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Qi Q, Kilpeläinen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, Sonestedt E, Chu AY, Renström F, Lin X, Angquist LH, Huang J, Liu Z, Li Y, Asif Ali M, Xu M, Ahluwalia TS, Boer JMA, Chen P, Daimon M, Eriksson J, Perola M, Friedlander Y, Gao Y-T, Heppe DHM, Holloway JW, Houston DK, Kanoni S, Kim Y-M, Laaksonen MA, Jääskeläinen T, Lee NR, Lehtimäki T, Lemaitre RN, Lu W, Luben RN, Manichaikul A, Männistö S, Marques-Vidal P, Monda KL, Ngwa JS, Perusse L, van Rooij FJA, Xiang Y-B, Wen W, Wojczynski MK, Zhu J, Borecki IB, Bouchard C, Cai Q, Cooper C, Dedoussis GV, Deloukas P, Ferrucci L, Forouhi NG, Hansen T, Christiansen L, Hofman A, Johansson I, Jørgensen T, Karasawa S, Khaw K-T, Kim M-K, Kristiansson K, Li H, Lin X, Liu Y, Lohman KK, Long J, Mikkilä V, Mozaffarian D, North K, Pedersen O, Raitakari O, Rissanen H, Tuomilehto J, van der Schouw YT, Uitterlinden AG, Zillikens CM, Franco OH, Shyong Tai E, Ou Shu X, Siscovick DS, Toft U, Verschuren MWM, Vollenweider P, Wareham NJ, Witteman JCM, Zheng W, Ridker PM, Kang JH, Liang L, Jensen MK, Curhan GC, Pasquale LR, Hunter DJ, Mohlke KL, Uusitupa M, Cupples AL, Rankinen T, Orho-Melander M, Wang T, Chasman DI, Franks PW, Sørensen TIA, Hu FB, Loos RJF, Nettleton JA, Qi L. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals. Hum Mol Genet 2014;23(25):6961-72.Abstract

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Valentino MD, McGuire AM, Rosch JW, Bispo PJM, Burnham C, Sanfilippo CM, Carter RA, Zegans ME, Beall B, Earl AM, Tuomanen EI, Morris TW, Haas W, Gilmore MS. Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster. Nat Commun 2014;5:5411.Abstract

Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the United States. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with other unencapsulated nasopharyngeal S. pneumoniae. They also possess putative adhesins that have not been described in encapsulated pneumococci. These findings suggest that the unencapsulated strains capable of causing conjunctivitis utilize a pathogenesis strategy substantially different from that described for S. pneumoniae at other infection sites.

Wiecek E, Dakin SC, Bex P. Metamorphopsia and letter recognition. J Vis 2014;14(14)Abstract

Acuity is the most commonly used measure of visual function, and reductions in acuity are associated with most eye diseases. Metamorphopsia-a perceived distortion of visual space-is another common symptom of visual impairment and is currently assessed qualitatively using Amsler (1953) charts. In order to quantify the impact of metamorphopsia on acuity, we measured the effect of physical spatial distortion on letter recognition. Following earlier work showing that letter recognition is tuned to specific spatial frequency (SF) channels, we hypothesized that the effect of distortion might depend on the spatial scale of visual distortion just as it depends on the spatial scale of masking noise. Six normally sighted observers completed a 26 alternate forced choice (AFC) Sloan letter identification task at five different viewing distances, and the letters underwent different levels of spatial distortion. Distortion was controlled using spatially band-pass filtered noise that spatially remapped pixel locations. Noise was varied over five spatial frequencies and five magnitudes. Performance was modeled with logistic regression and worsened linearly with increasing distortion magnitude and decreasing letter size. We found that retinal SF affects distortion at midrange frequencies and can be explained with the tuning of a basic contrast sensitivity function, while object-centered distortion SF follows a similar pattern of letter object recognition sensitivity and is tuned to approximately three cycles per letter (CPL). The interaction between letter size and distortion makes acuity an unreliable outcome for metamorphopsia assessment.

Dagi LR, Tiedemann LM, Heidary G, Robson CD, Hall AM, Zurakowski D. Using spectral-domain optical coherence tomography to detect optic neuropathy in patients with craniosynostosis. J AAPOS 2014;18(6):543-9.Abstract

BACKGROUND: Detecting and monitoring optic neuropathy in patients with craniosynostosis is a clinical challenge due to limited cooperation, and subjective measures of visual function. The purpose of this study was to appraise the correlation of peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain ocular coherence tomography (SD-OCT) with indication of optic neuropathy based on fundus examination. METHODS: The medical records of all patients with craniosynostosis presenting for ophthalmic evaluation during 2013 were retrospectively reviewed. The following data were abstracted from the record: diagnosis, historical evidence of elevated intracranial pressure, current ophthalmic evaluation and visual field results, and current peripapillary RNFL thickness. RESULTS: A total of 54 patients were included (mean age, 10.6 years [range, 2.4-33.8 years]). Thirteen (24%) had evidence of optic neuropathy based on current fundus examination. Of these, 10 (77%) demonstrated either peripapillary RNFL elevation and papilledema or depression with optic atrophy. Sensitivity for detecting optic atrophy was 88%; for papilledema, 60%; and for either form of optic neuropathy, 77%. Specificity was 94%, 90%, and 83%, respectively. Kappa agreement was substantial for optic atrophy (κ = 0.73) and moderate for papilledema (κ = 0.39) and for either form of optic neuropathy (κ = 0.54). Logistic regression indicated that peripapillary RNFL thickness was predictive of optic neuropathy (P < 0.001). Multivariable analysis demonstrated that RNFL thickness measurements were more sensitive at detecting optic neuropathy than visual field testing (likelihood ratio = 10.02; P = 0.002). Sensitivity and specificity of logMAR visual acuity in detecting optic neuropathy were 15% and 95%, respectively. CONCLUSIONS: Peripapillary RNFL thickness measured by SD-OCT provides adjunctive evidence for identifying optic neuropathy in patients with craniosynostosis and appears more sensitive at detecting optic atrophy than papilledema.

Lundgren P, Wilde Å, Löfqvist C, Smith LEH, Hård A-L, Hellström A. Weight at first detection of retinopathy of prematurity predicts disease severity. Br J Ophthalmol 2014;98(11):1565-9.Abstract
OBJECTIVE: To investigate whether postnatal weight at first detection of retinopathy of prematurity (ROP) can predict preterm infants who will develop severe ROP warranting treatment. DESIGN: This modern, population-based cohort included 147 infants born at gestational age (GA) <32 weeks in the Gothenburg region during 2011-2012 and screened for ROP at Sahlgrenska University hospital. GA, birth weight (BW), and weekly postnatal weight from birth until postmenstrual age (PMA) 40 weeks data were retrospectively retrieved. Birth weight SD scores (BWSDS) were calculated. ROP data, including first detected ROP stage, maximal ROP stage, ROP treatment, and PMA at first detected sign of ROP were also retrieved. Weight SDS (WSDS) at first ROP detection was calculated. RESULTS: Stepwise multivariate logistic regression analysis revealed that the best fit-model of risk factors for developing severe ROP warranting treatment included; GA (OR=0.28, CI 95% 0.12 to 0.66, p<0.01) and WSDS at first ROP detection (OR=0.22, CI 95% 0.05 to 0.89, p<0.05). CONCLUSIONS: Low weight and low WSDS at first ROP detection can be useful predictors for ROP warranting treatment.
Vodopivec I, Lobo A-M, Prasad S. Ocular inflammation in neurorheumatic disease. Semin Neurol 2014;34(4):444-57.Abstract

Neuroimmunologic and systemic rheumatic diseases are frequently accompanied by inflammation of the eye, ocular adnexa, and orbital tissues. An understanding of the diverse forms of ophthalmic pathology in these conditions aids the clinician in making appropriate preventative, diagnostic, therapeutic, and prognostic decisions. In this review, the authors address ocular inflammation in neurorheumatic disease in three sections: first, they highlight current perspectives on immune mechanisms in the development of these disorders; next, they provide a framework for the recognition and evaluation of ophthalmologic inflammatory entities; finally, they discuss in detail several inflammatory conditions that affect the nervous system and the eye, emphasizing the features that should alert neurologists to initiate ophthalmologic evaluation. The conditions discussed include multiple sclerosis, neuromyelitis optica, chronic relapsing inflammatory optic neuropathy, Susac syndrome, Cogan syndrome, acute posterior multifocal placoid pigment epitheliopathy, Vogt-Koyanagi-Harada disease, Behçet disease, sarcoidosis, systemic lupus erythematosus, granulomatosis with polyangiitis (Wegener granulomatosis), polyarteritis nodosa, giant cell arteritis, IgG4-related disease, and Sjögren syndrome.

Prabakaran S, Hemberg M, Chauhan R, Winter D, Tweedie-Cullen RY, Dittrich C, Hong E, Gunawardena J, Steen H, Kreiman G, Steen JA. Quantitative profiling of peptides from RNAs classified as noncoding. Nat Commun 2014;5:5429.Abstract

Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences--including introns and several classes of noncoding RNAs (ncRNAs)--do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here we use computational methods to identify the products of non-canonical translation in mouse neurons by analysing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from antisense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential.

Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term Effects of Therapy with Ranibizumab on Diabetic Retinopathy Severity and Baseline Risk Factors for Worsening Retinopathy. Ophthalmology 2014;Abstract

PURPOSE: To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR). DESIGN: Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials. PARTICIPANTS: Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness ≥275 μm. METHODS: Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan-Meier methods to calculate cumulative probabilities by group. MAIN OUTCOME MEASURES: Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR. RESULTS: At month 36, a greater proportion of ranibizumab-treated eyes had ≥2- or ≥3-step DR improvement compared with sham/0.5 mg crossover. A ≥3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively (P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy. CONCLUSIONS: Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti-vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion.

Davies EC, Jakobiec FA, Stagner AM, Iwamoto MA. A Rapidly Enlarging Recurrent Eyebrow Pilomatrixoma in a Nonagenarian. Ophthal Plast Reconstr Surg 2014;Abstract

A rapidly growing, large (horizontal diameter of 3.1 cm) eyebrow lesion in a nonagenarian patient was found on pathologic examination to demonstrate an admixture of islands of anucleated, washed out eosinophilic "ghost" cells with surrounding nucleated, small germinal basaloid cells. Further analysis disclosed adipophilin granular positivity in the necrotic zones, negative nuclear staining for androgen receptor and strong nuclear positivity for Ki67 in the basaloid cells (proliferation index of 50%). These findings are consistent with a highly mitotically active pilomatrixoma. The lesion recurred after initial resection but returned the same histopathologic features as the primary. Several clinical features were notably atypical for pilomatrixoma-specifically, the age of the patient, rapid lesion growth and recurrence, and clinical appearance and large size of the mass. The immunohistochemical findings can help to distinguish this tumor from other skin neoplasms, especially sebaceous carcinoma in an older individual.

Jakobiec FA, Rai R, Rashid A, Kanoff J, Mukai S. Dystrophic hyaloid artery remnants and other abnormalities in a buphthalmic eye with retinoblastoma. Surv Ophthalmol 2014;59(6):636-642.Abstract

Partial persistence of the hyaloid artery unaccompanied by hyperplastic primary vitreous has not been previously reported in association with retinoblastoma. We describe an 18-month-old child with such a finding who had a retinoblastoma that was undifferentiated, extensively necrotic, heavily calcified, and completely filled the eyeball. The enucleated globe harbored a nonperfused, fossilized remnant of the hyaloid artery due to DNA/calcium deposition in the vascular wall. This structure inserted into a lenticular, extracapsular, fibrous plaque corresponding to a Mittendorf dot. The tumor had induced a placoid cataractous lens, obliterated the anterior and posterior chambers, caused glaucoma leading to buphthalmos, and extended into the optic nerve and extraocularly to involve the orbit. We conclude that the retinoblastoma arose early in ocular morphogenesis, at around 4 months gestation, when the programmed involution of the hyaloid artery begins. This process would typically end at 7-8 months gestation, but was aborted by the tumor. The patient died 6 weeks after surgery without receiving further treatment because of the parents' resistance.

Liu Y, Garrett ME, Yaspan BL, Bailey JC, Loomis SJ, Brilliant M, Budenz DL, Christen WG, Fingert JH, Gaasterland D, Gaasterland T, Kang JH, Lee RK, Lichter P, Moroi SE, Realini A, Richards JE, Schuman JS, Scott WK, Singh K, Sit AJ, Vollrath D, Weinreb R, Wollstein G, Zack DJ, Zhang K, Pericak-Vance MA, Haines JL, Pasquale LR, Wiggs JL, Allingham RR, Ashley-Koch AE, Hauser MA. DNA copy number variants of known glaucoma genes in relation to primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2014;55(12):8251-8.Abstract

PURPOSE: We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG). METHODS: Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC. RESULTS: Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls. CONCLUSIONS: The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.

Cronin T, Vandenberghe LH, Hantz P, Juttner J, Reimann A, Kacsó A-E, Huckfeldt RM, Busskamp V, Kohler H, Lagali PS, Roska B, Bennett J. Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med 2014;6(9):1175-90.Abstract

In this report, we describe the development of a modified adeno-associated virus (AAV) capsid and promoter for transduction of retinal ON-bipolar cells. The bipolar cells, which are post-synaptic to the photoreceptors, are important retinal targets for both basic and preclinical research. In particular, a therapeutic strategy under investigation for advanced forms of blindness involves using optogenetic molecules to render ON-bipolar cells light-sensitive. Currently, delivery of adequate levels of gene expression is a limiting step for this approach. The synthetic AAV capsid and promoter described here achieves high level of optogenetic transgene expression in ON-bipolar cells. This evokes high-frequency (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use.

Swaminathan SS, Oh D-J, Kang MH, Rhee DJ. Aqueous outflow: segmental and distal flow. J Cataract Refract Surg 2014;40(8):1263-72.Abstract
UNLABELLED: The elevated intraocular pressure (IOP) of primary open-angle glaucoma is caused by impaired outflow of aqueous humor through the trabecular meshwork. Within the juxtacanalicular region, alterations of both extracellular matrix homeostasis and the cellular tone of trabecular meshwork endothelial and the inner wall of Schlemm canal cells affect outflow. Newer pharmacologic agents that target trabecular meshwork and Schlemm canal cell cytoskeleton lower IOP. Aqueous drainage occurs nonhomogenously with greater flow going through certain portions of the TM and less going through other portions-a concept known as segmental flow, which is theoretically the result of outflow being dependent on the presence of discrete pores within Schlemm canal. The limited long-term success of trabecular meshwork bypass surgeries implicates the potential impact of resistance in Schlemm canal itself and collector channels. Additionally, others have observed that outflow occurs preferentially near collector channels. These distal structures may be more important to aqueous outflow than previously believed. FINANCIAL DISCLOSURE: Dr. Rhee is a consultant to Aerie Pharmaceuticals, Alcon Laboratories, Inc., Allegan, Inc., Aquesys, Inc., Glaukos Corp., Ivantis, Inc., Johnson & Johnson, Merck Sharp & Dohme Corp. and Santen, Inc., and has received research funding from Alcon Laboratories, Inc., Merck Sharp & Dohme Corp., and Ivantis, Inc. No other author has a financial or proprietary interest in any material or method mentioned.
Rezende FA, Lapalme E, Qian CX, Smith LE, SanGiovanni JP, Sapieha P. Omega-3 supplementation combined with anti-vascular endothelial growth factor lowers vitreal levels of vascular endothelial growth factor in wet age-related macular degeneration. Am J Ophthalmol 2014;158(5):1071-1078.e1.Abstract
PURPOSE: To determine the influence of omega-3 supplementation on vitreous vascular endothelial growth factor A (VEGF-A) levels in patients with exudative age-related macular degeneration (wet AMD) receiving intravitreal anti-VEGF treatment. DESIGN: Prospective, randomized, open-label, single-center, clinical trial, consecutive interventional case series. METHODS: The study included 3 cohorts with wet AMD and a control group with epiretinal membrane or macular hole. Twenty wet AMD patients being treated with anti-VEGF were randomized to daily supplementation of antioxidants, zinc, and carotenoids with omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid; group 1, n = 10) or without omega-3 fatty acids (group 2, n = 10). They were compared with an anti-VEGF treatment-naïve wet AMD group (group 3, n = 10) and an epiretinal membrane or macular hole group (group 4, n = 10). Primary outcome was vitreal VEGF-A levels (at the time of anti-VEGF injection). Secondary outcomes were plasma VEGF-A and central foveal thickness. Patients with new submacular hemorrhage or any other treatment within 3 months were excluded. Final analyses included 9, 6, 7, and 8 patients in groups 1 through 4, respectively. RESULTS: Patients receiving omega-3s (group 1) had significantly lower levels of vitreal VEGF-A (141.11 ± 61.89 pg/mL) when compared with group 2 (626.09 ± 279.27 pg/mL; P = .036) and group 3 (735.48 ± 216.43 pg/mL; P = .013), but similar levels to group 4 (235.81 ± 33.99 pg/mL; P = .215). All groups showed similar values for plasma VEGF-A and central foveal thickness measurements. CONCLUSIONS: This study demonstrated that omega-3 supplementation combined with anti-VEGF treatment is associated with decreased vitreal VEGF-A levels in wet AMD patients.

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