Early thrombus formation is required of eccentric and heterogenous neointimal hyperplasia under disturbed flow.

BACKGROUND: Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared to laminar flow in the arterial inflow and the venous outflow. We hypothesize that early thrombus formation is required for eccentric and heterogenous NIH under disturbed flow. METHOD: Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were harvested transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry and en face staining. RESULT: Under disturbed flow, both mouse and human AVF showed eccentric and heterogenous NIH. Maladapted vein wall was characterized by eccentric and heterogenous neointima that was composed of a different abundance of thrombus and smooth muscle cells (SMC). PF4-cre × mT/mG reporter mice AVF showed that GFP-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cells loss and continue to accumulate under disturbed flow. Neither disturbed flow with limited endothelial cell loss nor non-disturbed flow induced heterogenous neointima in different animal models. CONCLUSION: Early thrombus contributes to late heterogenous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss and thrombus formation are critical to form eccentric and heterogenous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogenous NIH.

Heterogeneous gene expression during early arteriovenous fistula remodeling suggests that downregulation of metabolism predicts adaptive venous remodeling.

Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a 'normal' AVF (nAVF) group and an 'outliers' (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.

Disturbed flow in the juxta-anastomotic area of an arteriovenous fistula correlates with endothelial loss, acute thrombus formation, and neointimal hyperplasia.

Clinical failure of arteriovenous neointimal hyperplasia (NIH) fistulae (AVF) is frequently due to juxta-anastomotic NIH (JANIH). Although the mouse AVF model recapitulates human AVF maturation, previous studies focused on the outflow vein distal to the anastomosis. We hypothesized that the juxta-anastomotic area (JAA) has increased NIH compared with the outflow vein. AVF was created in C57BL/6 mice without or with chronic kidney disease (CKD). Temporal and spatial changes of the JAA were examined using histology and immunofluorescence. Computational techniques were used to model the AVF. RNA-seq and bioinformatic analyses were performed to compare the JAA with the outflow vein. The jugular vein to carotid artery AVF model was created in Wistar rats. The neointima in the JAA shows increased volume compared with the outflow vein. Computational modeling shows an increased volume of disturbed flow at the JAA compared with the outflow vein. Endothelial cells are immediately lost from the wall contralateral to the fistula exit, followed by thrombus formation and JANIH. Gene Ontology (GO) enrichment analysis of the 1,862 differentially expressed genes (DEG) between the JANIH and the outflow vein identified 525 overexpressed genes. The rat jugular vein to carotid artery AVF showed changes similar to the mouse AVF. Disturbed flow through the JAA correlates with rapid endothelial cell loss, thrombus formation, and JANIH; late endothelialization of the JAA channel correlates with late AVF patency. Early thrombus formation in the JAA may influence the later development of JANIH.NEW & NOTEWORTHY Disturbed flow and focal endothelial cell loss in the juxta-anastomotic area of the mouse AVF colocalizes with acute thrombus formation followed by late neointimal hyperplasia. Differential flow patterns between the juxta-anastomotic area and the outflow vein correlate with differential expression of genes regulating coagulation, proliferation, collagen metabolism, and the immune response. The rat jugular vein to carotid artery AVF model shows changes similar to the mouse AVF model.

A central arteriovenous fistula reduces systemic hypertension in a mouse model.

Objective: A central arteriovenous fistula (AVF) has been proposed as a potential novel solution to treat patients with refractory hypertension. We hypothesized that venous remodeling after AVF creation in the hypertensive environment reduces systemic blood pressure but results in increased AVF wall thickness compared with remodeling in the normotensive environment. Methods: A central AVF was performed in C57BL6/J mice previously made hypertensive with angiotensin II (Ang II); mice were sacrificed on postoperative day 7 or 21. Results: In mice treated with Ang II alone, the mean systolic blood pressure increased from 90 ± 5 mmHg to 160 ± 5 mmHg at day 21; however, in mice treated with both Ang II and an AVF, the blood pressure decreased with creation of an AVF. There were significantly more PCNA-positive cells, SM22α/PCNA-positive cells, collagen I deposition, and increased Krüppel-like Factor 2 immunoreactivity in hypertensive mice with an AVF compared with normotensive mice with an AVF. Conclusions: These data show that a central AVF decreases systemic hypertension as well as induces local alterations in venous remodeling.

Sex hormones impact early maturation and immune response in the arteriovenous fistula mouse model.

Arteriovenous fistulae (AVF) fail to mature more frequently in female patients compared with male patients, leading to inferior outcomes and decreased utilization. Since our mouse AVF model recapitulates sex differences in human AVF maturation, we hypothesized that sex hormones mediate these differences during AVF maturation. C57BL/6 mice (9-11 wk) were treated with aortocaval AVF surgery and/or gonadectomy. AVF hemodynamics were measured via ultrasound (days 0-21). Blood was collected for FACS and tissue for immunofluorescence and ELISA (days 3 and 7); wall thickness was assessed by histology (day 21). Inferior vena cava shear stress was higher in male mice (P = 0.0028) after gonadectomy, and they had increased wall thickness (22.0 ± 1.8 vs. 12.7 ± 1.2 µm; P < 0.0001). Conversely, female mice had decreased wall thickness (6.8 ± 0.6 vs. 15.3 ± 0.9 µm; P = 0.0002). Intact female mice had higher proportions of circulating CD3+ T cells on day 3 (P = 0.0043), CD4+ (P = 0.0003) and CD8+ T cells (P = 0.005) on day 7, and CD11b+ monocytes on day 3 (P = 0.0046). After gonadectomy, these differences disappeared. In intact female mice, CD3+ T cells (P = 0.025), CD4+ T cells (P = 0.0178), CD8+ T cells (P = 0.0571), and CD68+ macrophages (P = 0.0078) increased in the fistula wall on days 3 and 7. This disappeared after gonadectomy. Furthermore, female mice had higher IL-10 (P = 0.0217) and TNF-α (P = 0.0417) levels in their AVF walls than male mice. Sex hormones mediate AVF maturation, suggesting that hormone receptor signaling may be a target to improve AVF maturation.NEW & NOTEWORTHY After arteriovenous fistula creation, females have lower rates of maturation and higher rates of failure than males. In a mouse model of venous adaptation that recapitulates human fistula maturation, sex hormones may be mechanisms of the sexual dimorphism: testosterone is associated with reduced shear stress, whereas estrogen is associated with increased immune cell recruitment. Modulating sex hormones or downstream effectors suggests sex-specific therapies and could address disparities in sex differences in clinical outcomes.

Executive summary: Japanese guidelines for allergic conjunctival diseases 2021.

Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD. Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.

Endothelial Cell TGF-ß (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.

BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-ß (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-ß signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-ß receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-ß receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-ß signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-ß signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-ß signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell-targeted TGF-ß inhibition may be a translational strategy to improve AVF patency.

Multicenter prospective observational study of fungal keratitis in Japan: analyses of culture-positive cases.

PURPOSE: To investigate the clinical characteristics and causative fungi in patients with fungal keratitis in Japan, and to determine factors related to the prognosis. STUDY DESIGN: Multicenter prospective observational study. METHODS: Eligible patients were enrolled from November 2011 to October 2013 at the 1st stage and from April 2015 to March 2016 at the 2nd stage. The corneal foci were scraped, and the scrapings were cultured in potato dextrose agar. The isolated fungi were identified by gene analyses. Data were collected from the clinical records and statistically analyzed by Cox and logistic regression analyses. RESULTS: Ninety-four fungal strains were isolated from 93 cases, including 42 yeast-like fungi and 52 filamentous fungi. The fungi affected the deep layers of the cornea in 23 cases (24.7%) and the peripheral cornea in 29 cases (31.2%). The incidences of lid swelling/redness, ciliary injection, anterior chamber cells/flare, anterior chamber fibrin, and hyphate ulcer in cases of filamentous fungi were significantly higher than in yeast-like fungi. No history of topical steroids, absence of a main lesion in the peripheral cornea, and best-corrected visual acuity (BCVA) of more than 0.04 at the first visit were related to a shorter healing time. No history of ocular surgery, absence of lesion at one-third deep stromal layer and BCVA of more than 0.04 at the first visit were correlated with BCVA at 3 months after the initial examination. CONCLUSION: Fungal keratitis is caused by various species of fungi and can become refractory due to poor prognosis factors.

Multicenter prospective observational study of fungal keratitis in Japan: analyses of in vitro susceptibility tests for combinations of drugs.

PURPOSE: To determine the effects of a combination of two antifungal drugs against causative fungi of fungal keratitis in Japan. STUDY DESIGN: Multicenter prospective observational study. METHODS: Eighteen isolates of yeast-like fungi and 22 isolates of filamentous fungi collected by the Multicenter Prospective Observational Study of Fungal Keratitis in Japan were studied. Specially manufactured minimum inhibitory concentration (MIC) measurement plates were used to test the effectiveness of 10 combinations of two antifungal drugs against the isolates. The combinations were pimaricin (PMR) + voriconazole (VRCZ), PMR + fluconazole (FLCZ), PMR + miconazole (MCZ), PMR + micafungin (MCFG), VRCZ + FLCZ, VRCZ + MCZ, VRCZ + MCFG, VRCZ + amphotericin-B (AMPH-B), MCZ + FLCZ, and MCZ + MCFG. The checkerboard microdilution method was used, and the fractional inhibitory concentration (FIC) index was calculated based on the guidelines of The Clinical & Laboratory Standards Institute (CLSI). RESULTS: In yeast-like fungi, additive effects were observed between PMR and MCFG in 77.8% of the isolates, and they were also observed between the azoles. Synergistic effects were observed on 11.1% of the isolates for MCZ and FLCZ. On the other hand, antagonistic effects were present between PMR and azoles with 88.9% between PMR and VRCZ, 72.2% between PMR and FLCZ, and 94.4% between PMR and MCZ. In filamentous fungi, additive effects were observed between PMR and MCFG in 40.9% of the isolates, and between VRCZ and MCZ in 40.9% of the isolates. Antagonistic effects were observed for PMR and the azoles. CONCLUSIONS: The combination of drugs prescribed for fungal keratitis incurs a possibility of synergistic, additive, indifferent, or antagonistic effects, depending on drug combinations and fungal strains.

A multicenter clinical trial of orthokeratology in school-aged children and adolescents in Japan.

PURPOSE: This study investigated the safety and efficacy of orthokeratology in myopic children in Japan. STUDY DESIGN: Prospective clinical trial. METHODS: This study enrolled myopic children aged 6-16 years with a spherical equivalent of -1.00 D to -4.00 D and astigmatism of -1.5 D or lower, whose parents could manage contact lens use and could provide written informed consent. The children were treated with orthokeratology lenses (BREATH-O CORRECT R, Universal View Co., Ltd.) for 3 years. Slit-lamp findings, visual acuity, intraocular pressure, subjective refraction, corneal topography, corneal endothelial cell density, corneal thickness, and axial length were regularly assessed. RESULTS: This study included 96 eyes of 48 patients (average age, 10.7 ± 2.08 years). The average baseline spherical equivalent was -2.46 ± 0.97 D. The average baseline uncorrected visual acuity was 0.74 ± 0.32 logMAR, with significant improvement to -0.08 ± 0.18 logMAR at 4 weeks and 0.02 ± 0.21 logMAR at 3 years (both p < 0.001, Dunnett's test). The average baseline corneal endothelial cell density was 3053 ± 181 cells/mm2 and 3028 ± 213 cells/mm2 at postoperative 3 years (p = 0.9933, Dunnett's test). The average axial length was 24.70 ± 0.78 mm at baseline, 24.77 ± 0.80 mm at 12 weeks, and 25.32 ± 0.85 mm at 36 months. Although mild corneal epithelial disorders occurred in 18% of eyes, they were successfully treated with eye drops, enabling resumption of lens usage. No serious adverse events were observed. CONCLUSION: Orthokeratology lens (BREATH-O CORRECT R) use in children demonstrated good efficacy and safety during 3 years of follow-up.

Japanese guidelines for allergic conjunctival diseases 2020.

The definition, classification, pathogenesis, test methods, clinical findings, criteria for diagnosis, and therapies of allergic conjunctival disease are summarized based on the Guidelines for Clinical Management of Allergic Conjunctival Disease 2019. Allergic conjunctival disease is defined as "a conjunctival inflammatory disease associated with a Type I allergy accompanied by some subjective or objective symptoms." Allergic conjunctival disease is classified into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. Representative subjective symptoms include ocular itching, hyperemia, and lacrimation, whereas objective symptoms include conjunctival hyperemia, swelling, folliculosis, and papillae. Patients with vernal keratoconjunctivitis, which is characterized by conjunctival proliferative changes called giant papilla accompanied by varying extents of corneal lesion, such as corneal erosion and shield ulcer, complain of foreign body sensation, ocular pain, and photophobia. In the diagnosis of allergic conjunctival diseases, it is required that type I allergic diathesis is present, along with subjective and objective symptoms accompanying allergic inflammation. The diagnosis is ensured by proving a type I allergic reaction in the conjunctiva. Given that the first-line drug for the treatment of allergic conjunctival disease is an antiallergic eye drop, a steroid eye drop will be selected in accordance with the severity. In the treatment of vernal keratoconjunctivitis, an immunosuppressive eye drop will be concomitantly used with the abovementioned drugs.

Reduced steroid-induced intraocular pressure elevation in tacrolimus-treated refractory allergic ocular diseases.

PURPOSE: To determine whether topical tacrolimus can lessen steroid-induced intraocular pressure (IOP) elevation. STUDY DESIGN: Open cohort post hoc analysis study. METHODS: Five hundred eleven patients with vernal keratoconjunctivitis or atopic keratoconjunctivitis (mean age 17.0 ± 9.2 years) were studied. All 511 patients were treated with topical tacrolimus with or without topical steroids, and the changes in IOP were measured monthly for 3 months. The elevation in IOP induced by use of topical steroids was calculated using mixed linear regression analyses. The relationship between the elevation in IOP within 4 weeks and the use or nonuse of tacrolimus reported in published data was analyzed using metaregression analysis to estimate the effects of tacrolimus on the IOP in eyes treated with topical steroids. RESULTS: The mean topical steroid-induced IOP elevation in tacrolimus-treated eyes was lower, by 5.2 mmHg (P = 0.04), than that in earlier published data without tacrolimus as the control. In the tacrolimus-treated eyes, the mean betamethasone-induced IOP elevation was 1.3 mmHg without discontinuation of the steroid. Metaregression analysis indicated that glaucoma history and younger age had significant effects on topical steroid-induced IOP elevation, by 4.0 mmHg (P = 0.002) and 3.9 mmHg (P = 0.01), respectively. In tacrolimus-treated eyes, the most significant effect on the IOP was associated with glaucoma history or medication; however, its effect on the IOP was limited to 1.7 mmHg elevation (P = 0.006). CONCLUSIONS: Topical tacrolimus may lessen the steroid-induced elevation in IOP in younger individuals and may be a good adjunctive therapy to avoid IOP elevation in refractory cases.

Presence of Acanthamoeba and diversified bacterial flora in poorly maintained contact lens cases.

Acanthamoeba can cause visually destructive Acanthamoeba keratitis (AK) in contact lens (CL) users. The purpose of this study was to determine whether Acanthamoeba was present in the CL cases of CL wearers and to develop techniques to prevent the contaminations. To accomplish this, 512 CL case samples were collected from 305 healthy CL wearers. Using real-time PCR, Acanthamoeba DNA was detected in 19.1% of CL cases, however their presence was not directly associated with poor CL case care. Instead, the presence of Acanthamoeba DNA was associated with significant levels of many different bacterial species. When the CL cases underwent metagenomic analysis, the most abundant bacterial orders were Enterobacteriales followed by Burkholderiales, Pseudomonadales, and Flavobacteriales. The presence of Acanthamoeba was characterized by Propionibacterium acnes and Rothia aeria and was also associated with an increase in the α diversity. Collectively, Acanthamoeba contamination occurs when a diversified bacterial flora is present in CL cases. This can effectively be prevented by careful and thorough CL case care.

Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study.

INTRODUCTION: Diquafosol is a P2Y2 receptor agonist that has been shown to be effective in the treatment of dry eye disease (DED) in short-term studies; however, its long-term safety and effectiveness have not been evaluated in a real-world setting. METHODS: This prospective, multicentre, open-label observational study was conducted in patients with DED over 12 months. Safety endpoints included the incidence of adverse drug reactions (ADRs) and serious ADRs. Effectiveness endpoints included change from baseline in keratoconjunctival staining score, tear film break-up time (BUT) and Dry Eye-related Quality of Life Score (DEQS). RESULTS: A total of 580 patients were included, most of whom were female (82.9%). The proportion of patients who completed 12 months of observation was 55.0%, the most common reason for discontinuation was patient decision (54.6%). The incidence of ADRs was 10.7% and was highest during the first month of treatment (5.5%); no serious ADRs were reported. Compared with baseline, significant improvements in all effectiveness outcomes, including keratoconjunctival fluorescein staining score, BUT and DEQS summary score, were observed at each evaluation during the treatment period (p < 0.001). CONCLUSION: The present, real-world study showed that diquafosol 3.0% ophthalmic solution was well tolerated and effective in the long-term treatment of DED.

Air pollution significantly associated with severe ocular allergic inflammatory diseases.

Ambient air pollution is a well-recognized risk for various diseases including asthma and heart diseases. However, it remains unclear whether air pollution may also be a risk of ocular allergic diseases. Using a web-based, nation-wide, cross-sectional study design, we examined whether the level of ambient air pollution is significantly associated with the prevalence of ocular allergic diseases. A web-based questionnaire was posted to invite the participants who are members of the Japan Ophthalmologist Association and their family members. The answers from 3004 respondents were used to determine whether there were significant associations between the level of the pollutants and the prevalence of ocular allergic diseases. The study period was between March to May 2017. The data of the air pollutants during 2012 to 2016 were obtained from the National Institute for Environmental Studies. The prevalence of allergic diseases was calculated by post stratification and examined for significant associations with the level of pollutants using multiple logistic regression analyses. The prevalence of seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis (AKC), and vernal keratoconjunctivitis (VKC) in Japan was 45.4%, 14.0%, 5.3%, and 1.2%, respectively. The high prevalence of the severe forms of allergic conjunctivitis, including AKC and VKC, were significantly associated with the levels of the air pollutants. The prevalence of AKC was significantly associated with the levels of NO2 with an odds ratio (OR) of 1.23 (per quintile). The prevalence of VKC was significantly associated with the levels of NOx and PM10 with ORs of 1.72 and 1.54 respectively. The significant associations between the prevalence of AKC and VKC and the levels of air pollutants indicate that clinicians need to be aware that air pollutants may pose serious risks of vision threatening severe ocular allergy.

Characterization of doxycycline-dependent inducible Simian Virus 40 large T antigen immortalized human conjunctival epithelial cell line.

PURPOSE: To present the properties of a newly developed immortalized human conjunctival epithelial cell (iHCjEC) line. METHODS: iHCjECs were developed to induce Simian Virus 40 large T-antigen (SV40LT) by incorporating lentivirus in a tetracycline (Tet)-regulated gene-expression system into primary cultures of human conjunctival epithelial cells. The population doubling time and morphology of the iHCjECs were analyzed. The expressions of CK13, CK19, CK12, and MUC1, MUC4, MUC16, and MUC5AC were determined by real time PCR and immunohistochemically under different culture conditions. The organotypic culture model in which iHCjECs were cultured on rabbit conjunctival fibroblast-embedded collagen gel was used to characterize the iHCjECs. RESULTS: The iHCjECs cultured with doxycycline (Dox) continued to proliferate for at least 20 passages and had a cobblestone-like appearance. The expressions of CK13 and CK19 but not CK12 were detected in the iHCjECs, and the expression of CK13 increased in culture media lacking Dox (Dox-). The expressions of MUC1, MUC4, MUC16, and MUC5AC were detected in iHCjECs, and a relatively strong immunostaining of MUC5AC was detected with Dox(-) added 5% FBS. Stratified iHCjECs were observed in organotypic culture at 5 days. CONCLUSION: The iHCjECs had high proliferation rates and abilities to control the differentiation potency to control the expression of SV40 LT-antigen with Tet-regulated gene-expression system. They are able to express the mucin gene repertoire of their native epithelia. The iHCjECs can be a useful experimental cell line to study conjunctival epithelial cell characteristics and for pathophysiological and toxicological studies.

Topical Tacrolimus for Chronic Allergic Conjunctival Disease with and without Atopic Dermatitis.

Purpose/Aim: This study evaluated the efficacy of topical 0.1% tacrolimus ophthalmic suspension for treating chronic allergic conjunctival disease with and without atopic dermatitis. Materials and Methods: This study was conducted as a prospective observational post-market survey. Our large-scale study protocol was accepted by the Pharmaceuticals and Medical Devices Agency in Japan and included patients who were prescribed topical tacrolimus for the treatment of chronic allergic conjunctival disease from May 2008 to Aug 2010 in Japan. Topical tacrolimus was instilled 2 times daily for 6 months. The primary endpoint was the change from baseline in papillae-limbus-cornea clinical signs score (based on the presence of papillae, giant papillae, Trantas' dots, limbal swelling, and corneal epithelial signs). Remission rate following topical tacrolimus treatment was investigated using generalized estimating equations. Results: A total of 1821 subjects were included in the analyses. Six months into treatment, 83.0% and 87.7% of subjects with and without atopic dermatitis, respectively, were in remission (based on the papillae-limbus-cornea grading score). Topical tacrolimus treatment was equally effective in improving papillae-limbus-cornea grading scores from baseline in both study groups after 6 months of treatment. Additionally, the odds ratio for remission increased over time. The concomitant use of topical steroids improved papillae-limbus-cornea grading scores, including papillary signs with a statistically significant, but low odds ratio. Conclusion: Tacrolimus ophthalmic suspension is useful for treating chronic allergic conjunctival disease with and without atopic dermatitis. Clinical response to local tacrolimus therapy is dependent upon treatment duration.

In Vivo Confocal Microscopic Observations of Vortex Keratopathy in Patients with Amiodarone-Induced Keratopathy and Fabry Disease.

PURPOSE: To compare the morphology of two types of vortex keratopathy: amiodarone-induced keratopathy and the Fabry disease-associated keratopathy. PATIENTS AND METHODS: Eight patients who were receiving oral amiodarone therapy and 3 patients with Fabry disease, a mother and her 2 daughters, were examined by slit-lamp biomicroscopy and in vivo confocal microscopy (IVCM) regularly. RESULTS: Amiodarone-induced keratopathy developed in 7 of the 8 patients, and it was detected as early as 7 days by IVCM and 14 days by slit-lamp biomicroscopy. The in vivo confocal microscopic images showed a clustering of corneal epithelial cells with a highly reflective cytoplasm in both types of keratopathy. In the amiodarone-induced keratopathy, the highly reflective epithelial cells were first found at the center of the cornea and then spread to the periphery with increasing time on amiodarone. In Fabry disease, the highly reflective epithelial cells were consistently observed extending from the limbus to the central cornea. CONCLUSION: These findings suggest that the corneal epithelial cells most likely endocytose amiodarone from the tear film in the amiodarone-induced keratopathy. In Fabry disease, globotriaosylceramide deposits are taken up by the lysosomes of the limbal epithelial stem cells, and they differentiate and migrate to the center of the cornea to form the whorl pattern.

Incidence of endophthalmitis and the perioperative practices of cataract surgery in Japan: Japanese Prospective Multicenter Study for Postoperative Endophthalmitis after Cataract Surgery.

PURPOSE: To prospectively survey the incidence of endophthalmitis following cataract surgery and investigate the current perioperative practices in Japan. METHODS: Patients who underwent cataract surgery from January 2012 to December 2013 were included. Information on perioperative practices were recorded prospectively. Clinical characteristics were examined in cases with endophthalmitis. RESULTS: A total of 63,244 patients who underwent cataract surgery in 205 facilities were enrolled. The detailed information about the current perioperative scenario surrounding cataract surgery in Japan was evaluated for the preoperative, intraoperative, and postoperative practices, i.e., patient background, prophylactic antibiotic regimen, modes of disinfection or disinfectant use, preoperative procedure, surgical method, surgical materials, surgical complication, or others. Postoperative endophthalmitis developed in 25 patients within 8 weeks postoperatively (incidence 0.04%). However, since outbreaks of toxic anterior segment syndrome (TASS) after implantation of intraocular lenses contaminated with aluminum (HOYA iSert 251 and 255) were reported, 10,261 cases implanted with the lenses had been excluded (as having a risk for non-infectious late-onset TASS). In the remaining 52,983 cases, postoperative endophthalmitis developed in 13 cases within 8 weeks postoperatively (incidence 0.025%). CONCLUSIONS: This prospective survey identified the current perioperative practices representing cataract surgery and the incidence of endophthalmitis following cataract surgery (0.025%) in Japan. We believe this information can serve as a guide for future improvement in risk-reduction strategies.