Publications by authors named "Daisuke Muramatsu"

41 Publications

Long-Term Outcome of Eyes with Vitrectomy for Submacular and/or Vitreous Hemorrhage in Neovascular Age-Related Macular Degeneration.

J Ophthalmol 2021 2;2021:2963822. Epub 2021 Nov 2.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

Purpose: To study long-term clinical outcomes in patients with submacular hemorrhage (SMH) and/or vitreous hemorrhage (VH) associated with neovascular age-related macular degeneration (nAMD) and the real-world clinical situation of adding anti-VEGF therapy after pars plana vitrectomy (PPV).

Methods: In this retrospective case series, 25 eyes with SMH and/or VH associated with nAMD were treated by PPV and followed up for at least 24 months. When exudative changes were unresolved or recurred after PPV, additional intravitreal anti-VEGF therapy was given.

Results: The reasons for performing PPV were SMH (8 eyes) and VH (17 eyes) associated with nAMD. Mean best-corrected visual acuity (BCVA) of eyes with SMH improved significantly at 6 months ( < 0.01) and 12 months ( < 0.05) after PPV. Mean BCVA of eyes with VH improved at 1, 3, 6, 12, 18, and 24 months ( < 0.01) and at the final visit ( < 0.05). Post-PPV anti-VEGF therapy was initiated in 6 of 8 (75.0%) eyes with SMH and 7 of 17 (47.1%) eyes with VH. Of the 13 eyes given anti-VEGF therapy after PPV, 11 eyes had anti-VEGF therapy initiated within 10 months after surgery. Dry macula rate after PPV was 50.0% in SMH and 70.6% in VH.

Conclusions: BCVA improved in eyes with SMH at 6 and 12 months after PPV, and the BCVA was maintained until the end of the study. BCVA improved significantly in eyes with VH at all time points after PPV. In eyes undergoing PPV for nAMD, recurrence of exudative changes after 11 months from the initial PPV was rare.
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http://dx.doi.org/10.1155/2021/2963822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577947PMC
November 2021

In vitro anti-inflammatory and anti-lipid accumulation properties of taxifolin-rich extract from the Japanese larch, .

Heliyon 2020 Dec 10;6(12):e05505. Epub 2020 Dec 10.

Aureo Science Co., Ltd., Hokudai Business Spring, North 21, West 12, Kita-ku, Sapporo, Hokkaido, 001-0021 Japan.

The Japanese larch, () is known to contain abundant taxifolin (dihydroquercetin) in its xylem. In this study, to assess the bioactivities of taxifolin rich methanol extract of (LK-ME), anti-inflammatory effect, and the anti-lipid accumulation effect of LK-ME were investigated. The results showed that nitric oxide (NO) and reactive oxygen species (ROS) were reduced after treatment with LK-ME, and that lipid accumulation in adipocyte differentiated 3T3-L1 cells was inhibited after the cells were grown in medium containing LK-ME. Taxifolin, the major compound contained in LK-ME, and its related compounds, quercetin and luteolin also exhibited similar effects with LK-ME. The LK-ME exhibits relatively strong anti-inflammatory and anti-lipid accumulation activities compared with that of similar amounts of taxifolin contained in LK-ME, suggesting that other minor compounds contained in LK-ME is involved in the effects. These results indicate the potential of taxifolin-rich extract for use as a supplement to prevent excess inflammation and obesity.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734230PMC
December 2020

Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention .

Br J Ophthalmol 2020 12 13;104(12):1755-1761. Epub 2020 Mar 13.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Background/aims: To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO).

Methods: Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment.

Results: Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term.

Conclusion: For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785163PMC
December 2020

Real-world management of treatment-naïve diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study.

Br J Ophthalmol 2020 09 29;104(9):1209-1215. Epub 2019 Nov 29.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background/aims: To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME).

Methods: Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C).

Results: The mean 2-year improvement of BCVA was -0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was -0.09±0.39, -0.02±0.40 and -0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively.

Conclusion: Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577088PMC
September 2020

Cell cytotoxity and anti-glycation activity of taxifolin-rich extract from Japanese larch, .

Heliyon 2019 Jul 13;5(7):e02047. Epub 2019 Jul 13.

Aureo Science Co., Ltd., Hokudai Business Spring, North 21, West 12, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan.

The larches, the genus of plants are known as a natural source of taxifolin (dihydroquercetin), and extracts of its taxifolin rich xylem are used in dietary supplements to maintain health. In the present study, to assess biological activities of a methanol extract of the Japanese larch, (LK-ME), the effects of LK-ME on cell viability, inflammatory cytokine expression, and glycation were investigated. The effects of taxifolin which is known to be a main compound of LK-ME, and its related flavonoids, quercetin and luteolin were also examined. The results show that taxifolin exhibits lower growth inhibition activity and lesser induction activity of inflammatory cytokines in a human monocyte derived cell line, THP-1 cells, while in vitro anti-glycation activities of taxifolin were inhibiting at comparable levels to those of quercetin and luteolin. The growth inhibition and the cytokine induction activities, and the anti-glycation effects of LK-ME are assumed to have properties similar to taxifolin. The results of high performance liquid chromatography (HPLC) analysis indicated that taxifolin was detected as the main peak of LK-ME at the absorbance of 280 nm, and the concentration of taxifolin was measured as 3.12 mg/ml. The actual concentration of taxifolin in LK-ME is lower than the concentration estimated from the IC values calculated by the results of glycation assays, suggesting that other compounds contained in LK-ME are involved in the anti-glycation activity.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627962PMC
July 2019

Successful Treatment of Necrotizing Retinitis with Epstein-Barr Virus-Positive Ocular Fluid by Intravitreal Methotrexate Injection.

Ocul Immunol Inflamm 2020 May 3;28(4):552-555. Epub 2019 Jul 3.

Department of Ophthalmology, Tokyo Medical University , Tokyo, Japan.

Purpose: To present a case of necrotizing retinitis with Epstein-Barr virus (EBV)-positive ocular fluid in a patient with sudden unilateral vision loss, which was successfully treated with intravitreal methotrexate (MTX) injections.

Methods: Retrospective case report.

Results: An 83-year-old female who had been on methylprednisolone for 20 years due to interstitial pneumonia developed vitreous opacity and extensive necrotizing retinitis with retinal hemorrhage sparing the posterior pole in the left eye. Multiplex polymerase chain reaction (PCR) for viral DNA using vitreous sample was positive for EBV but negative for herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Real-time PCR detected EBV-DNA in aqueous humor but not in peripheral blood sample. Serologic testing was negative for , syphilis, and HIV. The patient did not respond to systemic ganciclovir or acyclovir. Subsequent treatment with intravitreal MTX resulted in immediate clinical improvement correlating with a decrease in copy number of EBV-DNA.

Conclusion: Intravitreal MTX may be an effective treatment option for patients with necrotizing retinitis and EBV-positive ocular fluid not responding to conventional antiviral therapy.
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http://dx.doi.org/10.1080/09273948.2019.1609047DOI Listing
May 2020

Aureobasidium pullulans-cultured fluid induces IL-18 production, leading to Th1-polarization during influenza A virus infection.

J Biochem 2018 Jan;163(1):31-38

Laboratory for Biologics Development, Research Center for Zoonosis Control, Hokkaido University, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido 001-0020, Japan.

Several microbial molecules with pathogen-associated molecular patterns stimulate host innate immune responses. The innate immune system plays a crucial role in activating acquired immune response via cytokine production and antigen presentation. Previous studies have shown that Aureobasidium pullulans-cultured fluid (AP-CF), which contains β-glucan, exhibits adjuvant activity and renders mice resistance to influenza A virus infection; however, the underlying mechanism remains elusive. In this study, we investigated the innate immune response to AP-CF. We found that intraperitoneal administration of AP-CF increased the serum level of IL-18 and the number of splenic IFN-γ producing CD4+ cells during influenza A virus infection. The adjuvant effect of AP-CF was distinct from that of alum, which is known to have the ability to stimulate a Th2 immune response. In addition, AP-CF injection barely increased the number of peritoneal neutrophils and inflammatory macrophages, whereas alum injection markedly increased the number of neutrophils and inflammatory macrophages, suggesting that AP-CF is a weak inducer of inflammation compared to alum. AP-CF induced IL-18 production by DC2.4 cells, a dendritic cell line, and by peritoneal exudate cells that include peritoneal macrophages. Collectively, our findings indicate that AP-CF is an adjuvant that promotes the Th1 response during influenza A virus infection.
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http://dx.doi.org/10.1093/jb/mvx062DOI Listing
January 2018

Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly.

Elife 2017 08 1;6. Epub 2017 Aug 1.

Cellular Memory Laboratory, RIKEN, Wako, Japan.

SUV39H is the major histone H3 lysine 9 (H3K9)-specific methyltransferase that targets pericentric regions and is crucial for assembling silent heterochromatin. SUV39H recognizes trimethylated H3K9 (H3K9me3) via its chromodomain (CD), and enriched H3K9me3 allows SUV39H to target specific chromosomal regions. However, the detailed targeting mechanisms, especially for naïve chromatin without preexisting H3K9me3, are poorly understood. Here we show that Suv39h1's CD (Suv39h1-CD) binds nucleic acids, and this binding is important for its function in heterochromatin assembly. Suv39h1-CD had higher binding affinity for RNA than DNA, and its ability to bind nucleic acids was independent of its H3K9me3 recognition. Suv39h1 bound major satellite RNAs , and knockdown of major satellite RNAs lowered Suv39h1 retention on pericentromere. Suv39h1 mutational studies indicated that both the nucleic acid-binding and H3K9me-binding activities of Suv39h1-CD were crucial for its pericentric heterochromatin assembly. These results suggest that chromatin-bound RNAs contribute to creating SUV39H's target specificity.
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http://dx.doi.org/10.7554/eLife.25317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538823PMC
August 2017

Aureobasidium pullulans produced β-glucan is effective to enhance Kurosengoku soybean extract induced Thrombospondin-1 expression.

Sci Rep 2017 06 6;7(1):2831. Epub 2017 Jun 6.

Aureo Science Co., Ltd., Hokudai Business Spring, North 21, West 12, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan.

Black yeast, Aureobasidium pullulans is extracellularly produced β-(1,3), (1,6)-D-glucan (β-glucan) under certain conditions. In this study, using Glycine max cv. Kurosengoku (Kurosengoku soybeans), the production of β-glucan through fermentation of A. pullulans was evaluated, and the effects of A. pullulans cultured fluid (AP-CF) containing β-glucan made with Kurosengoku soybeans (kAP-CF) on a human monocyte derived cell line, Mono Mac 6 cells were investigated. Concentration of β-glucan in kAP-CF reached the same level as normal AP-CF. An anti-angiogenic protein, Thrombospondin-1 (THBS1) was effectively induced after the stimulation with kAP-CF for comparison with AP-CF. The THBS1 is also induced after stimulation with hot water extract of Kurosengoku soybeans (KS-E), while the combined stimulation of β-glucan with KS-E more effectively induced THBS1 than that with KS-E alone. These results suggest effects of A. pullulans-produced β-glucan on the enhancement of Kurosengoku soybean-induced THBS1 expression.
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http://dx.doi.org/10.1038/s41598-017-03053-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460285PMC
June 2017

EFFICACY OF THE INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE WITH VITRECTOMY FOR RETINAL DETACHMENT ASSOCIATED WITH MYOPIC MACULAR HOLES.

Retina 2017 Mar;37(3):466-471

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To evaluate the anatomical and functional outcome of the inverted internal limiting membrane (ILM) flap technique with vitrectomy for retinal detachment associated with macular hole (MHRD) in highly myopic eyes.

Methods: In this retrospective observational study, 21 eyes with MHRD that underwent vitrectomy with conventional ILM peeling (ILM-peeling group, n = 11) or the inverted ILM flap technique (ILM flap group, n = 10) combined with C3F8 tamponade were enrolled in this study. The initial retinal reattachment rate, macular hole closure rate, and postoperative visual acuity at the final visit were compared between the ILM-peeling group and ILM flap group.

Results: There was no significant difference in the retinal reattachment rate between ILM-peeling and ILM flap groups (91% and 100%, respectively). The macular hole closure rate in the ILM flap group was 80% (8 of 10 eyes), and was significantly higher than 36% (4 of 11 eyes) in the ILM-peeling group (P = 0.039). Among 12 eyes that achieved macular hole closure, there was no significant difference in median visual acuity after vitrectomy between the ILM flap group and ILM-peeling group (logMAR unit [Snellen acuity]: 1.0 [20/200] and 0.76 [20/125], respectively, P = 0.300).

Conclusion: Compared with conventional ILM peeling, the inverted ILM flap technique was more effective for macular hole closure after vitrectomy for MHRD in myopic eye but showed no advantage in the postoperative visual outcome in this study.
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http://dx.doi.org/10.1097/IAE.0000000000001211DOI Listing
March 2017

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

Retina 2017 Dec;37(12):2317-2325

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

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.
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http://dx.doi.org/10.1097/IAE.0000000000001490DOI Listing
December 2017

Pericentric H3K9me3 Formation by HP1 Interaction-defective Histone Methyltransferase Suv39h1.

Cell Struct Funct 2016 Dec 12;41(2):145-152. Epub 2016 Oct 12.

Graduate School of Biostudies, Kyoto University.

Pericentric regions form epigenetically organized, silent heterochromatin structures that accumulate histone H3 lysine 9 tri-methylation (H3K9me3) and heterochromatin protein 1 (HP1), a methylated H3K9-binding protein. At pericentric regions, Suv39h is the major enzyme that generates H3K9me3. Suv39h also interacts directly with HP1. However, the importance of HP1 interaction for Suv39h-mediated H3K9me3 formation at the pericentromere is not well characterized. To address this question, we introduced HP1 binding-defective, N-terminally truncated mouse Suv39h1 (ΔN) into Suv39h-deficient cells. Pericentric H3K9me3-positive cells were not detected by endogenous-level expression of ΔN. Notably, ΔN could induce pericentric accumulation of H3K9me3 as wild type Suv39h1 did if it was overexpressed. These findings demonstrate that the N-terminal region of Suv39h1, presumably via HP1-Suv39h1 interaction, is required for Suv39h1-mediated pericentric H3K9me3 formation, but can be overridden if Suv39h1 is overproduced, indicating that Suv39h1-mediated heterochromatin formation is controlled by multiple modules, including HP1.
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http://dx.doi.org/10.1247/csf.16013DOI Listing
December 2016

Knockout mouse production assisted by Blm knockdown.

J Reprod Dev 2016 20;62(1):121-5. Epub 2015 Nov 20.

Cellular Memory Laboratory, RIKEN, Saitama 351-0198, Japan.

Production of knockout mice using targeted embryonic stem cells (ESCs) is a powerful approach for investigating the function of specific genes in vivo. Although the protocol for gene targeting via homologous recombination (HR) in ESCs is already well established, the targeting efficiency varies at different target loci and is sometimes too low. It is known that knockdown of the Bloom syndrome gene, BLM, enhances HR-mediated gene targeting efficiencies in various cell lines. However, it has not yet been investigated whether this approach in ESCs is applicable for successful knockout mouse production. Therefore, we attempted to answer this question. Consistent with previous reports, Blm knockdown enhanced gene targeting efficiencies for three gene loci that we examined by 2.3-4.1-fold. Furthermore, the targeted ESC clones generated good chimeras and were successful in germline transmission. These data suggest that Blm knockdown provides a general benefit for efficient ESC-based and HR-mediated knockout mouse production.
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http://dx.doi.org/10.1262/jrd.2015-122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768786PMC
January 2017

Macular hole formation following intravitreal injection of ranibizumab for branch retinal vein occlusion: a case report.

BMC Res Notes 2015 Aug 19;8:358. Epub 2015 Aug 19.

Tokyo Medical University, Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.

Background: Macular hole formation after anti-vascular endothelial growth factor therapy is a rare complication. We report macular hole formation after intravitreal ranibizumab injection for branch retinal vein occlusion.

Case Presentation: A 63-year-old Asian male was treated with intravitreal ranibizumab injection for chronic macular edema with branch retinal vein occlusion in his right eye. Before treatment, best-corrected visual acuity in his right eye was 20/200. Nine days after injection, a full thickness macular hole developed with reduction of macular edema. After pars plana vitrectomy combined with cataract surgery, the macular hole was successfully closed, and the best-corrected visual acuity in his right eye improved to 20/40.

Conclusion: The possibility of an infrequent complication like macular hole should be considered for intravitreal ranibizumab for macular edema with branch retinal vein occlusion.
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http://dx.doi.org/10.1186/s13104-015-1324-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541740PMC
August 2015

Noninvasive vascular imaging of ruptured retinal arterial macroaneurysms by Doppler optical coherence tomography.

BMC Ophthalmol 2015 Jul 22;15:79. Epub 2015 Jul 22.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku, Tokyo, 1600023, Japan.

Background: To describe Doppler optical coherence tomography (OCT) imaging of ruptured retinal arterial macroaneurysms (RAMs).

Methods: Four eyes of four patients with ruptured RAMs were prospectively studied. Vascular imaging was obtained using swept-source Doppler OCT, and compared with indocyanine green angiography images.

Results: En face projection of Doppler OCT images clearly showed RAMs at the corresponding locations of lesions in the indocyanine green angiography images. In Doppler OCT images, RAMs were located in the inner retina in three eyes and in the medium layer of the retina in one eye. In one eye, detection of RAMs by standard OCT was difficult because of the presence of inner retinal hemorrhage. In one eye, disappearance of blood flow after direct laser photocoagulation could be confirmed by Doppler OCT images.

Conclusions: Doppler OCT imaging may potentially function as a noninvasive complementary procedure with indocyanine green angiography.
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http://dx.doi.org/10.1186/s12886-015-0077-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510894PMC
July 2015

Oral administration of the Aureobasidium pullulans-derived β-glucan effectively prevents the development of high fat diet-induced fatty liver in mice.

Sci Rep 2015 Jul 16;5:10457. Epub 2015 Jul 16.

1] Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan [2] Department of Matrix Medicine, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Aureobasidium pullulans-derived β-glucan (AP-PG) consisting of a β-(1,3)-linked glucose main chain and β-(1,6)-linked glucose branches is taken as a supplement to improve health. This study demonstrates that oral administration of AP-PG is effective to prevent the development of high-fat diet (HFD)-induced fatty liver in mice. Here, C57BL/6N mice were fed with a normal diet or HFD, and AP-PG diluted in drinking water was administered orally. After 16 weeks, the serological analysis showed that HFD-induced high blood cholesterol and triglyceride levels were reduced by the oral administration of AP-PG. Further, HFD induced-fatty liver was significantly reduced by the oral administration of AP-PG. The triglyceride accumulation in the liver was also significantly reduced in mice administered AP-PG. Liver injury as indicated by an increase in serum alanine aminotransferase (ALT) in the HFD-fed mice was significantly reduced in the mice administered AP-PG orally, and the gene expression of cholesterol 7 alpha-hydroxylase (CYP7A1) which is known to be involved in cholesterol degradation in the liver was significantly increased in the AP-PG administered mice. These results suggest the possibility that the oral administration of AP-PG is effective to prevent the development of non-alcoholic fatty liver disease (NAFLD).
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http://dx.doi.org/10.1038/srep10457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503978PMC
July 2015

Noninvasive vascular imaging of polypoidal choroidal vasculopathy by Doppler optical coherence tomography.

Invest Ophthalmol Vis Sci 2015 May;56(5):3179-86

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To noninvasively investigate the vascular architecture of polypoidal lesions in polypoidal choroidal vasculopathy (PCV) using Doppler optical coherence tomography (OCT), and to evaluate the clinical usefulness of Doppler OCT for the assessment of therapeutic effects in PCV.

Methods: Fifteen eyes of 15 patients with treatment-naïve PCV were prospectively studied. Vascular imaging was obtained using 1060-nm swept-source Doppler OCT, and compared with indocyanine green angiography (ICGA) images. The therapeutic effect of three consecutive intravitreal aflibercept injections was evaluated with ICGA and Doppler OCT.

Results: In Doppler OCT images, polypoidal lesions were clearly detected at the corresponding locations of lesions in the ICGA images. By being insensitive to dye leakage, Doppler OCT identified the complicated vascular structure in the polypoidal lesions. The identified mean area of the polypoidal lesions in the Doppler OCT images (0.04 mm(2)) was significantly smaller than that of the ICGA images (0.13 mm(2)). Polypoidal lesions were located in the retinal pigment epithelial detachment in 13 eyes, in the choroid in one eye, and in both the retinal pigment epithelial detachment and choroid in one eye. After intravitreal aflibercept treatment, areas of polypoidal lesions in the ICGA images were decreased in 14 of 15 eyes. This therapeutic effect was clearly confirmed in the Doppler OCT images.

Conclusions: Doppler OCT imaging clearly detected fine vascular structures at the polypoidal lesions in PCV. Doppler OCT might be useful for the diagnosis and evaluation of therapeutic effects in PCV.
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http://dx.doi.org/10.1167/iovs.14-16252DOI Listing
May 2015

Stimulation of macrophages with the β-glucan produced by aureobasidium pullulans promotes the secretion of tumor necrosis factor-related apoptosis inducing ligand (TRAIL).

PLoS One 2015 13;10(4):e0124809. Epub 2015 Apr 13.

Department of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

A β-glucan produced by Aureobasidium pullulans (AP-PG) is consisting of a β-(1,3)-linked main chain with β-(1,6)-linked glucose side residues. Various β-glucans consisting of β-(1,3)-linked main chain including AP-PG are believed to exhibit anti-tumor activities, and actually, anti-tumor activities of AP-PG in mice have been demonstrated. In this study, we demonstrate that stimulation with AP-PG induces TRAIL expression in mouse and human macrophage-like cell lines. TRAIL is known to be a cytokine which specifically induces apoptosis in transformed cells, but not in untransformed cells. The expression of TRAIL mRNA after stimulation with AP-PG was increased in RAW264.7 cells, Mono Mac 6 cells, and macrophage-differentiated THP-1 cells. The mRNA expression of TNF-α and FasL is only weakly increased after stimulation with AP-PG. The induction activity of TRAIL by curdlan, a bacterial β-glucan, was very similar to that by AP-PG in RAW264.7 cells, but weaker in macrophage-differentiated THP-1 cells. Activation of caspases was found in HeLa cells after treatment with the supernatant of cultured medium from AP-PG-stimulated Mono Mac 6 cells, and was inhibited by the anti-TRAIL neutralizing antibody. These findings suggest that the stimulation with AP-PG effectively induces TRAIL in macrophages, and that it may be related to apoptosis induction of tumor cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395393PMC
April 2016

Three-dimensional vascular imaging of proliferative diabetic retinopathy by Doppler optical coherence tomography.

Am J Ophthalmol 2015 Mar 9;159(3):528-38.e3. Epub 2014 Dec 9.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To evaluate the 3-dimensional architecture of neovascularization in proliferative diabetic retinopathy using Doppler optical coherence tomography (OCT).

Design: Prospective, nonrandomized clinical trial.

Methods: Seventeen eyes of 14 patients with proliferative diabetic retinopathy were prospectively studied. Prototype Doppler OCT was used to evaluate the 3-dimensional vascular architecture at vitreoretinal adhesions.

Results: Proliferative membranes were detected in all eyes with proliferative diabetic retinopathy by standard OCT images. Doppler OCT images detected blood flow by neovascularization of the disc in 12 eyes and neovascularization elsewhere in 11 eyes. Doppler OCT images showed the 3-dimensional extent of new vessels at various stages of neovascularization, and the extent of new vessels could be clearly confirmed at vitreoretinal adhesions.

Conclusions: Doppler OCT is useful for the detection and evaluation of the 3-dimensional vascular structure of neovascularization, and can assist in the noninvasive assessment of proliferative diabetic retinopathy.
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http://dx.doi.org/10.1016/j.ajo.2014.12.002DOI Listing
March 2015

Copper(I) 2-hydroxyethoxide-promoted cross-coupling of aryl- and alkenyldimethylsilanes with organic halides.

Chem Commun (Camb) 2014 Dec;50(96):15156-8

Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan.

Fluoride-free cross-coupling of aryl- and alkenyldimethylsilanes with organic halides proceeded in the presence of monocopper(I) alkoxide of ethylene glycol.
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http://dx.doi.org/10.1039/c4cc07371aDOI Listing
December 2014

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

Clin Ophthalmol 2014 22;8:1877-81. Epub 2014 Sep 22.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

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.
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http://dx.doi.org/10.2147/OPTH.S70468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181636PMC
October 2014

Complete pyridine-nucleotide-specific conversion of an NADH-dependent ferredoxin reductase.

Biochem J 2014 Sep;462(2):257-65

§Graduate School of Science and Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan.

The coenzyme specificity of enzymes is one of the critical parameters for the engineered production of biological compounds using bacteria. Since NADPH is produced abundantly in photosynthetic organisms, conversion of an NADH-specific enzyme into an NADPH-specific one is a useful approach for the efficient carbon-neutral production of biological compounds in photosynthetic organisms. In the present study, an NADH-specific ferredoxin reductase component, BphA4 of biphenyl dioxygenase BphA from Acidovorax sp. strain KKS102, was changed to an NADPH-dependent form using a method combining structure-based systematic mutations and site-directed random mutagenesis. The resultant CRG mutant, in which Glu175-Thr176-Gln177 of an NADH-recognition loop in the wild-type BphA4 was replaced with Cys175-Arg176-Gly177, was highly specific and active for NADPH, and its biochemical and structural properties for NADPH were nearly the same as those of the wild-type BphA4 for NADH. In addition, this mutation project was assessed by a semi-empirical prediction method of mutation effects, and the results suggested that the CRG mutant was one of the best NADPH-specific mutants.
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http://dx.doi.org/10.1042/BJ20140384DOI Listing
September 2014

Stimulation with the Aureobasidium pullulans-produced β-glucan effectively induces interferon stimulated genes in macrophage-like cell lines.

Sci Rep 2014 Apr 24;4:4777. Epub 2014 Apr 24.

1] Aureo Science Co., Ltd., Hokudai Business Spring, North 21, West 12, Kita-ku, Sapporo, Hokkaido, 001-0021 Japan [2] Aureo Co., Ltd., 54-1 Kazusakoito, Kimitsu, Chiba, 292-1149 Japan.

A β-(1,3),(1,6)-D-glucan produced by A. pullulans (AP-PG) is known to be an immune stimulating agent. In this study, we demonstrate that the stimulation with AP-PG effectively induces the interferon (IFN) stimulated genes (ISGs) in macrophage-like cell lines. The ISGs, Mx1, ISG15, and viperin mRNAs were significantly increased in RAW264.7 cells after stimulation with AP-PG. The stimulation with AP-PG transiently induced IFN-β mRNA. However, the expression of viperin mRNA was also increased after stimulation with AP-PG even when new protein synthesis was completely blocked by treatment with cycloheximide. Further, in IFN-α receptor knockdown RAW264.7 cells, AP-PG stimulation more effectively induced viperin mRNA compared with that of IFN-α stimulation. The phosphorylation of Ser 727 in STAT1 involved in the enhancement of STAT1 activation was immediately increased after stimulation with AP-PG. In addition, viperin mRNA expression induced after stimulation with IFN-α was significantly increased by combined stimulation with AP-PG. These results suggest that stimulation with AP-PG effectively induces the ISGs through the induction of IFN and the enhancement of STAT1-mediated transcriptional activation.
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http://dx.doi.org/10.1038/srep04777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998088PMC
April 2014

Hormonal regulation and developmental role of Krüppel homolog 1, a repressor of metamorphosis, in the silkworm Bombyx mori.

Dev Biol 2014 Apr 4;388(1):48-56. Epub 2014 Feb 4.

National Institute of Agrobiological Sciences, Ohwashi 1-2, Tsukuba, Ibaraki 305-8634, Japan. Electronic address:

Juvenile hormone (JH) has an ability to repress the precocious metamorphosis of insects during their larval development. Krüppel homolog 1 (Kr-h1) is an early JH-inducible gene that mediates this action of JH; however, the fine hormonal regulation of Kr-h1 and the molecular mechanism underlying its antimetamorphic effect are little understood. In this study, we attempted to elucidate the hormonal regulation and developmental role of Kr-h1. We found that the expression of Kr-h1 in the epidermis of penultimate-instar larvae of the silkworm Bombyx mori was induced by JH secreted by the corpora allata (CA), whereas the CA were not involved in the transient induction of Kr-h1 at the prepupal stage. Tissue culture experiments suggested that the transient peak of Kr-h1 at the prepupal stage is likely to be induced cooperatively by JH derived from gland(s) other than the CA and the prepupal surge of ecdysteroid, although involvement of unknown factor(s) could not be ruled out. To elucidate the developmental role of Kr-h1, we generated transgenic silkworms overexpressing Kr-h1. The transgenic silkworms grew normally until the spinning stage, but their development was arrested at the prepupal stage. The transgenic silkworms from which the CA were removed in the penultimate instar did not undergo precocious pupation or larval-larval molt but fell into prepupal arrest. This result demonstrated that Kr-h1 is indeed involved in the repression of metamorphosis but that Kr-h1 alone is incapable of implementing normal larval molt. Moreover, the expression profiles and hormonal responses of early ecdysone-inducible genes (E74, E75, and Broad) in transgenic silkworms suggested that Kr-h1 is not involved in the JH-dependent modulation of these genes, which is associated with the control of metamorphosis.
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http://dx.doi.org/10.1016/j.ydbio.2014.01.022DOI Listing
April 2014

Sustained delivery of a HIF-1 antagonist for ocular neovascularization.

J Control Release 2013 Dec 12;172(3):625-33. Epub 2013 Oct 12.

Department of Ophthalmology, Baltimore, USA; Department of Neuroscience, Baltimore, USA.

Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.
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http://dx.doi.org/10.1016/j.jconrel.2013.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871855PMC
December 2013

Copper(I)-catalyzed alkylation of aryl- and alkenylsilanes activated by intramolecular coordination of an alkoxide.

Angew Chem Int Ed Engl 2013 Nov 9;52(48):12719-22. Epub 2013 Oct 9.

Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588 (Japan).

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http://dx.doi.org/10.1002/anie.201306882DOI Listing
November 2013

Axial length as a factor associated with visual outcome after vitrectomy for diabetic macular edema.

Invest Ophthalmol Vis Sci 2013 Oct 21;54(10):6834-40. Epub 2013 Oct 21.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To investigate whether axial length predicts visual acuity outcome after vitrectomy for diffuse macular edema secondary to diabetic retinopathy.

Methods: Fifty-one eyes of 41 patients with diabetic macular edema (DME) who underwent vitrectomy were reviewed retrospectively. Clinical data, including axial length measured by partial coherence interferometry, postoperative best-corrected visual acuity (BCVA), and postoperative status of integrity of the photoreceptor layer observed by optical coherence tomography, were recorded. The relationship between axial length and postoperative BCVA or visibility of the junction between the inner and outer segment (IS/OS) line at 12 months after surgery were analyzed. Logistic regression analyses were performed to examine predictors related to postoperative BCVA.

Results: Median BCVA improved significantly (P < 0.0001) after surgery (0.4 logMAR units; range, 0-1.5) compared to baseline (0.69 logMAR units; range, 0.22-1.22). Median axial length was significantly longer (P = 0.017) when postoperative BCVA was below 0.4 logMAR units (23.51 mm; range, 22.30-26.10) compared to over 0.4 logMAR units (23.02 mm; range, 22.10-24.65). A significant negative correlation was observed between postoperative logMAR and axial length (n = 51, rs = -0.35, P = 0.012). Median axial length was significantly longer (P = 0.039) in eyes with visible IS/OS line (23.54 mm; range, 22.39-26.10) than in those without visible IS/OS line (23.02 mm; range, 22.13-24.65) at 12 months after surgery. Multivariate logistic regression analysis showed that short axial length (odds ratio: 0.3, P = 0.009) increased the risk of poor visual outcome after surgery.

Conclusions: Longer axial length predicts better postoperative BCVA after vitrectomy for diffuse macular edema secondary to diabetic retinopathy.
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http://dx.doi.org/10.1167/iovs.13-12519DOI Listing
October 2013

Pericentric heterochromatin generated by HP1 protein interaction-defective histone methyltransferase Suv39h1.

J Biol Chem 2013 Aug 7;288(35):25285-25296. Epub 2013 Jul 7.

the Cellular Memory Laboratory, RIKEN, Wako, Saitama 351-0198, Japan,; CREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan. Electronic address:

Pericentric regions form epigenetically organized silent heterochromatin structures that accumulate histone H3 lysine 9 trimethylation (H3K9me3) and HP1. At pericentric regions, Suv39h is the major enzyme that generates H3K9me3. Suv39h also interacts directly with HP1, a methylated H3K9-binding protein. However, it is not well characterized how HP1 interaction is important for Suv39h accumulation and Suv39h-mediated H3K9me3 formation at the pericentromere. To address this, we introduced the HP1 binding-defective N-terminally truncated mouse Suv39h1 (ΔN) into Suv39h-deficient embryonic stem cells. Interestingly, pericentric accumulation of ΔN and ΔN-mediated H3K9me3 was observed to recover, but HP1 accumulation was only marginally restored. ΔN also rescued DNA methyltransferase Dnmt3a and -3b accumulation and DNA methylation of the pericentromere. In contrast, other pericentric heterochromatin features, such as ATRX protein association and H4K20me3, were not recovered. Finally, derepressed major satellite repeats were partially silenced by ΔN expression. These findings clearly showed that the Suv39h-HP1 binding is dispensable for pericentric H3K9me3 and DNA methylation, but this interaction and HP1 recruitment/accumulation seem to be crucial for complete formation of heterochromatin.
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http://dx.doi.org/10.1074/jbc.M113.470724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757193PMC
August 2013
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