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Barhoumi A, Salvador-Culla B, Kohane DS. Nonlinear Optics: NIR-Triggered Drug Delivery by Collagen-Mediated Second Harmonic Generation (Adv. Healthcare Mater. 8/2015). Adv Healthc Mater 2015;4(8):1108.Abstract

In the study presented by D. S. Kohane and co-workers on page 1159, fluorescein molecules are initially bound to collagen fibers through UV-sensitive bonds. Collagen fibers are exposed to NIR light, which is upconverted to UV light through second harmonic generation. The UV-sensitive bonds absorb the upconverted UV light and undergo an irreversible cleavage releasing the fluorescein molecules.

Conde P, Rodriguez M, van der Touw W, Jimenez A, Burns M, Miller J, Brahmachary M, Chen H-M, Boros P, Rausell-Palamos F, Yun TJ, Riquelme P, Rastrojo A, Aguado B, Stein-Streilein J, Tanaka M, Zhou L, Zhang J, Lowary TL, Ginhoux F, Park CG, Cheong C, Brody J, Turley SJ, Lira SA, Bronte V, Gordon S, Heeger PS, Merad M, Hutchinson J, Chen S-H, Ochando J. DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity 2015;42(6):1143-58.Abstract

Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.

García-Pérez MA, Peli E. Aniseikonia Tests: The Role of Viewing Mode, Response Bias, and Size-Color Illusions. Transl Vis Sci Technol 2015;4(3):9.Abstract

PURPOSE: To identify the factors responsible for the poor validity of the most common aniseikonia tests, which involve size comparisons of red-green stimuli presented haploscopically. METHODS: Aniseikonia was induced by afocal size lenses placed before one eye. Observers compared the sizes of semicircles presented haploscopically via color filters. The main factor under study was viewing mode (free viewing versus short presentations under central fixation). To eliminate response bias, a three-response format allowed observers to respond if the left, the right, or neither semicircle appeared larger than the other. To control decisional (criterion) bias, measurements were taken with the lens-magnified stimulus placed on the left and on the right. To control for size-color illusions, measurements were made with color filters in both arrangements before the eyes and under binocular vision (without color filters). RESULTS: Free viewing resulted in a systematic underestimation of lens-induced aniseikonia that was absent with short presentations. Significant size-color illusions and decisional biases were found that would be mistaken for aniseikonia unless appropriate action is taken. CONCLUSIONS: To improve their validity, aniseikonia tests should use short presentations and include control conditions to prevent contamination from decisional/response biases. If anaglyphs are used, presence of size-color illusions must be checked for. TRANSLATIONAL RELEVANCE: We identified optimal conditions for administration of aniseikonia tests and appropriate action for differential diagnosis of aniseikonia in the presence of response biases or size-color illusions. Our study has clinical implications for aniseikonia management.

Grob SR, Campbell AA, Gross A, Cestari DM. Hemorrhage Within the Optic Nerve From a Cavernous Hemangioma of the Optic Disc. J Neuroophthalmol 2015;35(3):277-9.Abstract

A 49-year-old woman with a known right optic disc cavernous hemangioma experienced pain with eye movements and worsening of a superior visual field defect. While she retained 20/20 visual acuity in each eye, findings on magnetic resonance imaging were consistent with a hemorrhage in the anterior portion of the right intraorbital optic nerve. Her visual function stabilized spontaneously. We are unaware of previous reports of hemorrhage into the optic nerve from a cavernous hemangioma of the optic disc.

Rajaiya J, Zhou X, Barequet I, Gilmore MS, Chodosh J. Novel model of innate immunity in corneal infection. In Vitro Cell Dev Biol Anim 2015;Abstract

The cornea functions as the major refractive interface for vision and protects the internal eye from insult. Current understanding of innate immune responses to corneal infection derives from a synthesis of in vitro and in vivo analyses. However, monolayer cell cultures and mouse models do not accurately duplicate all aspects of innate immunity in human patients. Here, we describe a three-dimensional culture system that incorporates human cells and extracellular matrix to more completely simulate the human cornea for studies of infection. Human corneal stromal fibroblasts were mixed with type I collagen in 3-μm pore size transwell inserts, and overlayed with Matrigel to simulate a human corneal stroma and epithelial basement membrane. These were then infected with a cornea-tropic adenovirus, and exposed on their inferior side to leukocytes derived from human peripheral blood. Subsequent analyses were performed with histology, confocal microscopy, ELISA, and fluorescence-activated cell sorting (FACS). CXCL8, a neutrophil chemokine shown previously as the first cytokine induced in infection of human corneal cells, increased upon adenovirus infection of facsimiles in a dose-responsive fashion. Myeloperoxidase-positive cells infiltrated infected corneal facsimiles in a sub-Matrigel location, possibly due to CXCL8 colocalization with heparan sulfate, a Matrigel constituent. Cellular infiltration was significantly inhibited by treatment with chemical inhibitors of p38 MAPK and Src kinase, both constituents of a signaling cascade previously suggested to regulate inflammation after adenovirus infection. FACS analysis determined that both virus and corneal fibroblasts were necessary for the induction of leukocyte migration into the facsimiles. The corneal facsimile, literally a cornea in a test tube, permits mechanistic studies on human tissue in a highly tractable system.

de Almeida LM, Pires C, Cerdeira LT, de Oliveira TGM, McCulloch JA, Perez-Chaparro PJ, Sacramento AG, Brito AC, da Silva JL, de Araújo MRE, Lincopan N, Martin MJ, Gilmore MS, Mamizuka EM. Complete Genome Sequence of Linezolid-Susceptible Staphylococcus haemolyticus Sh29/312/L2, a Clonal Derivative of a Linezolid-Resistant Clinical Strain. Genome Announc 2015;3(3)Abstract

We report the whole-genome sequence (WGS) of an in vitro susceptible derivative revertant mutant from a bloodstream isolate involved in a nosocomial outbreak in Brazil. The WGS comprises 2.5 Mb with 2,500 protein-coding sequences, 16rRNA genes, and 60 tRNA genes.

Yu D, Zheng J, Zhu R, Wu N, Guan A, Cho K-S, Chen DF, Luo G. Computer-aided analyses of mouse retinal OCT images - an actual application report. Ophthalmic Physiol Opt 2015;35(4):442-9.Abstract

PURPOSE: There is a need for automated retinal optical coherence tomography (OCT) image analysis tools for quantitative measurements in small animals. Some image processing techniques for retinal layer analysis have been developed, but reports about how useful those techniques are in actual animal studies are rare. This paper presents the use of a retinal layer detection method we developed in an actual mouse study that involves wild type and mutated mice carrying photoreceptor degeneration. METHODS: Spectral domain OCT scanning was performed by four experimenters over 12 months on 45 mouse eyes that were wild-type, deficient for ephrin-A2 and ephrin-A3, deficient for rhodopsin, or deficient for rhodopsin, ephrin-A2 and ephrin-A3. The thickness of photoreceptor complex between the outer plexiform layer and retinal pigment epithelium was measured on two sides of the optic disc as the biomarker of retinal degeneration. All the layer detection results were visually confirmed. RESULTS: Overall, 96% (8519 out of 9000) of the half-side images were successfully processed using our technique in a semi-automatic manner. There was no significant difference in success rate between mouse lines (p = 0.91). Based on a human observer's rating of image quality for images successfully and unsuccessfully processed, the odds ratios for 'easily visible' images and 'not clear' images to be successfully processed is 62 and 4, respectively, against 'indistinguishable' images. Thickness of photoreceptor complex was significantly different across the quadrants compared (p < 0.001). It was also found that the average thickness based on 4-point sparse sampling was not significantly different from the full analysis, while the range of differences between the two methods could be up to about 6 μm or 16% for individual eyes. Differences between mouse lines and progressive thickness reduction were revealed by both sampling measures. CONCLUSIONS: Although the thickness of the photoreceptor complex layer is not even, manual sparse sampling may be as sufficiently accurate as full analysis in some studies such as ours, where the error of sparse sampling was much smaller than the effect size of rhodopsin deficiency. It is also suggested that the image processing method can be useful in actual animal studies. Even for images poorly visible to human eyes the image processing method still has a good chance to extract the complex layer.

Aiello LP, Ayala AR, Antoszyk AN, Arnold-Bush B, Baker C, Bressler NM, Elman MJ, Glassman AR, Jampol LM, Melia M, Nielsen J, Wolpert HA, Wolpert HA. Assessing the Effect of Personalized Diabetes Risk Assessments During Ophthalmologic Visits on Glycemic Control: A Randomized Clinical Trial. JAMA Ophthalmol 2015;133(8):888-96.Abstract

IMPORTANCE: Optimization of glycemic control is critical to reduce the number of diabetes mellitus-related complications, but long-term success is challenging. Although vision loss is among the greatest fears of individuals with diabetes, comprehensive personalized diabetes education and risk assessments are not consistently used in ophthalmologic settings. OBJECTIVE: To determine whether the point-of-care measurement of hemoglobin A1c (HbA1c) and personalized diabetes risk assessments performed during retinal ophthalmologic visits improve glycemic control as assessed by HbA1c level. DESIGN, SETTING, AND PARTICIPANTS: Ophthalmologist office-based randomized, multicenter clinical trial in which investigators from 42 sites were randomly assigned to provide either a study-prescribed augmented diabetes assessment and education or the usual care. Adults with type 1 or 2 diabetes enrolled into 2 cohorts: those with a more-frequent-than-annual follow-up (502 control participants and 488 intervention participants) and those with an annual follow-up (368 control participants and 388 intervention participants). Enrollment was from April 2011 through January 2013. INTERVENTIONS: Point-of-care measurements of HbA1c, blood pressure, and retinopathy severity; an individualized estimate of the risk of retinopathy progression derived from the findings from ophthalmologic visits; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant's understanding. These interventions were performed at enrollment and at routine ophthalmic follow-up visits scheduled at least 12 weeks apart. MAIN OUTCOMES AND MEASURES: Mean change in HbA1c level from baseline to 1-year follow-up. Secondary outcomes included body mass index, blood pressure, and responses to diabetes self-management practices and attitudes surveys. RESULTS: In the cohort with more-frequent-than-annual follow-ups, the mean (SD) change in HbA1c level at 1 year was -0.1% (1.5%) in the control group and -0.3% (1.4%) in the intervention group (adjusted mean difference, -0.09% [95% CI, -0.29% to 0.12%]; P = .35). In the cohort with annual follow-ups, the mean (SD) change in HbA1c level was 0.0% (1.1%) in the control group and -0.1% (1.6%) in the intervention group (mean difference, -0.05% [95% CI, -0.27% to 0.18%]; P = .63). Results were similar for all secondary outcomes. CONCLUSIONS AND RELEVANCE: Long-term optimization of glycemic control is not achieved by a majority of individuals with diabetes. The addition of personalized education and risk assessment during retinal ophthalmologic visits did not result in a reduction in HbA1c level compared with usual care over 1 year. These data suggest that optimizing glycemic control remains a substantive challenge requiring interventional paradigms other than those examined in our study. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01323348.

Huang T, Zheng Y, Qi Q, Xu M, Ley SH, Li Y, Kang JH, Wiggs J, Pasquale LR, Chan AT, Rimm EB, Hunter DJ, Manson JAE, Willett WC, Hu FB, Qi L. DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts. Diabetes 2015;64(9):3146-54.Abstract

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity.

Lee H-S, Hos D, Blanco T, Bock F, Reyes NJ, Mathew R, Cursiefen C, Dana R, Saban DR. Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. Invest Ophthalmol Vis Sci 2015;56(5):3140-8.Abstract

PURPOSE: The contribution of lymphangiogenesis (LA) to allergy has received considerable attention and therapeutic inhibition of this process via targeting VEGF has been considered. Likewise, certain inflammatory settings affecting the ocular mucosa can trigger pathogenic LA in the naturally avascular cornea. Chronic inflammation in allergic eye disease (AED) impacts the conjunctiva and cornea, leading to sight threatening conditions. However, whether corneal LA is involved is completely unknown. We addressed this using a validated mouse model of AED. METHODS: Allergic eye disease was induced by ovalbumin (OVA) immunization and chronic OVA exposure. Confocal microscopy of LYVE-1-stained cornea allowed evaluation of corneal LA, and qRT-PCR was used to evaluate expression of VEGF-C, -D, and -R3 in these mice. Administration of VEGF receptor (R) inhibitor was incorporated to inhibit corneal LA in AED. Immune responses were evaluated by in vitro OVA recall responses of T cells, and IgE levels in the serum. RESULTS: Confocal microscopy of LYVE-1-stained cornea revealed the distinct presence of corneal LA in AED, and corroborated by increased corneal expression of VEGF-C, -D, and -R3. Importantly, prevention of corneal LA in AED via VEGFR inhibition was associated with decreased T helper two responses and IgE production. Furthermore, VEGFR inhibition led a significant reduction in clinical signs of AED. CONCLUSIONS: Collectively, these data reveal that there is a distinct involvement of corneal LA in AED. Furthermore, VEGFR inhibition prevents corneal LA and consequent immune responses in AED.

Robert M-C, Khreim N, Todani A, Melki SA. Anterior chamber gas bubble emergence pattern during femtosecond LASIK-flap creation. Br J Ophthalmol 2015;99(9):1201-5.Abstract

AIM: To characterise the emergence pattern of cavitation bubbles into the anterior chamber (AC) following femtosecond laser-assisted in situ keratomileusis (LASIK)-flap creation METHODS: Retrospective review of patients undergoing femtosecond LASIK surgery at Boston Laser, a private refractive surgery practice in Boston, Massachusetts, between December 2008 and February 2014. Patient charts were reviewed to identify all cases with gas bubble migration into the AC. Surgical videos were examined and the location of bubble entry was recorded separately for right and left eyes. RESULTS: Five thousand one hundred and fifty-eight patients underwent femtosecond LASIK surgery. Air bubble migration into the AC, presumably via the Schlemm's canal and trabecular meshwork, occurred in 1% of cases. Patients with AC bubbles had an average age of 33±8 years with a measured LASIK flap thickness of 96±21 μm. The occurrence of gas bubbles impaired iris registration in 64% of cases. Gas bubbles appeared preferentially in the nasal or inferior quadrants for right (92% of cases) and left (100% of cases) eyes. This bubble emergence pattern is significantly different from that expected with a random distribution (p<0.0001) and did not seem associated with decentration of the femtosecond laser docking system. CONCLUSIONS: The migration of gas bubbles into the AC is a rare occurrence during femtosecond laser flap creation. The preferential emergence of gas bubbles into the nasal and inferior quadrants of the AC may indicate a distinctive anatomy of the nasal Schlemm's canal.

Kita T, Clermont AC, Murugesan N, Zhou Q, Fujisawa K, Ishibashi T, Aiello LP, Feener EP. Plasma Kallikrein-Kinin System as a VEGF-Independent Mediator of Diabetic Macular Edema. Diabetes 2015;64(10):3588-99.Abstract

This study characterizes the kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma prekallikrein (PPK) and plasma kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.

Ciolino JB, McLaurin EB, Marsico NP, Ackerman SL, Williams JM, Villanueva L, Hollander DA. Effect of alcaftadine 0.25% on ocular itch associated with seasonal or perennial allergic conjunctivitis: a pooled analysis of two multicenter randomized clinical trials. Clin Ophthalmol 2015;9:765-72.Abstract

PURPOSE: Seasonal and perennial allergic conjunctivitis represent the majority of cases of ocular allergy. This analysis was designed to evaluate the efficacy and safety of once-daily alcaftadine 0.25% in preventing ocular itching associated with seasonal or perennial allergic conjunctivitis. SUBJECTS AND METHODS: Pooled data from two double-masked, multicenter, placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis were analyzed. Subjects randomized to receive treatment with alcaftadine 0.25% or placebo were challenged with seasonal (grass, ragweed, trees) or perennial (cat dander, cat hair, dog dander, dust mites, cockroach) allergens, 16 hours after treatment instillation. The primary efficacy measure was subject-evaluated mean ocular itching at 3 minutes post-CAC. Secondary measures included ocular itching at 5 and 7 minutes post-CAC. The proportion of subjects with minimal itch (itch score <1) and zero itch (itch score =0), and safety were also assessed. RESULTS: A total of 189 subjects enrolled in the two studies were treated with alcaftadine or placebo. Overall, 129 subjects were challenged with seasonal allergens and 60 subjects were challenged with perennial allergens. Alcaftadine 0.25% achieved a statistically significant reduction in mean itch score at 3, 5, and 7 minutes post-CAC compared with placebo in subjects challenged with seasonal allergens (P<0.0001 at all time points) and those challenged with perennial allergens (P<0.0001 at all time points). A higher percentage of subjects treated with alcaftadine compared with placebo achieved minimal itch (P≤0.001 versus placebo at all time points) and zero itch (P<0.05 at all time points except 7 minutes for perennial) when challenged with either seasonal or perennial allergens. No treatment-related or serious adverse events were reported. CONCLUSION: Once-daily alcaftadine 0.25% ophthalmic solution was well tolerated and demonstrated effective relief of ocular itching in subjects challenged with allergens classic for triggering either seasonal or perennial allergic conjunctivitis.

Stagner AM, Jakobiec FA. Demonstration of a Borst-Jadassohn-Like Phenomenon in Sebaceous Carcinoma of the Eyelid. Ophthal Plast Reconstr Surg 2015;Abstract

A 77-year-old male presented with a diffuse, papular erythematous conjunctival mass that demonstrated on pathologic examination lobules of tumor in the conjunctival substantia propria and tarsus. The cells displayed numerous cytoplasmic vacuoles with extreme nuclear pleomorphism, consistent with sebaceous carcinoma. The overlying palpebral conjunctival epithelium exhibited regions of carcinoma in situ containing some vacuolated cells, alternating with a more classical appearance of pagetoid spread among normal surviving keratinocytes. Further analysis disclosed vesicular positivity for adipophilin and positive nuclear staining for androgen receptor. One tumor focus harbored exaggerated collections of intraepithelial tumor cells. These simulated the Borst-Jadassohn phenomenon of large nests of alien appearing cells normally encountered within the epidermis of the skin. This is the first description of this pattern created by an eyelid sebaceous carcinoma growing within the conjunctival epithelium.

Gilmore MS, Rauch M, Ramsey MM, Himes PR, Varahan S, Manson JM, Lebreton F, Hancock LE. Pheromone killing of multidrug-resistant Enterococcus faecalis V583 by native commensal strains. Proc Natl Acad Sci U S A 2015;112(23):7273-8.Abstract

Multidrug-resistant Enterococcus faecalis possess numerous mobile elements that encode virulence and antibiotic resistance traits as well as new metabolic pathways, often constituting over one-quarter of the genome. It was of interest to determine how this large accretion of mobile elements affects competitive growth in the gastrointestinal (GI) tract consortium. We unexpectedly observed that the prototype clinical isolate strain V583 was actively killed by GI tract flora, whereas commensal enterococci flourished. It was found that killing of V583 resulted from lethal cross-talk between accumulated mobile elements and that this cross-talk was induced by a heptapeptide pheromone produced by native E. faecalis present in the fecal consortium. These results highlight two important aspects of the evolution of multidrug-resistant enterococci: (i) the accretion of mobile elements in E. faecalis V583 renders it incompatible with commensal strains, and (ii) because of this incompatibility, multidrug-resistant strains sharing features found in V583 cannot coexist with commensal strains. The accumulation of mobile elements in hospital isolates of enterococci can include those that are inherently incompatible with native flora, highlighting the importance of maintaining commensal populations as means of preventing colonization and subsequent infection by multidrug-resistant strains.

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