Publications by authors named "Shigeru Kinoshita"

571 Publications

Comparison of penetrating keratoplasty outcomes with or without microwave thermokeratoplasty.

Sci Rep 2021 Mar 16;11(1):5995. Epub 2021 Mar 16.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan.

Microwave thermokeratoplasty (MTK) is a surgical procedure for the correction of pathologic corneal steepening. The purpose of this study was to examine the postoperative outcomes of eyes with advanced keratoconus that underwent femtosecond-laser zig-zag penetrating keratoplasty (z-PK) following MTK for reshaping of the central cornea. This study involved 32 eyes of 32 consecutive advanced keratoconus patients; i.e., 25 eyes of 25 patients who underwent MTK prior to z-PK (MTK + z-PK group), and 7 eyes of 7 patients who underwent z-PK alone (z-PK group). In all treated eyes, visual acuity (VA) and corneal topography were measured before surgery and at 6-months postoperative. At 6-months postoperative, the mean uncorrected distance VA (logarithm of the minimum angle of resolution) and surface regularity index (SRI) of the MTK + z-PK group was 0.62 ± 0.39 (mean ± standard deviation) and 1.26 ± 0.45, respectively, while that in the z-PK group was 1.02 ± 0.18 and 7.64 ± 3.22, respectively. Both variables were significantly better in the MTK + z-PK group than in the z-PK group (P < 0.05). The findings in this study reveal that MTK prior to z-PKP is effective for improving UDVA and reducing the irregularity of corneal topography in patients with advanced keratoconus.
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http://dx.doi.org/10.1038/s41598-021-85470-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966373PMC
March 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Authors:
Zheng Li Zhenxun Wang Mei Chin Lee Matthias Zenkel Esther Peh Mineo Ozaki Fotis Topouzis Satoko Nakano Anita Chan Shuwen Chen Susan E I Williams Andrew Orr Masakazu Nakano Nino Kobakhidze Tomasz Zarnowski Alina Popa-Cherecheanu Takanori Mizoguchi Shin-Ichi Manabe Ken Hayashi Shigeyasu Kazama Kenji Inoue Yosai Mori Kazunori Miyata Kazuhisa Sugiyama Tomomi Higashide Etsuo Chihara Ryuichi Ideta Satoshi Ishiko Akitoshi Yoshida Kana Tokumo Yoshiaki Kiuchi Tsutomu Ohashi Toshiya Sakurai Takako Sugimoto Hideki Chuman Makoto Aihara Masaru Inatani Kazuhiko Mori Yoko Ikeda Morio Ueno Daniel Gaston Paul Rafuse Lesya Shuba Joseph Saunders Marcelo Nicolela George Chichua Sergo Tabagari Panayiota Founti Kar Seng Sim Wee Yang Meah Hui Meng Soo Xiao Yin Chen Anthi Chatzikyriakidou Christina Keskini Theofanis Pappas Eleftherios Anastasopoulos Alexandros Lambropoulos Evangelia S Panagiotou Dimitrios G Mikropoulos Ewa Kosior-Jarecka Augustine Cheong Yuanhan Li Urszula Lukasik Monisha E Nongpiur Rahat Husain Shamira A Perera Lydia Álvarez Montserrat García Héctor González-Iglesias Andrés Fernández-Vega Cueto Luis Fernández-Vega Cueto Federico Martinón-Torres Antonio Salas Çilingir Oguz Nevbahar Tamcelik Eray Atalay Bilge Batu Murat Irkec Dilek Aktas Burcu Kasim Yury S Astakhov Sergei Y Astakhov Eugeny L Akopov Andreas Giessl Christian Mardin Claus Hellerbrand Jessica N Cooke Bailey Robert P Igo Jonathan L Haines Deepak P Edward Steffen Heegaard Sonia Davila Patrick Tan Jae H Kang Louis R Pasquale Friedrich E Kruse André Reis Trevor R Carmichael Michael Hauser Michele Ramsay Georg Mossböck Nilgun Yildirim Kei Tashiro Anastasios G P Konstas Miguel Coca-Prados Jia Nee Foo Shigeru Kinoshita Chie Sotozono Toshiaki Kubota Michael Dubina Robert Ritch Janey L Wiggs Francesca Pasutto Ursula Schlötzer-Schrehardt Ying Swan Ho Tin Aung Wai Leong Tam Chiea Chuen Khor

JAMA 2021 02;325(8):753-764

Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

CD63 extracellular vesicles from retinal pigment epithelial cells participate in crosstalk with macrophages in the innate inflammatory axis.

Exp Eye Res 2021 Apr 19;205:108496. Epub 2021 Feb 19.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan. Electronic address:

The aim of the study is to clarify the participation of extracellular vesicles (EV) secreted by murine primary retinal pigment epithelial (mpRPE) cells in the cell to cell communication with macrophages (Mps), firstly described by the authors in 2016. In ocular inflammation, Mps act as sources of tumor necrosis factor-α (TNF-α), an activator of RPE cells. TNF-α stimulates the production of monocyte chemotactic protein (MCP-1) by RPE cells, thereby causing greater recruitment of Mps to the sub-RPE space. Murine RAW 264.7 Mps cells were co-cultured with C57BL/6 mouse mpRPE cells, either together or separated in transwells, vertically or horizontally connectable, with 0.40 or 0.03 μm membrane filters. The association of EV with mpRPE or RAW 264.7 was quantified by fluorescence cell sorting (FACS) using Qdot655 streptavidin-conjugated biotinylated EV. Increased levels of CD63 EV were detected in co-cultures by western blotting or FACS analysis, in accordance with the increased production of nanoparticles (50-150 nm) detected by Nanosight tracking analysis. The gene expressions of cytokines, MCP-1, IL-6, IL-8, and VEGF in mpRPE cells and the corresponding proteins were increased in co-cultures even in transwells, vertically connected with 0.40 μm membrane filters, while the repressed TNF-α protein production was not affected. Most of the CD63 EVs produced by mpRPE cells in co-cultures were associated with Raw264.7, but not with mpRPE cells. Semi-purified CD63 EV secreted from mpRPE cells, increased the secretion of MCP-1, IL-6, and VEGF in co-cultures with RAW 264.7. Culture chamber separation horizontally connected with 0.03 μm membrane filters reduced this increased secretion. Collectively, mpRPE derived CD63 EV partly participate in the sub-retinal innate inflammation. To evaluate the functional damage of RPE cells upon chronic exposure to here defined EVs will be the critical issue to uncover their roles in chronic retinal degenerative diseases.
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http://dx.doi.org/10.1016/j.exer.2021.108496DOI Listing
April 2021

Efficacy and safety of 0.01% atropine for prevention of childhood myopia in a 2-year randomized placebo-controlled study.

Jpn J Ophthalmol 2021 Feb 14. Epub 2021 Feb 14.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Kyoto, 602-0841, Japan.

Purpose: Atropine eye drops prevent the progression of myopia, but their use has not been tested in the Japanese schoolchildren population. Here, we evaluate the efficacy and safety of 0.01% atropine eye drops for myopia control in Japanese children.

Study Design: Multicenter (7 university hospitals), randomized, double-masked, placebo-controlled trial.

Methods: Participants were 171 Japanese schoolchildren aged 6 to 12 years, with progressive myopia, spherical equivalence (SE) of -1.00 to -6.00 diopters (D), and astigmatism of ≤1.5 D. They were randomized to receive either 0.01% atropine (n=85) or placebo (n=86) eye drops once nightly OU for 24 months. Primary and secondary efficacy endpoints were changes in SE and axial length (AL), respectively, from baseline to month 24.

Results: Data from 168 subjects were analyzed. At month 24, compliance was similar in both groups (atropine: 83.3%; placebo: 85.7%). The least squares mean change in SE and AL from baseline were, respectively, -1.26 D (95% confidence interval [CI]: -1.35, -1.17) and 0.63 mm (0.59, 0.67) for atropine and -1.48 D (- 1.57, -1.39) and 0.77 mm (0.73, 0.81) for placebo. Inter-group differences were 0.22 D (95% CI: 0.09, 0.35; P < 0.001) for SE and - 0.14 mm (-0.20, -0.08; P < 0.001) for AL. Three patients experienced mild allergic conjunctivitis side effects, with no inter-group difference in incidence (atropine: 2.4%; 2/84 patients; placebo: 1.4%; 1/84 patients).

Conclusion: With good compliance, 0.01% atropine is effective and safe for preventing the progression of childhood myopia.
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http://dx.doi.org/10.1007/s10384-021-00822-yDOI Listing
February 2021

Mapping of susceptible variants for cold medicine-related Stevens-Johnson syndrome by whole-genome resequencing.

NPJ Genom Med 2021 Feb 11;6(1). Epub 2021 Feb 11.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Stevens-Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.
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http://dx.doi.org/10.1038/s41525-021-00171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878485PMC
February 2021

Clinical Implication of Patchy Pattern Corneal Staining in Dry Eye Disease.

Diagnostics (Basel) 2021 Feb 3;11(2). Epub 2021 Feb 3.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Corneal fluorescein staining in a form that is commonly called a "patchy pattern (PP)" is sometimes seen with or without superficial punctate keratopathy (SPK) in dry-eye diseases (DEDs). Here, we investigated the differences in the clinical features of DED patients with and without PP corneal staining (PPCS). This study involved 35 DEDs with PPCS (PPCS group) and 30 DEDs with SPK and without PPCS (non-PPCS group). The tear meniscus radius (TMR, mm), spread grade (SG) of the tear-film lipid layer (i.e., SG 1-5, 1 being best), noninvasive breakup time (NIBUT, seconds), fluorescein breakup time (FBUT, seconds), corneal epithelial damage (CED, 15 points maximum), conjunctival epithelial damage (CjED, six points maximum), the Schirmer's 1 test (ST1, mm), and the prevalence of Sjögren's syndrome (SS) were examined, and then compared between the two groups. Our findings revealed that between the groups (PPCS vs. non-PPCS), there was a statistically significant difference ( < 0.05) in CjED (3.1 ± 1.9 vs. 1.3 ± 1.6), ST1 (5.6 ± 7.4 vs. 14.8 ± 11.4), and the prevalence of SS (60.0% vs. 16.7%). Our findings suggest that DEDs and dry-eye patients with PPCS may indicate not only SS itself, but also the ophthalmological characteristics compatible with SS.
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http://dx.doi.org/10.3390/diagnostics11020232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913618PMC
February 2021

Human leukocyte antigen B*0702 is protective against ocular Stevens-Johnson syndrome/toxic epidermal necrolysis in the UK population.

Sci Rep 2021 Feb 3;11(1):2928. Epub 2021 Feb 3.

Academic Unit of Ophthalmology, Birmingham and Midland Eye Centre, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Dudley Road, Birmingham, B18 7QU, UK.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are part of a disease continuum of vesiculobullous mucocutaneous reactions affecting the skin and mucous membranes including the ocular surface. Manifestations of disease range from mild dry eye to progressive conjunctival cicatrisation, limbal epithelial stem cell failure and corneal blindness. In Far Eastern and South East Asian populations where SJS/TEN is prevalent, numerous human leukocyte antigen (HLA) gene variants at the A, B and C loci have been identified as risk factors for developing SJS/TEN with severe ocular complications (SOC). By contrast, the incidence of SJS/TEN with SOC in European countries is relatively low. To date, ocular SJS/TEN risk altering alleles have not been widely investigated in European populations. In this study, we analysed the association of HLA -A, -B and -C alleles with SJS/TEN in 33 patients residing in the UK with age matched controls. The data showed statistically significant novel negative allele association with HLA-B*0702 and a trend with HLA-C*0702 in the patient group, indicating these alleles are protective. Further characterisation of protective and risk alleles in other ethnic groups is required to fully elucidate the putative role of these alleles in the susceptibility of SJS/TEN with or without severe ocular complications in patients in the UK.
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http://dx.doi.org/10.1038/s41598-021-82400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859395PMC
February 2021

Epigenetic regulation of the epithelial mesenchymal transition induced by synergistic action of TNF-α and TGF-β in retinal pigment epithelial cells.

Biochem Biophys Res Commun 2021 Mar 28;544:31-37. Epub 2021 Jan 28.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan. Electronic address:

To clarify the influence of tumor necrosis factor (TNF)-α on fibrotic phenotypes induced by transforming growth factor (TGF)-β in retinal pigment epithelial cells (RPECs) by epigenetic regulation. Human primary retinal pigment epithelial cells (RPECs including ARPE19) were used in cultures in the presence or absence of TNF-α and/or TGF-β2. RT2 Profiler™ (Qiagen) was used for PCR Array for fibrosis and epithelial mesenchymal transition (EMT). Microarray analysis by 3D gene DNA chip was outsourced to Toray Industries Inc. Quantification of histone acetyl transferase (HAT)-related and histone deacetylase (HDAC) related gene expression were also analyzed. HDAC and HAT activity was measured using an EpiQuik HDAC and HAT Activity/Inhibition Assay Kit (Epigentek). CD44, MMP-9, HAT, and HDAC in RPECs were analyzed by western blotting. Analysis of expression of the EMT/fibrosis related CD44 and MMP-9 phenotypes induced by TNF-α+TGF-β2 revealed four alterations in RPECs: 1) abolition of TGF-β2-induced α-SMA by TNF-α; 2) synergy between TNF-α+TGF-β2 for induction of CD44 and MMP-9 phenotypes 3) no inhibition of HDAC activity by either TNF-α or TGF-β2; and 4) significant inhibition of HAT activity by either TNF-α or TGF-β2, but no synergy. The HDAC activation through HAT inhibition by TNF-α+TGF-β was counteracted by HDAC inhibitors, leading to the inhibition of EMT/fibrosis. EMT/fibrotic CD44 and MMP-9 phenotypes were epigenetically upregulated by concerted action of TNF-α and TGF-β in RPECs. The intervention in epigenetic regulation may hold potential in preventing intraocular proliferative diseases.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.060DOI Listing
March 2021

The Relationship between Subjective Symptoms and Quality of Life in Conjunctivochalasis Patients.

Diagnostics (Basel) 2021 Jan 27;11(2). Epub 2021 Jan 27.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

The purpose of this study was to evaluate the differences in subjective symptoms between patients with conjunctivochalasis (CCh) and dry eye (DE), and examine the relationship between subjective symptoms and quality of life (QOL). In 75 eyes of 75 CCh patients and 122 eyes of 122 DE patients, 12 subjective symptoms classified into four groups depending on the mechanisms associated with symptoms (ITF: instability of tear film, IF: increased friction, R: reflex, and DTC: delayed tear clearance) were evaluated by use of a visual analogue scale (VAS). Fifteen items related to DE symptoms and their influence on daily life were evaluated by use of the dry eye-related quality-of-life score (DEQS) questionnaire, with overall degree of QOL impairment calculated as a QOL score. The correlation between the Total VAS score and QOL score were evaluated. Between the CCh and DE patients, significant differences in subjective symptoms were found in eye dryness, pain, tearing sensitivity to light, and heavy eyelids, while tearing was higher in CCh. A significant strong correlation was found between QOL score and Total VAS score, ITF, and IF in CCh patients. The QOL of CCh patients is strongly determined by decreased tear-film stability and increased friction during blinking.
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http://dx.doi.org/10.3390/diagnostics11020179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911897PMC
January 2021

Human leucocyte antigen association of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications in Han Chinese.

Br J Ophthalmol 2021 Jan 13. Epub 2021 Jan 13.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Background/aims: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by cold medicine (CM) may result in severe ocular complications (SOCs). The purpose of this study was to investigate the human leucocyte antigen (HLA) polymorphism pattern in CM-induced patients with SJS/TEN developing SOCs.

Methods: All participants, including patients with SJS/TEN (n=33) and control patients (n=98), were enrolled through visits to the clinic from 2016 to 2017. SOCs were diagnosed (n=26) via a chart review or eye examination. Patient saliva was collected with commercialised kits and genotyped with PCR assays followed by hybridisation with sequence-specific oligonucleotide (SSO) probes (PCR-SSO) using commercial bead-based typing kits.

Results: In all patients with SJS/TEN with SOCs, the HLA-A*02:07 carrier frequency was significantly higher than that in controls (OR=3.24, 95% CI=1.09 to 9.60, p=0.049), as was the genotype frequency (OR=3.89, 95% CI=1.49 to 10.16, p=0.007). In patients with CM-SJS/TEN with SOCs, the HLA-A*02:07 carrier frequency was higher than that in controls (OR=5.56, 95% CI=1.52 to 20.00, p=0.016), as was the allele frequency (OR=6.67, 95% CI=2.33 to 20.00, p=0.001). In patients with CM-SJS/TEN with SOCs, the HLA-B*46:01 allele frequency was significantly higher than that in controls (OR=3.85, 95% CI=1.52 to 10.00, p=0.008).

Conclusions: The HLA-A*02:07 and HLA-B*46:01 alleles were significantly associated with SOCs among Han Chinese patients with CM-SJS/TEN. These findings demonstrate the genetic diversity in SJS pathogenesis among different ethnic groups.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317105DOI Listing
January 2021

Outcomes of combined gonioscopy-assisted transluminal trabeculotomy and goniosynechialysis in primary angle closure: a retrospective case series.

Int Ophthalmol 2021 Apr 3;41(4):1223-1231. Epub 2021 Jan 3.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: To evaluate the additional intraocular pressure (IOP) lowering effect of gonioscopy-assisted transluminal trabeculotomy (GATT) to contemporary goniosynechialysis (GSL) in endeavouring to abolish subsequent occlusion after chronic iridotrabecular contact in primary angle closure (PAC) patients.

Methods: A retrospective case series of all PAC eyes underwent GATT + GSL with or without phacoemulsification and intraocular lens implantation (PEA + IOL) from December 2016 to May 2018 were recruited. IOP and the number of anti-glaucoma medications were compared pre- and post-operatively by Wilcoxon signed-rank test. Repeated measure ANOVA was used to evaluate the difference in IOP change after the operation between a subgroup of operations (GATT + GSL + PEA + IOL and GATT + GSL) and the arc of cutting of trabeculotomy.

Results: Thirty-nine eyes of 30 patients, 37 chronic angle closure glaucoma (CACG), 1 acute primary angle closure (APAC), and 1 plateau iris syndrome were recruited. Mean preoperative IOP was 21.8 ± 5.4 mmHg. Mean post-operative IOP was lowered to 15.1 ± 3.8 mmHg at 1 month, 14.4 ± 1.2 mmHg at 3 months, 14.8 ± 2.1 mmHg at 6 months, 14.5 ± 0.8 mmHg at 1 year, and 15 at 2 years (P < 0.001, P = 0.0012, P = 0.001, P = 0.028, and P = 0.317 (n = 1), consecutively). Mean of overall post-operative IOP at the last follow-up was 15.1 ± 4.4 mmHg (P < 0.001). Mean preoperative number of anti-glaucoma medications was 3.5 ± 1.4. Mean post-operative number of anti-glaucoma medications was reduced to 1.5 ± 1.4 at 1 month, 0.9 ± 0.9 at 3 months, 1.4 ± 1.4 at 6 months, 1.5 ± 0.5 at 1 year, and 2 at 2 years (P < 0.001, P = 0.01, P = 0.002, P = 0.028, and P = 0.317 (n = 1), respectively). Mean of overall post-operative number of anti-glaucoma medications was 1.1 ± 1.2 (P < 0.001). There was no significant difference found between the IOP lowering effect in subgroup analysis.

Conclusion: GATT + GSL could significantly reduce IOP and number of anti-glaucoma medications from baseline compared to the last follow-up; however, there seemed not to be any superiority to the effects found in previous studies reported about GSL + PEA or PEA alone in PAC patients.
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http://dx.doi.org/10.1007/s10792-020-01676-yDOI Listing
April 2021

Novel use of a chemically modified siRNA for robust and sustainable in vivo gene silencing in the retina.

Sci Rep 2020 12 18;10(1):22343. Epub 2020 Dec 18.

Global Alliances and External Research, Santen Pharmaceutical Co., Ltd, Nara, Japan.

Despite efficient and specific in vitro knockdown, more reliable and convenient methods for in vivo knockdown of target genes remain to be developed particularly for retinal research. Using commercially available and chemically modified siRNA so-called Accell siRNA, we established a novel in vivo gene silencing approach in the rat retina. siRNA designed for knockdown of the house keeping gene Gapdh or four retinal cell type-specific genes (Nefl, Pvalb, Rho and Opn1sw) was injected into the vitreous body, and their retinal mRNA levels were quantified using real-time PCR. Intravitreal injection of siRNA for Gapdh resulted in approximately 40-70% reduction in its retinal mRNA levels, which lasted throughout a 9-day study period. Furthermore, all the selected retinal specific genes were efficiently down-regulated by 60-90% following intravitreal injection, suggesting injected siRNA penetrated into major retinal cell types. These findings were consistent with uniform distribution of a fluorescence-labeled siRNA injected into the vitreous body. Interestingly, gene silencing of Grin1, a core subunit of NMDA receptor, was accompanied by significant prevention from NMDA-induced retinal ganglion cell death. Thus, we provide single intravitreal injection of Accell siRNA as a versatile technique for robust and sustainable in vivo retinal gene silencing to characterize their biological functions under physiological and pathophysiological conditions.
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http://dx.doi.org/10.1038/s41598-020-79242-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749170PMC
December 2020

Potential Functional Restoration of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy by ROCK Inhibitor (Ripasudil).

Am J Ophthalmol 2020 Dec 11;224:185-199. Epub 2020 Dec 11.

Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.

Purpose: Rho-associated kinase (ROCK) inhibitors have been successfully used as a rescue strategy in eyes that failed to clear after descemetorhexis without endothelial graft for treatment of Fuchs endothelial corneal dystrophy (FECD). The functional mechanisms by which ROCK inhibitors modulate corneal endothelial cell regeneration in FECD patients have, however, not been clarified. Here, we analyzed the effect of the ROCK inhibitor ripasudil on corneal endothelial cells of FECD patients and normal donors using ex vivo tissue and in vitro cellular models.

Design: Experimental study: laboratory investigation.

Methods: This institutional study used endothelial cell-Descemet membrane lamellae from FECD patients (n = 450) undergoing Descemet membrane endothelial keratoplasty (FECD ex vivo model), normal research-grade donor corneas (n = 30) after scraping off central endothelial cells (ex vivo wound healing model), normal donor corneas (n = 20) without endothelial injury, and immortalized cell lines (n = 3) generated from FECD patients (FECD in vitro model). Descemet membrane lamellae were dissected into halves and incubated for 24-72 hours in storage medium with or without a single dose of 30 μM ripasudil. The effects of ripasudil on expression of genes and proteins related to endothelial cell proliferation, migration, functionality, and endothelial-to-mesenchymal transition were analyzed and complemented by functional assays on FECD cell lines.

Results: A single dose of ripasudil induced significant upregulation of genes and proteins related to cell cycle progression, cell-matrix adhesion and migration, as well as endothelial barrier and pump function up to 72 hours, whereas classical markers of endothelial-to-mesenchymal transition were downregulated in both FECD and normal specimens compared to unstimulated controls ex vivo. In addition to stimulation of proliferation and migration, ripasudil-induced changes in expression of functional signature genes could be also verified in FECD cell lines in vitro.

Conclusions: These data support the concept that inhibition of ROCK signaling represents a potent tool in regenerative therapies in FECD patients through reactivation of cell proliferation and migration as well as restoration of endothelial pump and barrier function without inducing adverse phenotypic changes.
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http://dx.doi.org/10.1016/j.ajo.2020.12.006DOI Listing
December 2020

Defining Dry Eye from a Clinical Perspective.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Cornea & Refractive Surgery, Massachusetts Eye & Ear, Boston, MA 02114, USA.

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.
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http://dx.doi.org/10.3390/ijms21239271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730816PMC
December 2020

Mitochondria as a Platform for Dictating the Cell Fate of Cultured Human Corneal Endothelial Cells.

Invest Ophthalmol Vis Sci 2020 Dec;61(14):10

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: Aiming to clarify the role of mitochondria in cell fate decision of cultured human corneal endothelial cell (cHCEC) subpopulations.

Methods: The mitochondrial respiratory ability were examined with Mito stress and Mito fuel flex test assays using an extracellular flux analyzer (XFe24; Agilent Technologies; Santa Clara, CA) for human corneal endothelium tissues, mature cHCECs and a variety of cell state transitioned cHCECs. Tricarboxylic acid cycle and acetyl-coenzyme A-related enzymes was analyzed by proteomics for cell lysates using liquid chromatography-tandem mass spectrometry for cHCEC subpopulations.

Results: The maximum oxygen consumption rate was found to become stable depending on the maturation of cHCECs. In the Mito stress tests, culture supplements, epidermal growth factor, SB203580, and SB431543 significantly repressed oxygen consumption rate, whereas a Rho-associated protein kinase inhibitor Y-27632 increased. Tricarboxylic acid cycle and mitochondria acetyl-coenzyme A-related enzymes were selectively upregulated in mature cHCECs, but not in cell state transitioned cHCECs. The maximum oxygen consumption rate was found to be higher in healthy human corneal endothelium tissues than those with deeply reduced cell density. An upregulated tricarboxylic acid cycle was linked with metabolic rewiring converting cHCECs to acquire the mitochondria-dependent oxidative phenotype.

Conclusions: Mitochondrial metabolic intermediates and energy metabolism are tightly linked to the endothelial cell fate and function. These findings will help us to standardize a protocol for endothelial cell injection.
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http://dx.doi.org/10.1167/iovs.61.14.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718813PMC
December 2020

Pluripotent epigenetic regulator OBP-801 maintains filtering blebs in glaucoma filtration surgery model.

Sci Rep 2020 12 1;10(1):20936. Epub 2020 Dec 1.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-8566, Japan.

Inhibition of fibrosis is indispensable for maintaining filtering blebs after glaucoma filtration surgery (GFS). The purpose of this study was to investigate the ability of a pluripotent epigenetic regulator OBP-801 (OBP) to ameliorate extracellular matrix formation in a rabbit model of GFS. Rabbits that underwent GFS were treated with OBP. The gene expression profiles and intraocular pressure (IOP) were monitored until 30 postoperative days. The bleb tissues were evaluated for tissue fibrosis at 30 postoperative days. In in vitro models, OBP interfered the functions of diverse genes during the wound-healing process. In in vivo GFS models, the expressions of TGF-β3, MMP-2, TIMP-2 and 3, LOX, COL1A and SERPINH1 were significantly inhibited at 30 postoperative days in the OBP group compared with those in the vehicle control group. OBP treatment involving subconjunctival injection or eye drops showed no adverse effects, and reduced levels of α-SMA and collagen deposition at the surgical wound site. OBP maintained the long-lived bleb without scar formation, and IOP was lower at 30 postoperative days compared with the vehicle control group. These findings suggest that OBP is an effective and useful candidate low-molecular-weight agent for improving wound healing and surgical outcomes in a rabbit model of GFS.
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http://dx.doi.org/10.1038/s41598-020-77811-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708845PMC
December 2020

Topical application of toll-like receptor 3 inhibitors ameliorates chronic allergic skin inflammation in mice.

J Dermatol Sci 2021 Feb 24;101(2):141-144. Epub 2020 Nov 24.

Department of Dermatology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1016/j.jdermsci.2020.11.007DOI Listing
February 2021

Long-term course of contrast sensitivity in eyes after laser-assisted in-situ keratomileusis for myopia.

Indian J Ophthalmol 2020 Dec;68(12):2981-2984

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: To evaluate the long-term contrast sensitivity (CS) after laser in-situ keratomileusis (LASIK) for myopia.

Methods: This retrospective, single-center, cohort study involved 190 eyes of 95 patients who underwent bilateral LASIK between January 2001 and October 2007. This study includes patients who underwent CS and higher-order aberration (HOA) measurements in a five-year postoperative period. For all enrolled patients, visual acuity, refractive error (RE) in diopters (D), CS at 3-, 6-, 12-, and 18-cycles per degree (cpd), and HOA in a 4 mm area of the dilated pupil were measured before surgery and 6 months, 1 year, and 5 years after it.

Results: The mean RE measured before the surgery and after 6 months, 1 year, and 5 years after was -6.08 ± 2.50D, -0.26 ± 0.65D, -0.28 ± 0.65D, and -0.48 ± 0.80D, respectively. There were no clinically significant changes between preoperative results and the measures taken 6 months, 1 year, and 5 years after surgery. The slight increase in HOA had little effect on CS over the mid to long-term postoperative period.

Conclusion: Our findings show that CS does not clinically change post LASIK. Although we were unable to identify the specific mechanism, we theorize that after LASIK there is a possibility for the compensation of HOA.
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http://dx.doi.org/10.4103/ijo.IJO_1916_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857006PMC
December 2020

Association of HLA polymorphisms and acetaminophen-related Steven-Johnson syndrome with severe ocular complications in Thai population.

Br J Ophthalmol 2020 Nov 23. Epub 2020 Nov 23.

Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background/aims: To investigate the association of genetic polymorphisms of human leucocyte antigens (HLA) class I and II genes with acetaminophen-related Steven-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) who developed severe ocular complications (SOC) in the Thai population.

Methods: A prospective case-control study including 20 unrelated Thai acetaminophen-related SJS/TEN patients with SOC and 60 Thai healthy volunteers, recruited at three university hospitals in Bangkok, Thailand, from September 2014 to August 2019. HLA genes were analysed using PCR amplification followed by hybridisation with sequence-specific oligonucleotide (SSO) probes with bead-based typing kits. The carrier and gene frequencies of individual HLA alleles in patients were compared with those in control volunteers based on dominant assumption using Fisher's exact test.

Results: Among HLA class I polymorphisms, HLA-A*33:03, HLA-B*44:03 and HLA-C*07:01 were significantly associated with acetaminophen-related SJS/TEN and SOC with high ORs (95% CI, corrected p value; Pc) in carrier frequency of 5.4 (1.8 to 16.3, Pc=0.0274), 9.0 (95% CI 2.7 to 30.4, Pc=0.0034), and 9.3 (2.8 to 30.2, Pc=0.0022), respectively. There were no significant HLA class II associations with the disease after corrected for a total number of alleles tested.

Conclusion: HLA-B*44:03 was strongly associated with acetaminophen-related SJS/TEN patients who developed SOC in Thai population. In addition, we also found moderate to strong associations with HLA-A*33:03 and HLA-C*07:01 suggesting their potential roles in the pathogenesis of SOC in acetaminophen-related SJS/TEN.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317315DOI Listing
November 2020

Pterygium excision with modified bare sclera technique combined with mitomycin C.

Jpn J Ophthalmol 2021 Jan 18;65(1):89-96. Epub 2020 Nov 18.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: Numerous surgical methods, with varying rates of recurrence, have been applied for the treatment of pterygium. Adjuvant mitomycin C (MMC) application has shown promising results in the prevention of recurrence. Here we propose and describe modified bare sclera technique combined with the intraoperative application of MMC for pterygium excision.

Study Design: Retrospective study.

Methods: Primary pterygium patients who underwent pterygium excision via the bare sclera combined with 0.04% MMC technique from January 2014 to December 2016 were reviewed. In all patients, the subconjunctival pterygium strand was exposed and then sufficiently excised in combination with the safe use of MMC; i.e., the prevention of MMC dilution and diffusion to surrounding tissue. Surgical complications, recurrence rates, and recurrence onset were recorded.

Results: This study involved 32 primary pterygium eyes (grade T1 = 22 eyes; 68.7%). The mean postoperative follow-up period was 26.4 ± 14.5 months (range: 12-60 months). MMC was applied for 1-3 min. The mean complete epithelialization was 12.6 ± 7.6 days and no surgical complications were observed. In 1 patient with double-head primary pterygium, recurrence occurred at 15-months postoperative.

Conclusions: The modified bare sclera technique combined with MMC application was found to be safe, effective, and presents good cosmetic appearance for the treatment of primary pterygium when safety points are strictly applied.
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http://dx.doi.org/10.1007/s10384-020-00786-5DOI Listing
January 2021

Oral Mucosal Epithelial Transplantation and Limbal-Rigid Contact Lens: A Therapeutic Modality for the Treatment of Severe Ocular Surface Disorders.

Cornea 2020 Nov;39 Suppl 1:S19-S27

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.
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http://dx.doi.org/10.1097/ICO.0000000000002566DOI Listing
November 2020

Predictive biomarkers for the progression of ocular complications in chronic Stevens-Johnson syndrome and toxic Eeidermal necrolysis.

Sci Rep 2020 11 3;10(1):18922. Epub 2020 Nov 3.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

This study aimed to clarify predictive biomarkers of mild and severe ocular complications of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) by examining the cytokines in tears. In 121 chronic-phase SJS/TEN eyes, cytokines in tear samples collected using Schirmer test strips were measured, and ocular sequelae severity was evaluated using an Ocular Surface Grading Score (OSGS) involving 7 components (conjunctivalization, neovascularization, opacification, keratinization, symblepharon, and upper/lower conjunctival-sac shortening), with findings categorized into grades 0-3 (maximum total OSGS: 21). Changes in cytokines between the mild and severe groups (mild: total OSGS of 10 or less, severe: total OSGS of 11 or more), and changes between SJS/TEN cases with and without each of the 7 components, were compared. In the severe group, there was significant upregulation of interleukin (IL)-8 (P < 0.01) and Granzyme B (GrzB) (P < 0.05). IL-8 was significantly upregulated in eyes with conjunctivalization, neovascularization, or opacification, GrzB was upregulated in eyes with keratinization, interferon-γ-inducible protein 10 (IP-10) was downregulated in eyes with conjunctivalization or neovascularization, and IL-1α was upregulated in eyes with opacification (all: P < 0.05). IL-8 and IP-10 was involved in conjunctivalization and neovascularization, while GrzB was involved in keratinization. IL-8 and GrzB in tears may reflect SJS/TEN-related ocular sequelae severity.
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http://dx.doi.org/10.1038/s41598-020-76064-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609677PMC
November 2020

Regulation of gene expression by miRNA-455-3p, upregulated in the conjunctival epithelium of patients with Stevens-Johnson syndrome in the chronic stage.

Sci Rep 2020 10 14;10(1):17239. Epub 2020 Oct 14.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Hirokoji, Kawaramachi, Kamigyoku, Kyoto, 602-0841, Japan.

To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage. Using oligonucleotide microarrays, we performed comprehensive miRNA analysis of the conjunctival epithelium of SJS/TEN patients with severe ocular complications (SOC) in the chronic stage (n = 3). Conjunctival epithelium of patients with conjunctival chalasis (n = 3) served as the control. We confirmed the down- and up-regulation of miRNA of interest by quantitative real-time polymerase chain reaction (RT-PCR) assays using the conjunctival epithelium from 6 SJS/TEN with SOC patients and 7 controls. We focused on miRNA-455-3p, which is significantly upregulated in the conjunctival epithelium of the SJS/TEN patients, and investigated its function by inhibiting miR-455-3p in primary human conjunctival epithelial cells (PHCjEs). Comprehensive miRNA expression analysis showed that the expression of 5 kinds of miRNA was up-regulated more than fivefold, and that the expression of another 5 kinds of miRNA was down-regulated by less than one-fifth. There was a significant difference between the SJS/TEN patients and the controls [analysis of variance (ANOVA) p < 0.05]. Quantitative miRNA PCR assay showed that hsa-miR-31* and hsa-miR-455-3p were significantly up-regulated in the conjunctival epithelium of the SJS/TEN patients. Comprehensive gene expression analysis of PHCjEs transfected with the hsa-miR-455-3p inhibitor and quantitative RT PCR assay showed that ANKRD1, CXCL8, CXCL2, GEM, PTGS2, RNASE8, IL6, and CXCL1 were down-regulated by the hsa-miR-455-3p inhibitor. Quantitative RT-PCR, focused on the genes that tended to be up-regulated in SJS/TEN with SOC, revealed that the expression of IL1A, KPRP, IL36G, PPP1R3C, and ADM was significantly down-regulated in PHCjEs transfected with the hsa-miR-455-3p inhibitor. Our results suggest that miRNA-455-3p could regulate many genes including innate immune related genes in human conjunctival epithelium, and that its up-regulation contributes to the pathogenesis on the ocular surface in SJS/TEN patients with the SOC in the chronic stage. Our findings may lead to the development of new treatments using the miRNA-455-3p inhibitor.
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http://dx.doi.org/10.1038/s41598-020-74211-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560850PMC
October 2020

Microorganism detection and contamination rate of donor eyes in Japan.

Jpn J Ophthalmol 2020 Nov 14;64(6):577-584. Epub 2020 Sep 14.

Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan.

Purpose: To evaluate the microorganism detection and contamination rate of donor eyes.

Study Design: Retrospective study.

Methods: In this retrospective study, we reviewed all donor cornea data collected from Kyoto Prefectural University of Medicine (KPUM) Eye Bank, Kyoto, Japan from April 2015 to June 2018, including microbiologic data obtained from conjunctival swabs and preservation medium and findings of postoperative infection from the medical records.

Results: During the study period, 77 eyes from 44 deceased individuals (mean age at time of death: 75 ± 17.3 years [range, 30-102 years]) were donated to the KPUM Eye Bank after being harvested using standard safety precautions and disinfection procedures. In 49 of the 77 eyes (63.6%), the conjunctival-swab culture revealed microorganisms, with the 3 most commonly detected being methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-sensitive S aureus (MSSA), and methicillin-resistant S aureus (MRSA). The data revealed positive microorganism detection in only 4 (5.2%) of the 77 donor-cornea storage-medium cultures. Positive microorganism detection was found in all the age groups, with no statistical difference between the groups (P > .05). In the eyes enucleated ≥ 2.5 h postmortem, a higher positive microorganism detection occurred (P = .03). During the postoperative follow-up period, there was no record of corneal infection.

Conclusions: The preenucleation conjunctival-swab-culture findings revealed that the rate of positive microorganism detection was similar for advanced-age and younger-age donors and that a shorter elapsed time from donor death to postmortem enucleation resulted in less donor-microorganism contamination.
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http://dx.doi.org/10.1007/s10384-020-00772-xDOI Listing
November 2020

Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure.

Ophthalmology 2021 Apr 6;128(4):504-514. Epub 2020 Sep 6.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address:

Purpose: To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group.

Design: Prospective observational study.

Participants: This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014.

Methods: All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded.

Main Outcome Measures: The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period.

Results: At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean ± standard deviation central corneal ECD was 1257 ± 467 cells/mm (range, 601-2067 cells/mm), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed.

Conclusions: The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery.
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http://dx.doi.org/10.1016/j.ophtha.2020.09.002DOI Listing
April 2021

Global Consensus on the Management of Limbal Stem Cell Deficiency.

Cornea 2020 Oct;39(10):1291-1302

Singapore Eye Research Institute, Singapore, Singapore.

Purpose: In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD.

Methods: An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study.

Results: A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established.

Conclusions: This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.
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http://dx.doi.org/10.1097/ICO.0000000000002358DOI Listing
October 2020

Choroidal detachment-induced secondary angle-closure after trabeculectomy in patient with ocular venous congestion: A case report.

Am J Ophthalmol Case Rep 2020 Sep 15;19:100782. Epub 2020 Jun 15.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of 
Medicine, Kyoto, Japan.

Purpose: To report a particular circumstance that led to the abnormal complication of choroidal detachment (CD)-induced secondary angle-closure after trabeculectomy with mitomycin C (MMC).

Observations: An 82-year-old Japanese male patient with underlying chronic obstructive pulmonary disease and suspicion of ocular venous congestion in both eyes whom diagnosed as primary open-angle glaucoma with uncontrolled intraocular pressure (IOP) of his left eye then underwent an uneventful trabeculectomy with MMC. After the surgery, his left eye had high IOP with a shallow anterior chamber (A/C) but the bleb was hyperfiltration. The high CD was found by B-scan ultrasonography behind the iris and after conservative treatment, the CD was improved, A/C was deepened, and IOP was lower to 16 mmHg.

Conclusion And Importance: CD-induced secondary angle-closure after trabeculectomy with MMC is a complication to be considered in patients with shallow A/C and high IOP. Fundus examination should be done to rule out this condition before any aggressive treatment as CD can resolve spontaneously with time. Clinicians should be aware of this condition especially in patients with any signs of ocular venous congestion as there have been few reports mentioned about the complication in the patients.
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http://dx.doi.org/10.1016/j.ajoc.2020.100782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306613PMC
September 2020

sp. nov., isolated from meibum of human meibomian glands, and emended descriptions of and .

Int J Syst Evol Microbiol 2020 Apr;70(4):2457-2462

Microbe Division / Japan Collection of Microorganisms, RIKEN BioResource Research Center, Tsukuba, Japan.

An anaerobic and aerotolerant bacterium, strain M12, was isolated from the meibum of inflamed human meibomian glands. Cells of the strain was Gram-stain-positive, non-spore-forming and non-motile rods. Growth on trypticase soy agar plates supplemented with 5 % sheep blood was fastest at 30-37 °C under anaerobic conditions. The 16S rRNA gene sequence of the strain revealed that it belongs to the genus with a 98.0 % similarity value to the closest species, . Genome analysis of the strain with type strains of the other species resulted in digital DNA-DNA hybridization values of 32.3-22.3% and average nucleotide identity (OrthoANI) values of 86.7-73.6 %. Biochemical and physiological analyses using API rapid ID 32A and API Coryne kits revealed relatively low reactivity of the strain compared with and . The most abundant major cellular fatty acid was iso-C. Fermentation end-products from glucose were propionate, lactate, succinate and acetate. The diagnostic diamino acid of the peptidoglycan was diaminopimelic acid. Major menaquinones were MK-9(H), MK-9(H) and MK-9. The major peaks of the MALDI-TOF mass spectrometry spectrum were at 3493, 3712, 6986 and 7424 Da. The DNA G+C content was 59.9 mol%. Based on these findings, we propose a novel species, . The type strain of is M12 (=JCM 33380=DSM 109769). On the basis of further genomic analysis, we also provide emended descriptions of (Prévot 1938) Scholz and Kilian 2016 and (Aubin . 2016) Nouioui 2018.
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http://dx.doi.org/10.1099/ijsem.0.004058DOI Listing
April 2020

Corneal dystrophies.

Nat Rev Dis Primers 2020 06 11;6(1):46. Epub 2020 Jun 11.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore.

Corneal dystrophies are broadly defined as inherited disorders that affect any layer of the cornea and are usually progressive, bilateral conditions that do not have systemic effects. The 2015 International Classification of Corneal Dystrophies classifies corneal dystrophies into four classes: epithelial and subepithelial dystrophies, epithelial-stromal TGFBI dystrophies, stromal dystrophies and endothelial dystrophies. Whereas some corneal dystrophies may result in few or mild symptoms and morbidity throughout a patient's lifetime, others may progress and eventually result in substantial visual and ocular disturbances that require medical or surgical intervention. Corneal transplantation, either with full-thickness or partial-thickness donor tissue, may be indicated for patients with advanced corneal dystrophies. Although corneal transplantation techniques have improved considerably over the past two decades, these surgeries are still associated with postoperative risks of disease recurrence, graft failure and other complications that may result in blindness. In addition, a global shortage of cadaveric corneal graft tissue critically limits accessibility to corneal transplantation in some parts of the world. Ongoing advances in gene therapy, regenerative therapy and cell augmentation therapy may eventually result in the development of alternative, novel treatments for corneal dystrophies, which may substantially improve the quality of life of patients with these disorders.
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http://dx.doi.org/10.1038/s41572-020-0178-9DOI Listing
June 2020