involved in HLA transcription and transportation on CM cell lines. Murine xenografts showed a comparable HLA class I expression as their respective cell lines. Conclusions: Our data indicate that subsets of CM have positive HLA class I expression, and HLA class I and PD-L1/PD-1 are expressed independently. When one considers immunotherapy, one should also analyze HLA class I expression, whose downregulation can limit the efficacy of T cell-mediated therapies.
Wan MJ, Chiu H, Shah AS, Hunter DG. Long-term Surgical Outcomes for Large-angle Infantile Esotropia. Am J Ophthalmol 2018;189:155-159.Abstract
PURPOSE: To report the long-term surgical outcomes for a cohort of children with large-angle infantile esotropia. DESIGN: Multicenter, nonrandomized clinical study. METHODS: Setting: Two tertiary-care pediatric hospitals. STUDY POPULATION: Children with large-angle (≥55 prism diopters) infantile esotropia. INTERVENTION: Surgical treatment of infantile esotropia. MAIN OUTCOME MEASURE: Success rate at final follow-up (postoperative deviation ≤ 10 prism diopters and no need for retreatment). RESULTS: A total of 88 patients with large-angle infantile esotropia were treated during the 13-year study period. Treatment was bilateral medial rectus muscle recessions in 70 patients, botulinum toxin-augmented surgery in 15 patients, and 3-muscle surgery in 3 patients. After a mean follow-up of 40 months, 20 patients (23%) had a successful outcome compared to 68 treatment failures (77%). Of the 68 treatment failures, 59 had residual or recurrent esotropia and 9 had sequential exotropia. On multivariate logistic regression, treatment modality was the only factor significantly associated with a successful outcome. Specifically, patients treated with botulinum toxin-augmented surgery were more likely to have a successful outcome compared to patients treated with bilateral medial rectus muscle recessions. For the 26 patients (30%) who underwent retreatment, the mean number of procedures was 2.1, and 7 (27%) had a deviation of ≤10 prism diopters at final follow-up. CONCLUSIONS: The overall success rate for treatment of large-angle infantile esotropia was poor in this cohort, with most failures owing to recurrent or residual esotropia. Botulinum toxin-augmented surgery was associated with a higher success rate at final follow-up.