Direct penetration of spin-triplet superconductivity into a ferromagnet in Au/SrRuO3/Sr2RuO4 junctions.

Efforts have been ongoing to establish superconducting spintronics utilizing ferromagnet/superconductor heterostructures. Previously reported devices are based on spin-singlet superconductors (SSCs), where the spin degree of freedom is lost. Spin-polarized supercurrent induction in ferromagnetic metals (FMs) is achieved even with SSCs, but only with the aid of interfacial complex magnetic structures, which severely affect information imprinted to the electron spin. Use of spin-triplet superconductors (TSCs) with spin-polarizable Cooper pairs potentially overcomes this difficulty and further leads to novel functionalities. Here, we report spin-triplet superconductivity induction into a FM SrRuO3 from a leading TSC candidate Sr2RuO4, by fabricating microscopic devices using an epitaxial SrRuO3/Sr2RuO4 hybrid. The differential conductance, exhibiting Andreev-reflection features with multiple energy scales up to around half tesla, indicates the penetration of superconductivity over a considerable distance of 15 nm across the SrRuO3 layer without help of interfacial complex magnetism. This demonstrates potential utility of FM/TSC devices for superspintronics.

Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials.

BACKGROUND: Neovascular age-related macular degeneration (AMD) has a poor prognosis if left untreated, frequently resulting in legal blindness. Ranibizumab is approved for treating neovascular AMD. However, further guidance is needed to assist ophthalmologists in clinical practice to optimise treatment outcomes. METHODS: An international retina expert panel assessed evidence available from prospective, multicentre studies evaluating different ranibizumab treatment schedules (ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE) and a literature search to generate evidence-based and consensus recommendations for treatment indication and assessment, retreatment and monitoring. RESULTS: Ranibizumab is indicated for choroidal neovascular lesions with active disease, the clinical parameters of which are outlined. Treatment initiation with three consecutive monthly injections, followed by continued monthly injections, has provided the best visual-acuity outcomes in pivotal clinical trials. If continued monthly injections are not feasible after initiation, a flexible strategy appears viable, with monthly monitoring of lesion activity recommended. Initiation regimens of fewer than three injections have not been assessed. Continuous careful monitoring with flexible retreatment may help avoid vision loss recurring. Standardised biomarkers need to be determined. CONCLUSION: Evidence-based guidelines will help to optimise treatment outcomes with ranibizumab in neovascular AMD.

Light-controlled retinal stimulation on rabbit using CMOS-based flexible multi-chip stimulator.

We implemented a light-sensing function on CMOS-based multi-chip stimulator for retinal prosthesis. Using the light-sensing circuitry attached to each stimulation electrode, the flexible multi-chip stimulator is capable of image-based patterned stimulation. We verified the function of the light-controlled decision based on the light intensity measured just beside the stimulation site. We also experimentally demonstrated in vivo retinal stimulation on rabbit's retina with light-controlled decision. The result of the present work is a simplified demonstration for the concept of retinal prosthesis with on-site imaging.

Analysis of soluble vascular endothelial growth factor receptor-1 secreted from cultured corneal and oral mucosal epithelial cell sheets in vitro.

BACKGROUND: In clinical trials, eyes transplanted with cultured oral mucosal epithelial cell sheets have shown increased neovascularisation compared with eyes treated with cultured corneal epithelial cell sheets. As reported recently, soluble vascular endothelial growth factor receptor-1 (soluble VEGFr-1) is a main factor to maintain a corneal avascularity. AIM: To investigate soluble VEGFr-1 of cultured corneal epithelial cells (CCE) and cultured oral mucosal epithelial cells (COE) in vitro. METHODS: Rabbit corneal and oral mucosal epithelial cells were co-cultured with mitomycin C-treated NIH/3T3 cells on culture plates. After CCE and COE were multilayered, culture medium was replaced by basal medium and incubated. Protein secretion of soluble VEGFr-1 was assessed in conditioned medium from CCE and COE by ELISA. Angiogenic potential was examined by invasion, migration assays with human umbilical vein endothelial cells (HUVECs) in addition to recombinant soluble VEGFr-1. RESULTS: CCE secreted a significantly higher amount of soluble VEGFr-1 than did COE. Recombinant soluble VEGFr-1 significantly suppressed HUVEC migration induced by COE, without suppression in CCE. In conclusion, these findings suggest that low protein levels of soluble VEGFr-1 may lead to corneal neovascularisation after COE sheet transplantation.

Comprehensive gene-expression profile in murine oxygen-induced retinopathy.

BACKGROUND/AIMS: To investigate the correlation between the clinical course and gene-expression pattern in murine oxygen-induced retinopathy (OIR), a commonly used model of retinopathy of prematurity (ROP). METHODS: OIR was induced in C57BL/6N mice by placing postnatal day 7 (P7) pups in 75% oxygen for 5 days. The clinical course of the OIR was evaluated on retinal flat-mounts after fluorescein isothiocyanate-conjugated dextran perfusion from P12 to P21. The expression values of 94 genes, selected by microarray analyses, were determined daily from P12 through P21 by RT-PCR with TaqMan low-density array (TLDA) and analysed by hierarchical clustering. RESULTS: TLDA cluster analyses showed a homology of gene-expression pattern between P12 and P13 and between P16 and P17. Many genes associated with inflammation were upregulated on P12 and P13 when the degree of both central avascular area and central vasoconstriction were maximal, and the upregulation of the genes continued to P21. At P16 and P17 when extraretinal neovascularisation became most noticeable, several genes associated with angiogenesis, for example, vascular endothelial growth factor-A and angiopoietin-2, were most upregulated. CONCLUSION: The gene-expression pattern was well correlated with the clinical appearance in murine OIR. These findings should contribute to the understanding of the pathological conditions in ROP.

Abnormal fundus autofluorescence patterns in myopic choroidal neovascularisation.

BACKGROUND/AIMS: To investigate fundus autofluorescence (FAF) findings in eyes with myopic choroidal neovascularisation (CNV). METHODS: Observational case series. Twenty-seven consecutive eyes with CNV for at least 1 year were included. FAF patterns, time after the onset of CNV seen on FAF and FAF changes were evaluated. RESULTS: The following patterns were observed: pattern I (n = 2), relative hypoautofluorescence around the CNV surrounded by hyperautofluorescence a mean of 17 months after CNV onset; pattern II (n = 11), small lobular or multilobular well-defined FAF defects within a relatively hypoautofluorescent region surrounded by hyperautofluorescence a mean of 35 months after onset; pattern III (n = 4), large lobular or multilobular well-defined FAF defects surrounded by hyperautofluorescence a mean of 59 months after onset; and pattern IV (n = 10), large lobular or crescent-shaped well-defined FAF defects a mean of 107 months after onset. Well-defined FAF defects corresponded to chorioretinal atrophy on colour fundus photographs. During the follow-up period, two eyes with pattern I evolved into pattern II. Lobular or multilobular well-defined FAF defects enlarged in 11 eyes (pattern II, nine eyes; pattern III, two eyes). CONCLUSION: Autofluorescent changes progress over time through pattern grading. A pattern classification might be helpful to predict chorioretinal atrophy changes around myopic CNV.

Differential expression of MUC16 in human oral mucosal epithelium and cultivated epithelial sheets.

Cultivated oral mucosal epithelial sheet transplantation is a new surgical strategy to treat severe ocular surface disorders such as chemical burns, ocular cicatricial pemphigoid, and Stevens-Johnson syndrome. MUC16 is thought to be the most important membrane-associated mucin on the ocular surface because it forms a protective barrier on the epithelial cell surface. In this study, we studied MUC16 expression in mRNA and protein levels and compared the expression patterns between cultivated oral mucosal epithelial cell sheet and oral mucosal tissue. Specimens (5x5 mm) of oral mucosal tissue harvested from healthy volunteers were used. The oral mucosal epithelial cells were cultured on temperature-responsive culture dishes to generate stratified cell sheets. Cultivated oral mucosal epithelial cells formed three- to five-cell thick stratified sheets for 2 weeks. Scanning electron micrographs revealed that the apical surfaces of the oral mucosal tissue and the oral mucosal sheets were covered with dense microvilli/microplicae. Real-time PCR showed significantly more MUC16 transcripts in the cultivated oral mucosal sheets and corneal epithelial sheets than in the oral mucosal tissue (P=0.023 and 0.008, respectively, Mann-Whitney rank sum test). These findings were confirmed by immunohistochemical examination using an MUC16 antibody to the protein. MUC16 protein was localized to the apical cells of the oral mucosal sheets, but the human oral mucosal tissue did not express MUC16 protein in any cell layers. In this study, interestingly, the expression of membrane-associated mucin MUC16 differs between human oral mucosal epithelia and cultivated epithelial sheets. MUC16 expressed in the oral mucosal sheets may contribute to ocular surface reconstruction after oral mucosal sheet transplantation.

Marked vascular changes of polypoidal choroidal vasculopathy after photodynamic therapy.

AIMS: To clarify vascular changes of polypoidal choroidal vasculopathy (PCV) after photodynamic therapy (PDT). METHODS: Thirty-one eyes underwent PDT with verteporfin and were followed every 3 months with indocyanine green angiography (ICGA) using confocal scanning ophthalmoscope and optical coherence tomography (OCT) for over 15 months and the findings recorded. RESULTS: The mean follow-up period was 19.2 months. Regression of the polypoidal lesions were confirmed once in 29 eyes (94%) on ICGA and OCT. Some lesions recurred at the initial regions (n = 5 eyes), at different regions connected to the branching vascular network (n = 4 eyes), and at both regions (n = 1 eye) (mean 11.4 (SD 1.9) months) after initial PDT. The branching vascular network remained in all eyes and enlarged in 13 eyes (42%) at the final visit. The vascular features of residual branching vascular networks changed (n = 7 eyes); fibrinous subretinal exudation developed (n = 4 eyes), and the retinal pigment epithelium was elevated similar to vascularised pigment epithelial detachment (n = 3 eyes). CONCLUSION: Polypoidal lesions of PCV are treatable with PDT; however, they often recur. The branching vascular networks do not regress and allow the recurrence of polypoidal lesions at the network termini. Alterations of the vascular features may occur; careful observation is needed after PDT.

Abnormal keratocytes and stromal inflammation in chronic phase of severe ocular surface diseases with stem cell deficiency.

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS), ocular cicatricial pemphigoid (OCP) and alkali burns are associated with chronic, severe inflammation of the ocular surface that occasionally lead to corneal stem cell deficiencies. The corneal stroma in these diseases has not been studied comprehensively. The purpose of this study was to determine whether the keratocytes in the stroma were normal and whether the stroma remained inflamed in the chronic phase of these diseases. METHODS: Five pathological corneas, two with SJS, two with OCP and one with an alkali burn were examined. Corneal specimens were obtained during lamellar keratoplasty and the histological sections were immunostained with antibodies against CD34 and several cell surface antigens. The level of expression of proteoglycans (lumican, keratocan, biglycan) and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP) 1alpha, MIP1beta) were examined by quantitative real-time RT-PCR. RESULTS: The number of CD34-positive cells in the stroma was decreased and the expression level of biglycan increased in all of the pathological corneas. The numbers of CD45-positive and CD14-positive cells were increased in four of the five pathological corneas. The expression level of MIP1alpha and MIP1beta were markedly increased in all of the pathological corneas. CONCLUSIONS: These findings indicate that the keratocytes are abnormal and inflammation is still present in the corneal stroma in the chronic phase of SJS, OCP and alkali burns.

Multi-finger structure and pulsed-powering operation scheme for CMOS LSI-based flexible stimulator for retinal prosthesis.

Multi-finger structure was proposed to improve flexibility of the CMOS LSI-based multi-chip retinal stimulator. A dual-finger retinal stimulator was fabricated and its functionality was demonstrated in retinal stimulation experiments on rabbit's retina, We also proposed an idea of pulsed-powering operation scheme for the multi-chip flexible retinal stimulator. We compared the pulsed-powering scheme with conventional one in a simulation, and show that the pulsed-powering can be an alternative operation scheme for the neural stimulator that provides an improved safety to the biological tissue.

Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy.

AIMS: The aim of the study was to assess the short-term efficacy of intravitreal injections of bevacizumab for polypoidal choroidal vasculopathy (PCV). METHODS: Intravitreal bevacizumab (1 mg) was injected into 11 eyes of 11 patients with PCV in this retrospective, interventional case series. The main outcome measure was the change in the polypoidal vessels on indocyanine green angiography (IA) 3 months after injection. The foveal height determined by optical coherence tomography and the best-corrected visual acuity (BCVA) also were evaluated before and after treatment. RESULTS: At baseline, subretinal fluid was observed in five eyes and a pigment epithelial detachment in eight eyes. The foveal height 1 month after injection decreased significantly (p = 0.023), but at 3 months, no significant decrease was observed, although an additional injection was administrated in five of 11 eyes. The IA at 3 months showed resolution of polyps in one eye but residual or enlarged lesions in the other ten eyes. The BCVA did not improve significantly, although the subjects had relatively good BCVA at baseline (mean 0.45). CONCLUSION: Intravitreal injection of bevacizumab may reduce the fluid from PCV but seems to be ineffective for diminishing its choroidal vascular changes.

The metabolic syndrome and retinal microvascular signs in a Japanese population: the Funagata study.

AIMS: To determine the relationship of metabolic syndrome and its components with retinopathy and other retinal microvascular signs in a Japanese population. METHODS: The Funagata study recruited 1961 (53.3% of eligible) Japanese aged 35 or older. The metabolic syndrome was diagnosed primarily using definitions of the International Diabetes Federation. Retinopathy and retinal microvascular signs were assessed from fundus photographs. Retinal arteriolar and venular diameters were measured using a computer-assisted programme. RESULTS: Data were available for analysis in 1638 persons for retinopathy and retinal microvascular signs and 921 persons for retinal vessel diameters. Various components of the metabolic syndrome were associated with retinal microvascular signs: a larger waist circumference was associated with wider venular diameter and retinopathy lesions; a higher blood pressure level was associated with focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar wall reflex and narrower arteriolar diameter; and a higher triglyceride level was associated with enhanced arteriolar wall reflex. Overall, persons with the metabolic syndrome were more likely to have retinopathy (odds ratio 1.64, 95% CI: 1.02 to 2.64) and wider venular diameter 4.69 microm (95% CI: 1.20 to 8.19 microm) than persons without the metabolic syndrome. CONCLUSION: We report associations of metabolic syndrome components with retinopathy and wider venular diameter in Japanese adults. These data suggest that metabolic abnormalities, indicated by metabolic syndrome components, are associated with microvascular changes in the retina. There was no synergistic effect of the metabolic syndrome on retinal microvascular changes beyond its individual components.

In vivo stimulation on rabbit retina using CMOS LSI-based multi-chip flexible stimulator for retinal prosthesis.

We have performed in vivo electric stimulation experiments on rabbit retina to demonstrate feasibility of CMOS LSI-based multi-chip flexible neural stimulator for retinal prosthesis. We have developed new packaging structure with an improved flexibility and device control system which totally controls the LSI-based multi-chip stimulator, counter electrode, and stimulation generator. We have implanted the fabricated multi-chip stimulator into sclera pocket for STS (Suprachoroidal Transretinal Stimulation) configuration. We successfully obtained EEP (Electrically Evoked Potential) on visual cortex evoked by the multi-chip stimulator.

Laboratory investigation of microelectronics-based stimulators for large-scale suprachoroidal transretinal stimulation (STS).

This paper describes the technological developments underlying the realization of a reliable and reproducible microchip-based stimulator with a large number of stimulus electrodes. A microchip-based stimulator with over 500 electrodes for suprachoroidal transretinal stimulation (STS) is proposed in this paper, and an example is presented. To enhance reliability and reproducibility for such a large array, we introduce a flip-chip bonding technique and place microchips on the reverse side of a substrate. A square microchip of size 600 microm was fabricated using 0.35 microm standard CMOS process technology. Twelve microchips were flip-chip bonded on a polyimide substrate through Au bumps. To evaluate the feasibility of the proposed device, we successfully fabricated a stimulator with 12 microchips and 118 electrodes made of Pt/Au bumps, and demonstrated their operation in a saline solution for 2 weeks. Also, to evaluate the device operation in vivo, a stimulator with one active IrO(x) electrode was implanted into the scleral pocket of a rabbit and electrical evoked potential (EEP) signals with a threshold of 100 microA were obtained. We also fabricated a simulator with 64 microchips that has 576 electrodes (9 electrodes in a microchip times 64 microchips).

Intravitreal injection of bevacizumab for choroidal neovascularisation associated with pathological myopia.

AIM: To assess the efficacy and safety of an intravitreal injection of bevacizumab (Avastin(R)) for myopic choroidal neovascularisation (mCNV). METHODS: Intravitreal bevacizumab (1 mg) was injected into eight eyes of eight patients with mCNV in this non-randomised, interventional case series. The best-corrected visual acuity (BCVA) was measured and the optical coherence tomography (OCT) and fluorescein angiography findings were examined before and after treatment. The minimum follow-up time was 3 months. RESULTS: The mean BCVA was 0.26 before treatment and 0.51 at the last visit (p = 0.009). The BCVA improved to two or more lines in six eyes (75%) and remained the same in two eyes (25%). Leakage from the mCNV on fluorescein angiography decreased in seven eyes (87.5%). The choroidal neovascularisation area on fluorescein angiography (p = 0.049) and the foveal thickness on OCT images decreased significantly (p = 0.027) after the treatment. No major complications developed. CONCLUSION: Intravitreal injection of bevacizumab seems to be an effective and safe treatment for mCNV.

Pars plana vitrectomy with peripheral retinotomy after injection of preoperative intravitreal tissue plasminogen activator: a modified procedure to drain massive subretinal haemorrhage.

AIMS: To report outcome of a modified procedure for draining massive subretinal haemorrhages (SRHs). METHODS: The charts of eight consecutive eyes from eight patients with massive SRHs extending to the periphery and involving two or more quadrants with haemorrhagic and bullous retinal detachment were reviewed. Tissue plasminogen activator (tPA) was injected intravitreally 12-24 h preoperatively; vitrectomy was carried out with peripheral retinotomy, drainage of the SRH from the retinotomy using perfluorocarbon liquid and gas tamponade with prone positioning postoperatively. RESULTS: The preoperative visual acuities ranged from light perception to 20/200. Most of the subretinal haematomas moved postoperatively to the vitreous cavity through the peripheral retinotomy using perfluorocarbon liquid. Residual SRHs were drained from the anterior chamber at the bedside after prone positioning overnight. SRH recurred in one eye 14 months postoperatively and was successfully retreated. No other serious complications developed. The final visual acuity improved in seven eyes (range 20/1000-20/60). Polypoidal lesions in choroidal vasculatures were present in three of seven patients. CONCLUSIONS: The technique seems safe and effective for treating massive SRH. However, visual recovery is limited by the underlying macular pathology. Polypoidal choroidal vasculopathy, other than age-related macular degeneration, may be another cause of massive SRHs.