Weinberger AD, Gilmore MS.
A CRISPR View of Cleavage. Cell 2015;161(5):964-6.
AbstractSeminal studies showed that CRISPR-Cas systems provide adaptive immunity in prokaryotes and promising gene-editing tools from bacteria to humans. Yet, reports diverged on whether some CRISPR systems naturally target DNA or RNA. Here, Samai and colleagues unify the studies, showing that a single type III CRISPR-Cas system cleaves both DNA and RNA targets, independently.
Weis B, Schmidt J, Maamar H, Raj A, Lin H, Tóth C, Riedmann K, Raddatz G, Seitz H-K, Ho AD, Lyko F, Linhart HG.
Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a. Oncogene 2015;34(14):1822-30.
AbstractAberrant de novo methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of de novo DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal cancer using RNA fluorescence in situ hybridization (FISH), quantitative PCR and immunostaining. Following conditional deletion of Dnmt3a in the colon of APC((Min/+)) mice, we analyzed tumor numbers, genotype of macroadenomas and laser dissected microadenomas, global and regional DNA methylation and gene expression. Our results showed increased Dnmt3a expression in colon adenomas of APC((Min/+)) mice and human colorectal cancer samples when compared with control tissue. Interestingly, in tumor tissue, RNA FISH analysis showed highest Dnmt3a expression in Lgr5-positive stem/progenitor cells. Deletion of Dnmt3a in APC((Min/+)) mice reduced colon tumor numbers by ~40%. Remaining adenomas and microadenomas almost exclusively contained the non-recombined Dnmt3a allele; no tumors composed of the inactivated Dnmt3a allele were detected. DNA methylation was reduced at the Oct4, Nanog, Tff2 and Cdkn1c promoters and expression of the tumor-suppressor genes Tff2 and Cdkn1c was increased. In conclusion, our results show that Dnmt3a is predominantly expressed in the stem/progenitor cell compartment of tumors and that deletion of Dnmt3a inhibits the earliest stages of intestinal tumor development.
Weiss JS, Møller HU, Aldave AJ, Seitz B, Bredrup C, Kivelä T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbé A, Kenyon KR, Kinoshita S, Lisch W.
IC3D classification of corneal dystrophies--edition 2. Cornea 2015;34(2):117-59.
AbstractPURPOSE: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. METHODS: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. RESULTS: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity "Epithelial recurrent erosion dystrophies" actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. CONCLUSIONS: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.
Wells JA, Glassman AR, Jampol LM, Aiello LP, Antoszyk AN, Baker CW, Bressler NM, Browning DJ, Connor CG, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW, Beck RW.
Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. JAMA Ophthalmol 2015;:1-8.
AbstractImportance: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment. Objective: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography. Design, Setting, and Participants: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015. Interventions: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol. Main Outcomes and Measures: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST. Results: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab. Conclusions and Relevance: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients. Trial Registration: clinicaltrials.gov Identifier: NCT01627249.
White ML, Chodosh J, Jang J, Dohlman C.
Incidence of Stevens-Johnson Syndrome and Chemical Burns to the Eye. Cornea 2015;34(12):1527-33.
AbstractPURPOSE: This population-based observational study was designed to estimate the incidence and distribution of SJS-spectrum (Stevens-Johnson syndrome, toxic epidermal necrolysis, and toxic epidermal Necrolysis/Stevens-Johnson syndrome overlap) and chemical burns (alkali or acid burn of the cornea/conjunctiva) in the United States and extrapolate these numbers to the world. METHODS: All patients evaluated in 961 hospital-based US emergency departments between July 1, 2010, and June 30, 2012 were identified retrospectively using the Nationwide Emergency Department Sample (NEDS) from the Agency for Healthcare Research and Quality. SJS-spectrum and chemical burn cases were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. RESULTS: A mean of 3834 new SJS-spectrum cases per year were identified in the United States, resulting in an incidence rate of 12.35 new cases per million per year. Similarly, a mean of 15,865 new chemical burn cases per year were identified, resulting in an incidence rate of 51.10 new cases per million per year. CONCLUSIONS: If the incidence of SJS-spectrum is approximately uniform the world-over, extrapolation from the US figure would amount to approximately 86,500 new cases per year in the world. Extrapolation of ocular chemical burns to the world is difficult because the incidence and severity are anticipated to be higher in the developing world than in the United States. Still, using a US incidence rate, a minimum of 357,710 burn accidents would be expected to occur worldwide every year; there are presently too few data available to calculate the degree of severity and bilaterality.
Wiecek E, Lashkari K, Dakin SC, Bex P.
A statistical analysis of metamorphopsia in 7106 amsler grids. Ophthalmology 2015;122(2):431-3.
Wirostko B, Rafii MJ, Sullivan DA, Morelli J, Ding J.
Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone. Ocul Surf 2015;13(3):204-212.e1.
AbstractImpaired corneal wound healing that occurs with ocular surface disease, trauma, systemic disease, or surgical intervention can lead to persistent corneal epithelial defects (PCED), which result in corneal scarring, ulceration, opacification, corneal neovascularization, and, ultimately, visual compromise and vision loss. The current standard of care can include lubricants, ointments, bandage lenses, amniotic membranes, autologous serum eye drops, and corneal transplants. Various inherent problems exist with application and administration of these treatments, which often may not result in a completely healed surface. A topically applicable compound capable of promoting corneal epithelial cell proliferation and/or migration would be ideal to accelerate healing. We hypothesize that human growth hormone (HGH) is such a compound. In a recent study, HGH was shown to activate signal transducer and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial migration in a co-culture system of corneal epithelial cells and fibroblasts. These effects require an intact communication between corneal epithelia and fibroblasts. Further, HGH promotes corneal wound healing in a rabbit debridement model, thus demonstrating the effectiveness of HGH in vivo as well. In conclusion, HGH may represent an exciting and effective topical therapeutic to promote corneal wound healing.
Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, Baumal CR, Johnson MW, Witkin DI, Leung J, Albini TA, Moshfeghi AA, Batlle IR, Sobrin L, Eliott D.
Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin. Ophthalmology 2015;122(7):1438-51.
AbstractPURPOSE: To describe a syndrome of hemorrhagic occlusive retinal vasculitis (HORV) that developed after seemingly uncomplicated cataract surgery. DESIGN: Retrospective case series. SUBJECTS: Eleven eyes of 6 patients from 6 different institutions. METHODS: Cases were identified after discussion among retina specialists. The findings on presentation, clinical course, and outcome of a series of 7 eyes of 4 patients were compared with a previous report of 4 eyes of 2 patients, and data from both series were combined for a comprehensive analysis. MAIN OUTCOME MEASURES: Historical data, examination findings, imaging results, systemic evaluation findings, treatment regimens, and visual outcomes. RESULTS: Eleven eyes of 6 patients underwent otherwise uncomplicated cataract surgery, receiving viscoelastic and prophylactic intracameral vancomycin during the procedure. Despite good initial vision on postoperative day 1, between 1 to 14 days after surgery, all eyes demonstrated painless vision loss resulting from HORV. Extensive ocular and systemic evaluations were unrevealing in all patients. All patients were treated with aggressive systemic and topical corticosteroids. Additional treatments included systemic antiviral medication in 4 patients, intravitreal antibiotics in 4 eyes, and pars plana vitrectomy in 4 eyes. Skin testing for vancomycin sensitivity showed negative results in 3 patients and was not performed in the others. Neovascular glaucoma developed in 7 eyes, and all eyes received intravitreal anti-vascular endothelial growth factor (VEGF) injection, panretinal photocoagulation, or both for retinal ischemia. Final visual acuity was less than 20/100 in 8 of 11 eyes. CONCLUSIONS: Postoperative HORV is an exceedingly rare and potentially devastating condition that can occur after otherwise uncomplicated cataract surgery. Although the precise cause remains unknown, this disease may represent a delayed immune reaction similar to vancomycin-induced leukocytoclastic vasculitis. Despite treatment with high-dose corticosteroids, antiviral medication, and early vitrectomy in many patients, visual outcomes typically were poor in this series. Early intervention with intravitreal anti-VEGF medication and panretinal photocoagulation may help to prevent additional vision loss resulting from neovascular glaucoma.
Wolfe JM, Boettcher SEP, Josephs EL, Cunningham CA, Drew T.
You look familiar, but I don't care: Lure rejection in hybrid visual and memory search is not based on familiarity. J Exp Psychol Hum Percept Perform 2015;41(6):1576-87.
AbstractIn "hybrid" search tasks, observers hold multiple possible targets in memory while searching for those targets among distractor items in visual displays. Wolfe (2012) found that, if the target set is held constant over a block of trials, reaction times (RTs) in such tasks were a linear function of the number of items in the visual display and a linear function of the log of the number of items held in memory. However, in such tasks, the targets can become far more familiar than the distractors. Does this "familiarity"- operationalized here as the frequency and recency with which an item has appeared-influence performance in hybrid tasks In Experiment 1, we compared searches where distractors appeared with the same frequency as the targets to searches where all distractors were novel. Distractor familiarity did not have any reliable effect on search. In Experiment 2, most distractors were novel but some critical distractors were as common as the targets while others were 4× more common. Familiar distractors did not produce false alarm errors, though they did slightly increase RTs. In Experiment 3, observers successfully searched for the new, unfamiliar item among distractors that, in many cases, had been seen only once before. We conclude that when the memory set is held constant for many trials, item familiarity alone does not cause observers to mistakenly confuse target with distractors. (PsycINFO Database Record
Wu J, Cho E, Willett WC, Sastry SM, Schaumberg DA.
Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up. JAMA Ophthalmol 2015;:1-10.
AbstractImportance: Despite strong biological plausibility, evidence from epidemiologic studies and clinical trials on the relations between intakes of lutein and zeaxanthin and age-related macular degeneration (AMD) has been inconsistent. The roles of other carotenoids are less thoroughly investigated. Objective: To investigate the associations between intakes of carotenoids and AMD. Design, Setting, and Participants: Prospective cohort study, with cohorts from the Nurses' Health Study and the Health Professionals Follow-up Study in the United States. A total of 63 443 women and 38 603 men were followed up, from 1984 until May 31, 2010, in the Nurses' Health Study and from 1986 until January 31, 2010, in the Health Professionals Follow-up Study. All participants were aged 50 years or older and were free of diagnosed AMD, diabetes mellitus, cardiovascular disease, and cancer at baseline. Main Outcomes and Measures: Predicted plasma carotenoid scores were computed directly from food intake, assessed by repeated food frequency questionnaires at baseline and follow-up, using validated regression models to account for bioavailability and reporting validity of different foods, and associations between predicted plasma carotenoid scores and AMD were determined. Results: We confirmed 1361 incident intermediate and 1118 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse by medical record review. Comparing extreme quintiles of predicted plasma lutein/zeaxanthin score, we found a risk reduction for advanced AMD of about 40% in both women and men (pooled relative risk comparing extreme quintiles = 0.59; 95% CI, 0.48-0.73; P for trend < .001). Predicted plasma carotenoid scores for other carotenoids, including β-cryptoxanthin, α-carotene, and β-carotene, were associated with a 25% to 35% lower risk of advanced AMD when comparing extreme quintiles. The relative risk comparing extreme quintiles for the predicted plasma total carotenoid index was 0.65 (95% CI, 0.53-0.80; P for trend < .001). We did not identify any associations of carotenoids, either as predicted plasma score or calculated intake, with intermediate AMD. Conclusions and Relevance: Higher intake of bioavailable lutein/zeaxanthin is associated with a long-term reduced risk of advanced AMD. Given that some other carotenoids are also associated with a lower risk, a public health strategy aimed at increasing dietary consumption of a wide variety of fruits and vegetables rich in carotenoids may reduce the incidence of advanced AMD.
Wu H, de Boer JF, Chen L, Chen TC.
Correlation of localized glaucomatous visual field defects and spectral domain optical coherence tomography retinal nerve fiber layer thinning using a modified structure-function map for OCT. Eye (Lond) 2015;29(4):525-33.
AbstractPurposeTo study the correlation between glaucomatous visual field (VF) defects assessed by standard automated perimetry (SAP) and peripapillary retinal nerve fiber layer (RNFL) thinning measured by spectral domain optical coherence tomography (OCT) using a modified OCT-based peripapillary RNFL structure-function map.Patients and methodsPerimetric glaucoma patients and age-matched normal control subjects were recruited from a university hospital clinic. All eyes underwent testing with the Spectralis spectral domain OCT and SAP on the same day. An OCT-based correspondence map, which correlated VF areas with peripapillary RNFL sectors was created to evaluate the relationship between glaucomatous RNFL thinning and VF loss in six nerve fiber layer bundle areas. Correlations of RNFL thinning with corresponding VF defects were examined using Spearman rank-order correlations. To demonstrate the association between localized VF defects and RNFL thickness, the theoretical curves were made according to an established log-linear model. The measured RNFL thickness values and VF defects were presented in the same scatterplot for each sector.ResultsFifty-six glaucoma patients and 85 normal subjects were included in the study. Significant association between localized VF loss and RNFL thinning was found in corresponding areas. Data from the current study fit well with established log-linear models, which compare RNFL thickness values with VF defects.ConclusionAnalysis of RNFL thinning in eyes with localized glaucomatous VF defects showed good structure-function correlation in a new OCT-based structure-function correspondence map.