Potential Benefits of Integrin αvß3 Antagonists in a Mouse Model of Experimental Dry Eye.

PURPOSE: The purpose of this study was to extensively evaluate the efficacy of integrin αvß3 antagonists for the treatment of experimental dry eye (EDE). METHODS: Vitronectin, an αvß3 ligand, was used to induce tumor necrosis factor-α gene expression in human THP-1 macrophages. To induce EDE, C57BL/6 mice were housed in a low-humidity controlled environment chamber and injected subcutaneously with scopolamine for 7 days. Subsequently, αvß3 antagonists, including RGDfD, c(RGDfD), c(RGDiD), c(RGDfK), ATN-161, SB273005, and cilengitide, were administered topically to EDE animals under controlled environment chamber conditions. Corneal epithelial damage in EDE was assessed by fluorescein staining. The density of conjunctival goblet cells and secretion of tears was measured by period acid-Schiff staining and phenol red-impregnated cotton threads, respectively. Inflammation markers, including tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-17A, and metalloproteinase (MMP)-9, in the pooled cornea and conjunctiva tissues were examined by real-time polymerase chain reaction. RESULTS: The inhibitory effects of αvß3 antagonists on the vitronectin-induced tumor necrosis factor-α gene expression and integrin-mediated inflammatory signaling were validated in THP-1 macrophages. αvß3 antagonists ameliorated the impairment of the corneal epithelial barrier with varying therapeutic efficacies, compared with vehicle-treated mice. c(RGDfD) and c(RGDiD) significantly protected against goblet cell loss, tear reduction, and proinflammatory gene expression in EDE. CONCLUSIONS: Topical applications of αvß3 antagonists yield therapeutic benefits in EDE by promoting corneal epithelial defect healing and reducing inflammation. Antagonistic targeting αvß3 may be a novel promising strategy to treat patients with dry eye disease.

Dialysis Modality and Incident Stroke Among Patients With End-Stage Kidney Disease: A Registry-Based Cohort Study.

BACKGROUND: Patients with end-stage kidney disease undergoing dialysis are at significant risk of stroke. Whether dialysis modality is associated with cerebrovascular disease is unclear. This study compared the risk of incident stroke in patients undergoing peritoneal dialysis or hemodialysis. METHODS: Thirty-nine thousand five hundred forty-two patients without a history of stroke who initiated dialysis between January 1, 2010, and December 31, 2014 were retrospectively studied using Taiwan's National Health Insurance Research Database. We matched 3809 patients undergoing peritoneal dialysis (mean age 59±13 years; 46.5% women) and 11 427 patients undergoing hemodialysis (mean age 59±13 years; 47.3% women) by propensity score in a 1:3 ratio with follow-up through December 31, 2015. The primary outcome was incident acute ischemic stroke. Secondary outcomes included hemorrhagic stroke, acute coronary syndrome, and all-cause mortality. Cox proportional hazard models were conducted to determine hazard ratios of clinical outcomes according to the dialysis modality. RESULTS: During a median follow-up of 2.59 (interquartile range 1.50-3.93) years, acute ischemic stroke, hemorrhagic stroke, and acute coronary syndrome occurred in 783 (5.1%), 376 (2.5%), and 1350 (8.9%) patients, respectively. In a multivariable Cox model that accounted for the competing risk of death, acute ischemic stroke occurred more frequently in the peritoneal dialysis group than in the hemodialysis group (subdistribution hazard ratio, 1.32 [95% CI, 1.13-1.54]; P=0.0005). There were no significant treatment-related differences in the risk of hemorrhagic stroke (subdistribution hazard ratio, 0.89 [95% CI, 0.70-1.14]; P=0.3571) and acute coronary syndrome (subdistribution hazard ratio, 0.99 [95% CI, 0.88-1.12]; P=0.9080). Patients undergoing peritoneal dialysis were more likely to die from any cause than patients undergoing hemodialysis (adjusted hazard ratio, 1.24 [95% CI, 1.15-1.33]; P<0.0001). CONCLUSIONS: Peritoneal dialysis was associated with a significantly increased risk of acute ischemic stroke compared with hemodialysis. Further studies are needed to clarify whether more aggressive cerebrovascular preventive strategies might mitigate the excess risk for ischemic stroke among patients receiving peritoneal dialysis.

Retinal vasoproliferative tumor regression after intravitreal aflibercept.

Retinal vasoproliferative tumors (RVPTs) are rare benign retinal lesions typically located in the inferotemporal peripheral retina. Several treatment options exist for the management of RVPTs, but no consensus has been proposed. There are only a few reports on the use of anti-vascular endothelial growth factor with bevacizumab to treat exudative or neovascular retinal changes secondary to RVPTs. This report describes a 68-year-old female with a history of systemic hypertension that presented with a 2-week history of gradual loss of visual acuity in the right eye. Fundoscopic examination showed a RVPTs with atypical location that had a favorable response to two-intravitreal aflibercept injections 1 month apart, with resulting subretinal fluid absorption and tumor regression.

Association of diabetic retinopathy with risk of developing cardiovascular diseases in patients undergoing hemodialysis: A population-based cohort study.

BACKGROUND AND AIMS: While patients undergoing dialysis have substantially increased cardiovascular event rates compared with the general population, predicting individual risk remains difficult. Whether diabetic retinopathy (DR) is associated with cardiovascular diseases in this population is unclear. METHODS AND RESULTS: We conducted a nationwide cohort study of 27,686 incident hemodialysis patients with type 2 diabetes who were enrolled in Taiwan's National Health Insurance Research Database between January 1, 2010, and December 31, 2014, and had follow-up data until December 31, 2015. The primary outcome was a composite of macrovascular events, including acute coronary syndrome (ACS), acute ischemic stroke, and peripheral artery disease (PAD). A total of 10,537 (38.1%) patients had DR at baseline. We matched 9164 patients without DR (mean age, 63.7 years; 44.0% women) to 9164 patients with DR (mean age, 63.5 years; 43.8% women) by propensity score. During a median follow-up of 2.4 years, 5204 patients in the matched cohort experienced a primary outcome. The presence of DR was associated with a higher risk of a primary outcome (subdistribution hazard ratio [sHR] 1.07; 95% CI, 1.01-1.13), which reflected a higher risk of acute ischemic stroke (sHR 1.26; 95% CI, 1.14-1.39) and PAD (sHR 1.14; 95% CI, 1.05-1.25) but not ACS (sHR 0.99; 95% CI, 0.92-1.06). CONCLUSIONS: The presence of DR signifies an increased risk of acute ischemic stroke and PAD in hemodialysis patients with type 2 diabetes, independent of the known risk factors. These results highlight the need for more comprehensive cardiovascular assessment and management in hemodialysis patients with DR.

A short peptide derived from pigment epithelial-derived factor exhibits an angioinhibitory effect.

BACKGROUND: Pigment epithelial-derived factor (PEDF), a 50 kDa secreted glycoprotein, exhibits distinct effects on a range of cell types. PEDF has been shown to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis and widely accepted as a promising agent for treatment eye diseases related to neovascularization. A pool of short peptide fragments derived from PEDF reportedly manifests angioinhibitory activity. This study aims to determine the minimal PEDF fragment which can exert the anti-VEGF effect. METHODS: A series of shorter synthetic peptides, derived from the 34-mer (PEDF amino acid positions Asp44-Asn77), were synthesized. An MTT assay was used to evaluate the ability of the 34-mer-derived peptides to inhibit VEGF-induced proliferation of multiple myeloma RPMI8226 cells. Cell apoptosis was monitored by annexin V-FITC staining. Western blot analysis was used to detect phosphorylated kinases, including c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and the expression of apoptosis-associated proteins, including p53, bax and caspase-3. VEGF-mediated angiogenesis of human umbilical vein endothelial cells (HUVECs), rat aortic ring and mouse cornea were used to detect the angioinhibitory activity of the PEDF-derived peptides. RESULTS: The MTT assay showed that the anti-VEGF effect of a 7-mer (Asp64-Ser70) was 1.5-fold greater than the 34-mer. In addition, massive apoptosis (37%) was induced by 7-mer treatment. The 7-mer induced JNK phosphorylation in RPMI8226 cells. Cell apoptosis and apoptosis-associated proteins induced by the 7-mer were blocked by pharmacological inhibition of JNK, but not p38 MAPK. Moreover, the 7-mer prevented VEGF-mediated angiogenesis of endothelial cells (ECs), including tube formation, aortic EC spreading and corneal neovascularization in mice. CONCLUSIONS: This is the first study to show that the PEDF 7-mer peptide manifests anti-VEGF activity, further establishing its potential as an anti-angiogenic agent.

The Use of Autologous Serum to Reverse Severe Contact Lens-induced Limbal Stem Cell Deficiency.

PURPOSE: To describe the efficacy of autologous serum (AS) eye drops to reverse severe contact lens (CL)-induced limbal stem cell (LSC) deficiency (LSCD). METHODS: This is a prospective, uncontrolled, interventional case series that enrolled 20 eyes of 14 consecutive patients diagnosed with severe CL-induced LSCD at presentation, based on clinical examination, at a tertiary referral center for the period December 2016 to December 2018. All eyes underwent AS treatment for at least 2 weeks with a follow-up for at least 2 months. Demographic data and treatment outcomes were collected and analyzed. RESULTS: The mean patient age at presentation was 30.5 years (range, 19-49 years). The mean duration of soft contact lens wear was 15.6 years (SD, 7.58 years; range, 5-31 years). All study eyes had pain and blurred vision at presentation. All eyes had recurrent or persistent corneal epithelial defect, stromal scarring and opacity, and superficial vascularization and peripheral pannus at presentation. Aggressive treatment with AS succeeded in all eyes. Signs and symptoms of LSCD stabilized in all eyes within 2 weeks and resolved in 6 eyes (30.0%) in 2 weeks, 9 eyes (45.0%) in 4 weeks, and 5 eyes (25.0%) in 8 weeks. The mean follow-up time was 9.45 ± 1.79 weeks (range, 8-24 weeks). CONCLUSIONS: Early identification and aggressive treatment of the ocular surface disease with AS can medically reverse severe CL-induced LSCD and prevent the need for surgical intervention.