Role of Adrenomedullin 2/Intermedin in the Pathogenesis of Neovascular Age-Related Macular Degeneration.

Adrenomedullin 2 (AM2; also known as intermedin) is a member of the adrenomedullin (AM) peptide family. Similarly to AM, AM2 partakes in a variety of physiological activities. AM2 has been reported to exert protective effects on various organ disorders; however, its significance in the eye is unknown. We investigated the role of AM2 in ocular diseases. The receptor system of AM2 was expressed more abundantly in the choroid than in the retina. In an oxygen-induced retinopathy model, physiological and pathologic retinal angiogenesis did not differ between AM2-knockout (AM2-/-) and wild-type mice. In contrast, in laser-induced choroidal neovascularization, a model of neovascular age-related macular degeneration, AM2-/- mice had enlarged and leakier choroidal neovascularization lesions, with exacerbated subretinal fibrosis and macrophage infiltration. Contrary to this, exogenous administration of AM2 ameliorated the laser-induced choroidal neovascularization-associated pathology and suppressed gene expression associated with inflammation, fibrosis, and oxidative stress, including that of VEGF-A, VEGFR-2, CD68, CTGF, and p22-phox. The stimulation of human adult retinal pigment epithelial (ARPE) cell line 19 cells with TGF-ß2 and TNF-α induced epithelial-to-mesenchymal transition (EMT), whereas AM2 expression was also elevated. The induction of EMT was suppressed when the ARPE-19 cells were pretreated with AM2. A transcriptome analysis identified 15 genes, including mesenchyme homeobox 2 (Meox2), whose expression was significantly altered in the AM2-treated group compared with that in the control group. The expression of Meox2, a transcription factor that inhibits inflammation and fibrosis, was enhanced by AM2 treatment and attenuated by endogenous AM2 knockout in the early phase after laser irradiation. The AM2 treatment of endothelial cells inhibited endothelial to mesenchymal transition and NF-κB activation; however, this effect tended to be canceled following Meox2 gene knockdown. These results indicate that AM2 suppresses the neovascular age-related macular degeneration-related pathologies partially via the upregulation of Meox2. Thus, AM2 may be a promising therapeutic target for ocular vascular diseases.

Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-ß and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-ß and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.

OCULAR ANGIOGRAPHIC FEATURES IN JAPANESE PATIENTS WITH VAL30MET HEREDITARY TRANSTHYRETIN AMYLOIDOSIS.

PURPOSE: To investigate ocular angiographic features of hereditary transthyretin amyloidosis with transthyretin Val30Met mutation (hATTR-V30M) in Japanese patients. METHODS: We retrospectively reviewed 102 eyes of 51 patients with hATTR-V30M who underwent fluorescein angiograms and indocyanine green angiograms between 2012 and 2018. Systemic severity score, fluorescein angiograms, indocyanine green angiograms, and ocular amyloidosis presentations at the final angiograms and subsequent neovascular events were evaluated. Primary outcomes were the frequency of choroidal amyloid angiopathy and retinal amyloid angiopathy (RAA). Secondary outcomes were their correlations to the systemic severity score. RESULTS: Six eyes could not be evaluated by fluorescein angiogram because of vitreous opacity. Of 96 eyes evaluated, RAA was detected in 36 (37.5%). Neovascularization was not detected. Indocyanine green angiogram indicated choroidal amyloid angiopathy in 46/51 patients (90.2%), with distinct patterns-diffuse (n = 6), focal (n = 14), and punctiform (n = 26)-based on late-phase hypercyanescence. Retinal amyloid angiopathy and choroidal amyloid angiopathy grades were associated with systemic severity (ρ = 0.57 and 0.50, respectively; both P < 0.05). At 35.4 ± 28.4 (0-96) months, iris-rubeosis was observed in one eye and vitreous hemorrhage in two. CONCLUSION: Retinal amyloid angiopathy was less common and choroidal amyloid angiopathy was frequent, and their severity correlated with the systemic severity score. The frequencies of RAA and subsequent neovascular events in this study may suggest regional differences in the ocular angiographic features of hATTR-V30M.

Effects of reduced glutathione supplementation in semen freezing extender on frozen-thawed bull semen and in vitro fertilization.

During cryopreservation, spermatozoa may suffer cold and cryo-induced injuries -associated with alterations in cell defense systems- that are detrimental to their function and subsequent fertility. This study aimed to determine the efficacy of supplementing the semen freezing extender with the antioxidant reduced glutathione (GSH) in cattle. Semen was collected from four bulls and diluted in a freezing extender supplemented with or without GSH (0, 1, 5, and 10 mM) before the cooling step of the cryopreservation process. After thawing, the quality of the frozen-thawed semen was investigated for motility, viability, acrosomal and DNA integrity, and subsequent embryo development after in vitro fertilization of bovine oocytes. Additionally, semen from one of the bulls was used to analyze semen antioxidative potential, sperm penetration into oocytes, male pronucleus formation rate, and embryo DNA integrity. The sperm quality varied among bulls after GSH supplementation. One bull had decreased sperm total motility, and two bulls had decreased sperm DNA integrity. GSH supplementation had positive effects on embryo development for three bulls. Two of them showed both improved cleavage and blastocyst formation rates, while the other one only showed an improved cleavage rate. We observed positive effects on early male pronucleus formation and no negative effects on DNA integrity and cell number in blastocyst stage embryos. Although the effect varies depending on individual bulls and GSH concentration, GSH supplementation in semen may improve in vitro embryo production from frozen semen.

Differentially methylated CpG sites related to fertility in Japanese Black bull spermatozoa: epigenetic biomarker candidates to predict sire conception rate.

For semen suppliers, predicting the low fertility of service bull candidates before artificial insemination would help prevent economic loss; however, predicting bull fertility through in vitro assessment of semen is yet to be established. In the present study, we focused on the methylated CpG sites of sperm nuclear DNA and examined methylation levels to screen new biomarkers for predicting bull fertility. In frozen-thawed semen samples collected from Japanese Black bulls, for which the sire conception rate (SCR) was recorded, the methylation level of each CpG site was analyzed using human methylation microarray. According to regression analysis, 143 CpG sites related to SCR were significantly differentially methylated. Whole genome bisulfite sequence data were obtained from three semen samples and the differentially methylated regions (DMRs) that included the target CpG sites selected by human methylation microarray were confirmed. Using combined bisulfite restriction analysis, fertility-related methylation changes were detected in 10 DMRs. With the exception of one DMR, the methylation levels of these DMRs were significantly different between groups with high fertility (> 50%) and low fertility (< 40%). From multiple regression analysis of methylation levels and SCR, three DMRs were selected that could effectively predict bull fertility. We suggest that these fertility-related differences in spermatozoal methylation levels could be new epigenetic biomarkers for predicting bull fertility.

Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin-Receptor Activity-Modifying Protein 2 System.

Central retinal vein occlusion (CRVO) is an intractable disease that causes visual acuity loss with retinal ischemia, hemorrhage, and edema. In this study, we developed an experimental CRVO model in mice and evaluated the therapeutic potential of the pleiotropic peptide adrenomedullin (ADM) and its receptor activity-modifying protein 2 (RAMP2). The CRVO model, which had phenotypes resembling those seen in the clinic, was produced by combining i.p. injection of Rose bengal, a photoactivator dye enhancing thrombus formation, with laser photocoagulation. Retinal vascular area, analyzed using fluorescein angiography and fluorescein isothiocyanate-perfused retinal flat mounts, was decreased after induction of CRVO but gradually recovered from day 1 to 7. Measurements of retinal thickness using optical coherence tomography and histology revealed prominent edema early after CRVO, followed by gradual atrophy. Reperfusion after CRVO was diminished in Adm and Ramp2 knockout (KO) mice but was increased by exogenous ADM administration. CRVO also increased expression of a coagulation factor, oxidative stress markers, and a leukocyte adhesion molecule in both wild-type and Adm KO mice, and the effect was more pronounced in Adm KO mice. Using retinal capillary endothelial cells, ADM was found to directly suppress retinal endothelial injury. The retinoprotective effects of the Adm-Ramp2 system make it a novel therapeutic target for the treatment of CRVO.

Age-related changes in DNA methylation levels at CpG sites in bull spermatozoa and in vitro fertilization-derived blastocyst-stage embryos revealed by combined bisulfite restriction analysis.

Age-associated methylation changes in genomic DNA have been recently reported in spermatozoa, and these changes can contribute to decline in fertility. In a previous study, we analyzed the genome-wide DNA methylation profiles of bull spermatozoa using a human DNA methylation microarray and identified one CpG site (CpG-1) that potentially reflects age-related methylation changes. In the present study, cryopreserved semen samples from a Japanese Black bull were collected at five different ages, which were referred to as JD1-5: 14, 19, 28, 54, and 162 months, respectively, and were used for genome-wide DNA methylation analysis and in vitro fertilization (IVF). Distinct age-related changes in methylation profiles were observed, and 77 CpG sites were found to be differently methylated between young and adult samples (JD1-2 vs. JD4-5). Using combined bisulfite restriction analysis (COBRA), nine CpG sites (including CpG-1) were confirmed to exhibit significant differences in their age-dependent methylation levels. Eight CpG sites showed an age-dependent increase in their methylation levels, whereas only one site showed age-dependent hypomethylation; in particular, these changes in methylation levels occurred rapidly at a young age. COBRA revealed low methylation levels in some CpG regions in the majority of the IVF blastocyst-stage embryos derived from spermatozoa at JD2-5. Interestingly, bulls with different ages did not show differences in their methylation levels. In conclusion, our findings indicated that methylation levels at nine CpG sites in spermatozoa changed with increasing age and that some CpG regions were demethylated after fertilization. Further studies are required to determine whether age-dependent different methylation levels in bull spermatozoa can affect fertility.

[SWITCHING BIOLOGICS LED TO GOOD CONTROL IN SEVERE CHILDHOOD ASTHMA: A CASE REPORT].

The two biologic therapies, anti-IgE (omalizumab) and anti-IL-5 antibodies (mepolizumab), are used in the treatment of severe pediatric asthma. We present here a case study of a 13-year-old girl with severe asthma who switched from omalizumab to mepolizumab therapy and achieved good control over her asthma. The patient was diagnosed with asthma at one year of age and presented with poor disease control, even while taking high doses of inhaled corticosteroids (ICS). As such, she was considered to have severe persistent asthma. At 10 years old, she began omalizumab therapy which improved asthma control. However, after two years of this therapy, she manifested frequent acute exacerbations. At 12 years old, she switched to mepolizumab and has since maintained good control of asthma. Additionally, total serum IgE levels and peripheral eosinophil counts decreased. As the underlying mechanisms of omalizumab and mepolizumab therapy are distinct, it is recommended to use either one if the other proves ineffective.

Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy.

Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

CHANGES IN PLASMA VASCULAR ENDOTHELIAL GROWTH FACTOR LEVEL AFTER INTRAVITREAL INJECTION OF BEVACIZUMAB, AFLIBERCEPT, OR RANIBIZUMAB FOR DIABETIC MACULAR EDEMA.

PURPOSE: The aim of this study was to investigate the changes in plasma vascular endothelial growth factor (VEGF) level depending on the severity of diabetic retinopathy (DR) or diabetic macular edema (DME) and after intravitreal injection of bevacizumab, aflibercept, or ranibizumab for treatment of DME. METHODS: Plasma VEGF level was evaluated in 72 patients with DR and changes were measured in 42 patients with DME receiving intravitreal injections of bevacizumab, aflibercept, or ranibizumab at the initial injection. RESULTS: There were no correlations between plasma VEGF level and the severity of DME or DR. Baseline plasma VEGF level (51.9 pg/mL) was significantly reduced using bevacizumab to 11.9 pg/mL after 1 week and 24.1 pg/mL after 4 weeks (P = 0.0130 and 0.0201, respectively). In aflibercept-treated eyes, plasma VEGF decreased from 52.2 pg/mL to 7.8 pg/mL and 12.6 pg/mL, respectively, at the same time points (both P < 0.001). No such reductions were observed in patients receiving ranibizumab. CONCLUSION: Baseline plasma VEGF level showed no correlations with DR or DME severity, whereas intravitreal injection of bevacizumab or aflibercept significantly reduced plasma VEGF for up to 4 weeks and ranibizumab produced no such effects. Changes in plasma VEGF level seemed not to be critical in progression or treatment of DME and DR.

Assessment of diabetic retinopathy using two ultra-wide-field fundus imaging systems, the Clarus® and Optos™ systems.

BACKGROUND: The ability to image wide fundus fields and to conduct swift, non-invasive examinations is increasingly important with the escalation in patients with diabetic retinopathy (DR). METHODS: Fifty eyes of 28 consecutive patients with DR were examined in this prospective observational study. A total of 46 eyes, 25 right and 21 left eyes, of 27 patients (male, 19; female, 8) were ultimately included in the analysis. All patients underwent comprehensive ophthalmological examination. A single image each was obtained using two ultra-wide-field (UWF) imaging systems: Optos® (Optos Carfornia®, Optos PLC, Dunfermline, United Kingdom) and Clarus™ (CLARUS 500™, Carl Zeiss Meditec Inc., Californea, USA), without mydriasis. The total retinal area captured and the obscured retinal area were compared between the two systems using nonparametric Wilcoxon matched-pairs signed-rank analysis. Early Treatment of Diabetic Retinopathy Study (ETDRS) and International Clinical DR severity were analyzed by κ statistics. RESULTS: The Optos® allowed capture of larger areas of the fundus than the Clarus™ (465 ± 117 vs. 243 ± 39 disc areas, P < 0.0001). In 85% (39/46) of Optos® images and 7% (3/46) of Clarus™ images, a slightly obscured area was observed within the ETDRS-7 field area. κ values for ETDRS DR severity and International Clinical DR severity between the Optos® and Clarus™ images were 0.88 and 0.79, respectively. Severity was higher according to Clarus™ images in two eyes in which the ETDRS DR severity grading differed between the systems. Severity was higher in four Clarus™ images and in a single Optos® image in five eyes in which the International Clinical DR severity grading differed between the systems. CONCLUSION: The Optos® and Clarus™ UWF retinal imaging systems were useful for examining eyes with DR, using single images obtained without mydriasis. The systems were both generally consistent in assessing DR severity, with some partial discrepancies. It is important to understand the characteristics of each respective UWF retinal imaging system when using them to assess DR.

Clinical Characteristics of Stroke Occurring while Bathing.

BACKGROUND: Stroke can occur during any human activity. Although cardiac arrests or drowning accidents while bathing have been studied extensively, there are few studies focusing on stroke occurring while bathing. The objectives of this study were to evaluate the clinical characteristics of stroke occurring while bathing and the association between stroke and drowning accidents. METHODS: Clinical data prospectively acquired between January 2011 and December 2015 on 1939 patients with stroke (1224 cerebral infarctions [CIs], 505 intracerebral hemorrhages [ICHs], and 210 subarachnoid hemorrhages [SAHs]) were reviewed to identify patients who sustained a stroke while bathing. The ratio of bathing-related strokes to strokes occurring during other activities was evaluated. Moreover, the demographics of these 2 groups were compared in each stroke type. RESULTS: Among the 1939 patients, 78 (CI, 32; ICH, 28; and SAH, 18) sustained a stroke while bathing. The ratio of bathing to other activities in the SAH group was the highest (8.6%), followed by the ICH group (5.5%), whereas that in the CI group was the lowest (2.6%). Regardless of stroke type, only a minority of patients were found to have collapsed inside the bathtub. CONCLUSIONS: The higher ratio of bathing in hemorrhagic strokes may indicate that there is a small risk of hemorrhagic stroke while bathing in vulnerable subjects. This retrospective study did not establish a causal relationship between bathing and stroke nor identify risk factors, which means that future prospective studies are warranted. The finding that the great majority of bathing-related stroke patients were found to have collapsed outside the bathtub suggests that the involvement of stroke in drowning accidents in the bathtub may be small.

Pathophysiological function of endogenous calcitonin gene-related peptide in ocular vascular diseases.

Calcitonin gene-related peptide (CGRP; official name CALCA) has a variety of functions and exhibits both angiogenic and anti-inflammatory properties. We previously reported the angiogenic effects of the CGRP family peptide adrenomedullin in oxygen-induced retinopathy; however, the effects of CGRP on ocular angiogenesis remain unknown. Herein, we used CGRP knockout (CGRP(-/-)) mice to investigate the roles of CGRP in ocular vascular disease. Observation of pathological retinal angiogenesis in the oxygen-induced retinopathy model revealed no difference between CGRP(-/-) and wild-type mice. However, much higher levels of the CGRP receptor were present in the choroid than the retina. Laser-induced choroidal neovascularization (CNV), a model of exudative age-related macular degeneration, revealed more severe CNV lesions in CGRP(-/-) than wild-type mice, and fluorescein angiography showed greater leakage from CNV in CGRP(-/-). In addition, macrophage infiltration and tumor necrosis factor (TNF)-α production were enhanced within the CNV lesions in CGRP(-/-) mice, and the TNF-α, in turn, suppressed the barrier formation of retinal pigment epithelial cells. In vivo, CGRP administration suppressed CNV formation, and CGRP also dose dependently suppressed TNF-α production by isolated macrophages. From these data, we conclude that CGRP suppresses the development of leaky CNV through negative regulation of inflammation. CGRP may thus be a promising therapeutic agent for the treatment of ocular vascular diseases associated with inflammation.

Dynamics of macular hole closure in gas-filled eyes within 24 h of surgery observed with swept source optical coherence tomography.

BACKGROUND/AIMS: To investigate the dynamics of macular hole (MH) closure in gas-filled eyes starting 20 min after vitrectomy using swept source optical coherence tomography (SS-OCT). METHODS: Twenty consecutive eyes with MH underwent vitrectomy with internal limiting membrane peeling and gas tamponade. SS-OCT imaging was performed approximately 20 min after the operation, and then once a day, until MH closure was confirmed. The correlation between the base, top and minimum hole diameters and the duration required for MH closure was investigated. RESULTS: MH closure in gas-filled eyes was confirmed in 1 eye on day 0, 10 eyes on day 1, 2 eyes on day 2, and 3 eyes on day 3, at which times face-down posturing was discontinued without MH recurrence. SS-OCT revealed a distinct closure pattern within the first 24 h postoperatively. MHs closing by day 1 had a significantly smaller minimum diameter (312.5 ± 105.2 µm) than holes closing on day 2 or later (510.8 ± 153.5 µm; p = 0.019). CONCLUSIONS: SS-OCT enables tomographic images of MH in gas-filled eyes immediately postoperatively, thus permitting early discontinuation of, or no necessity for, face-down positioning upon confirmation of MH closure.

Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system.

Adrenomedullin (AM) is a vasoactive peptide that possesses various bioactivities. AM receptors are dimers consisting of CLR with one of two accessory proteins, RAMP2 or RAMP3. The functional difference between CLR/RAMP2 and CLR/RAMP3 and the relationship between the two receptors remain unclear. To address these issues, we generated RAMP2 and RAMP3 knockout (-/-) mice and have been studying their physiological activities in the vascular system. AM-/- and RAMP2-/- mice die in utero due to blood vessel abnormalities, which is indicative of their essential roles in vascular development. In contrast, RAMP3-/- mice were born normally without any major abnormalities. In adult RAMP3-/- mice, postnatal angiogenesis was normal, but lymphangiography using indocyanine green (ICG) showed delayed drainage of subcutaneous lymphatic vessels. Moreover, chyle transport by intestinal lymphatics was delayed in RAMP3-/- mice, which also showed more severe interstitial edema than wild-type mice in a tail lymphedema model, with characteristic dilatation of lymphatic capillaries and accumulation of inflammatory cells. In scratch-wound assays, migration of isolated RAMP3-/- lymphatic endothelial cells was delayed as compared to wild-type cells, and AM administration failed to enhance the re-endothelialization. The delay in re-endothelialization was due to a primary migration defect rather than a decrease in proliferation. These results suggest that RAMP3 regulates drainage through lymphatic vessels, and that the AM-RAMP3 system could be a novel therapeutic target for controlling postoperative lymphedema.

Potential improvements for dual directional view displays.

Dual directional view (DDV) displays show different images to different viewers. For example, the driver of a car looking at a central DDV display could view navigation information, while the passenger, looking from a different angle, could be watching a movie. This technology, which has now established itself on the dashboards of high-end Jaguar, Mercedes, and Range Rover cars, is manufactured by Sharp Corporation using a well-known parallax barrier technique. Unfortunately parallax barriers are associated with an inevitable drop in brightness compared with a single view display. A parallax barrier-based DDV display typically has less than half the transmission of a single view display. Here we present a solution to these problems via the use of a combined microlens and parallax barrier system, which can not only boost the brightness by 55% from a parallax barrier-only system but increase the head freedom by 25% and reduce crosstalk also. However, the use of microlenses (which must be positioned between the polarizers of the LCD) can adversely affect the contrast ratio of the display. Careful choice of the LCD mode is therefore required in order to create a DDV display that is both high in brightness and contrast ratio. The use of a single-domain vertically aligned nematic (VAN) liquid crystal (LC) mode, together with a microlens plus parallax barrier system can achieve this with a contrast ratio of 1700∶1 measured at 30° to normal incidence.

Detection of fovea-threatening diabetic macular edema by optical coherence tomography to maintain good vision by prophylactic treatment.

BACKGROUND/AIMS: To establish a screening and treatment method for fovea-threatening diabetic macular edema (DME) using spectral-domain optical coherence tomography (SD-OCT). In order to maintain good visual acuity (VA), focal/grid laser treatment for screened fovea-threatening DME was evaluated based on macular thickness map images produced by SD-OCT. METHODS: In 66 diabetic eyes with no visual deterioration, the sensitivity and the specificity of SD-OCT without the use of mydriatics for the detection of fovea-threatening DME were determined. A definite diagnosis of DME was made under mydriasis, using slitlamp biomicroscopy with a contact lens. Eyes with fovea-threatening DME then underwent prophylactic focal/grid laser treatment. The main outcome measures were corrected VA and central macular thickness (CMT). RESULTS: A definitive diagnosis of DME was made in 5 of the 66 eyes, while macular thickening above the 99th percentile was detected in 11 (Cirrus®) or 13 (RS-3000®) eyes by SD-OCT. The focal/grid laser treatment of the 5 eyes with fovea-threatening DME successfully maintained good VA, which was 0.91 ± 0.76 (average: 20/22; 0.04 ± 0.12 logMAR) before treatment and 0.89 ± 0.70 (average: 20/22; 0.05 ± 0.15 logMAR; p = 0.88) 1 year afterwards. The average CMT was stable before and after focal/grid lasering at 302 ± 29 and 329 ± 55 µm, respectively (p = 0.99). CONCLUSIONS: The detection of fovea-threatening DME is feasible by SD-OCT without using mydriatics. Prophylactic treatment, such as with focal/grid lasers, was effective in maintaining good VA by avoiding an otherwise highly likely foveal involvement. © 2014 S. Karger AG, Basel.

Effect of Laser wavelength on delivering appropriate laser burns through the opaque lens using a pattern scan laser.

BACKGROUND/AIMS: We evaluated the effects of pattern scan laser (PSL) wavelength in delivering appropriate laser burns to the retina of eyes with an opaque lens. METHODS: Sixteen shots of 2 × 2 square grids (64 laser spots) were delivered using green (532-nm), yellow (577-nm) and red (647-nm) lasers to the retinas of mice with mild cataract induced by chloral hydrate (400 mg/kg). Three eyes with clear lenses served as controls. One week after laser coagulation, the ratio of appropriate burns, defined as coagulation restricted to the outer half of the retina without retinal or choroidal hemorrhage, was investigated histologically. RESULTS: With the green laser, we confirmed only 3.0 ± 2.0 appropriate burns in eyes with an opaque lens, in contrast to 13.7 ± 4.0 effective burns in eyes with a clear lens. On the other hand, the yellow and red lasers produced 18 ± 5.2 and 13 ± 1.5 appropriate burns, respectively, in eyes with an opaque lens. CONCLUSION: Although all three PSL wavelengths successfully delivered appropriate burns restricted to the outer half of the retina in eyes with an opaque lens, the longer-wavelength yellow and red lasers were significantly more effective than the green laser. PSL may be a treatment option to accompany anti-vascular endothelial growth factor drug therapy.

Long-term surgical results of trabeculectomy for secondary glaucoma in Val30Met hereditary transthyretin amyloidosis.

This study reports the long-term results of trabeculectomy (LEC) for secondary glaucoma in hereditary transthyretin (ATTRv) amyloidosis patients and its correlation with prior vitrectomy. A retrospective case series was conducted involving 31 consecutive eyes of 20 ATTRv amyloidosis patients who underwent LEC between 2007 and 2020. The mean follow-up period was 73.2 ± 37.0 months (range: 20-181 months). Postoperative intraocular pressures (IOPs) were evaluated based on the following criteria: (a) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for laser suture lysis, (b) IOP between 6 and 15 mmHg without additional glaucoma surgeries, except for laser suture lysis, and (c) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for needling and laser suture lysis. Kaplan-Meier analysis revealed survival rates after LEC of 0.52 at 36 months, 0.42 at 60 months, and 0.25 at 84 months under criterion (a); 0.49 at 36 months, 0.27 at 60 months, and 0.11 at 84 months under criterion (b); and 0.76 at 36 months, 0.71 at 60 months, and 0.65 at 84 months under criterion (c). Eyes with a history of small gauge transconjunctival vitrectomy (SGTV) exhibited a tendency towards lower survival rates, although no statistically significant difference was observed (log-rank test; p = 0.193 under criterion (a) and p = 0.0553 under criterion (b)). Our findings suggest that LEC and additional needling procedures can provide some control over IOP; however, the overall postoperative outcomes of LEC for ATTRv amyloidosis remain unsatisfactory, even in the era of SGTV with reduced conjunctival scarring.

Microhook ab interno trabeculotomy for secondary glaucoma in patients with hereditary transthyretin amyloidosis.

PURPOSE: To report surgical outcomes of a Microhook ab interno trabeculotomy (µLOT) procedure for glaucoma secondary to hereditary transthyretin amyloidosis (ATTRv). STUDY DESIGN: Retrospective case series. METHODS: Medical records of patients with glaucoma secondary to ATTRv with transthyretin Val30Met variant, who underwent µLOT, were retrospectively reviewed. Surgical success was categorized according to the postoperative intraocular pressures (IOPs, mmHg) as follows: (a) 6 ≤ IOP ≤ 21; (b) 6 ≤ IOP ≤ 18; and (c) 6 ≤ IOP ≤ 15, without light perception loss or additional glaucoma surgery. Secondary outcomes were glaucoma medication scores and postoperative complications. RESULTS: This study included 18 eyes (13 patients, 6 men). The mean follow-up period was 25.2±9.8 months (7-38 months). Kaplan-Meier analysis indicated success rates of (a) 1.00 at 6, 1.00 at 12, and 0.43 at 24 months; (b), 1.00 at 6, 0.93 at 12, and 0.43 at 24 months; (c) 0.94 at 6, 0.75 at 12, and 0.27 at 24 months after operation. Postoperative IOPs were significantly reduced from the baseline of 25.2±5.8 mmHg to 11.5±2.7 at 3, 12.3±4.1 at 6, and 13.8±3.9 at 12 months (Dunnett's test). Medication scores were also improved at 3 and 6 months but without a significant reduction at 12 months. There were no severe complications requiring surgical intervention except for additional glaucoma surgery. CONCLUSION: µLOT for secondary glaucoma in ATTRv is safe and effective 1 year after surgery, but the effects diminish after 2 years.