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2014

Cunningham C, Wolfe J. The role of object categories in hybrid visual and memory search. J Exp Psychol Gen. 2014;143(4):1585–99.
In hybrid search, observers search for any of several possible targets in a visual display containing distracting items and, perhaps, a target. Wolfe (2012) found that response times (RTs) in such tasks increased linearly with increases in the number of items in the display. However, RT increased linearly with the log of the number of items in the memory set. In earlier work, all items in the memory set were unique instances (e.g., this apple in this pose). Typical real-world tasks involve more broadly defined sets of stimuli (e.g., any "apple" or, perhaps, "fruit"). The present experiments show how sets or categories of targets are handled in joint visual and memory search. In Experiment 1, searching for a digit among letters was not like searching for targets from a 10-item memory set, though searching for targets from an N-item memory set of arbitrary alphanumeric characters was like searching for targets from an N-item memory set of arbitrary objects. In Experiment 2, observers searched for any instance of N sets or categories held in memory. This hybrid search was harder than search for specific objects. However, memory search remained logarithmic. Experiment 3 illustrates the interaction of visual guidance and memory search when a subset of visual stimuli are drawn from a target category. Furthermore, we outline a conceptual model, supported by our results, defining the core components that would be necessary to support such categorical hybrid searches.
Emami-Naeini P, Dohlman T, Omoto M, Hattori T, Chen Y, Lee HS, Chauhan S, Dana R. Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival.. Graefes Arch Clin Exp Ophthalmol. 2014;252(11):1755–62.
PURPOSE: To investigate the effect of VEGF-C and VEGF-D blockade via soluble VEGFR-3 (sVEGFR-3) on T cell allosensitization, corneal neovascularization, and transplant survival. METHODS: Corneal intrastromal suture placement and allogeneic transplantation were performed on BALB/c mice to evaluate the effect of sVEGFR-3 on corneal neovascularization. Soluble VEGFR-3 trap was injected intraperitoneally to block VEGF-C/D (every other day starting the day of surgery). Immunohistochemical staining of corneal whole mounts was performed using anti-CD31 (PECAM-1) and anti-LYVE-1 antibodies to quantify the levels of hem- and lymphangiogenesis, respectively. Mixed lymphocyte reaction (MLR) was performed to assess indirect and direct host T cell allosensitization and the frequencies of IFN-γ-producing T cells in the draining lymph nodes were assessed using flow cytometry. Graft opacity and survival was evaluated by slit-lamp biomicroscopy. RESULTS: Treatment with sVEGFR-3 resulted in a significant blockade of lymphangiogenesis 2 weeks post-transplantation and significantly prolonged corneal allograft survival compared to the control group at 8 weeks post-transplantation (87.5 % vs. 50 %), and this was associated with significant reduction in the frequencies of allosensitized T cells and decreased frequencies of IFN-γ-producing CD4 T cells. CONCLUSIONS: Soluble VEGFR-3 suppresses corneal lymphangiogenesis and allograft rejection and may offer a viable therapeutic modality for corneal neovascularization and corneal transplantation.
Hernandez S, Gong J, Chen L, Wu IH, Sun J, Keenan H, King G. Characterization of circulating and endothelial progenitor cells in patients with extreme-duration type 1 diabetes.. Diabetes Care. 2014;37(8):2193–201.

OBJECTIVE: We characterized and correlated endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in the Joslin Medalist Study in patients with type 1 diabetes for 50 years or longer. RESEARCH DESIGN AND METHODS: EPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared. RESULTS: Medalists' EPC and CPC levels equaled those of their nondiabetic age-matched controls, were 10% higher than those in younger type 1 diabetic patients, and were 20% higher than those in age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than in those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than in those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than those from nondiabetic controls. CONCLUSIONS: Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues.

Jakobiec F, Trief D, Rashid A, Rose M, Minckler D, Vanderveen D, Mukai S. New insights into the development of infantile intraocular medulloepithelioma.. Am J Ophthalmol. 2014;158(6):1275–1296.e1.
PURPOSE: To define the maturational sequence of 3 infantile intraocular medulloepitheliomas. DESIGN: Retrospective clinicohistopathologic and immunohistochemical study. METHODS: Immunoreactivity of paraffin sections for CRX (cone-rod homebox transcription factor) and NeuN (biomarker for neuronal differentiation) were investigated together with other biomarkers, including S100, glial fibrillary acidic protein, epithelial membrane antigen, and various cytokeratins. RESULTS: Three infants (aged 1, 6, and 8 months) had iris neovascularization, 2 had anterior ciliary body tumors, and 1 a posterior tumor associated with a retinochoroidal coloboma. Each tumor displayed a premedullary monolayer of cuboidal epithelium that was S100(+), NeuN(-), and CRX(-) and that transitioned into a multilaminar medullary epithelium forming neurotubules with adluminal cells that were CRX(+). NeuN first appeared in ablumenal neurotubular cells in 1 tumor and was also discovered among neuroblast-appearing cells in another. The third tumor associated with a coloboma was CRX(-) and NeuN(-). CONCLUSIONS: A simple premedullary epithelial monolayer appears to be the fundamental source for the tumor and its multilaminar medullary epithelium. CRX(+) and NeuN(+) cells within the multilayered medullary layer approximate expression patterns similar to those found in retinal development and differentiation. Discovery of these biomarkers in the neoplastic ciliary epithelium in a small number of tumors indicates preliminarily that the most anterior layers of the optic cup have a retained retinal and neuroglial differentiation potentiality. The third case was CRX(-) and NeuN(-) and possibly arose from embryonic pigment epithelium at the edge of the retinochoroidal coloboma. These immunohistochemical findings offer histogenetic and potential diagnostic insights.
Kodati S, Chauhan S, Chen Y, Dohlman T, Karimian P, Saban D, Dana R. CCR7 is critical for the induction and maintenance of Th17 immunity in dry eye disease.. Invest Ophthalmol Vis Sci. 2014;55(9):5871–7.

PURPOSE: We characterized antigen-presenting cell (APC)-relevant chemokine receptor expression in dry eye disease (DED), and investigated the effect of topical CC chemokine receptor (CCR)-7 blockade specifically on Th17 cell immunity and dry eye disease severity. METHODS: We induced DED in female C57BL/6 mice. Chemokine receptor expression by corneal APCs was characterized using immunohistochemistry. To determine the functional role of CCR7 in DED, mice were treated topically with either anti-CCR7, a control isotype antibody, or left untreated, and clinical disease severity, Th17 responses, and molecular markers of DED were quantified. RESULTS: Frequencies of CD11b(+) cells and their chemokine expression were increased in the cornea of DED mice. Mice treated topically with anti-CCR7 antibody displayed a significant reduction in clinical disease severity and Th17 response compared to the isotype and untreated groups. Topical CCR7 blockade was effective in ameliorating DED in its acute and chronic stages. CONCLUSIONS: Our findings suggest that CCR7-mediated trafficking of APCs drives the induction and maintenance of Th17 immunity in DED and that CCR7 blockade is effective in suppressing the immunopathogenic mechanisms in DED.

Kwon M, Bao P, Millin R, Tjan B. Radial-tangential anisotropy of crowding in the early visual areas. J Neurophysiol. 2014;112(10):2413–22.
Crowding, the inability to recognize an individual object in clutter (Bouma H. Nature 226: 177-178, 1970), is considered a major impediment to object recognition in peripheral vision. Despite its significance, the cortical loci of crowding are not well understood. In particular, the role of the primary visual cortex (V1) remains unclear. Here we utilize a diagnostic feature of crowding to identify the earliest cortical locus of crowding. Controlling for other factors, radially arranged flankers induce more crowding than tangentially arranged ones (Toet A, Levi DM. Vision Res 32: 1349-1357, 1992). We used functional magnetic resonance imaging (fMRI) to measure the change in mean blood oxygenation level-dependent (BOLD) response due to the addition of a middle letter between a pair of radially or tangentially arranged flankers. Consistent with the previous finding that crowding is associated with a reduced BOLD response [Millin R, Arman AC, Chung ST, Tjan BS. Cereb Cortex (July 5, 2013). doi:10.1093/cercor/bht159], we found that the BOLD signal evoked by the middle letter depended on the arrangement of the flankers: less BOLD response was associated with adding the middle letter between radially arranged flankers compared with adding it between tangentially arranged flankers. This anisotropy in BOLD response was present as early as V1 and remained significant in downstream areas. The effect was observed while subjects' attention was diverted away from the testing stimuli. Contrast detection threshold for the middle letter was unaffected by flanker arrangement, ruling out surround suppression of contrast response as a major factor in the observed BOLD anisotropy. Our findings support the view that V1 contributes to crowding.
Marques LM, Lapenta OM, Merabet L, Bolognini N, Boggio PS. Tuning and disrupting the brain-modulating the McGurk illusion with electrical stimulation.. Front Hum Neurosci. 2014;8:533.

In the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audio-visual integrated output occurs irrespective of the number of eye-fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion-type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area.

Panigrahy D, Adini I, Mamluk R, Levonyak N, Bruns C, D’Amore P, Klagsbrun M, Bielenberg D. Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration.. Pathology. 2014;46(5):416–23.

Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF). A soluble isoform of Nrp1 (sNrp1) has not been described in the mouse. Our goal was to examine the expression of mouse sNrp1 during liver development and regeneration.sNrp1 was cloned from mouse liver. The expression of sNrp1 and VEGF was examined in mouse liver during post-natal development and regeneration using northern blot, western blot, in situ hybridisation, and immunohistochemical analyses. HGF/NRP1 binding was examined in vitro.A novel 588-amino acid sNrp1 isoform was found to contain the ligand binding regions of Nrp1. The adult liver expressed more sNrp1 than full-length Nrp1. In vivo, hepatocytes constitutively expressed VEGF and sNrp1 in the quiescent state. sNrp1 was highly up-regulated at P20, a time point coinciding with a plateau in liver and body weights. Following hepatectomy, endogenous levels of sNrp1 decreased during the rapid growth phase, and VEGF levels were highest just prior to and during the angiogenic phase. sNrp1 levels again rose 5-10 days post-hepatectomy, presumably to control regeneration. HGF protein bound NRP1 and binding was competed with sNRP1.We cloned a novel mouse sNrp1 isoform from liver and provide evidence that this endogenous angiogenesis inhibitor may regulate VEGF or HGF bioavailability during normal physiological growth and development as well as during liver regeneration.

Peacock Z, Boulos T, Miller J, Gardiner M, Chuang SK, Troulis M. Orbital fractures and ocular injury: is a postoperative ophthalmology examination necessary?. J Oral Maxillofac Surg. 2014;72(8):1533–40.
PURPOSE: To determine whether formal ophthalmology evaluation is necessary after operative repair of orbital fractures and the association of an ocular injury to the severity of facial injury. PATIENTS AND METHODS: This was a retrospective cohort study of patients with orbital fractures undergoing operative repair from 2005 to 2013. Subjects were included if they had undergone reconstruction of orbital floor fractures and had data from pre- and postoperative examinations by the oral and maxillofacial surgery and ophthalmology services available. The predictor variables included the service performing the ocular examination (oral and maxillofacial surgery or ophthalmology) and the number of fractures present. The outcome variables were the presence of pre- and postoperative ocular injuries. Logistic regression models were used to determine the relationship of the fracture number to ocular injury. RESULTS: A total of 28 subjects had undergone repair of orbital fractures with preoperative and postoperative examinations performed by both services. Preoperative ocular injuries were found in 17 of the 28 subjects. Those detected by oral and maxillofacial surgeons were limited to changes in visual acuity, pupillary response, and extraocular muscle dysfunction in 11 subjects. Two subjects had new postoperative ocular findings that were considered minor and did not alter management. An increasing number of facial fractures was associated with an increased risk of ocular trauma. Those with 3 or more fractures had an odds ratio of 14.625 (95% confidence interval, 2.191 to 97.612, P = .006) for the presence of ocular injury. CONCLUSIONS: Operative repair of orbital fractures did not lead to new ocular injuries that would change the management. Thus, those without preoperative ocular injuries will not require a formal postoperative ophthalmology examination. However, the subjects with more fractures had an increased likelihood of ocular injuries.
Rezende F, Lapalme E, Qian C, Smith L, 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.
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.