Presumed Necrotizing Viral Retinitis after Intravitreal Triamcinolone Injection: Case Report

A 56-year-old man presented with anterior chamber inflammation, increased intraocular pressure, peripheral retinal infiltration, and generalized retinal arterial obstruction suggesting acute retinal necrosis five months after intravitreal triamcinolone acetonide injection (IVTA). He was treated with intravenous antiviral agents and aspirin. Shortly after treatment, retinal infiltrations were resolved, and partial recanalization of the obstructed vessel was observed. Viral retinitis may occur as an opportunistic infection following IVTA due to the local immune modulatory effect of the steroid; hence, close observation following IVTA is necessary

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Correction: Volume69, Issue6 Page1306-1306 DOI10.2337/db20-er06a Published JUN 2020To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P valuePeer reviewe

Abstract 292: Notch Inhibition Stabilizes the Progression of Small Abdominal Aortic Aneurysm in a Mouse Model

The progression of abdominal aortic aneurysm (AAA) involves a sustained influx of proinflammatory macrophages, which exacerbate tissue injury by releasing cytokines, chemokines and matrix metalloproteinases (MMPs). While multiple factors are involved in disease pathogenesis, the critical stimulus is the differentiation and infiltration of naïve macrophages (Mϕ) towards classical (M1) activation. In contrast, Mϕ can also be programmed to M2-macrophages which inhibit the inflammatory response and promote tissue repair. Previously, we showed that Notch deficiency reduces the development of AAA in the angiotensin II (AngII)-induced mouse model by preventing infiltration of Mϕ. Because of its regulatory roles in macrophage differentiation, we examined if Notch inhibition in a mouse model prevents progression of small AAA and if these effects are associated with Mϕ-differentiation. Notch inhibition (DAPT) started at day 3 or 8 of AngII infusion arrested the progression of AAA in Apoe -/- mice as demonstrated by a decreased luminal diameter and aortic width. The abdominal aortae treated with DAPT showed decreased MMPs expression and presence of elastin precursors including tropoelastin. Marginal adventitial thickening observed in DAPT-treated Apoe -/- mice was not associated with increased total macrophage content. Instead, DAPT-treated abdominal aortae showed increased expression of Cd206 positive M2-macrophages and decreased expression of Il12 positive M1-macrophages. Increased expression of IL12 positive M1 macrophages and its strong correlation with active Notch1 signaling (NICD) was also observed in the infrarenal aortae from AAA patients. Notch1 deficiency promoted M2-differentiation of Mϕ by upregulating transforming growth factor ( Tgf)-β2 expression in bone marrow-derived Mϕ at basal levels and in response to IL4. Protein expression of Tgf-β2 and its downstream pSmad2 also increased in DAPT-treated Apoe -/- mice, indicating a potential link between Notch and Tgf-β2 signaling in the M2-differentiation of Mϕ. Overall, Notch inhibition stabilizes the progression of AAA by macrophage-differentiation-dependent mechanisms and provides insights for novel therapeutic strategies to prevent the progression of small AAA.</jats:p

Pharmacological Inhibitor of Notch Signaling Stabilizes the Progression of Small Abdominal Aortic Aneurysm in a Mouse Model

Background The progression of abdominal aortic aneurysm ( AAA ) involves a sustained influx of proinflammatory macrophages, which exacerbate tissue injury by releasing cytokines, chemokines, and matrix metalloproteinases. Previously, we showed that Notch deficiency reduces the development of AAA in the angiotensin II –induced mouse model by preventing infiltration of macrophages. Here, we examined whether Notch inhibition in this mouse model prevents progression of small AAA and whether these effects are associated with altered macrophage differentiation. Methods and Results Treatment with pharmacological Notch inhibitor ( DAPT [N‐(N‐[3,5‐difluorophenacetyl]‐L‐alanyl)‐S‐phenylglycine t‐butyl ester] ) at day 3 or 8 of angiotensin II infusion arrested the progression of AAA in Apoe −/− mice, as demonstrated by a decreased luminal diameter and aortic width. The abdominal aortas of Apoe −/− mice treated with DAPT showed decreased expression of matrix metalloproteinases and presence of elastin precursors including tropoelastin and hyaluronic acid. Marginal adventitial thickening observed in the aorta of DAPT ‐treated Apoe −/− mice was not associated with increased macrophage content, as observed in the mice treated with angiotensin II alone. Instead, DAPT ‐treated abdominal aortas showed increased expression of Cd206‐positive M2 macrophages and decreased expression of Il12‐positive M1 macrophages. Notch1 deficiency promoted M2 differentiation of macrophages by upregulating transforming growth factor β2 in bone marrow–derived macrophages at basal levels and in response to IL4. Protein expression of transforming growth factor β2 and its downstream effector pS mad2 also increased in DAPT ‐treated Apoe −/− mice, indicating a potential link between Notch and transforming growth factor β2 signaling in the M2 differentiation of macrophages. Conclusions Pharmacological inhibitor of Notch signaling prevents the progression of AAA by macrophage differentiation–dependent mechanisms. The study also provides insights for novel therapeutic strategies to prevent the progression of small AAA . </jats:sec

New loci and coding variants confer risk for age-related macular degeneration in East Asians

加齢黄斑変性の発症に関わるアジア人特有の遺伝子変異を発見. 京都大学プレスリリース. 2015-02-05.Updated 30 March 2015. [Corrigendum] doi:10.1038/ncomms7817Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2, 119 patients with exudative AMD and 5, 691 controls, with independent replication in 4, 226 patients and 10, 289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10[-22]). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17mmoll-1 (P=5.82 × 10[-21]) in East Asians (n=7, 102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10[-18]), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10[-11]) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10[-8]). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature

Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development.Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF.Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling

Inhibition of Notch1 Signaling Reduces Abdominal Aortic Aneurysm in Mice by Attenuating Macrophage-Mediated Inflammation

OBJECTIVE: Activation of inflammatory pathways plays a critical role in the development of abdominal aortic aneurysms (AAA). Notch1 signaling is a significant regulator of the inflammatory response; however, its role in AAA is unknown. METHODS AND RESULTS: In an angiotensin II (AngII)-induced mouse model of AAA, activation of Notch1 signaling was observed in the aortic aneurysmal tissue of Apoe(−/−) mice and a similar activation of Notch1 was observed in aneurysms of humans undergoing AAA repair. Notch1 haploinsufficiency significantly reduced the incidence of AAA in Apoe(−/−) mice in response to AngII. Reconstitution of bone marrow-derived cells from Notch1(+/−); Apoe(−/−) mice (donor) in lethally irradiated Apoe(−/−) mice (recipient) decreased occurrence of aneurysm. Flow cytometry and immunohistochemistry demonstrated that Notch1 haploinsufficiency prevented the influx of inflammatory macrophages at the aneurysmal site by causing defects in macrophage migration and proliferation. Additionally, there was an overall reduction in the inflammatory burden in the aorta of the Notch1(+/−);Apoe(−/−) mice as compared to the Apoe(−/−) mice. Lastly, pharmacologic inhibition of Notch1 signaling also prevented AAA formation and progression in Apoe(−/−) mice. CONCLUSION: Our data suggest that decreased levels of Notch1 protect against the formation of AAA by preventing macrophage recruitment and attenuating the inflammatory response in the aorta

Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study

AbstractExtranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non–B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT

Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes

Abstract Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identify twelve loci, of which four are novel ( $$P \, < \, 1.19\times {10}^{-8}$$ P < 1.19 × 10 − 8 ). Substantial genetic sharing between PCV and typical nAMD is noted (r g = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; $$P=1.05\times {10}^{-6}$$ P = 1.05 × 10 − 6 ) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population