Kinya Tsubota

Global metabolomics reveals metabolic dysregulation in ischemic retinopathy

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets.xa0Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (nxa0=xa09) and non-diabetic controls (nxa0=xa011) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (nxa0=xa011) and non-diabetic controls (nxa0=xa020)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to-proline pathway could be used as a therapeutic target in diabetic retinopathy.

Differences in the clinical features of two types of Vogt-Koyanagi-Harada disease: serous retinal detachment and optic disc swelling

PurposeTo elucidate the clinical differences between serous retinal detachment (RD)-type and optic disc (OD) swelling-type Vogt-Koyanagi-Harada (VKH) disease.MethodsWe performed a retrospective review of 96 patients with new-onset, active VKH disease. Patients were classified into serous RD-type or OD swelling-type VKH disease groups by means of optical coherence tomography and fluorescein angiography, and the differences between the 2 groups were analyzed.ResultsEighty-two patients were classified as having RD-type VKH disease (34 men and 48 women, aged 40.5xa0±xa012.6xa0years) and 14 patients as having OD swelling-type VKH disease (1 man and 13 women, aged 54.6xa0±xa011.6xa0years). Patients with the OD swelling type had older onset (Pxa0<xa00.001) and were more proportionately female (Pxa0=xa00.02) than those with the RD type. OD swelling-type VKH disease had a longer interval between disease onset and treatment initiation (22.4xa0±xa014.0xa0days vs 12.6xa0±xa014.7xa0days; Pxa0=xa00.02) and a higher frequency of chronic disease (64.3 vs 30.5xa0%; Pxa0=xa00.03) than did serous RD-type VKH disease. In the OD swelling type, patients with pretreatment visual acuity (VA) lower than 20/20 developed chronic disease more frequently than did those with VA of 20/20 or better (Pxa0=xa00.02).ConclusionsPatients with OD swelling-type VKH disease are more likely to be female, have older onset, and develop chronic disease than patients with RD-type VKH disease. In OD swelling-type VKH disease, worse VA before treatment is associated with the development of chronic disease.

PERSISTENT OVERPRODUCTION OF INTRAOCULAR VASCULAR ENDOTHELIAL GROWTH FACTOR AS A CAUSE OF LATE VITREOUS HEMORRHAGE AFTER VITRECTOMY FOR PROLIFERATIVE DIABETIC RETINOPATHY.

Purpose: The purpose of this study was to investigate whether vitreous levels of vascular endothelial growth factor (VEGF) predict late vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy, and how VEGF level changes in patients with postoperative late VH. Methods: Eighty-five eyes of 68 patients with proliferative diabetic retinopathy who underwent vitrectomy were analyzed retrospectively. Vitreous samples were collected from eyes undergoing primary vitrectomy and from eyes with late VH undergoing second vitrectomy. Vitreous VEGF levels were measured using enzyme-linked immunosorbent assay. The relationship between VEGF level and late VH (>4 weeks) occurring during follow-up as well as clinical findings, and changes in VEGF level in eyes with late VH undergoing second vitrectomy were analyzed. Results: Late VH occurred in 20 (24%) of 85 eyes, and 9 eyes required second vitrectomy. Vitreous levels of VEGF were significantly higher (median: 1,945 pg/mL; P < 0.0001) in eyes with late VH than in those without. Preexisting iris neovascularization (P < 0.0001), hypertension (P = 0.002), and proteinuria (P = 0.040) were also significant risk factors of late VH. Multivariate logistic regression analysis showed that a higher vitreous VEGF level was independently associated with a risk of postoperative late VH in patients with proliferative diabetic retinopathy (odds ratio: 20.8, 95% confidence interval: 2.72–159.47; P = 0.003). Vitreous VEGF level at second vitrectomy in patients with late VH was significantly lower compared with that at primary vitrectomy, but remained elevated (median: 1,610 pg/mL; P = 0.023). Conclusion: In patients with proliferative diabetic retinopathy, high intraocular VEGF level at primary vitrectomy was identified as an independent risk factor of postoperative late VH. Persistent overproduction of intraocular VEGF may be associated with postoperative late VH.

Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa.

Infectious agents have been identified as a major cause of specific types of human cancers worldwide. Several microorganisms have been identified as potential aggravators of ocular adnexal neoplasms; however, given the rarity of these neoplasms, large epidemiological studies are difficult to coordinate. This study aimed to conduct an exhaustive search for pathogenic DNA in lymphoproliferative disorders (LPD) of the ocular adnexa in a total of 70 patients who were diagnosed with LPD of the ocular adnexa between 2008 and 2013. Specimens were screened for bacterial, viral, fungal, and parasitic DNA by multiplex polymerase chain reaction (PCR) and quantitative real-time PCR. Among cases of conjunctival mucosa-associated lymphoid tissue lymphoma, human herpes virus (HHV)-6, HHV-7, chlamydia, Epstein-Barr virus (EBV) and bacterial 16S ribosomal DNA were detected. In cases of IgG4-related ocular disease, similar pathogens were detected but in a larger number of patients. Our PCR assays detected DNAs of various infectious agents in tumor specimens, especially HHV6, HHV7, and EBV, with different positive rates in various types of LPD. Chronic inflammatory stimulation or activation of oncogenes from these infectious agents might be involved in the pathogenesis of LPD of the ocular adnexa.

Aqueous immune mediators in malignant uveal melanomas in comparison to benign pigmented intraocular tumors.

BackgroundTo examine the usefulness of measuring immune mediators in aqueous humor samples for differentiating malignant uveal melanoma from benign pigmented intraocular tumors.MethodsThirteen eyes of 13 patients with uveal melanoma were studied, and 13 eyes of 13 patients with benign pigmented intraocular tumors served as controls. Undiluted samples of aqueous humor were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 35 immune mediators comprising 14 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T cell expressed and secreted, monokine induced by interferon-γ, basic fibroblast growth factor, Fas ligand, granzyme A, granzyme B, eotaxin, interferon-inducible T-cell alpha chemoattractant, fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, vascular endothelial growth factor, angiogenin, tumor necrosis factor-α, lymphotoxin-α, and CD40L.ResultsAqueous humor levels of angiogenin, IL-8, and MCP-1 were significantly higher in eyes with malignant melanoma than in those with benign tumors (pu2009<u20090.05).ConclusionsAngiogenin, IL-8, and MCP-1 levels in aqueous humor may be potential markers for distinguishing malignant uveal melanoma from benign pigmented intraocular tumors, and may be a useful adjunct to histomorphology, diagnostic imaging, and other biomarkers for the diagnosis and appropriate clinical management of malignant uveal melanoma.

Retrospective study of threshold time for the conventional treatment of branch retinal artery occlusion.

Purpose To investigate the medical backgrounds of patients and the treatment periods from the onset of branch retinal artery occlusion to obtaining improved final visual acuity. Methods This was a retrospective case series study. A total of 68 consecutive patients (69 eyes) with branch retinal artery occlusion who visited Tokyo Medical University Hospital from 2007 to 2012 were included in this study. All patients underwent ophthalmic examinations and visual acuity tests. We reviewed their medical records for systemic conditions, as well as the periods from onset of symptoms to treatment. Participants were categorized into 2 groups: group A (n=36), which received any treatment within 24 hours from onset, and group B (n=33), which visited our hospital after 24 hours from onset. Best corrected visual acuity (BCVA) changes from the first to final visit and the relationships between systemic condition and visiting time to BCVA were assessed. Results At the first visit, 59% of the patients had BCVA over 20/40; the ratio was increased to 74% at the final visit. BCVA improved more than 2 lines for 35% of the patients and was unchanged for 57% of those receiving conventional treatment. BCVA over 20/40 was significantly lower in hyperlipidemia patients. Hypertension, diabetes mellitus, and significant carotid stenosis were not correlated. The mean BCVA at baseline (0.91±1.03) significantly recovered to 0.35±0.91 after treatment in group A (P<0.001, Student’s t-test). The mean BCVA at baseline (0.30±0.64) was 0.25±0.61 at the final visit in group B (no significant change). Conclusion Conventional treatment within 24 hours from onset was acceptable for branch retinal artery occlusion.