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Ying Y, Ueta T, Jiang S, Lin H, Wang Y, Vavvas D, Wen R, Chen Y-G, Luo Z. Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. Oncotarget 2017;8(20):32794-32806.Abstract
Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.
Phanphruk W, Alkharashi M, Bilge A, Hunter DG. Sedated suture adjustment in children undergoing adjustable-suture strabismus surgery. J AAPOS 2017;Abstract
PURPOSE: To study methods and adverse events of postoperative, sedated suture adjustment after strabismus surgery in the post-anesthesia care unit (PACU). METHODS: We reviewed the postoperative experience of all children ≤18 years of age undergoing adjustable suture strabismus surgery at Boston Children's Hospital over a 3-year period. Time in the hospital, adverse events, and surgical outcomes were reviewed to evaluate safety and healthcare resource utilization. RESULTS: Of 356 patients, 113 required suture adjustment in the PACU, including 24 adjusted while awake and 89 adjusted under sedation. For sedation, sequential boluses of propofol were administered until adjustment was complete. Complete data from the sedated adjustment was available in 76 patients. The median initial bolus was 30 mg; the median total propofol rate was 273 mcg/kg/min. Twelve patients (16%) required only a single bolus of propofol. Of remaining 64 patients, median time from initial to final propofol dose was 7 minutes. Median anesthesiologist time in the PACU was 13 minutes. In the sedated adjustment group, there were no clinically significant adverse events, and the pain score never exceeded 6 (of a possible 10). Median duration of PACU stay was shortest in the group not requiring adjustment. CONCLUSIONS: Sedated suture adjustment allows for fine-tuning of postoperative binocular alignment in children and uncooperative adults. No adverse events were observed in our study group, but the procedure does increase the time patients spend in the hospital. This work will inform disclosure of risks and benefits of sedated adjustment while allowing for more accurate assessment of the cost and quality of adjustable sutures in children.
Satitpitakul V, Kheirkhah A, Crnej A, Hamrah P, Dana R. Determinants of Ocular Pain Severity in Patients With Dry Eye Disease. Am J Ophthalmol 2017;179:198-204.Abstract
PURPOSE: To quantify the severity of ocular pain in patients with dry eye disease (DED) and evaluate factors associated with pain severity. DESIGN: Cross-sectional study. METHODS: Eighty-four patients with DED were asked to score their severity level of ocular pain using a 10-point scale, with 10 indicating the most severe pain. All patients also had a comprehensive ophthalmic assessment including a detailed history, Ocular Surface Disease Index (OSDI) questionnaire, and ocular surface examination. Regression analysis was used to determine the factors associated with ocular pain severity. RESULTS: The mean OSDI score was 45.6 ± 23.1. At least some degree of ocular pain (score >1) was reported by 88.1% of patients, including mild pain (scores 2-4) in 46.4%, moderate pain (scores 5-7) in 34.5%, and severe pain (scores 8-10) in 7.1% of patients. Ocular pain levels significantly correlated with the OSDI score (rs = 0.49, P < .001). Regression analysis showed that the severity of ocular pain had a significant association with use of antidepressant medications (P = .045) but not with tear breakup time, corneal fluorescein staining, or ocular medications used by patients. In patients without pain, a significant correlation was seen between OSDI and corneal fluorescein staining scores (rs = 0.67, P = .01). However, such a correlation was not observed in those with ocular pain. CONCLUSIONS: A majority of patients with DED report some degree of ocular pain, which correlates only moderately with the OSDI score. Severity of ocular pain correlates with nonocular comorbidities such as use of antidepressant medications rather than with clinical signs of DED.
Lonfat N, Cepko C. Epigenomics of Retinal Development in Mice and Humans. Neuron 2017;94(3):420-423.Abstract
In this issue of Neuron, Aldiri et al. (2017) present an analysis of epigenetic changes during retinal development, and use these data to probe reprogramming of retinal iPSC cells, as well as the origin of retinoblastoma cells.
Sun Y, Lin Z, Liu C-H, Gong Y, Liegl R, Fredrick TW, Meng SS, Burnim SB, Wang Z, Akula JD, Pu WT, Chen J, Smith LEH. Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos. J Exp Med 2017;214(6):1753-1767.Abstract
Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor-deficient (Vldlr(-/-) ) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα-induced protein 3 (TNFAIP3) in Vldlr(-/-) photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)-activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)-sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr(-/-) mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal-induced STAT3/VEGFA pathway.
Omoto M, Suri K, Amouzegar A, Li M, Katikireddy KR, Mittal SK, Chauhan SK. Hepatocyte Growth Factor Suppresses Inflammation and Promotes Epithelium Repair in Corneal Injury. Mol Ther 2017;25(8):1881-1888.Abstract
Corneal injuries are among the major causes of ocular morbidity and vision impairment. Optimal epithelial wound healing is critical for the integrity and transparency of the cornea after injury. Hepatocyte growth factor (HGF) is a mitogen and motility factor that primarily regulates epithelial cell function. Herein, we investigate the effect of HGF on proliferation of corneal epithelial cells (CECs) in inflamed conditions both in vitro and in vivo. We demonstrate that HGF not only promotes CEC proliferation in homeostatic conditions but also reverses the anti-proliferative effect of the inflammatory environment on these cells. Furthermore, using a mouse model of ocular injury, we show that HGF treatment suppresses ocular inflammation and actively augments CEC proliferation, leading to improved and accelerated corneal epithelial repair. These findings have potential translational implications and could provide a framework for the development of novel HGF-based therapies for corneal epithelial defects.
Saint-Geniez M, Rosales MAB. Eyeing the Fountain of Youth. Cell Stem Cell 2017;20(5):583-584.Abstract
Stem cell-based disease modeling is an emerging technology for the mechanistic study and therapeutic screening of complex ocular pathologies. In this issue of Cell Stem Cell, Saini et al. (2017) show that iPSC-derived RPE cells from age-related macular degeneration patients express increased levels of pro-inflammatory factors that can be normalized by the anti-aging drug nicotinamide.
Olivares AM, Han Y, Soto D, Flattery K, Marini J, Molemma N, Haider A, Escher P, Deangelis MM, Haider NB. The nuclear hormone receptor gene Nr2c1 (Tr2) is a critical regulator of early retina cell patterning. Dev Biol 2017;429(1):343-355.Abstract
Nuclear hormone receptors play a major role in the development of many tissues. This study uncovers a novel role for testicular receptor 2 (Tr2, Nr2c1) in defining the early phase of retinal development and regulating normal retinal cell patterning and topography. The mammalian retina undergoes an overlapping yet biphasic period of development to generate all seven retinal cell types. We discovered that Nr2c1 expression coincides with development of the early retinal cells. Loss of Nr2c1 causes a severe vision deficit and impacts early, but not late retina cell types. Retinal cone cell topography is disrupted with an increase in displaced amacrine cells. Additionally, genetic background significantly impacts phenotypic outcome of cone photoreceptor cells but not amacrine cells. Chromatin-IP experiments reveal NR2C1 regulates early cell transcription factors that regulate retinal progenitor cells during development, including amacrine (Satb2) and cone photoreceptor regulators thyroid and retinoic acid receptors. This study supports a role for Nr2c1 in defining the biphasic period of retinal development and specifically influencing the early phase of retinal cell fate.
Laíns I, Duarte D, Barros AS, Martins AS, Gil J, Miller JB, Marques M, Mesquita T, Kim IK, da Cachulo ML, Vavvas D, Carreira IM, Murta JN, Silva R, Miller JW, Husain D, Gil AM. Human plasma metabolomics in age-related macular degeneration (AMD) using nuclear magnetic resonance spectroscopy. PLoS One 2017;12(5):e0177749.Abstract
PURPOSE: To differentiate the plasma metabolomic profile of patients with age related macular degeneration (AMD) from that of controls, by Nuclear Magnetic Resonance (NMR) spectroscopy. METHODS: Two cohorts (total of 396 subjects) representative of central Portugal and Boston, USA phenotypes were studied. For each cohort, subjects were grouped according to AMD stage (early, intermediate and late). Multivariate analysis of plasma NMR spectra was performed, followed by signal integration and univariate analysis. RESULTS: Small changes were detected in the levels of some amino acids, organic acids, dimethyl sulfone and specific lipid moieties, thus providing some biochemical information on the disease. The possible confounding effects of gender, smoking history and age were assessed in each cohort and found to be minimal when compared to that of the disease. A similar observation was noted in relation to age-related comorbidities. Furthermore, partially distinct putative AMD metabolite fingerprints were noted for the two cohorts studied, reflecting the importance of nutritional and other lifestyle habits in determining AMD metabolic response and potential biomarker fingerprints. Notably, some of the metabolite changes detected were noted as potentially differentiating controls from patients diagnosed with early AMD. CONCLUSION: For the first time, this study showed metabolite changes in the plasma of patients with AMD as compared to controls, using NMR. Geographical origins were seen to affect AMD patients´ metabolic profile and some metabolites were found to be valuable in potentially differentiating controls from early stage AMD patients. Metabolomics has the potential of identifying biomarkers for AMD, and further work in this area is warranted.
Ibberson CB, Stacy A, Fleming D, Dees JL, Rumbaugh K, Gilmore MS, Whiteley M. Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nat Microbiol 2017;2:17079.Abstract
Identifying genes required by pathogens during infection is critical for antimicrobial development. Here, we use a Monte Carlo simulation-based method to analyse high-throughput transposon sequencing data to determine the role of infection site and co-infecting microorganisms on the in vivo 'essential' genome of Staphylococcus aureus. We discovered that co-infection of murine surgical wounds with Pseudomonas aeruginosa results in conversion of ∼25% of the in vivo S. aureus mono-culture essential genes to non-essential. Furthermore, 182 S. aureus genes are uniquely essential during co-infection. These 'community dependent essential' (CoDE) genes illustrate the importance of studying pathogen gene essentiality in polymicrobial communities.
Kheirkhah A, Crnej A, Ren A, Mullins A, Satitpitakul V, Hamrah P, Schaumberg D, Dana R. Patients' Perceived Treatment Effectiveness in Dry Eye Disease. Cornea 2017;36(8):893-897.Abstract
PURPOSE: Patients' perceptions of the effectiveness of a treatment, or perceived treatment effectiveness (PTE), play an important role in medicine. This study aimed to evaluate patients' PTE in dry eye disease (DED) and investigate factors contributing to these patients' perceptions. METHODS: This cross-sectional study included 66 patients with DED. At enrollment, all patients had comprehensive ophthalmic assessment. In addition, to evaluate the patient's PTE, they were asked to use a 10-point scale ranging from "strongly disagree (score 1)" to "strongly agree (score 10)" to score their views on whether their DED treatments had been effective. Changes in clinical parameters of DED over time during their care were also evaluated retrospectively and correlated with the patients' PTE. RESULTS: The mean age of patients was 55.7 years; 79% were women. Regarding patients' PTE, 36.4% strongly (score 10) and 53.0% moderately (scores 6-9) believed that their DED treatment had been effective. However, 10.6% thought that their treatment had not been effective (scores 1-5). Less favorable PTE for the DED treatment was significantly associated with a younger age (P < 0.001), current use of antidepressant medications (P = 0.01), and a higher Ocular Surface Disease Index score (P = 0.01) at enrollment. CONCLUSIONS: A majority of patients with DED have positive perceptions regarding the effectiveness of their treatments. Less favorable perceptions are associated with more severe ocular symptoms and nonocular parameters such as younger age and current antidepressant use. In DED management, assessing patients' PTE should be considered as an important part of clinical practice.
Laíns I, Miller JB, Park DH, Tsikata E, Davoudi S, Rahmani S, Pierce J, Silva R, Chen TC, Kim IK, Vavvas D, Miller JW, Husain D. Structural Changes Associated with Delayed Dark Adaptation in Age-Related Macular Degeneration. Ophthalmology 2017;124(9):1340-1352.Abstract
PURPOSE: To examine the relationship between dark adaptation (DA) and optical coherence tomography (OCT)-based macular morphology in age-related macular degeneration (AMD). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with AMD and a comparison group (>50 years) without any vitreoretinal disease. METHODS: All participants were imaged with spectral-domain OCT and color fundus photographs, and then staged for AMD (Age-related Eye Disease Study system). Both eyes were tested with the AdaptDx (MacuLogix, Middletown, PA) DA extended protocol (20 minutes). A software program was developed to map the DA testing spot (2° circle, 5° superior to the fovea) to the OCT B-scans. Two independent graders evaluated the B-scans within this testing spot, as well as the entire macula, recording the presence of several AMD-associated abnormalities. Multilevel mixed-effects models (accounting for correlated outcomes between 2 eyes) were used for analyses. MAIN OUTCOME MEASURES: The primary outcome was rod-intercept time (RIT), defined in minutes, as a continuous variable. For subjects unable to reach RIT within the 20 minutes of testing, the value of 20 was assigned. RESULTS: We included 137 eyes (n = 77 subjects), 72.3% (n = 99 eyes) with AMD and the remainder belonging to the comparison group. Multivariable analysis revealed that even after adjusting for age and AMD stage, the presence of any abnormalities within the DA testing spot (ß = 4.8, P < 0.001), as well as any abnormalities in the macula (ß = 2.4, P = 0.047), were significantly associated with delayed RITs and therefore impaired DA. In eyes with no structural changes within the DA testing spot (n = 76, 55.5%), the presence of any abnormalities in the remaining macula was still associated with delayed RITs (ß = 2.00, P = 0.046). Presence of subretinal drusenoid deposits and ellipsoid zone disruption were a consistent predictor of RIT, whether located within the DA testing spot (P = 0.001 for both) or anywhere in the macula (P < 0.001 for both). Within the testing spot, the presence of classic drusen or serous pigment epithelium detachment was also significantly associated with impairments in DA (P ≤ 0.018). CONCLUSIONS: Our results suggest a significant association between macular morphology evaluated by OCT and time to dark-adapt. Subretinal drusenoid deposits and ellipsoid zone changes seem to be strongly associated with impaired dark adaptation.
Gong Y, Fu Z, Liegl R, Chen J, Hellström A, Smith LEH. ω-3 and ω-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr 2017;106(1):16-26.Abstract
Neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, threaten the visual health of children and adults. Current treatment options, including anti-vascular endothelial growth factor therapy and laser retinal photocoagulation, have limitations and are associated with adverse effects; therefore, the identification of additional therapies is highly desirable. Both clinical and experimental studies show that dietary ω-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) reduce retinal and choroidal angiogenesis. The ω-3 LC-PUFA metabolites from 2 groups of enzymes, cyclooxygenases and lipoxygenases, inhibit [and the ω-6 (n-6) LC-PUFA metabolites promote] inflammation and angiogenesis. However, both of the ω-3 and the ω-6 lipid products of cytochrome P450 oxidase 2C promote neovascularization in both the retina and choroid, which suggests that inhibition of this pathway might be beneficial. This review summarizes our current understanding of the roles of ω-3 and ω-6 LC-PUFAs and their enzymatic metabolites in neovascular eye diseases.
Lebreton F, Manson AL, Saavedra JT, Straub TJ, Earl AM, Gilmore MS. Tracing the Enterococci from Paleozoic Origins to the Hospital. Cell 2017;169(5):849-861.e13.Abstract
We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425-500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.

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