Publications by authors named "Shigeo Yoshida"

283 Publications

Plasma levels of amino acids and derivatives in retinopathy of prematurity.

Int J Med Sci 2021 27;18(15):3581-3587. Epub 2021 Aug 27.

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Retinopathy of prematurity (ROP) is a retinal disease that causes blindness in premature infants. This study aimed to reveal the changes in amino acids and derivatives in the plasma of ROP patients compared with premature infants without ROP. Metabolomics targeting amino acids and their derivatives was conducted to assess their plasma levels in ROP patients (=58) and premature infants without ROP (=25), and KEGG pathway analysis was used to identify the involved pathways. Among the 31 assessed metabolites, the levels of 4 amino acids were significantly altered in the ROP group. Creatinine was downregulated in the plasma of the ROP patients, while the levels of citrulline, arginine, and aminoadipic acid were upregulated in the ROP group. Significant correlations were identified between the ROP stage and plasma levels of citrulline, creatinine, and aminoadipic acid. The involved pathways included biosynthesis of amino acids, arginine and proline metabolism, and arginine biosynthesis. The plasma levels of citrulline, creatinine, arginine, and aminoadipic acid were significantly changed in ROP patients. These metabolites could be considered potential biomarkers of ROP, and their related metabolic pathways might be involved in ROP pathogenesis.
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http://dx.doi.org/10.7150/ijms.63603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436098PMC
August 2021

Altered Fecal Microbiome and Metabolome in a Mouse Model of Choroidal Neovascularization.

Front Microbiol 2021 26;12:738796. Epub 2021 Aug 26.

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.

Purpose: Choroidal neovascularization (CNV) is the defining feature of neovascular age-related macular degeneration (nAMD). Gut microbiota might be deeply involved in the pathogenesis of nAMD. This study aimed to reveal the roles of the gut microbiome and fecal metabolome in a mouse model of laser-induced CNV.

Methods: The feces of C57BL/6J mice with or without laser-induced CNV were collected. Multi-omics analyses, including 16S rRNA gene sequencing and untargeted metabolomics, were conducted to analyze the changes in the gut microbial composition and the fecal metabolomic profiles in CNV mice.

Results: The gut microbiota was significantly altered in CNV mice. The abundance of was significantly upregulated in the feces of CNV mice, while 16 genera, including , , and , were significantly more abundant in the controls than in the CNV group. Fecal metabolomics identified 73 altered metabolites (including 52 strongly significantly altered metabolites) in CNV mice compared to control mice. Correlation analysis indicated significant correlations between the altered fecal metabolites and gut microbiota genera, such as and . Moreover, KEGG analysis revealed six pathways associated with these altered metabolites, such as the ABC transporter, primary bile acid biosynthesis and steroid hormone biosynthesis pathways.

Conclusion: The study identified an altered fecal microbiome and metabolome in a CNV mouse model. The altered microbes, metabolites and the involved pathways might be associated with the pathogenesis of nAMD.
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http://dx.doi.org/10.3389/fmicb.2021.738796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427291PMC
August 2021

Visual Outcomes and Prognostic Factors of Large Submacular Hemorrhages Secondary to Polypoidal Choroidal Vasculopathy.

Clin Ophthalmol 2021 24;15:3557-3562. Epub 2021 Aug 24.

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

Purpose: Patients with polypoidal choroidal vasculopathy (PCV) may develop large submacular hemorrhages (SMHs), which may result in severe visual loss. This study was performed to determine the visual outcomes and prognostic factors of large SMHs secondary to PCV.

Patients And Methods: We retrospectively reviewed the medical records of patients diagnosed with PCV who developed a large SMH. The best-corrected visual acuity (BCVA) data were collected at the SMH development, 1 month, 1 year after the SMH development, and at the final visit. Patients' medical information also were collected and included age, gender, systemic hypertension, current regular use of an anticoagulant or antiplatelet medication, the initial area of the SMH, breakthrough vitreous hemorrhage, ocular treatment, and fellow eye status. Univariate and multiple regression analyses were performed to determine the prognostic factors for the BCVA 1 year after the development of large SMHs.

Results: Thirty eyes of 29 patients were included in this study. The mean area of the SMHs at the development was 17.0 disc areas. The mean follow-up period after the development of SMHs was 53.5 months. The mean BCVA at the development, 1 month, and 1 year after the development, and at the final visit were 20/151, 20/263, 20/138, and 20/152, respectively. Multiple regression analyses indicated that a SMH 20 disc areas or larger was a significant negative factor, and the BCVA 1 month after the development was a significant positive factor affecting the BCVA 1 year after the development of large SMHs.

Conclusion: The increase in the initial area of SMH was correlated inversely with the BCVA 1 year after the development of SMH. The BCVA 1 month after the development may predict the BCVA 1 year after the development of a large SMH.
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http://dx.doi.org/10.2147/OPTH.S327138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403222PMC
August 2021

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration.

BMC Endocr Disord 2021 Aug 19;21(1):168. Epub 2021 Aug 19.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Background: Thyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling.

Case Presentation: A 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels.

Conclusions: We describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.
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http://dx.doi.org/10.1186/s12902-021-00834-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375170PMC
August 2021

Metabolomics Analyses of Mouse Retinas in Oxygen-Induced Retinopathy.

Invest Ophthalmol Vis Sci 2021 08;62(10)

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Purpose: Retinal neovascularization is a severe pathological process leading to irreversible blindness. This study aims to identify the altered metabolites and their related pathways that are involved in retinal neovascularization.

Methods: To reveal the global metabolomic profile change in the retinal neovascularization process, an untargeted metabolomics analysis of oxygen-induced retinopathy (OIR) mice retinas was carried out first, followed by the validation of amino acids and their derivatives through a targeted metabolomics analysis. The involved pathways were predicted by bioinformatic analysis.

Results: By untargeted metabolomics, a total of 58 and 49 metabolites altered significantly in OIR retinas under cationic and anionic modes, respectively. By bioinformatics analysis, "ABC transporters," "central carbon metabolism in cancer." and "alanine, aspartate, and glutamate metabolism" were the most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the changed metabolites. By targeted metabolomics, no significant change was found in the assessed amino acids and their derivatives at postnatal day (P) 12, whereas significantly altered amino acids and their derivatives were recognized at P13, P17, and P42 in OIR retinas.

Conclusions: The metabolomic profile was significantly altered in the neovascularized retinas. In particular, numerous amino acids and their derivatives were significantly changed in OIR retinas. These altered metabolites, together with their associated pathways, might be involved in the pathogenesis of retinal neovascular diseases.
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http://dx.doi.org/10.1167/iovs.62.10.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363770PMC
August 2021

Low-Computational-Cost Technique for Modeling Macro Fiber Composite Piezoelectric Actuators Using Finite Element Method.

Materials (Basel) 2021 Aug 2;14(15). Epub 2021 Aug 2.

Research Institute for Applied Mechanics, Kyushu University, Fukuoka 816-8580, Japan.

The large number of interdigitated electrodes (IDEs) in a macro fiber composite (MFC) piezoelectric actuator dictates using a very fine finite element (FE) mesh that requires extremely large computational costs, especially with a large number of actuators. The situation becomes infeasible if repeated finite element simulations are required, as in control tasks. In this paper, an efficient technique is proposed for modeling MFC using a finite element method. The proposed technique replaces the MFC actuator with an equivalent simple monolithic piezoceramic actuator using two electrodes only, which dramatically reduces the computational costs. The proposed technique was proven theoretically since it generates the same electric field, strain, and displacement as the physical MFC. Then, it was validated with the detailed FE model using the actual number of IDEs, as well as with experimental tests using triaxial rosette strain gauges. The computational costs for the simplified model compared with the detailed model were dramatically reduced by about 74% for memory usage, 99% for result file size, and 98.6% for computational time. Furthermore, the experimental results successfully verified the proposed technique with good consistency. To show the effectiveness of the proposed technique, it was used to simulate a morphing wing covered almost entirely by MFCs with low computational cost.
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http://dx.doi.org/10.3390/ma14154316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347699PMC
August 2021

Role of interferons in diabetic retinopathy.

World J Diabetes 2021 Jul;12(7):939-953

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.

Diabetic retinopathy (DR) is one of the major causes of visual impairment and irreversible blindness in developed regions. Aside from abnormal angiogenesis, inflammation is the most specific and might be the initiating factor of DR. As a key participant in inflammation, interferon-gamma (IFN-γ) can be detected in different parts of the eye and is responsible for the breakdown of the blood-retina barrier and activation of inflammatory cells and other cytokines, which accelerate neovascularization and neuroglial degeneration. In addition, IFN-γ is involved in other vascular complications of diabetes mellitus and angiogenesis-dependent diseases, such as diabetic nephropathy, cerebral microbleeds, and age-related macular degeneration. Traditional treatments, such as anti-vascular endothelial growth factor agents, vitrectomy, and laser photocoagulation therapy, are more effective for angiogenesis and not tolerable for every patient. Many ongoing clinical trials are exploring effective drugs that target inflammation. For instance, IFN-α acts against viruses and angiogenesis and is commonly used to treat malignant tumors. Moreover, IFN-α has been shown to contribute to alleviating the progression of DR and other ocular diseases. In this review, we emphasize the roles that IFNs play in the pathogenesis of DR and discuss potential clinical applications of IFNs in DR, such as diagnosis, prognosis, and therapeutic treatment.
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http://dx.doi.org/10.4239/wjd.v12.i7.939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311473PMC
July 2021

Accelerated Progression of Diabetic Retinopathy in a Patient with Acquired Lipodystrophy Following Hematopoietic Stem Cell Transplantation.

Retin Cases Brief Rep 2021 Jul 16. Epub 2021 Jul 16.

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

Purpose: To report a case of bilateral proliferative diabetic retinopathy and lipemia retinalis in a patient with acquired lipodystrophy.

Methods: A retrospective case report.

Results: A 23-year-old woman with a diagnosis of acquired lipodystrophy was referred for ophthalmic evaluation. She had been diagnosed with acute lymphocytic leukemia at the age of 3 years and undergone hematopoietic stem cell transplantation. Best-corrected visual acuity was 20/20 in both eyes; however, funduscopy revealed bilateral diabetic retinopathy and lipemia retinalis, neither of which was apparent 2 years earlier. She had a glycated hemoglobin level of 9.6% and a triglyceride level of 7,394 mg/dL with creamy appearance of serum. Fluorescein angiography showed bilateral neovascularization.

Conclusion: Accelerated progression of diabetic retinopathy in the present case appeared to be associated with the onset of lipemia retinalis. We encourage continued ophthalmologic monitoring of patients who underwent hematopoietic stem cell transplantation in childhood for possible accelerated course of diabetic retinopathy.
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http://dx.doi.org/10.1097/ICB.0000000000001180DOI Listing
July 2021

Gene Mutation Presenting at Age 2 Years With Autoimmune Retinopathy and Steroid-Responsive Acute Liver Failure: A Case Report and Literature Review.

Front Immunol 2021 28;12:687280. Epub 2021 May 28.

Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and gene mutations.
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http://dx.doi.org/10.3389/fimmu.2021.687280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194255PMC
May 2021

Clinical Characteristics and Outcomes in 314 Japanese Patients with Bacterial Endophthalmitis: A Multicenter Cohort Study from J-CREST.

Pathogens 2021 Mar 24;10(4). Epub 2021 Mar 24.

Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya 6638501, Japan.

Bacterial endophthalmitis is an intraocular infection that causes rapid vison loss. Pathogens can infect the intraocular space directly (exogenous endophthalmitis (ExE)) or indirectly (endogenous endophthalmitis (EnE)). To identify predictive factors for the visual prognosis of Japanese patients with bacterial endophthalmitis, we retrospectively examined the bacterial endophthalmitis characteristics of 314 Japanese patients and performed statistics using these clinical data. Older patients, with significantly more severe clinical symptoms, were prevalent in the ExE group compared with the EnE group. However, the final best-corrected visual acuity (BCVA) was not significantly different between the ExE and EnE groups. Bacteria isolated from patients were not associated with age, sex, or presence of eye symptoms. , and were more prevalent in ExE patients than EnE patients and contributed to poor final BCVA. The presence of eye pain, bacterial identification, and poor BCVA at baseline were risk factors for final visual impairment.
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http://dx.doi.org/10.3390/pathogens10040390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063932PMC
March 2021

Outcomes of a 2-year treat-and-extend regimen with aflibercept for diabetic macular edema.

Sci Rep 2021 Feb 24;11(1):4488. Epub 2021 Feb 24.

Department of Ophthalmology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.

This prospective, open-label, single-arm, non-randomized clinical trial, assessed the efficacy of a 2-year treat-and-extend (T&E) regimen involving intravitreal aflibercept injection (IAI), with the longest treatment interval set to 16 weeks, and adjunct focal/grid laser in diabetic macula edema (DME) patients. We examined 40 eyes (40 adults) with fovea-involving DME from 8 Japanese centers between April 2015 and February 2017. Participants received IAI with an induction period featuring monthly injections and a subsequent T&E period featuring 8-16-week injection interval, adjusted based on optical coherence tomography findings. The primary endpoints were mean changes in the best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Thirty patients (75%) completed the 2-year follow-up. The mean BCVA and CST changed from 60.5 ± 15.6 letters and 499.2 ± 105.6 µm at baseline to 66.6 ± 17.1 letters (P = 0.217) and 315.2 ± 79.0 µm (P < 0.001), respectively, after 2 years. The treatment interval was extended to 12 and 16 weeks in 6.7% and 66.7% of patients, respectively, at the end of 2 years. The T&E aflibercept regimen with the longest treatment interval set to 16 weeks, with adjunct focal/grid laser may be a rational 2-year treatment strategy for DME.
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http://dx.doi.org/10.1038/s41598-021-83811-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904904PMC
February 2021

Treat-and-extend therapy with aflibercept for diabetic macular edema: a prospective clinical trial.

Jpn J Ophthalmol 2021 May 9;65(3):354-362. Epub 2021 Feb 9.

Department of Ophthalmology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.

Purpose: To investigate the efficacy and safety of a treat-and-extend (T&E) regimen using aflibercept (Eylea) for diabetic macular edema (DME).

Study Design: Prospective, open-label, multicenter, single-arm, nonblinded clinical study.

Methods: Forty eyes of 40 patients with DME received a T&E regimen of intravitreal aflibercept injection (IAI) with the longest treatment interval set to 16 weeks and adjunct focal/grid laser for 1 year. An intent-to-treat analysis was performed using the same last-observation-carried-forward method. A per-protocol analysis was also performed for patients who completed a 1-year T&E regimen. The primary endpoints were mean changes in best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Secondary endpoints included IAI-interval extension and resultant IAI numbers and the association between an early response to IAI and final BCVA gain at 1 year.

Results: Thirty-one patients (77.5%) completed the 1-year aflibercept T&E regimen. In these per-protocol participants, the mean CST improvement/reduction was 187.3 ± 145.0 µm (P < .001), but the mean BCVA gain was limited to 4.3 ± 12.2 letters (P = .782). Subanalysis revealed that eyes that gained ≥ 4 letters (median at week 12) after the initial 3 consecutive IAIs (induction phase) achieved greater vision improvement (13.8 ± 9.5 letters) than did the residual eyes (- 4.3 ± 9.2 letters) at 1 year (P < .001). Treatment intervals were extended to 12 and 16 weeks in 16.1% (5/31) and 45.2% (14/31) of the patients, respectively. The mean IAI number was 7.0 ± 1.1.

Conclusions: The results of this study suggest that although the BCVA improvement might be somewhat less than that of frequent treatment, a T&E aflibercept regimen with the longest treatment interval set to 16 weeks is a realizable rational strategy for DME treatment over 1 year.
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http://dx.doi.org/10.1007/s10384-021-00820-0DOI Listing
May 2021

Four-year outcomes of intravitreal aflibercept treatment for neovascular age-related macular degeneration using a treat-and-extend regimen in Japanese patients.

Ther Adv Ophthalmol 2021 Jan-Dec;13:2515841420984586. Epub 2021 Jan 15.

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

Objective: The purpose of our study was to determine the 4-year visual and anatomic outcomes of intravitreal aflibercept treatment for neovascular age-related macular degeneration (AMD) using a treat-and-extend (TAE) regimen.

Methods: We retrospectively reviewed the medical records of 39 patients with neovascular AMD who were treated continuously with intravitreal aflibercept injections using the TAE regimen for at least 4 years. The outcome measures were the best-corrected visual acuity (BCVA) and central macular thickness (CMT) on spectral-domain optical coherence tomography. The BCVAs were measured as decimal values and converted to the corresponding Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical analysis. The Wilcoxon signed-rank test was used to compare the differences in BCVAs and CMTs.

Results: The mean ETDRS letter scores improved significantly from 63.9 at baseline to 70.4, 67.8, 67.2, and 67.3 at 1, 2, 3, and 4 years, respectively. The mean baseline CMT was 380 µm, which decreased significantly to 229, 231, 221, and 210 µm at 1, 2, 3, and 4 years, respectively. The mean numbers of injections were 7.9, 6.0, 5.5, and 5.4 at 1, 2, 3, and 4 years, respectively. The percentages of patients with a treatment interval of 12 weeks or more were 46.2%, 46.2%, 43.6%, and 46.2% at 1, 2, 3, and 4 years, respectively. At year 4, 30.8% of the patients had a treatment interval of 7 weeks or less, whereas 25.6% had 16 weeks or more.

Conclusion: Intravitreal aflibercept TAE treatment may be an effective and efficient method for treating patients with neovascular AMD up to 4 years of follow-up. The TAE regimen is a potential tool to optimize appropriate treatment intervals, avoiding both undertreatment and overtreatment of neovascular AMD.
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http://dx.doi.org/10.1177/2515841420984586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812394PMC
January 2021

Correlation between improvement in visual acuity and QOL after Ranibizumab treatment for age-related macular degeneration patients: QUATRO study.

BMC Ophthalmol 2021 Jan 23;21(1):58. Epub 2021 Jan 23.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: To evaluate the correlation between visual acuity improvement and vision-related QOL after ranibizumab treatment in Japanese patients with AMD.

Methods: In this one-year prospective, interventional, open-label, multicenter study involving four sites, patients with neovascular AMD were enrolled and observed for 12 months. Treatment-naïve patients received 0.5 mg ranibizumab as needed after three initial monthly doses. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at every visit. Evaluations with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and patient satisfaction questionnaire were performed at baseline and 3 and 12 months after initial treatment. The primary endpoint was change in BCVA and QOL 3 months after ranibizumab treatment. QOL outcomes were also assessed in the better and poor BVCA subgroups.

Results: The study enrolled 100 patients. The mean logMAR BCVA after treatment improved significantly from 0.43 to 0.30 at 3 months (p< 0.0001), and 0.28 at 12 months (p< 0.0001). The mean NEI-VFQ-25 composite scores improved from 79.48 to 84.13 at 3 months (p< 0.0001), and 86.0 at 12 months (p< 0.0001). The 3 and 12-month changes in NEI-VFQ-25 score and BCVA showed significant correlation. In the poor baseline visual acuity group (decimal BCVA ≤0.5), there was a significant correlation between the changes in the NEI-VFQ-25 score and BCVA (p=0.02) but not in the better baseline visual acuity group (decimal BCVA > 0.6, p=0.1) at 3 months. There were no significant differences in the satisfaction questionnaire score from baseline to at 3 months (p=0.54) and 12 months (p=0.23). The average CMT improved significantly from 340 to 264 μm at 3 months (p< 0.0001) and to 268 μm at 12 months (p< 0.0001).

Conclusions: Intravitreal ranibizumab treatment resulted in improvement in visual acuity, anatomical change, and visual function change in Japanese AMD patients. Significant improvement was seen in patient visual function, and this was correlated with changes in VA, except immediately after loading dose treatment in patients with higher baseline VA. The patients' satisfaction with the treatment remained unchanged during the study period.

Trial Registration: This study is registered at UMIN Clinical Trials Registry ( UMIN000012013 ). Registered October 10, 2013, as prospective study.
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http://dx.doi.org/10.1186/s12886-021-01816-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825175PMC
January 2021

Ultra-Widefield OCT in Retinopathy of Autoimmune Polyendocrine Syndrome Type 1.

Ophthalmol Retina 2021 01;5(1)

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

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http://dx.doi.org/10.1016/j.oret.2020.06.007DOI Listing
January 2021

Association between quantitative lower limb arterial calcification and bilateral severe knee osteoarthritis.

Mod Rheumatol 2021 Sep 25;31(5):1059-1065. Epub 2021 Jan 25.

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: To investigate whether lower limb arterial calcification (LLAC) quantified using computed tomography (CT) was a risk factor for bilateral severe knee osteoarthritis (OA).

Methods: This cross-sectional study included patients who were scheduled for surgical treatment of primary varus knee OA. Knee OA was evaluated using the Kellgren-Lawrence (KL) classification, KL grades 3 and 4 were defined as severe OA. The LLAC score in the bilateral whole leg CT was quantitatively measured and categorized into low or high groups based on the median value. A modified Poisson regression model was used to examine the relationship between the categorized LLAC score and the presence of bilateral severe knee OA with adjustment for possible confounders.

Results: Of a total of 252 patients examined, multivariable modified Poisson regression analysis showed a significant association between higher LLAC score and the presence of bilateral severe knee OA (adjusted risk ratio = 1.28; 95% confidence interval [CI], 1.12-1.48;  < .001). A substantial interaction was observed between male sex and high LLAC ( for interaction = .03).

Conclusion: LLAC was associated with bilateral severe knee OA, and the LLAC score may be a useful measurement to identify patients at risk of bilateral severe knee OA.
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http://dx.doi.org/10.1080/14397595.2020.1868120DOI Listing
September 2021

Incidence of endophthalmitis after intravitreal injection of an anti-VEGF agent with or without topical antibiotics.

Sci Rep 2020 12 17;10(1):22122. Epub 2020 Dec 17.

Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Yoshida, Japan.

Intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is the standard treatment modality in various types of retinal diseases. However, endophthalmitis remains the most serious complication. Despite the lack of evidence that antibiotics prevent endophthalmitis, topical antibiotics are still used routinely in Japan. We conducted a retrospective multicenter study by analyzing records from patients who underwent IVI of anti-VEGF agents with or without antibiotic treatment. In the analysis of a total of 147,440 eyes, the incidence of endophthalmitis was 0.007%: 0.005% with no use of antibiotics, 0.009% with antibiotic pretreatment, 0.012% with posttreatment, and 0.005% with pre- and posttreatment. There was no statistically significant difference among the four groups (chi-square test, p = 0.57). Most facilities used masks, sterilized gloves, and drapes. Nine of the 10 eyes that developed endophthalmitis received topical antibiotics, and all infected eyes underwent IVI with aflibercept, not the prefilled syringe delivery system. In four patients who received multiple IVI, the detection of causative bacteria revealed resistance to used antibiotics. Data from this large population, treated with or without antibiotics, suggests that antibiotic prophylaxis does not reduce the rate of endophthalmitis after IVI.
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http://dx.doi.org/10.1038/s41598-020-79377-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747565PMC
December 2020

The limitations of mono- and combination antibiotic therapies on immature biofilms in a murine model of implant-associated osteomyelitis.

J Orthop Res 2021 02 23;39(2):449-457. Epub 2020 Dec 23.

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Treatment of implant-associated orthopedic infections remains challenging, partly because antimicrobial treatment is ineffective after a mature biofilm covers the implant surface. Currently, the relative efficacy of systemic mono- and combination standard-of-care (SOC) antibiotic therapies over the course of mature biofilm formation is unknown. Thus, we assessed the effects of cefazoline (CEZ), gentamicin (GM), and vancomycin, with or without rifampin (RFP), on Staphylococcus aureus biofilm formation during the establishment of implant-associated osteomyelitis in a murine tibia model. Quantitative scanning electron microscopy of the implants harvested on Days 0, 3, and 7 revealed that all treatments except CEZ monotherapy significantly reduced biofilm formation when antibiotics started at Day 0 (0.46- to 0.25-fold; p < 0.05). When antibiotics commenced 3 days after the infection, only GM monotherapy significantly inhibited biofilm growth (0.63-fold; p < 0.05), while all antibiotics inhibited biofilm formation in combination with RFP (0.56- to 0.44-fold; p < 0.05). However, no treatment was effective when antibiotics commenced on Day 7. To confirm these findings, we assessed bacterial load via colony-forming unit and histology. The results showed that GM monotherapy and all combination therapies reduced the colony-forming unit in the implant (0.41- to 0.23-fold; p < 0.05); all treatments except CEZ monotherapy reduced the colony-forming unit and staphylococcus abscess communities in the tibiae (0.40- to 0.10-fold; p < 0.05). Collectively, these findings demonstrate that systemic SOC antibiotics can inhibit biofilm formation within 3 days but not after 7 days of infection. The efficacy of SOC monotherapies, CEZ particularly, is very limited. Thus, combination treatment with RFP may be necessary to inhibit implant-associated osteomyelitis.
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http://dx.doi.org/10.1002/jor.24956DOI Listing
February 2021

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis.

Sci Rep 2020 11 27;10(1):20787. Epub 2020 Nov 27.

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.
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http://dx.doi.org/10.1038/s41598-020-77735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695735PMC
November 2020

Changes in metamorphopsia after the treat-and-extend regimen of anti-VEGF therapy for macular edema associated with branch retinal vein occlusion.

PLoS One 2020 28;15(10):e0241343. Epub 2020 Oct 28.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

This study aims to investigate the changes in metamorphopsia after administering the treat-and-extend regimen of anti-vascular endothelial growth factor therapy for branch retinal vein occlusion-associated macular edema. We retrospectively examined 27 patients (27 eyes) with macula edema due to branch retinal vein occlusion who received intravitreal injections of anti-vascular endothelial growth factor agents using the treat-and-extend regimen for ≥18 months. We evaluated best-corrected visual acuity, central macular thickness, macular edema recurrence, and amount of metamorphopsia quantified by M-CHARTS. The best-corrected visual acuity (logarithm of minimum angle of resolution) and central macular thickness significantly improved at 18 months compared to baseline, the median value (interquartile range [IQR]), 0.30 (0.15-0.52) and 459 (373-542) μm at baseline, and 0 (-0.08-0.16) and 267 (232-306) μm at 18 months. The M-CHARTS score (the mean of vertical and horizontal scores) significantly decreased at 1, 6, and 12 months compared to baseline, but worsened at 18 month, the median value (IQR), 0.45 (0.250-0.925), 0.4 (0.15-0.70), 0.4 (0.150-0.625), 0.4 (0.225-0.550) and 0.45 (0.225-0.750) at baseline, 1 month, 6 months, 12 months and 18 months, respectively. The median cumulative number of macular edema recurrences was 2 (IQR, 0.5-3.0) at 18 months. Simple linear regression and multivariate analyses revealed that the change in the mean M-CHARTS score at 18 months was significantly correlated with the baseline score and the cumulative number of macular edema recurrences. Anti-vascular endothelial growth factor therapy using the treat-and-extend regimen improved metamorphopsia in branch retinal vein occlusion-related macular edema in the short to mid-term follow-up period, but not in the long term. Macular edema recurrence may be associated with persistent metamorphopsia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241343PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592807PMC
December 2020

The Role of Inflammation in Age-Related Macular Degeneration.

Int J Biol Sci 2020 23;16(15):2989-3001. Epub 2020 Sep 23.

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

Age-related macular degeneration (AMD) is a blinding eye disease which incidence gradually increases with age. Inflammation participates in AMD pathogenesis, including choroidal neovascularization and geographic atrophy. It is also a kind of self-protective regulation from injury for the eyes. In this review, we described inflammation in AMD pathogenesis, summarized the roles played by inflammation-related cytokines, including pro-inflammatory and anti-inflammatory cytokines, as well as leukocytes (macrophages, dendritic cells, neutrophils, T lymphocytes and B lymphocytes) in the innate or adaptive immunity in AMD. Possible clinical applications such as potential diagnostic biomarkers and anti-inflammatory therapies were also discussed. This review overviews the inflammation as a target of novel effective therapies in treating AMD.
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http://dx.doi.org/10.7150/ijbs.49890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545698PMC
September 2020

Review of clinical studies and recommendation for a therapeutic flow chart for diabetic macular edema.

Graefes Arch Clin Exp Ophthalmol 2021 Apr 30;259(4):815-836. Epub 2020 Sep 30.

Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto 1-7-1, Nagasaki-shi, Nagasaki, 852-8523, Japan.

Diabetic macular edema (DME), characterized by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in patients with diabetes. The management of DME has changed considerably in recent years, especially following the development of intravitreal anti-vascular endothelial growth factor therapy which has emerged as a first-line therapy for center-involved DME. Laser treatment, intravitreal steroid therapy, and vitrectomy are also important treatment options for DME. We believe that it is important to choose the most appropriate treatment option for DME based on the clinical evidences, in addition to the careful consideration of individual patients' general or ocular condition, DME characteristics, patients' motivation, and compliance to the treatment in real-world clinical practice. In this review, we have summarized important clinical evidences for the main treatments for DME, presented an expert review for these evidences, and proposed a recommended therapeutic flow chart for DME. We hope that our review of the clinical evidences and the recommended therapeutic flow chart for DME will contribute to better treatment outcome for DME.
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http://dx.doi.org/10.1007/s00417-020-04936-wDOI Listing
April 2021

Increased vitreal levels of interleukin-10 in diabetic retinopathy: a Meta-analysis.

Int J Ophthalmol 2020 18;13(9):1477-1483. Epub 2020 Sep 18.

Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.

Aim: To conduct a Meta-analysis for the change of interleukin-10 (IL-10) concentration in vitreous samples of patients with diabetic retinopathy (DR).

Methods: Systemic search for literature was conducted from the databases of PubMed, Web of Science and Cochrane Library by August 2019. Statistical analyses including standard mean difference (SMD) and its 95% confidence interval (CI) were performed by using RevMan 5.3 software.

Results: Totally 194 studies were screened and finally 11 studies were included in the Meta-analysis. The concentration of IL-10 in the DR group was higher than in the control group (=0.003, SMD: 0.77, 95%CI: 0.25-1.28). Significant heterogeneity was found among all studies (<0.00001, =92%). The subgroup analysis showed that the concentration of IL-10 increased in vitreous samples from patients with DR compared to the non-DR controls (=0.004, SMD: 1.44, 95%CI: 0.46-2.42). Moreover, the concentration of IL-10 in samples of proliferative diabetic retinopathy (PDR) patients was significantly higher than that of non-proliferative diabetic retinopathy (NPDR) patients (=0.01, SMD: 0.61, 95%CI: 0.13-1.08).

Conclusion: The vitreal concentration of IL-10 is significantly increased in patients with DR. Further studies are needed to reveal the mechanisms of IL-10 in DR.
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http://dx.doi.org/10.18240/ijo.2020.09.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459223PMC
September 2020

Plasma metabolites in treatment-requiring retinopathy of prematurity: Potential biomarkers identified by metabolomics.

Exp Eye Res 2020 10 21;199:108198. Epub 2020 Aug 21.

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China. Electronic address:

Retinopathy of prematurity (ROP) is a potentially blinding condition caused by disruption of retinal vascularization and metabolism. This study aims to identify altered metabolites from plasma in patients with treatment-requiring ROP (TR-ROP) compared with controls. An untargeted metabolomics analysis was performed to reveal the metabolomic profiles of the plasma between TR-ROP patients (n = 38) and age-matched infants (n = 23). The Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the potential signaling pathways of the changed metabolites. Under positive ion mode, a total of 29 metabolites were significantly altered in plasma between TR-ROP patients and controls, and 23 altered metabolites were identified under negative ion mode. KEGG analyses indicated that "protein digestion and absorption" and "aminoacyl-tRNA biosynthesis" were the most enriched pathways of the altered metabolites. These results demonstrated that metabolomic profiles changed in plasma of TR-ROP, and the altered metabolites could be served as potential biomarkers for the diagnosis and prognosis of TR-ROP patients. Besides, the metabolomic profiles might provide clues to discover novel therapeutic strategies in ROP treatment.
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http://dx.doi.org/10.1016/j.exer.2020.108198DOI Listing
October 2020

Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial.

Jpn J Ophthalmol 2020 Sep 18;64(5):455-461. Epub 2020 Aug 18.

Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Purpose: To evaluate the safety and efficacy of BBG (Brilliant Blue G250) for lens capsular staining during cataract surgery with continuous curvilinear capsulorhexis.

Study Design: Prospective clinical study.

Methods: This clinical trial enrolled 30 eyes of 30 patients who underwent cataract surgery with BBG (0.25 mg/mL Brilliant Blue G250) for capsular staining. Visualization of the lens capsule and the ease of capsulorhexis with BBG staining were evaluated in five grades (grade 0 to 4) by the Independent Data Monitoring Committee and the surgeons. The safety of BBG was also evaluated in terms of ocular and systemic tolerance for 7 days after surgery.

Results: The use of BBG improved visualization of the lens capsule and complete capsulorhexis was performed in all patients. The major endpoint (Independent Data Monitoring Committee evaluation) showed that use of BBG improved visualization of the lens capsule and the ease of capsulorhexis (grades 2 to 4); the committee's grading results were similar to those of the surgeons. Frequent complications observed in more than two eyes were conjunctival injection, corneal edema and intraocular pressure elevation. No severe complications were observed in ocular and systemic evaluations.

Conclusion: BBG staining contributed to improved visualization of the lens capsule and aided in the completion of capsulorhexis during cataract surgery. The use of BBG for capsular staining also exhibited favorable safety results.
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http://dx.doi.org/10.1007/s10384-020-00763-yDOI Listing
September 2020

Small RNA Sequencing Reveals Transfer RNA-derived Small RNA Expression Profiles in Retinal Neovascularization.

Int J Med Sci 2020 6;17(12):1713-1722. Epub 2020 Jul 6.

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

Retinal neovascularization (RNV) is characterized in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and retinal vein occlusion (RVO), which leads to severe vision loss and even blindness. To reveal the altered transfer RNA-derived small RNA (tsRNA)s in RNV, and to investigate the underlying mechanisms of the altered tsRNAs involved in RNV, we carried out a small RNA sequencing to profile tsRNA expressions in the retinas of mice with oxygen-induced retinopathy (OIR) and control mice. A total of 45 tsRNAs were significantly changed (fold change ≥ 1.5 and < 0.05) in the retinas of OIR mice compared with controls. Validation by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in four selected tsRNAs was consistent with the results of small RNA sequencing. Bioinformatics analyses identified 153 altered target genes of the four validated tsRNAs. These altered target genes were largely enriched in developmental process, cell periphery and protein binding, as well as Th1 and Th2 cell differentiation pathway. Our study suggests tsRNAs play key roles in the pathogenesis of RNV, indicating their therapeutic potential to treat patients with RNV. Moreover, small RNA sequencing is a useful tool to identify changes in tsRNA expression, an important indicator of the progress of retinal diseases.
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http://dx.doi.org/10.7150/ijms.46209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378657PMC
June 2021

Management of Recurrent Pterygium with Severe Symblepharon Using Mitomycin C, Double Amniotic Membrane Transplantation, Cryopreserved Limbal Allograft, and a Conjunctival Flap.

Int Med Case Rep J 2020 21;13:201-209. Epub 2020 May 21.

Department of Ophthalmology, Kurume University School of Medicine, Fukuoka, Japan.

Purpose: The aim of this study was to evaluate the clinical outcomes of management of recurrent pterygium with severe symblepharon using mitomycin C, double amniotic membrane transplantation, cryopreserved limbal allograft, and a conjunctival flap.

Patients And Methods: This retrospective case series included 10 eyes of 10 patients with recurrent pterygium with severe symblepharon. Eight patients have diplopia in primary gaze. All patients underwent pterygium excision, application of mitomycin C (MMC), double amniotic membrane transplantation (AMT), cryopreserved limbal allograft (CLA) transplantation, and placement of a conjunctival flap. Outcome measures were visual acuity, astigmatism, and recurrence. Recurrence was defined as the presence of fibrovascular proliferative tissue crossing the limbus.

Results: The patients' mean age was 73.8 years. The mean follow-up period was 3.0 years. The mean preoperative and postoperative best-corrected visual acuities (logMAR conversion) were 0.43 and 0.30, respectively. The mean preoperative and postoperative astigmatism were -3.89 diopters and -1.54 diopters, respectively, and there was a significant difference. No recurrence occurred in any of the eyes. Symblepharon was released in all eyes. Diplopia in primary gaze was resolved in all eyes.

Conclusion: Management of recurrent pterygium with severe symblepharon using MMC, double AMT, CLA, and a conjunctival flap was an effective treatment.
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http://dx.doi.org/10.2147/IMCRJ.S245256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247734PMC
May 2020

Periostin and tenascin-C interaction promotes angiogenesis in ischemic proliferative retinopathy.

Sci Rep 2020 06 9;10(1):9299. Epub 2020 Jun 9.

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

Ischemic proliferative retinopathy (IPR), such as proliferative diabetic retinopathy (PDR), retinal vein occlusion and retinopathy of prematurity is a major cause of vision loss. Our previous studies demonstrated that periostin (PN) and tenascin-C (TNC) are involved in the pathogenesis of IPR. However, the interactive role of PN and TNC in angiogenesis associated with IPR remain unknown. We found significant correlation between concentrations of PN and TNC in PDR vitreous humor. mRNA and protein expression of PN and TNC were found in pre-retinal fibrovascular membranes excised from PDR patients. Interleukin-13 (IL-13) promoted mRNA and protein expression of PN and TNC, and co-immunoprecipitation assay revealed binding between PN and TNC in human microvascular endothelial cells (HRECs). IL-13 promoted angiogenic functions of HRECs. Single inhibition of PN or TNC and their dual inhibition by siRNA suppressed the up-regulated angiogenic functions. Pathological pre-retinal neovessels of oxygen-induced retinopathy (OIR) mice were attenuated in PN knock-out, TNC knock-out and dual knock-out mice compared to wild-type mice. Both in vitro and in vivo, PN inhibition had a stronger inhibitory effect on angiogenesis compared to TNC inhibition, and had a similar effect to dual inhibition of PN and TNC. Furthermore, PN knock-out mice showed scant TNC expression in pre-retinal neovessels of OIR retinas. Our findings suggest that interaction of PN and TNC facilitates pre-retinal angiogenesis, and PN is an effective therapeutic target for IPR such as PDR.
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http://dx.doi.org/10.1038/s41598-020-66278-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283227PMC
June 2020

Papillomacular retinoschisis associated with glaucoma: Response to topical carbonic anhydrase inhibitor.

Am J Ophthalmol Case Rep 2020 Sep 19;19:100741. Epub 2020 May 19.

Department of Ophthalmology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Purpose: We report the clinical courses of two patients with papillomacular retinoschisis in eyes with advanced glaucomatous optic neuropathy.

Observations: In case 1, a 67-year-old woman was diagnosed with papillomacular retinoschisis and normal tension glaucoma in the left eye. Her medication was switched from topical latanoprost to brinzolamide, resulting in gradual improvement in the papillomacular retinoschisis thereafter. In case 2, a 76-year-old man was diagnosed with papillomacular retinoschisis, foveal detachment, and normal tension glaucoma in the left eye. His medication was switched from topical tafluprost/timolol to brinzolamide, resulting in gradual improvement in the papillomacular retinoschisis and foveal detachment thereafter.

Conclusionsand Importance: Papillomacular retinoschisis may occur in eyes with advanced glaucomatous optic neuropathy. Topical brinzolamide therapy may lead to improvement of papillomacular retinoschisis.
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http://dx.doi.org/10.1016/j.ajoc.2020.100741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260430PMC
September 2020
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