Publications by authors named "Hyung Keun Lee"

121 Publications

The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease.

Invest Ophthalmol Vis Sci 2021 Apr;62(4):14

Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Comparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)-induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice.

Methods: After DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated.

Results: The mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive: 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.7- and 2.1-fold, P < 0.001). Interestingly, DR1 and DR2 immunostaining patterns stained independently in DE-induced LGs. CD3+ and CD19+ cell infiltration was significantly increased by DR2i (P < 0.001) but not by DR1i. Furthermore, IFN-γ, IL-17, and TNF-α were significantly upregulated by DR2i compared with the blow-only condition. The severity of corneal erosion and inflammation was also aggravated by DR2i.

Conclusions: Upregulation of DR1 and DR2 was observed in DE-induced mouse LGs. As the inflammatory conditions are aggravated by the inhibition of DRs, especially DR2, their activity may be an important factor preserving ocular surface homeostasis.
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http://dx.doi.org/10.1167/iovs.62.4.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039574PMC
April 2021

Exacerbation of Granular Corneal Dystrophy Type 2 After Small Incision Lenticule Extraction.

Cornea 2021 Apr;40(4):519-524

*Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea; †Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; ‡Woolfson Eye Institute, Atlanta, GA; and §Saevit Eye Hospital, Goyang-Si, Gyeonggi-Do, Korea.

Purpose: To report the outcome of unilateral small incision lenticule extraction (SMILE) in a patient with granular corneal dystrophy type 2 (GCD2).

Methods: Slit-lamp photography and Fourier domain optical coherence tomography were used to document the clinical course and appearance of the corneas in a patient with genetically determined GCD2 who underwent unilateral SMILE in the right eye.

Results: Slit-lamp examination of a 23-year-old woman revealed 2 faint opacities at the surgical interface approximately 2 months after the SMILE procedure had been performed on her right eye. Nine and 3 typical GCD2 deposits located immediately beneath the Bowman layer were observed in the right and left corneas, respectively. Over time, the deposits at the interface increased in size, density, and number in the right eye. Fourier domain optical coherence tomography performed 33 months after the SMILE procedure revealed deposits at the SMILE interface that were distinct from those located immediately beneath the Bowman layer. The severity of disease exacerbation was less in this patient than what is typically observed in others who have undergone laser-assisted in situ keratomileusis or photorefractive keratectomy.

Conclusions: SMILE is contraindicated in patients with GCD2, as are other corneal refractive surgical procedures. This case highlights the importance of genetic testing before the performance of refractive corneal procedures-especially for patients with corneal opacities on preoperative slit-lamp examination or a family history of corneal disease compatible with that of a corneal dystrophy.
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http://dx.doi.org/10.1097/ICO.0000000000002655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938913PMC
April 2021

Risk Factors Influencing the Occurrence and Severity of Symptomatic Dry Eye Syndrome: A Cross-sectional Study.

Ophthalmic Epidemiol 2021 Jan 31:1-7. Epub 2021 Jan 31.

Department of Preventive Medicine, Yonsei University College of Medicine , Seoul, Republic of Korea.

: We aimed to investigate the prevalence and risk factors of dry eye syndrome (DES) among a population-based cohort study.: This cross-sectional study was conducted on 475 subjects (184 men and 291 women) enrolled in the Study Group for Environmental Eye Disease at July 2013. Using the ocular surface disease index (OSDI), we measured the DES severity and defined DES as OSDI score ≥13. Current symptoms of DES and possible risk factors such as body mass index, occupations, comorbidities, exercise, smoking and drinking status were assessed by multivariate logistic regression.: Prevalence of DES was significantly higher in women (52.6%) than in men (41.9%) ( < .001). Compared to white-collar workers, blue-collar workers and unemployed persons showed significantly higher DES prevalence and severity. Compared to those with low BMI (<23.0 kg/m), people with extremely high BMI (≥30.0 kg/m) had significantly higher odds ratio (OR) of having DES after fully adjusted for sex, age, hypertension, diabetes, menopausal status, hormone replacement therapy, occupation, and lifestyle factors (OR: 2.83, 95% confidence interval: 1.04-7.71).: We found some novel factors which have been unknown to the relationship with DES through the five years observation of the cohort. The positive associations of unemployment status, blue-collar work, alcohol habit, and obesity with DES suggests a person's comprehensive condition, not individual factors, contribute significantly in developing DES. Further studies will be helpful to understand the underlying mechanisms.
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http://dx.doi.org/10.1080/09286586.2021.1879172DOI Listing
January 2021

The correction of conjunctivochalasis using high-frequency radiowave electrosurgery improves dry eye disease.

Sci Rep 2021 Jan 28;11(1):2551. Epub 2021 Jan 28.

Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

We aimed to determine the clinical impact of conjunctivochalasis (CCh) and its correction using high-frequency radiowave electrosurgery (HFR-ES), for signs and symptoms of dry eye disease (DED). Forty patients diagnosed with symptomatic CCh were prospectively enrolled. As a result, patients with CCh had moderate to severe DED and most of them exhibited meibomian gland dysfunction (MGD). Corneo-conjunctival fluorescein staining score (CFS) and all lid-parallel-conjunctival-folds scores (LIPCOFs) were positively correlated. Nasal LIPCOF significantly correlated with symptoms and tear volume. Central, temporal, and total LIPCOF significantly correlated with MG loss, MGD stage, and lipid layer thickness. Independent significant factors associated with total LIPCOF included CFS, tear break-up time, and MGD stage. One month following HFR-ES, CCh was completely resolved in all cases. Patient age and preoperative nasal LIPCOF were determinants of outcomes associated with postoperative improvements in symptoms. Ocular surface parameters significantly improved, but MGD-related signs did not. Collectively, CCh associated with MGD severity deteriorates not only tear film stability and reservoir capacity, leading to DED exacerbation. Therefore, CCh should be corrected in patients with DED and MGD. Younger patients with nasal CCh are likely to experience more symptomatic relief after HFR-ES. Particularly, management for MGD should be maintained after CCh correction.
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http://dx.doi.org/10.1038/s41598-021-82088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844232PMC
January 2021

A multicenter cross-sectional survey of dry eye clinical characteristics and practice patterns in Korea: the DECS-K study.

Jpn J Ophthalmol 2021 Mar 19;65(2):261-270. Epub 2021 Jan 19.

Department of Ophthalmology, Korea University College of Medicine, Seoul, Republic of Korea.

Purpose: To compare the proportions of patients satisfying Korean dry eye guidelines and Asia Dry Eye Society (ADES) diagnostic criteria and to describe the clinical characteristics and practice patterns of dry eye patients in Korea.

Study Design: Prospective observational study.

Methods: This study enrolled 160 patients, with 158 patients analyzed. ADES guidelines were applied to dry eye patients satisfying the Korean dry eye guidelines. Risk factors for dry eye (e.g. visual display terminal [VDT] use) were evaluated. Dry eye subtypes were categorized as aqueous-deficient or evaporative. Objective signs (e.g. corneal and keratoconjunctival staining scores, tear break-up time [TBUT], and Schirmer test) and symptoms (Dry Eye-Related Quality of Life Score [DEQS] and Ocular Surface Disease Index [OSDI] questionnaire) were evaluated. Treatment patterns were also recorded.

Results: Patients (mean age 43.1 years) were mainly women (85.4%), with a high proportion (77.2%) of VDT users. Concordance between Korean and ADES guidelines was high (94.3%), with most patients (94.3%) having tear film instability (TBUT ≤ 5 s). Evaporative dry eye occurred in 60.1% and aqueous-deficient in 39.9% of cases. Objective signs were significantly better in evaporative than in aqueous-deficient dry eye. The DEQS bothersome ocular symptoms' score was significantly higher in VDT users than in non-users. OSDI symptom severity and DEQS were significantly correlated (p < 0.001). The most common treatments were hyaluronic acid (33.5%) and diquafosol (15.2%), the latter used mainly for mild and evaporative dry eye.

Conclusion: The study showed high concordance between Korean and ADES diagnostic guidelines, with most patients having tear film instability.
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http://dx.doi.org/10.1007/s10384-020-00803-7DOI Listing
March 2021

Changes in retinal microvasculature and retinal layer thickness in association with apolipoprotein E genotype in Alzheimer's disease.

Sci Rep 2021 Jan 19;11(1):1847. Epub 2021 Jan 19.

Department of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Biomarker tests of Alzheimer's disease (AD) are invasive and expensive. Recent developments in optical coherence tomography (OCT) and OCT angiography (OCTA) have enabled noninvasive, cost-effective characterization of retinal layer vasculature and thickness. Using OCTA and OCT, we characterized retinal microvascular changes in the mild cognitive impairment (MCI) stage of AD and assessed their correlation with structural changes in each retinal neuronal layer. We also evaluated the effect of the APOE-ε4 genotype on retinal microvasculature and layer thickness. Retinal layer thickness did not differ between MCI patients (40 eyes) and controls (37 eyes, all p > 0.05). MCI patients had lower vessel density (VD) (p = 0.003) of the superficial capillary plexus (SCP) and larger foveal avascular zone area (p = 0.01) of the deep capillary plexus (DCP) than those of controls. VD of the SCP correlated with the ganglion cell layer (r = 0.358, p = 0.03) and inner plexiform layer thickness (r = 0.437, p = 0.007) in MCI patients. APOE-ε4-carrying MCI patients had a lower VD of the DCP than non-carriers (p = 0.03). In conclusion, retinal microvasculature was reduced in patients with AD-associated MCI, but retinal thickness was not changed; these changes might be affected by the APOE genotype. OCTA of the retinal microvasculature may be useful to detect vascular changes in AD.
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http://dx.doi.org/10.1038/s41598-020-80892-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815838PMC
January 2021

Fungal Keratitis Caused by Successfully Treated with Caspofungin.

Korean J Ophthalmol 2020 08;34(4):336-337

Department of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3341/kjo.2020.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419245PMC
August 2020

Antibacterial Nanopillar Array for an Implantable Intraocular Lens.

Adv Healthc Mater 2020 09 2;9(18):e2000447. Epub 2020 Aug 2.

Division of Nano-Bio Sensor/Chip Development, National NanoFab Center, Daejeon, 34141, Republic of Korea.

Postsurgical intraocular lens (IOL) infection caused by pathogenic bacteria can result in blindness and often requires a secondary operation to replace the contaminated lens. The incorporation of an antibacterial property onto the IOL surface can prevent bacterial infection and postoperative endophthalmitis. This study describes a polymeric nanopillar array (NPA) integrated onto an IOL, which captures and eradicates the bacteria by rupturing the bacterial membrane. This is accomplished by changing the behavior of the elastic nanopillars using bending, restoration, and antibacterial surface modification. The combination of the polymer coating and NPA dimensions can decrease the adhesivity of corneal endothelial cells and posterior capsule opacification without causing cytotoxicity. An ionic antibacterial polymer layer is introduced onto an NPA using an initiated chemical vapor deposition process. This improves bacterial membrane rupture efficiency by increasing the interactions between the bacteria and nanopillars and damages the bacterial membrane using quaternary ammonium compounds. The newly developed ionic polymer-coated NPA exceeds 99% antibacterial efficiency against Staphylococcus aureus, which is achieved through topological and physicochemical surface modification. Thus, this paper provides a novel, efficient strategy to prevent postoperative complications related to bacteria contamination of IOL after cataract surgery.
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http://dx.doi.org/10.1002/adhm.202000447DOI Listing
September 2020

Retraction Note: Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

BMC Ophthalmol 2020 06 23;20(1):251. Epub 2020 Jun 23.

Department of Ophthalmology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, 07345, South Korea.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12886-020-01524-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310420PMC
June 2020

Perivascular Stem Cell-Derived Cyclophilin A Improves Uterine Environment with Asherman's Syndrome via HIF1α-Dependent Angiogenesis.

Mol Ther 2020 08 20;28(8):1818-1832. Epub 2020 May 20.

Department of Biomedical Science, CHA University, Seongnam 13488, Korea. Electronic address:

Asherman's syndrome (AS) is characterized by intrauterine adhesions or fibrosis resulting from scarring inside the endometrium. AS is associated with infertility, recurrent miscarriage, and placental abnormalities. Although mesenchymal stem cells show therapeutic promise for the treatment of AS, the molecular mechanisms underlying its pathophysiology remain unclear. We ascertained that mice with AS, like human patients with AS, suffer from extensive fibrosis, oligo/amenorrhea, and infertility. Human perivascular stem cells (hPVSCs) from umbilical cords repaired uterine damage in mice with AS, regardless of their delivery routes. In mice with AS, embryo implantation is aberrantly deferred, which leads to intrauterine growth restriction followed by no delivery at term. hPVSC administration significantly improved implantation defects and subsequent poor pregnancy outcomes via hypoxia inducible factor 1α (HIF1α)-dependent angiogenesis in a dose-dependent manner. Pharmacologic inhibition of HIF1α activity hindered hPVSC actions on pregnancy outcomes, whereas stabilization of HIF1α activity facilitated such actions. Furthermore, therapeutic effects of hPVSCs were not observed in uterine-specific HIF1α-knockout mice with AS. Secretome analyses of hPVSCs identified cyclophilin-A as the major paracrine factor for hPVSC therapy via HIF1α-dependent angiogenesis. Collectively, we demonstrate that hPVSCs-derived cyclophilin-A facilitates HIF1α-dependent angiogenesis to ameliorate compromised uterine environments in mice with AS, representing the major pathophysiologic features of humans with AS.
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http://dx.doi.org/10.1016/j.ymthe.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403347PMC
August 2020

Matrix metalloproteinase 9-activatable peptide-conjugated hydrogel-based fluorogenic intraocular-lens sensor.

Biosens Bioelectron 2020 Aug 1;162:112254. Epub 2020 May 1.

Department of Chemical & Biomolecular Engineering, College of Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address:

The eye is an extension of the central nervous system (CNS) and contains aqueous humor (AH), which is a fluid rich in biomolecules secreted from intraocular tissues; thus, this organ allows for non-invasive visualization of early changes in CNS disorders. There is a growing interest in developing implantable devices, such as intraocular-lens (IOL), for specific medical uses, including intraocular monitoring. We describe a novel IOL-sensing system for detecting AH biomarkers via biocompatible enzyme-activatable fluorogenic hydrogel sensors. Matrix-metalloproteinase-9, a biomarker of degenerative CNS and eye disorders, was selected as a target. A peptide-probe-incorporated fluorogenic IOL (FIOL) was developed using diacrylamide-group-modified poly(ethyleneglycol) (PEGDAAm) biocompatible hydrogels, adjusting the hydrogel mesh size to allow selective penetration of the target while blocking non-targets, using label-free detection with semi-permanently implantable sensors, and demonstrating the clinical feasibility of FIOL through in vivo testing. This novel FIOL-based sensing system represents a promising approach for liquid biopsy of intraocular fluids.
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http://dx.doi.org/10.1016/j.bios.2020.112254DOI Listing
August 2020

Comparison of clinical outcomes between vector planning and manifest refraction planning in SMILE for myopic astigmatism.

J Cataract Refract Surg 2020 Aug;46(8):1149-1158

From the Department of Ophthalmology (Jun, E. K. Kim, Seo, Lee, T.-i. Kim), The Institute of Vision Research, Department of Ophthalmology (Jun, E.K. Kim, T.-i. Kim), Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Eyereum Eye Clinic (Kang, Jean), Seoul, South Korea; Research and Development (Arba-Mosquera), Biomedical Engineering Office, SCHWIND eye-tech-solutions, Kleinostheim, Germany; London Vision Clinic (Reinstein, Archer), London, United Kingdom; Department of Ophthalmology (Reinstein), Columbia University Medical Center, New York, NY, USA; Centre Hospitalier National d'Ophtalmologie (Reinstein), Paris, France; Biomedical Science Research Institute, University of Ulster (Reinstein, Archer), Coleraine, Northern Ireland.

Purpose: To compare clinical outcomes of small-incision lenticule extraction (SMILE) between manifest refraction (MR) and vector planning for myopic astigmatism with high ocular residual astigmatism (ORA).

Setting: Yonsei University College of Medicine and Eyereum Eye Clinic, Seoul, South Korea.

Design: Prospective, randomized, comparative case series.

Methods: Patients with myopic astigmatism and ORA of 0.75 diopters (D) or greater were randomized into the MR or vector planning group and underwent SMILE without applying any nomogram for cylinder correction. Visual acuity, MR, corneal topography, and corneal aberration were measured preoperatively and postoperatively. Outcomes at 6 months postoperatively were compared between the groups.

Results: The study comprised 114 patients (114 eyes): 58 eyes in MR planning and 56 eyes in vector planning. The mean uncorrected and corrected distance visual acuity, safety and efficacy indices were comparable between the 2 groups. Postoperative refractive cylinder reached statistically significant differences between the groups (-0.22 ± 0.18 D and -0.14 ± 0.16 D in the MR and vector planning groups, respectively, P = .02). Postoperative corneal toricity and ORA reached statistically significant lower in the vector planning group.

Conclusions: In myopic astigmatism with high ORA, MR and vector planning in SMILE were effective with comparable visual outcomes; vector planning showed statistically significant lower postoperative refractive and corneal astigmatism and ORA. Use of vector planning may improve refractive outcomes in SMILE cases with high ORA. However, the results may have been different had a nomogram adjustment been applied, as is often used for cylinder corrections with SMILE.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000100DOI Listing
August 2020

The Protective Effect of an Eye Wash Solution on the Ocular Surface Damage Induced by Airborne Carbon Black Exposure.

Cornea 2020 Aug;39(8):1040-1047

Department of Ophthalmology, Korea University College of Medicine, Seoul, South Korea; and.

Purpose: To investigate the effects of an eye wash solution on the ocular surface damage induced by airborne carbon black (CB) exposure.

Methods: Sprague-Dawley rats were exposed to ambient CB for 5 days. During the 5 days, a commercial eye wash solution (Eyebon-W) was used for irrigation twice daily on CB-exposed rat eyes; normal saline was used as the vehicle control. Lactic dehydrogenase (LDH) activity and matrix metallopeptidase (MMP)-9, histamine, and lactoferrin levels were measured in tears. The expression of inflammatory cytokines in the anterior segment of the eyeball was measured by Western blot analysis.

Results: The ocular surface staining scores, tear LDH activity, tear MMP-9, histamine, and lactoferrin concentrations, and the expression of interleukin-4 and interferon-γ in the eye were significantly increased in the CB group versus the normal control group. When compared with CB group, the Eyebon-W eye wash treatment significantly reversed these elevations induced by CB, including ocular staining scores, tear LDH activity, histamine and MMP-9 concentrations in the tear fluid, and the expression of interleukin-4 in the eye. On the other hand, saline irrigation only reduced the concentrations of histamine and MMP-9 in tear fluid and the expression of interferon-γ in the eye.

Conclusions: Both Eyebon-W eye wash treatment and saline irrigation reversed CB-induced ocular surface injury, but the efficacy of Eyebon-W was more significant than that of the saline solution when compared with CB group. The use of an eye wash solution seems to play a protective role for the ocular surface when exposed to airborne particulate matter.
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http://dx.doi.org/10.1097/ICO.0000000000002304DOI Listing
August 2020

HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease.

Invest Ophthalmol Vis Sci 2020 Jan;61(1)

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Purpose: The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED).

Methods: For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxia-inducible factor (HIF)-1α conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45+ cell apoptosis was determined with neutralizing TRAIL treatment.

Results: Desiccating stress significantly increased HIF-1α expression in LG-acinar cells. Furthermore, HIF-1α deficiency significantly enhanced the infiltration of CD45+ inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1α CKO. Interestingly, the main source of TRAIL was the CD45- LG-acinar cells, but not CD45+ immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1α-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1α and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice.

Conclusions: Our findings offer novel insight into the regulatory function of acinar cell-derived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.
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http://dx.doi.org/10.1167/iovs.61.1.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205192PMC
January 2020

Alterations of aqueous humor Aβ levels in Aβ-infused and transgenic mouse models of Alzheimer disease.

PLoS One 2020 10;15(1):e0227618. Epub 2020 Jan 10.

Department of Pharmacy, Yonsei University, Incheon, Republic of Korea.

Alzheimer's disease (AD) is an ageing-related neurodegenerative disease characterized and diagnosed by deposition of insoluble amyloid-β (Aβ) plaques in the brain. The plaque accumulation in the brain directly affects reduced levels of Aβ in cerebrospinal fluid (CSF) and blood, as Aβ can freely transport the blood-brain barrier, and clinical investigations have suggested these two biofluids as promising samples for in vitro diagnosis. Given that the human eye structurally resembles the brain and Aβ accumulation often observed in the ocular region of AD patients, in this study, we examined aqueous humor Aβ as another possible surrogate biomarker. First, using the acute Aβ-infused AD mouse model by injecting Aβ to the CSF in intracerebroventricular region of normal ICR mice, we investigated whether Aβ concentration in the aqueous humor in AD models is positively correlated with the concentration in the CSF. Then, we examined the correlation of aqueous humor Aβ levels with increased plaque deposition in the brain and reduced Aβ levels in both CSF and blood in adult and aged 5XFAD Alzheimer transgenic mice. Collectively, the synthetic Aβ injected into CSF immediately migrate to the aqueous humor, however, the age-dependently reducing pattern of Aβ levels in CSF and blood was not observed in the aqueous humor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227618PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953883PMC
April 2020

Interleukin-22 Induces the Infiltration of Visceral Fat Tissue by a Discrete Subset of Duffy Antigen Receptor for Chemokine-Positive M2-Like Macrophages in Response to a High Fat Diet.

Cells 2019 12 6;8(12). Epub 2019 Dec 6.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Interleukin-22 (IL-22) is a cytokine with important functions in host defense and inflammatory responses and has recently been suggested to play a role in immune-inflammatory system in the context of obesity and its metabolic consequences. The specific cellular targets and mechanisms of IL-22-mediated obesity are largely unknown however. We here identified a previously unknown subset of monocyte-derived Duffy antigen receptors for chemokines (DARC) macrophages in epididymal fat adipose tissue and found that they are preferentially recruited into the crown-like structures of adipose tissue in the mouse upon high fat diet-induced obesity. Importantly, DARC macrophages highly express the IL-22 receptor (IL-22Ra1). Exposure to recombinant IL-22 shifts macrophages to an alternative M2 polarization pathway and augments DARC expression via a STAT5b signaling axis. STAT5b directly binds to the DARC promoter and a STAT5 inhibitor abrogates the IL-22-mediated induction of DARC. These M2-like DARC subpopulations of monocytes/macrophages were elevated in obese db/db mice compared to WT lean mice. Furthermore, subsets of CD14 and/or CD16 monocytes/macrophages within human peripheral blood mononuclear cell populations express DARC and the prevalence of these subsets is enhanced by IL-22 stimuli. This suggested that IL-22 is a critical cytokine that promotes the infiltration of adipose tissue macrophages, that regulate inflammatory processes. Taken together, our present findings provide important insights into the molecular mechanism by which IL-22 signal modulates DARC expression in M2-like macrophages.
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http://dx.doi.org/10.3390/cells8121587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953014PMC
December 2019

Changes in Human Tear Proteome Following Topical Treatment of Dry Eye Disease: Cyclosporine A Versus Diquafosol Tetrasodium.

Invest Ophthalmol Vis Sci 2019 12;60(15):5035-5044

Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

Purpose: To compare the changes in human tear proteome and clinical effects following topical cyclosporine A (CsA) 0.05% or diquafosol tetrasodium (DQS) 3% treatment of dry eye disease (DED), and to identify biomarkers for determining disease severity and treatment effectiveness in DED.

Methods: A total of 18 patients were diagnosed with non-Sjögren DED. Nine patients in each group were treated with topical CsA 0.05% or DQS 3% for 4 weeks. Tear samples were collected after evaluation of tear breakup time, corneal and conjunctival erosion staining, and results of Schirmer's test 1 before and after treatment. Proteomes were characterized using liquid chromatography mass spectrometry, and proteins exhibiting a fold change >1.5 or <0.67 (P < 0.05) were considered differentially expressed (DEP).

Results: A total of 794 proteins were identified, with no significant difference observed between pretreatment and posttreatment conditions. Proteomic analysis identified 54 and 106 DEPs between treatment groups (CsA and DQS, respectively), with gene ontology analysis indicating that both treatments enhanced innate and adaptive immune responses and cellular detoxification. Protein-network analysis showed that inflammation associated with the immune response was primarily responsible for the therapeutic process in both groups.

Conclusions: These results provide insight into the broad scope of changes at the ocular surface in DED and indicated that although both drugs improved the clinical parameters, the activated tear-specific biomarkers differed significantly between treatments. Our findings suggest that the DEPs identified here and those correlated with the clinical parameters might represent candidate biomarkers for DED.
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http://dx.doi.org/10.1167/iovs.19-27872DOI Listing
December 2019

Cataract Surgery Practices in the Republic of Korea: A Survey of the Korean Society of Cataract and Refractive Surgery 2018.

Korean J Ophthalmol 2019 Oct;33(5):451-457

Department of Ophthalmology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

Purpose: To describe current cataract surgery practice patterns and changing trends among Korean ophthalmologists.

Methods: A survey of members of the Korean Society of Cataract and Refractive Surgery was performed in July 2018. One hundred and two (12.7%) of 801 questionnaires were returned for analysis. The data were analyzed using descriptive statistics and compared with previous surveys.

Results: Most of the respondents (75%) had been in practice for 6 or more years and performed an average of 31 cataract surgeries per month. The preferred method for cataract surgery was phacoemulsification (95%); 5% used a femtosecond laser. The use of topical anesthesia markedly increased from 69% (2012) to 80% (2018). The use of optical biometry exceeded that of ultrasound A-scan biometry. A multifocal intraocular lens was used by 76% of the respondents compared with 44% of the respondents in 2012. Topical nonsteroidal anti-inflammatory drugs were used by 70% of the respondents postoperatively. Most (59%) of these anti-inflammatory drugs were prescribed for 4 weeks.

Conclusions: This survey provided a comprehensive update of the present cataract surgery practices in the Republic of Korea. The results emphasized the increasing use of premium intraocular lenses, optical biometry, and topical anesthesia.
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http://dx.doi.org/10.3341/kjo.2019.0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791949PMC
October 2019

A visually distinguishable light interfering bioresponsive silica nanoparticle hydrogel sensor fabricated through the molecular imprinting technique.

J Mater Chem B 2019 12 11;7(45):7120-7128. Epub 2019 Oct 11.

Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea.

Methods of the early detection of diseases are based on recognition of the smallest change in the levels of a disease-specific biomarker in body fluids. Among them, monitoring protein concentrations is crucial because most diseases are caused by dysregulated protein levels, rather than DNA or RNA levels. Recent studies have indicated that the proteins in the aqueous humor can be used as biomarkers to predict brain diseases. Therefore, mounting an insertion type sensor on the intraocular lens is a compelling candidate platform for monitoring potential brain disease patients. In particular, molecular reactive sensors that use affinity binding, such as molecularly imprinted hydrogels, allow simple label-free detection, as well as high bio-applicability and biocompatibility. Herein, we describe the fabrication of an optical sensor using a silica nanoparticle conjugated bioresponsive hydrogel to analyze protein biomarkers by measuring light interference in smartphone images. Conformational changes in biotin-conjugated hydrogels were observed through the presence of avidin, as a substitution for a novel biomarker, in interconnecting hydrogel networks. Uniformly arrayed nanoparticles interfered with light differently when the distance between the silica nanoparticles was varied according to target moiety binding. A blue-shift of the reflected light was evident in avidin solutions of up to 100 nM and was induced by shrinkage of the hydrogel. The results indicate that our well-defined, label-free bioresponsive hydrogel demonstrated strong potential to be widely applied as a bioresponsive light interfering hydrogel sensor.
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http://dx.doi.org/10.1039/c9tb01579eDOI Listing
December 2019

Association Between Dyslipidemia and Dry Eye Syndrome Among the Korean Middle-Aged Population.

Cornea 2020 Feb;39(2):161-167

Cardiovascular and Metabolic Diseases Etiology Research Center, Seoul, Republic of Korea.

Purpose: Dry eye syndrome (DES) is a common eye disease caused by tear deficiency or excessive tear evaporation. Because the tear film layers play a major role in the pathogenesis of the evaporative dry eye, some previous articles have suggested the possible mechanism of dyslipidemia and DES. However, the previous results were inconsistent and few studies were conducted to find the independent relationship between dyslipidemia and DES. Therefore, we investigated the association of dyslipidemia with DES in middle-aged Korean adults.

Methods: This study was conducted on 2272 participants (854 men and 1418 women) enrolled in the Study Group for Environmental Eye Disease (2013-2017) after excluding people who have taken lipid-lowering medication. Participants with total cholesterol ≥240 mg/dL or high-density lipoprotein cholesterol <40 mg/dL or low-density lipoprotein cholesterol ≥160 mg/dL or triglycerides ≥200 mg/dL are defined as having dyslipidemia. Using the ocular surface disease index, we measured the DES severity and defined DES as an ocular surface disease index score ≥13.

Results: Men with dyslipidemia had an odds ratio of 1.29 (95% confidence interval, 0.97-1.71) for DES in an unadjusted model compared with those without DES. After adjusting for age, body mass index, hypertension, diabetes, occupations, smoking and drinking status, exercise, contact lens use, computer use, study cohorts, and calendar year of examinations, the adjusted odds ratio for DES was 1.40 (1.03-1.90) in men. However, there was no significant association between dyslipidemia and DES in women, even after stratifying by menopausal status.

Conclusions: Our findings suggest that dyslipidemia may be associated with the prevalence of DES in Korean men, but not in women.
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http://dx.doi.org/10.1097/ICO.0000000000002133DOI Listing
February 2020

Effects of Preservative-free 3% Diquafosol in Patients with Pre-existing Dry Eye Disease after Cataract Surgery: A Randomized Clinical Trial.

Sci Rep 2019 09 2;9(1):12659. Epub 2019 Sep 2.

The Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemungu, Seoul, 03722, Korea.

Dry eye disease (DED) after cataract surgery has become a critical concern, and various therapeutic options have been developed. Recently, preservative-free diquafosol ophthalmic solution has been introduced; however, its therapeutic effect on DED after cataract surgery has not been reported. We investigated the efficacy of preservative-free diquafosol in patients with pre-existing DED after cataract surgery. We divided subjects who were diagnosed with DED and scheduled to undergo cataract surgery, into 3 groups (preservative-free diquafosol, group 1; preservative-containing diquafosol, group 2; preservative-free hyaluronate, group 3), and each eye drops was administered 6 times daily after surgery. Tear break up time (TBUT), Ocular Surface Disease Index (OSDI), corneal staining score, lid margin abnormality, and meibum quality improved over time in group 1. Groups 1 and 2 had significantly superior TBUT, meibomian gland dysfunction grade, and meibomian gland expressibility throughout the study period than group 3. Meibum quality of group 1 was significantly better than group 2 at 1 and 3 months after surgery. Preservative-free diquafosol showed better efficacy in treating DED after cataract surgery than preservative-containing diquafosol or preservative-free hyaluronate. Preservative-free diquafosol may serve as a reliable option for the management of patients with pre-existing DED after phacoemulsification.
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http://dx.doi.org/10.1038/s41598-019-49159-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718409PMC
September 2019

Efficacy of Topical Cyclosporine Nanoemulsion 0.05% Compared with Topical Cyclosporine Emulsion 0.05% and Diquafosol 3% in Dry Eye.

Korean J Ophthalmol 2019 Aug;33(4):343-352

Department of Ophthalmology, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

Purpose: To evaluate the efficacy and safety of cyclosporine nanoemulsion 0.05% compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%.

Methods: This was a multicenter, randomized, evaluator-masked, active control, parallel, phase IV study. A total of 227 patients were randomly allocated to instill cyclosporine nanoemulsion 0.05% (CN) twice daily, cyclosporine emulsion 0.05% (CE) twice daily, or diquafosol sodium 3% (DQ) six times daily. Non-inferiority of CN was analyzed by primary endpoint (cornea and conjunctival staining scores at week 12). The secondary endpoints were scores of corneal staining, conjunctival staining, tear break-up time, Schirmer test, and Ocular Surface Disease Index at weeks 4 and 12.

Results: Primary endpoints showed statistically significant improvements in all groups. Primary endpoints were -6.60 for the CN group, -5.28 for the CE group, and -6.63 for the DQ group (National Eye Institute scale from 0 to 33), verifying the non-inferiority of CN compared to CE (95% confidence interval, -0.15 to 2.80, Δ>-2.88). In intergroup comparison between CN and CE groups, the CN group had significantly more decreased conjunctival staining score at week 12. Intergroup comparison between CN and DQ groups showed consistent statistically significant improvements in TBUT and Schirmer test in the CN group. In the DQ group, TBUT showed late statistically significant improvement at week 12 and Schirmer test showed relatively short-term statistically significant improvement at week 4.

Conclusions: Cyclosporine nanoemulsion 0.05% was equivalently efficient compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. In addition, CN showed significant improvements in several parameters for treatment of dry eyes.
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http://dx.doi.org/10.3341/kjo.2018.0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685820PMC
August 2019

Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

BMC Ophthalmol 2019 Jun 17;19(1):131. Epub 2019 Jun 17.

Department of Ophthalmology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, 07345, Republic of Korea.

Background: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ).

Methods: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment.

Results: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation.

Conclusions: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ.

Trial Registration: KCT0002180 , retrospectively registered on 23 December 2016.
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http://dx.doi.org/10.1186/s12886-019-1136-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580465PMC
June 2019

The Protective Effect of a Topical Mucin Secretagogue on Ocular Surface Damage Induced by Airborne Carbon Black Exposure.

Invest Ophthalmol Vis Sci 2019 01;60(1):255-264

Department of Ophthalmology, Korea University College of Medicine, Seoul, South Korea.

Purpose: Exposure to airborne particulate matter can induce ocular surface damage and inflammation. We evaluated the effects of a topical mucin secretagogue on the mitigation of ocular surface damage induced by exposure to airborne carbon black (CB).

Methods: Sprague-Dawley rats were exposed to ambient CB for 2 hours twice daily for 5 days. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage. Serum immunoglobulin (Ig) G and IgE levels and the sizes of cervical lymph nodes were also measured. The expressions of interleukin (IL)-4, IL-17, and interferon (IFN)-γ were measured by Western blot analysis. Diquafosol tetrasodium was instilled six times a day for 5 days, and the extent of ocular surface damage was evaluated.

Results: After exposure to airborne CB, the median corneal staining score and LDH activity were significantly increased. Serum IgG and IgE levels and the sizes of cervical lymph nodes were also significantly increased. Additionally, the expression of IL-4 and IFN-γ was elevated in the anterior segment of the eyeball. Furthermore, the expression of IL-4, IL-17, and IFN-γ was elevated in the cervical lymph nodes. When exposed to airborne black carbon, topical diquafosol tetrasodium significantly increased tear MUC5AC concentration and decreased tear LDH activity.

Conclusions: Exposure to airborne CB induced ocular surface damage and increased proinflammatory cytokines in the eyes and cervical lymph nodes. Topical mucin secretagogues seem to have a protective effect on the ocular surface against exposure to airborne particulate matters.
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http://dx.doi.org/10.1167/iovs.18-25964DOI Listing
January 2019

A Guanidine-Based Synthetic Compound Suppresses Angiogenesis via Inhibition of Acid Ceramidase.

ACS Chem Biol 2019 01 19;14(1):11-19. Epub 2018 Dec 19.

Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology , Yonsei University , Seoul 120-749 , Republic of Korea.

Angiogenesis generates new blood vessels from pre-existing vessels. Tumors induce the formation of new blood vessels to ensure sufficient oxygen and nutrients for their growth. Normally, angiogenesis is induced by various pro-angiogenesis factors, including vascular endothelial growth factor (VEGF). Inhibition of VEGF is a promising approach to cancer treatment. A guanidine-based synthetic compound, E2, was identified as a potent hit from 68 guanidine-based derivatives by screening for angiogenesis inhibitors showing antiproliferative activity in human umbilical vein endothelial cells (HUVECs). To explore the mode of action of E2, target proteins were investigated using phage display biopanning, and acid ceramidase 1 (ASAH1) was identified as an E2-binding protein. Drug affinity responsive target stability (DARTS) and ASAH1 activity assays revealed the direct binding of E2 to ASAH1. Moreover, siRNA knockdown of ASAH1 demonstrated its role as an angiogenesis factor. Consequently, E2 inhibited chemoinvasion and tube formation of HUVECs in a dose-dependent manner. E2 also potently suppressed neo-vascularization of chorioallantoic membranes in vivo. Collectively, these data suggest that E2 is a novel angiogenesis inhibitor and ASAH1 is proposed to be a new antiangiogenesis target.
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http://dx.doi.org/10.1021/acschembio.8b00558DOI Listing
January 2019

Pharmacological characterization of DA-8010, a novel muscarinic receptor antagonist selective for urinary bladder over salivary gland.

Eur J Pharmacol 2019 Jan 28;843:240-250. Epub 2018 Nov 28.

Dong-A ST Research Institute, Yongin 17073, Republic of Korea.

Several antimuscarinics have been commonly used for overactive bladder patients, but dry mouth as a major anticholinergic side effect remains a shortcoming to limit long-term use. The aim of this study was to elucidate the pharmacological properties of DA-8010, a novel muscarinic receptor antagonist selective for urinary bladder over salivary gland. DA-8010 exhibited a high binding affinity for human muscarinic M receptor with pK of 8.81 ± 0.05 and great potencies for human M receptor and rat bladder preparation. The potency of DA-8010 for bladder smooth muscle cells was 3.6-fold higher than that for salivary gland cells isolated from mice. Intravenous administration of DA-8010 dose-dependently inhibited rhythmic urinary bladder contractions induced by distension in rats, indicating the most potent activity (ID = 0.08 mg/kg) among the antimuscarinics tested. Taken together with the inhibitory effects of DA-8010 and other antimuscarinics on carbachol-induced salivary secretion in rats, the in vivo functional selectivity of DA-8010 for urinary bladder over salivary gland was 3.1-fold, 3.2-fold and 5.2-fold greater than those observed for solifenacin, oxybutynin and darifenacin, respectively. Furthermore, oral administration of DA-8010 in mice resulted in more selective and persistent binding for muscarinic receptors in the bladder rather than in the submaxillary gland, in comparison with other antimuscarinics. These findings suggest that DA-8010 is a potent muscarinic M receptor antagonist to be highly selective for bladder over salivary gland, which might be a promising agent with greater efficacy and less dry mouth in the treatment of overactive bladder.
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http://dx.doi.org/10.1016/j.ejphar.2018.11.037DOI Listing
January 2019

Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte.

Invest Ophthalmol Vis Sci 2018 11;59(13):5693-5703

Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the TGF-β-induced gene (TGFBI). However, the mechanisms underlying the accumulation of TGF-β-induced protein (TGFBIp) are poorly understood. Therefore, we evaluated the signaling cascade affecting the expression of TGFBIp using patient-derived cells.

Methods: Keratocyte primary cultures were prepared from corneas from the eye bank or from heterozygous or homozygous patients with GCD2 after penetrating or lamellar keratoplasty. GCD2 diagnoses were based on the results of a DNA analysis for the R124H TGFβI mutation. Keratocytes were treated with various cytokines and then analyzed using quantitative PCR (qPCR) array, qPCR, flow cytometry, ELISA, and Western blotting.

Results: TGFBI expression was counterregulated by IL-7 in corneal fibroblasts. IL-7 expression was significantly reduced in corneal fibroblasts from patients with GCD2. TGF-β and TGFBI expression were reduced on IL-7 treatment in corneal fibroblasts. Interestingly, the interplay between TGF-β and IL-7 was regulated by the RANKL/RANK signaling cascade. Also, IL-7 regulates the expression of a membrane-type matrix metalloproteinase (MT-MMP), which plays a crucial role in migration and neovascularization in the cornea.

Conclusions: These studies demonstrate that impaired IL-7 expression in patients with GCD2 affects disease pathogenesis via a failure to control TGF-β expression. The RANKL/RANK axis regulates TGF-β and TGFBI expression via IL-7-mediated MT-MMP regulation in corneal fibroblasts. These findings improve our understanding of the pathogenesis of GCD2.
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http://dx.doi.org/10.1167/iovs.18-25161DOI Listing
November 2018

Augmentation of GNSS by Low-Cost MEMS IMU, OBD-II, and Digital Altimeter for Improved Positioning in Urban Area.

Sensors (Basel) 2018 Nov 8;18(11). Epub 2018 Nov 8.

School of Electronics and Information Engineering, Korea Aerospace University, Goyang-si 10540, Korea.

This paper proposes an efficient multi-sensor system to complement GNSS (Global Navigation Satellite System) for improved positioning in urban area. The proposed system augments GNSS by low-cost MEMS IMU (Micro Electro Mechanical Systems Inertial Measurement Unit), OBD (On-Board Diagnostics)-II, and digital altimeter modules. For improved availability of time synchronization in urban area, an adaptive synchronization method is proposed to combine the external PPS (Pulse Per Second) signal and the internal onboard clock. For improved positioning accuracy and availability, a 17-state Kalman filter is formulated for efficient multi-sensor fusion, including OBD-II and digital altimeter modules. A strategy to apply different types of measurement updates is also proposed for improved performance in urban area. Four experiment results with field-collected measurements evaluates the performance of the proposed GNSS/IMU/OBD-II/altimeter system in various aspects, including accuracy, precision, continuity, and availability.
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http://dx.doi.org/10.3390/s18113830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264105PMC
November 2018

Comparison of Ocular Surface Mucin Expression After Topical Ophthalmic Drug Administration in Dry Eye-Induced Mouse Model.

J Ocul Pharmacol Ther 2018 11 16;34(9):612-620. Epub 2018 Oct 16.

1 Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine , Seoul, Korea.

Purpose: To determine the mucinogenic effect of dry eye (DE) treatment drugs currently in use, we compared the levels of mucin production and inflammatory cytokine expression on the ocular surfaces using a DE-induced mice model.

Methods: C57BL/6 mice were separated into 6 groups: a control group, DE-induced mice with the vehicle and treated with cyclosporine A (CsA), rebamipide (Reb), diquafosol tetrasodium (DQS), or prednisolone (Pred). The mRNA expression of MUC 1, 4, 16, 5AC, and proinflammatory cytokines on the corneal epithelia were determined by quantitative real-time polymerase chain reaction. Expression of each MUC was evaluated using flow cytometry and immunohistostaining. Conjunctival goblet cells were analyzed through periodic acid-Schiff (PAS) staining.

Results: Desiccating stress significantly decreased both mRNA and protein levels of all MUCs in the cornea. CsA mainly enhanced MUC5AC, with an increase in PAS-positive cells, whereas DQS chiefly increased membrane-associated mucins (MM). However, Reb only minimally increased expression of MUC5AC and Pred only increased MUC4. MUC16 did not show any significant change in any group. On the contrary, the mRNA levels of interleukin (IL)-1β, -6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were increased in the DE corneas of the control mice and were reduced by all treatments; in particular, IL-6 was significantly suppressed.

Conclusion: Topical DQS and CsA not only ameliorated ocular surface inflammation under desiccating stress but also upregulated both MM and secretory mucins (SM) and contributed to conjunctival goblet cell recovery, compared to Reb and Pred. Both anti-inflammatory and secretory factors should be considered simultaneously when measuring the treatment effect of DE drugs.
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http://dx.doi.org/10.1089/jop.2018.0005DOI Listing
November 2018

Standardization of the proceedings for preparing clinical trials of corneal xenotransplantation in South Korea.

Xenotransplantation 2019 01 4;26(1):e12448. Epub 2018 Aug 4.

Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1111/xen.12448DOI Listing
January 2019